Everything About Cancer

Childhood Brain Tumor

2008-07-31T07:56:00.000-07:00

Table of Contents

General Information
Cellular Classification
Stage Information
Medulloblastoma
Cerebellar astrocytoma
Ependymoma
Brain stem glioma
Cerebral astrocytoma
Craniopharyngioma
Central nervous system germ cell tumor
Pineal parenchymal tumors
Supratentorial primitive neuroectodermal tumor
Visual pathway and hypothalamic glioma
Treatment Option Overview
Childhood Medulloblastoma
Childhood Cerebellar Astrocytoma
Childhood Infratentorial Ependymoma
Childhood Brain Stem Glioma
Childhood Cerebral Astrocytoma
Childhood Supratentorial Ependymoma
Childhood Craniopharyngioma
Childhood Central Nervous System Germ Cell Tumor
Childhood Visual Pathway and Hypothalamic Glioma
Childhood Supratentorial Primitive Neuroectodermal and Pineal Tumors
Recurrent Childhood Brain Tumor
Recurrent central nervous system tumors in children under age 3

General Information

This treatment information summary on childhood brain tumors is an overview of diagnosis, classification, patient treatment, and prognosis. The National Cancer Institute created the PDQ database to increase the availability of new treatment information and its use in treating patients. Information and references from the most recently published literature are included after review by pediatric oncology specialists.

Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification.

Approximately 50% of brain tumors in children are infratentorial, with three fourths of these located in the cerebellum or fourth ventricle. Common infratentorial (posterior fossa) tumors include the following:

1. cerebellar astrocytoma (usually pilocytic but also fibrillary and high-grade)
2. medulloblastoma (primitive neuroectodermal tumor)
3. ependymoma (low-grade or anaplastic)
4. brain stem glioma (often diagnosed neuroradiologically without biopsy; may be high-grade or low-grade)
5. atypical teratoid

Supratentorial tumors include those tumors that occur in the sellar or suprasellar region and/or in the cerebrum or diencephalon. Sellar/suprasellar tumors comprise approximately 20% of childhood brain tumors and include the following:

1. craniopharyngioma
2. diencephalic (chiasm, hypothalamic, and/or thalamic) gliomas generally of low grade
3. germ cell tumors (germinoma and nongerminomatous)

Other tumors that occur supratentorially include the following:

1. low-grade astrocytoma or glioma (grade 1 or grade 2)
2. high-grade or malignant astrocytoma (anaplastic astrocytoma, glioblastoma multiforme (grade 3 or grade 4))
3. mixed glioma (low-grade or high-grade)
4. oligodendroglioma (low-grade or high-grade)
5. primitive neuroectodermal tumor (cerebral neuroblastoma)
6. ependymoma (low-grade or anaplastic)
7. meningioma
8. choroid plexus tumors (papilloma and carcinoma)
9. pineal parenchymal tumors (pineoblastoma, pineocytoma, or mixed pineal parenchymal tumor)
10. neuronal and mixed neuronal glial tumor (ganglioglioma, desmoplastic infantile ganglioglioma, dysembryoplastic neuroepithelial tumor)
11. metastasis (rare) from extra neural malignancies

Important general concepts that should be understood by those caring for a child who has a brain tumor include the following:

1. Selection of an appropriate therapy can only occur if the correct diagnosis is made and the stage of the disease is accurately determined.
2. Children with primary brain tumors represent a major therapy challenge that, for optimal results, requires the coordinated efforts of pediatric specialists in fields such as neurosurgery, neurology, rehabilitation, neuropathology, radiation oncology, medical oncology, neuroradiology, endocrinology, and psychology, who have special expertise in the care of patients with these diseases.1-3
3. More than one half of children diagnosed with brain tumors will survive 5 years from diagnosis. In some subgroups of patients, an even higher rate of survival and cure is possible. Each child's treatment should be approached with curative intent, and the possible long-term sequelae of the disease and its treatment should be considered before therapy is begun.
4. For the majority of childhood brain tumors, the optimal treatment regimen has not been determined. Children who have brain tumors should be considered for enrollment in a clinical trial when an appropriate study is available. Such clinical trials are being carried out by institutions and cooperative groups.
5. Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.4
6. The cause of the vast majority of childhood brain tumors remains unknown.5,6

References:

1. Heideman RL, Packer RJ, Albright LA, et al.: Tumors of the central nervous system. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. Philadelphia, PA: Lippincott-Raven, 3rd ed., 1997, pp 633-697.

2. Pollack IF: Brain tumors in children. New England Journal of Medicine 331(22): 1500-1507, 1994.

3. Cohen ME, Duffman PK, eds: Brain Tumors in Children: Principles of Diagnosis and Treatment, 2nd ed. New York: Raven Press, 1994.

4. Sanders J, Glader B, Cairo M, et al.: Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99(1): 139-141, 1997.

5. Kuijten RR, Bunin GR: Risk factors for childhood brain tumors. Cancer Epidemiology, Biomarkers and Prevention 2(3): 277-288, 1993.

6. Kuijten RR, Strom SS, Rorke LB, et al.: Family history of cancer and seizures in young children with brain tumors: a report from the Childrens Cancer Group (United States and Canada). Cancer Causes and Control 4(5): 455-464, 1993.

Cellular Classification

The classification of brain tumors is based on both histopathological characteristics and location in the brain.1 Undifferentiated neuroectodermal tumors of the cerebellum have historically been referred to as medulloblastomas, while tumors of identical histology in the pineal region would be diagnosed as pineoblastomas.1,2 The nomenclature of pediatric brain tumors is controversial and potentially confusing. Some pathologists advocate abandoning the traditional morphologically-based classifications such as medulloblastoma in favor of a terminology that relies more extensively on the phenotypic characteristics of the tumor.3 In such a system, medulloblastoma is referred to as primitive neuroectodermal tumor (PNET) and then subdivided on the basis of cellular differentiation. The most recent World Health Organization classification of brain tumors maintains the term "medulloblastoma" for posterior fossa undifferentiated tumors. It also maintains separate categories for primitive neuroectodermal tumors, ependymoblastomas, and pineal small round cell tumors (pineoblastomas). The pathologic classification of pediatric brain tumors is a specialized area that is undergoing evolution; review of the diagnostic tissue by a neuropathologist who has particular expertise in this area is strongly recommended.

References:

1. Kleihues P, Cavenee WK, eds.: Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency for Research on Cancer, 2000.

2. Burger PC, Sheithauer BW, Vogel FS: Surgical pathology of the nervous system and its coverings. New York: Churchill Livingstone, 3rd ed., 1991.

3. Rorke LB, Gilles FH, Davis RL, et al.: Revision of the World Health Organization classification of brain tumors for childhood brain tumors. Cancer 56(7, Suppl): 1869-1886, 1985.

Stage Information

Medulloblastoma

Cerebellar astrocytoma

Ependymoma

Brain stem glioma

Cerebral astrocytoma

Craniopharyngioma

These are symptomatic benign tumors arising from remnants of Rathke's pouch. There is no generally accepted staging system and metastasis is rare.1-3

Central nervous system germ cell tumor

Germ cell brain tumors usually arise in the pineal or suprasellar regions. Histologic subtypes include teratoma (both mature and immature), germinoma, choriocarcinomas, and nongerminomatous germ cell tumors (i.e., embryonal cell carcinoma, yolk cell tumor, and mixed germ cell tumors). These tumors have a propensity for subarachnoid spread. Every patient with a germinoma or malignant germ cell tumor should be evaluated with diagnostic imaging of the spinal cord and whole brain. The best method for evaluating spinal cord subarachnoid metastasis is MRI with gadolinium enhancement. Cerebrospinal fluid should be examined cytologically and levels of alpha-fetoprotein (AFP), and human chorionic gonadotropin (HCG) determined. AFP and/or HCG may be elevated in the serum of such patients. Prognosis is related to histology; patients with germinoma have a more favorable outcome than those with nongerminomatous germ cell tumors (nongerminomas).4-8

Pineal parenchymal tumors

(pineoblastoma, pineocytoma)

Supratentorial primitive neuroectodermal tumor

(PNET, cerebral neuroblastoma)

Visual pathway and hypothalamic glioma

References:

1. Lapras C, Patet JD, Mottolese C: Craniopharyngiomas in childhood: analysis of 42 cases. Progress in Experimental Tumor Research 30: 350-358, 1987.

2. Fischer EG, Welch K, Belli JA, et al.: Treatment of craniopharyngiomas in children: 1972-1981. Journal of Neurosurgery 62(4): 496-501, 1985.

3. Yasargil MG, Curcic M, Kis M, et al.: Total removal of craniopharyngiomas. Approaches and long-term results in 144 patients. Journal of Neurosurgery 73(1): 3-11, 1990.

4. Jennings MT, Gelman R, Hochberg F: Intracranial germ-cell tumors: natural history and pathogenesis. Journal of Neurosurgery 63(2): 155-167, 1985.

5. Packer RJ, Sutton LN, Rosenstock JG, et al.: Pineal region tumors of childhood. Pediatrics 74(1): 97-102, 1984.

6. Neuwelt EA, Frenkel EP: Germinomas and other pineal tumors: chemotherapeutic responses. In: Neuwelt EA, Ed.: Diagnosis and Treatment of Pineal Region Tumors. Baltimore: Williams and Wilkins, 1984, pp 332-343.

7. Matsutani M, Sano K, Takakura K, et al.: Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. Journal of Neurosurgery 86(3): 446-455, 1997.

8. Balmaceda C, Modak S, Finlay J: Central nervous system germ cell tumors. Seminars in Oncology 25(2): 243-250, 1998.

Treatment Option Overview

Many of the improvements in survival in childhood cancer have been made as a result of clinical trials that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare new therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with those previously obtained with existing therapy.

Because of the relative rarity of cancer in children, all patients with brain tumors should be considered for entry into a clinical trial. To determine and implement optimum treatment, treatment planning by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors is required. Radiation therapy of pediatric brain tumors is technically very demanding and should be carried out in centers that have experience in that area in order to ensure optimal results.

Debilitating effects on growth and neurologic development have frequently been observed following radiation therapy, especially in younger children.1-3 Secondary tumors have increasingly been diagnosed in long-term survivors.4 For this reason, the role of chemotherapy in allowing a delay in the administration of radiation therapy is under study, and preliminary results suggest that chemotherapy can be used to delay, and sometimes obviate, the need for radiation therapy in children with benign and malignant lesions.5-7 Long-term management of these patients is complex and requires a multidisciplinary approach.

References:

1. Packer RJ, Sutton LN, Atkins TE, et al.: A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: 2-year results. Journal of Neurosurgery 70(5): 707-713, 1989.

2. Johnson DL, McCabe MA, Nicholson HS, et al.: Quality of long-term survival in young children with medulloblastoma. Journal of Neurosurgery 80(6): 1004-1010, 1994.

3. Packer RJ, Sutton LN, Goldwein JW, et al.: Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma. Journal of Neurosurgery 74(3): 433-440, 1991.

4. Jenkin D: Long-term survival of children with brain tumors. Oncology (Huntington NY) 10(5): 715-719, (discussion 720, 722, 728), 1996.

5. Duffner PK, Horowitz ME, Krischer JP, et al.: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. New England Journal of Medicine 328(24): 1725-1731, 1993.

6. Packer RJ, Lange B, Ater J, et al.: Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood. Journal of Clinical Oncology 11(5): 850-856, 1993.

7. Mason WP, Grovas A, Halpern S, et al.: Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors. Journal of Clinical Oncology 16(1): 210-221, 1998.

Childhood Medulloblastoma

Childhood Cerebellar Astrocytoma

Childhood Infratentorial Ependymoma

Childhood Brain Stem Glioma

Childhood Cerebral Astrocytoma

Childhood Supratentorial Ependymoma

Childhood Craniopharyngioma

Treatment options:

Therapies for craniopharyngioma include surgery and conventional external radiation therapy, and in selected cases, stereotactic radiosurgery or intracavitary irradiation. In general, each of these modalities, either alone or in combination, can give a high rate of long-term disease control in the majority of patients. Debate centers on the relative morbidity of the different approaches.1-5 Treatment of cystic tumors with intracavitary chemotherapy has also been reported.6

References:

1. Fischer EG, Welch K, Belli JA, et al.: Treatment of craniopharyngiomas in children: 1972-1981. Journal of Neurosurgery 62(4): 496-501, 1985.

2. Regine WF, Kramer S: Pediatric craniopharyngiomas: long term results of combined treatment with surgery and radiation. International Journal of Radiation Oncology, Biology, Physics 24(4): 611-617, 1992.

3. Hetelekidis S, Barnes PD, Tao ML, et al.: 20-year experience in childhood craniopharyngioma. International Journal of Radiation Oncology, Biology, Physics 27(2): 189-195, 1993.

4. Backlund EO, Axelsson B, Bergstrand CG, et al.: Treatment of craniopharyngiomas--the stereotactic approach in a ten to twenty-three years' perspective. I. Surgical, radiological and ophthalmological aspects. Acta Neurochirurgica 99(1-2): 11-19, 1989.

5. Pollock BE, Lunsford LD, Kondziolka D, et al.: Phosphorus-32 intracavitary irradiation of cystic craniopharyngiomas: current technique and long-term results. International Journal of Radiation Oncology, Biology, Physics 33(2): 437-446, 1995.

6. Takahashi H, Nakazawa S, Shimura T: Evaluation of postoperative intratumoral injection of bleomycin for craniopharyngioma in children. Journal of Neurosurgery 62(1): 120-127, 1985.

Childhood Central Nervous System Germ Cell Tumor

Treatment options:

Surgery other than biopsy to establish the diagnosis rarely plays a role in the treatment of central nervous system (CNS) germinomas. The role of surgical resection for nongerminomatous germ cell tumors and teratomas remains to be defined.1 For germinomas, irradiation with doses of 5000-5500 cGy to the tumor and 2340-3600 cGy to the whole brain and spine is usually curative. In selected cases, germinoma can be effectively treated with local radiation therapy and pre-irradiation chemotherapy.1 Although experience with pre-irradiation chemotherapy has shown that the majority of these tumors respond to cyclophosphamide and platinum-containing drugs, the definitive role of chemotherapy has yet to be determined.1 Disseminated germinoma and nongerminoma germ cell tumors are often treated with craniospinal irradiation,2,3 although not all authors agree.4 The usual dose to the tumor is 5400 cGy with 3500-4000 cGy to the whole brain and spine, although it has been suggested that 4500 cGy to the tumor and 3000 cGy to the meninges may be adequate.5,6 Although nongerminomatous germ cell tumors, such as embryonal carcinoma, yolk cell tumor, and mixed germ cell tumors, may respond to chemotherapeutic agents such as bleomycin, cisplatin, etoposide, cyclophosphamide, and vinblastine, as do such histologies outside of the CNS, the role for chemotherapy as adjuvant therapy in addition to radiation therapy remains to be determined.7

References:

1. Matsutani M, Sano K, Takakura K, et al.: Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. Journal of Neurosurgery 86(3): 446-455, 1997.

2. Edwards MS, Hudgins RJ, Wilson CB, et al.: Pineal region tumors in children. Journal of Neurosurgery 68(5): 689-697, 1988.

3. Dearnaley DP, A'Hern RP, Whittaker S, et al.: Pineal and central nervous system germ cell tumors: Royal Marsden Hospital experience 1962-1987. International Journal of Radiation Oncology, Biology, Physics 18(4): 773-781, 1990.

4. Lindstadt D, Wara WM, Edwards MS, et al.: Radiotherapy of primary intracranial germinomas: the case against routine craniospinal irradiation. International Journal of Radiation Oncology, Biology, Physics 15(2): 291-297, 1988.

5. Fields JN, Fulling KH, Thomas PR, et al.: Suprasellar germinoma: radiation therapy. Radiology 164(1): 247-249, 1987.

6. Dattoli MJ, Newall J: Radiation therapy for intracranial germinoma: the case for limited volume treatment. International Journal of Radiation Oncology, Biology, Physics 19(2): 429-433, 1990.

7. Jennings MT, Gelman R, Hochberg F: Intracranial germ-cell tumors: natural history and pathogenesis. Journal of Neurosurgery 63(2): 155-167, 1985.

Childhood Visual Pathway and Hypothalamic Glioma

Childhood Supratentorial Primitive Neuroectodermal and Pineal Tumors

Recurrent Childhood Brain Tumor

Recurrence is not uncommon in both benign and malignant childhood brain tumors and may occur many years after initial treatment.1 Disease may occur at the primary tumor site or, especially in malignant tumors, at noncontiguous central nervous system sites. Systemic relapse is rare but may occur. At time of recurrence, a complete evaluation for extent of relapse is indicated for all malignant tumors and, at times, for lower-grade lesions. Biopsy or surgical re-resection may be necessary for confirmation of relapse, as other entities, such as secondary tumor and treatment-related brain necrosis, may be clinically indistinguishable from tumor recurrence. The need for surgical intervention must be individualized based on the initial tumor type, the length of time between initial treatment and the reappearance of the lesion, and the clinical picture.

Recurrent low-grade glial tumors:

Surgical resection, radiation therapy (especially if not previously given), and chemotherapy may result in prolonged disease stabilization for children with recurrent low-grade tumors. Resection is an option for those patients with a surgically accessible lesion and has the advantage of documenting the histology of the recurrent tumor. Radiation therapy, if not previously given, may result in tumor shrinkage and relatively long-term disease control. Chemotherapy with drugs such as carboplatin and vincristine has recently been shown to result in tumor shrinkage and disease control for children with low-grade glial neoplasms.2 Similar results have been demonstrated for hypothalamic and chiasmatic tumors treated with etoposide.3 Entry into phase I and phase II trials is indicated to identify more effective and less toxic agents.

Recurrent central nervous system germ cell tumors:

Germ cell tumors may be chemoresponsive. Patients may benefit from the types of regimens that are used in germ cell tumors in other locations, such as PVB (cisplatin, vinblastine, bleomycin) and VAC (vincristine, dactinomycin, cyclophosphamide). Patients with recurrent germ cell tumors for whom the standard chemotherapy options have failed may be entered into phase I and phase II studies that are designed to determine the activity and toxic effects of agents new to the treatment of this tumor.

Recurrent central nervous system tumors in children under age 3

Studies have addressed the treatment of infants who have progressive disease in spite of chemotherapy. Approaches that have been used include further surgery, chemotherapy, local and/or craniospinal radiotherapy, high-dose chemotherapy supported by autologous stem cell rescue, or combinations of chemotherapy and radiotherapy. Overall salvage rates have been less than optimal, but a subgroup of children, primarily those with localized disease at the time of relapse, may experience prolonged disease control and possible "cure" with treatment after recurrence.4-9 Treatment for young children with multiple recurrent and/or disseminated brain tumors is even more problematic and entry into phase I and II trials is indicated to identify more effective and less toxic agents.

References:

1. Jenkin D, Greenberg M, Hoffman H, et al.: Brain tumors in children: long-term survival after radiation treatment. International Journal of Radiation Oncology, Biology, Physics 31(3): 445-451, 1995.

2. Packer RJ, Lange B, Ater J, et al.: Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood. Journal of Clinical Oncology 11(5): 850-856, 1993.

3. Chamberlain MC, Grafe MR: Recurrent chiasmatic-hypothalamic glioma treated with oral etoposide. Journal of Clinical Oncology 13(8): 2072-2076, 1995.

4. Fisher PG, Needle MN, Cnaan A, et al.: Salvage therapy after postoperative chemotherapy for primary brain tumors in infants and very young children. Cancer 83(3): 566-574, 1998.

5. Gajjar A, Mulhern RK, Heideman RL, et al.: Medulloblastoma in very young children: outcome of definitive craniospinal irradiation following incomplete response to chemotherapy. Journal of Clinical Oncology 12(6): 1212-1216, 1994.

6. Goldwein JW, Glauser TA, Packer RJ, et al.: Recurrent intracranial ependymomas in children: survival, patterns of failure, and prognostic factors. Cancer 66(3): 557-563, 1990.

7. Dupuis-Girod S, Hartmann O, Benhamou E, et al.: Will high dose chemotherapy followed by autologous bone marrow transplantation supplant cranio-spinal irradiation in young children treated for medulloblastoma? Journal of Neuro-Oncology 27(1): 87-98, 1996.

8. Dunkel IJ, Boyett JM, et al, for the Children's Cancer Group: High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma. Journal of Clinical Oncology 16(1): 222-228, 1998.

9. Guruangan S, Dunkel IJ, Goldman S, et al.: Myeloablative chemotherapy with autologous bone marrow rescue in young children with recurrent malignant brain tumor. Journal of Clinical Oncology 16(7): 2486-2493, 1998.

Childhood Cerebellar Astrocytoma

2008-07-31T07:32:00.000-07:00

Table of Contents

General Information
Cellular Classification
Stage Information
Treatment Option Overview
Untreated Childhood Cerebellar Astrocytoma
Recurrent Childhood Cerebellar Astrocytoma

Childhood Brain Stem Glioma

2008-07-31T06:58:00.000-07:00

Table of Contents

General Information
Cellular Classification
Stage Information
Treatment Option Overview
Untreated Childhood Brain Stem Glioma
Diffuse intrinsic brain stem gliomas
Focal or low-grade brain stem gliomas
Neurofibromatosis
Recurrent Childhood Brain Stem Glioma

General Information

Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification.

Approximately 50% of brain tumors in children are infratentorial, with three fourths of these located in the cerebellum or fourth ventricle. Common infratentorial (posterior fossa) tumors include the following:

1. cerebellar astrocytoma (usually pilocytic but also fibrillary and high-grade)
2. medulloblastoma (primitive neuroectodermal tumor)
3. ependymoma (low-grade or anaplastic)
4. brain stem glioma (often diagnosed neuroradiographically without biopsy; may be high-grade or low-grade)
5. atypical teratoid

Supratentorial tumors include those tumors that occur in the sellar or suprasellar region and/or other areas of the cerebrum. Sellar/suprasellar tumors comprise approximately 20% of childhood brain tumors and include the following:

1. craniopharyngioma
2. diencephalic (chiasm, hypothalamic, and/or thalamic) gliomas generally of low grade
3. germ cell tumors (germinoma and nongerminomatous)

Other tumors that occur supratentorially include the following:

1. low-grade astrocytoma or glioma (grade 1 or grade 2)
2. high-grade or malignant astrocytoma (anaplastic astrocytoma, glioblastomas multiforme (grade 3 or grade 4))
3. mixed glioma (low-grade or high-grade)
4. oligodendroglioma (low-grade or high-grade)
5. primitive neuroectodermal tumor (cerebral neuroblastoma)
6. ependymoma (low-grade or anaplastic)
7. meningioma
8. choroid plexus tumors (papilloma and carcinoma)
9. pineal parenchymal tumors (pineoblastoma, pineocytoma, or mixed pineal parenchymal tumor)
10. neuronal and mixed neuronal glial tumor (ganglioglioma, desmoplastic infantile ganglioglioma, dysembryoplastic neuroepithelial tumor)
11. metastasis (rare) from extra neural malignancies

Important general concepts that should be understood by those caring for a child with a brain tumor include the following:

1. Selection of an appropriate therapy can only occur if the correct diagnosis is made and the stage of the disease is accurately determined.
2. Children with primary brain tumors represent a major therapy challenge that, for optimal results, requires the coordinated efforts of pediatric specialists in fields such as neurosurgery, neurology, rehabilitation, neuropathology, radiation oncology, medical oncology, neuroradiology, endocrinology, and psychology, who have special expertise in the care of patients with these diseases.1-3
3. More than one half of children diagnosed with brain tumors will survive 5 years from diagnosis. In some subgroups of patients, an even higher rate of survival and cure is possible. Each child's treatment should be approached with curative intent, and the possible long-term sequelae of the disease and its treatment should be considered before therapy is begun.
4. For the majority of childhood brain tumors, the optimal treatment regimen has not been determined. Children who have brain tumors should be considered for enrollment in clinical trials when an appropriate study is available. Such clinical trials are being carried out by institutions and cooperative groups.
5. Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.4
6. The cause of the vast majority of childhood brain tumors remains unknown.5,6

References:

1. Heideman RL, Packer RJ, Albright LA, et al.: Tumors of the central nervous system. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. Philadelphia, PA: Lippincott-Raven, 3rd ed., 1997, pp 633-697.

2. Pollack IF: Brain tumors in children. New England Journal of Medicine 331(22): 1500-1507, 1994.

3. Cohen ME, Duffman PK, eds: Brain Tumors in Children: Principles of Diagnosis and Treatment, 2nd ed. New York: Raven Press, 1994.

4. Sanders J, Glader B, Cairo M, et al.: Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99(1): 139-141, 1997.

5. Kuijten RR, Bunin GR: Risk factors for childhood brain tumors. Cancer Epidemiology, Biomarkers and Prevention 2(3): 277-288, 1993.

6. Kuijten RR, Strom SS, Rorke LB, et al.: Family history of cancer and seizures in young children with brain tumors: a report from the Childrens Cancer Group (United States and Canada). Cancer Causes and Control 4(5): 455-464, 1993.

Cellular Classification

Brain stem gliomas are classified according to their location, extent of spread, radiographic appearance, and histology. Brain stem gliomas may occur in the pons, the midbrain, the tectum, the dorsum of the medulla at the cervicomedullary junction, or in multiple regions of the brain stem. The tumor may contiguously involve the cerebellar peduncles, cerebellum and/or thalamus. The majority of childhood brain stem gliomas are diffuse, intrinsic tumors that involve the pons, often with contiguous involvement of other brain stem sites.1-4 Another prognostically more favorable subset is focal pilocytic astrocytomas. These most frequently arise in the tectum of the midbrain, focally, within the pons, or the cervicomedullary junction, and have a far better prognosis than diffuse intrinsic tumors.2,3,5-7

Primary tumors of the brain stem are often diagnosed based on clinical findings and on neuroimaging studies,8 and there is a substantial amount of histologic variability within an individual tumor. Histologic confirmation is usually unnecessary in diffuse, intrinsic tumors and is not obtained unless the diagnosis is in doubt. The majority of diffuse, intrinsic tumors are fibrillary or malignant gliomas. Biopsy is almost never indicated for diffuse intrinsic tumors involving the pons unless the diagnosis is in doubt. Biopsy specimens of intrinsic brain stem gliomas may be misleading because of sampling error. Biopsy may be indicated for brain stem tumors that are not diffuse and intrinsic. New approaches with stereotactic needle biopsy may make biopsy safer.9

References:

1. Cohen ME, Duffner PK, Heffner RR, et al.: Prognostic factors in brainstem gliomas. Neurology 36(5): 602-605, 1986.

2. Albright AL, Guthkelch AN, Packer RJ, et al.: Prognostic factors in pediatric brain-stem gliomas. Journal of Neurosurgery 65(6): 751-755, 1986.

3. Halperin EC, Wehn SM, Scott JW, et al.: Selection of a management strategy for pediatric brainstem tumors. Medical and Pediatric Oncology 17(2): 116-125, 1989.

4. Freeman CR, Farmer JP: Pediatric brain stem gliomas: a review. International Journal of Radiation Oncology, Biology, Physics 40(2): 265-271, 1998.

5. Epstein F, McCleary EL: Intrinsic brain-stem tumors of childhood: surgical indications. Journal of Neurosurgery 64(1): 11-15, 1986.

6. Edwards MS, Wara WM, Ciricillo SF, et al.: Focal brain-stem astrocytomas causing symptoms of involvement of the facial nerve nucleus: long-term survival in six pediatric cases. Journal of Neurosurgery 80(1): 20-25, 1994.

7. Pollack IF, Pang D, Albright AL, et al.: The long-term outcome in children with late-onset aqueductal stenosis resulting from benign intrinsic tectal tumors. Journal of Neurosurgery 80(4): 681-688, 1994.

8. Albright AL, Packer RJ, Zimmerman R, et al.: Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: a report from the Children's Cancer Group. Neurosurgery 33(6): 1026-1029, 1993.

9. Cartmill M, Punt J: Diffuse brain stem glioma. A review of stereotactic biopsies. Child's Nervous System 15(5): 235-237, 1999.

Stage Information

There is no generally applied staging system for childhood brain stem gliomas.1-3 It is uncommon for these tumors to have spread outside the brain stem itself at the time of initial diagnosis. Diffuse intrinsic tumors of the brain stem are associated with a very low likelihood of long-term survival. The less common tumors of the midbrain, especially in the tectal plate region, have been viewed separately from those of the brain stem because they are more likely to be low grade and to have a greater likelihood of long-term survival (approximately 80% 5-year progression-free survival versus less than 20% for tumors of the pons and medulla).1-8 Similarly, dorsally exophytic and cervicomedullary tumors may have a better prognosis than diffuse pontine gliomas. Spread of malignant brain stem tumors is usually contiguous; metastasis via the subarachnoid space has been reported in up to 30% of cases diagnosed antemortem.9 Such dissemination may occur prior to local relapse but usually occurs simultaneously with or after local disease relapse.

References:

1. Cohen ME, Duffner PK, Heffner RR, et al.: Prognostic factors in brainstem gliomas. Neurology 36(5): 602-605, 1986.

2. Albright AL, Guthkelch AN, Packer RJ, et al.: Prognostic factors in pediatric brain-stem gliomas. Journal of Neurosurgery 65(6): 751-755, 1986.

3. Freeman CR, Farmer JP: Pediatric brain stem gliomas: a review. International Journal of Radiation Oncology, Biology, Physics 40(2): 265-271, 1998.

4. Halperin EC, Wehn SM, Scott JW, et al.: Selection of a management strategy for pediatric brainstem tumors. Medical and Pediatric Oncology 17(2): 116-125, 1989.

5. Epstein F, McCleary EL: Intrinsic brain-stem tumors of childhood: surgical indications. Journal of Neurosurgery 64(1): 11-15, 1986.

6. Edwards MS, Wara WM, Ciricillo SF, et al.: Focal brain-stem astrocytomas causing symptoms of involvement of the facial nerve nucleus: long-term survival in six pediatric cases. Journal of Neurosurgery 80(1): 20-25, 1994.

7. Pollack IF, Pang D, Albright AL, et al.: The long-term outcome in children with late-onset aqueductal stenosis resulting from benign intrinsic tectal tumors. Journal of Neurosurgery 80(4): 681-688, 1994.

8. Mandell LR, Kadota R, Freeman C, et al.: There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a Pediatric Oncology Group phase III trial comparing conventional vs. hyperfractionated radiotherapy. International Journal of Radiation Oncology, Biology, Physics 43(5): 959-964, 1999.

9. Packer RJ, Allen J, Nielsen S, et al.: Brainstem glioma: clinical manifestations of meningeal gliomatosis. Annals of Neurology 14(2): 177-182, 1983.

Treatment Option Overview

Many of the improvements in survival in childhood cancer have been made as a result of clinical trials that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare new therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with those that were previously obtained with existing therapy.

Because of the relative rarity of cancer in children, all patients with brain tumors should be considered for entry into a clinical trial. To determine and implement optimum treatment, treatment planning by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors is required. Radiation therapy of pediatric brain tumors is technically very demanding and should be carried out in centers that have experience in that area in order to ensure optimal results.

Debilitating effects on growth and neurologic development have frequently been observed following radiation therapy, especially in younger children.1-3 For this reason, the role of chemotherapy in allowing a delay in the administration of radiation therapy is under study, and preliminary results suggest that chemotherapy can be used to delay, and sometimes obviate, the need for radiation therapy in children with benign and malignant lesions.4,5 Long- term management of these patients is complex and requires a multidisciplinary approach.

References:

1. Packer RJ, Sutton LN, Atkins TE, et al.: A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: 2-year results. Journal of Neurosurgery 70(5): 707-713, 1989.

2. Johnson DL, McCabe MA, Nicholson HS, et al.: Quality of long-term survival in young children with medulloblastoma. Journal of Neurosurgery 80(6): 1004-1010, 1994.

3. Packer RJ, Sutton LN, Goldwein JW, et al.: Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma. Journal of Neurosurgery 74(3): 433-440, 1991.

4. Duffner PK, Horowitz ME, Krischer JP, et al.: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. New England Journal of Medicine 328(24): 1725-1731, 1993.

5. Packer RJ, Lange B, Ater J, et al.: Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood. Journal of Clinical Oncology 11(5): 850-856, 1993.

Untreated Childhood Brain Stem Glioma

Diffuse intrinsic brain stem gliomas

Conventional treatment for children with diffuse intrinsic brain stem glioma is radiation therapy to involved areas. Such treatment will result in transient benefit for the majority of patients, but over 90% of patients will succumb to the disease within 18 months of diagnosis. The conventional dose of radiation therapy ranges between 5400 cGy and 6000 cGy given locally to the primary tumor site in single daily fractions.

Hyperfractionated (twice daily) radiation therapy techniques have been used to deliver a higher dose, and studies using doses as high as 7800 cGy have been completed. There is no evidence that these increased radiation therapy doses improve the duration or rate of survival for patients with diffuse and/or primary pontine tumors.1,2 Studies evaluating the efficacy of various radiosensitizers as a means for enhancing the therapeutic effect of this modality are under study but to date have failed to show significant improvement in outcome.2,3

The role of chemotherapy in the treatment of patients with newly diagnosed brain stem gliomas is limited.2,4,5 To date neither adjuvant or neoadjuvant chemotherapy nor immunotherapy when added to radiation therapy has been demonstrated to improve survival for children with diffuse intrinsic tumors. Studies using chemotherapy with radiation are ongoing. Children younger than 3 years of age with diffuse intrinsic tumors may benefit from chemotherapy to delay or modify radiation therapy.6

Focal or low-grade brain stem gliomas

Selected patients, primarily those with low-grade dorsally exophytic and focal tumors, may be treated surgically.7 Patients with extensive resection may be observed prior to the initiation of further therapy, preferably as part of a prospective clinical study.

Patients with small tectal lesions and hydrocephalus but no other neurological deficits may be treated with cerebrospinal fluid diversion and have follow-up with sequential neuroradiographic studies until there is evidence of progressive disease.7

Neurofibromatosis

Children with neurofibromatosis type I and brain stem gliomas may have a different prognosis than other patients who have intrinsic lesions. Patients with neurofibromatosis may present with a long history of symptoms or be identified on screening tests; a period of observation may be indicated before instituting any treatment.8 Brain stem gliomas in these children may be indolent and may require no specific treatment for years.9

References:

1. Freeman CR, Krischer JP, Sanford RA, et al.: Final results of a study of escalating doses of hyperfractionated radiotherapy in brain stem tumors in children: a Pediatric Oncology Group study. International Journal of Radiation Oncology, Biology, Physics 27(2): 197-206, 1993.

2. Mandell LR, Kadota R, Freeman C, et al.: There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a Pediatric Oncology Group phase III trial comparing conventional vs. hyperfractionated radiotherapy. International Journal of Radiation Oncology, Biology, Physics 43(5): 959-964, 1999.

3. Freeman CR, Kepner J, Kun LE, et al.: A detrimental effect of a combined chemotherapy-radiotherapy approach in children with diffuse intrinsic brain stem gliomas? International Journal of Radiation Oncology, Biology, Physics 47(3): 561-564, 2000.

4. Jenkin RD, Boesel C, Ertel I, et al.: Brain-stem tumors in childhood: a prospective randomized trial of irradiation with and without adjuvant CCNU, VCR, and prednisone. A report of the Children's Cancer Study Group. Journal of Neurosurgery 66(2): 227-233, 1987.

5. Blaney SM, Phillips PC, Packer RJ, et al.: Phase II evaluation of topotecan for pediatric central nervous system tumors. Cancer 78(3): 527-531, 1996.

6. Duffner PK, Horowitz ME, Krischer JP, et al.: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. New England Journal of Medicine 328(24): 1725-1731, 1993.

7. Vandertop WP, Hoffman HJ, Drake JM, et al.: Focal midbrain tumors in children. Neurosurgery 31(2): 186-194, 1992.

8. Bilaniuk LT, Molloy PT, Zimmerman RA, et al.: Neurofibromatosis type 1: brain stem tumours. Neuroradiology 39(9): 642-653, 1997.

9. Molloy PT, Bilaniuk LT, Vaughan SN, et al.: Brainstem tumors in patients with neurofibromatosis type 1: a distinct clinical entity. Neurology 45(10): 1897-1902, 1995.

Recurrent Childhood Brain Stem Glioma

Recurrence may occur in both benign and malignant childhood brain stem gliomas and may develop many years after initial treatment. Disease may occur at the primary tumor site or, especially in malignant tumors, at noncontiguous central nervous system sites. Systemic relapse is rare but may occur. At the time of recurrence, a complete evaluation to determine the extent of the relapse is indicated for all malignant tumors and, selectively, for more benign lesions. Biopsy or surgical resection should be considered for confirmation of relapse when other entities such as secondary tumor and treatment-related brain necrosis which may be clinically indistinguishable from tumor recurrence are in the differential. This confirmation is usually not necessary in children with diffuse, intrinsic tumors. Other tests, such as positron-emission tomography plus single-photon emission computed tomography, have not yet been shown to be reliable in distinguishing necrosis from tumor recurrence in brain stem gliomas. The need for surgical intervention must be individualized on the basis of the initial tumor type, the length of time between initial treatment and the reappearance of the mass lesion, and the clinical picture.

Chemotherapy with agents such as a carboplatin and vincristine may be effective in children with low-grade, recurrent exophytic gliomas.1 Patients with recurrent diffuse, intrinsic brain stem glioma should be considered for entry into trials of novel therapeutic approaches because there are no "standard" agents that have demonstrated a high degree of activity. Alternatively, palliative care may be indicated for such individuals.

References:

1. Packer RJ, Lange B, Ater J, et al.: Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood. Journal of Clinical Oncology 11(5): 850-856, 1993.

Adult Brain Tumor

2008-07-31T05:35:00.000-07:00

Table of Contents

General Information
Cellular Classification
Stage Information
Noninfiltrating astrocytomas
Well-differentiated mildly and moderately anaplastic astrocytomas
Anaplastic astrocytomas
Glioblastoma multiforme
Well-differentiated ependymomas
Anaplastic ependymomas
Ependymoblastomas
Well-differentiated oligodendrogliomas
Anaplastic oligodendrogliomas
Meningiomas
Malignant meningiomas
Treatment Option Overview
Adult Noninfiltrating Astrocytoma
Juvenile pilocytic and subependymal astrocytomas 1
Adult Well-Differentiated Mildly and Moderately Anaplastic Astrocytoma
Adult Anaplastic Astrocytoma
Adult Glioblastoma Multiforme
Adult Brain Stem Glioma
Adult Well-Differentiated Ependymoma
Myxopapillary ependymoma and well-differentiated ependymoma
Adult Malignant Ependymoma
Anaplastic ependymoma and ependymoblastoma
Adult Well-Differentiated Oligodendroglioma
Adult Anaplastic Oligodendroglioma
Mixed Gliomas
Mixed astrocytoma-ependymoma, mixed astrocytoma-oligodendroglioma, and mixed astrocytoma-ependymoma-oligodendroglioma
Adult Medulloblastoma
Adult Pineal Parenchymal Tumor
Pineocytoma and pineoblastoma
Pineal astrocytoma
Adult Central Nervous System Germ Cell Tumor
Germinoma, embryonal carcinoma, choriocarcinoma, and teratoma
Adult Craniopharyngioma
Adult Meningioma
Adult Malignant Meningioma
Malignant meningioma, hemangiopericytoma, and papillary meningioma
Recurrent Adult Brain Tumor

General Information

Prognoses of primary brain tumors are determined by histologic type, grade, postoperative size, and extent of the tumor and by the patient's age, the performance status, and the duration of symptoms.1,2 Some primary brain tumors are curable by surgery alone, and some are curable by surgery and radiation therapy; the remainder require surgery, radiation therapy, and chemotherapy. Tumors that require all 3 modalities are infrequently curable.3

Metastases to the brain from a primary tumor that is outside the central nervous system (CNS) are more common than primary tumors of the brain. The most common primary tumors that metastasize to the brain are lung, breast, melanoma, and kidney. Metastases to the brain are usually multiple, but solitary metastases may also occur. Brain involvement can occur with cancers of the nasopharyngeal region by direct extension along the cranial nerves or through the foramina at the base of the skull. Metastatic meningeal involvement can also occur, especially with leukemia, lymphoma, small cell lung cancer, breast cancer, and some primary CNS tumors (such as medulloblastoma and ependymal gliomas).

A lesion in the brain should not be assumed to be a metastasis just because a patient has had a previous cancer; such an assumption could result in overlooking appropriate treatment of a curable tumor. Primary brain tumors rarely spread to other areas of the body, but they can spread to other parts of the brain and to the spinal axis.

References:

1. Levin VA, Leibel SA, Gutin PH: Neoplasms of the central nervous system. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 2022-2082.

2. Mahaley MS, Mettlin C, Natarajan N, et al.: National survey of patterns of care for brain-tumor patients. Journal of Neurosurgery 71(6): 826-836, 1989.

3. Surawicz TS, Davis F, Freels S, et al.: Brain tumor survival; results from the National Cancer Data Base. Journal of Neuro-Oncology 40(2): 151-160, 1998.

Cellular Classification

Histological classification for adult brain tumors is as follows:1

Glial tumors:

astrocytic tumors
#noninfiltrating
--juvenile pilocytic subependymal
#infiltrating
--well-differentiated mildly and moderately anaplastic astrocytoma anaplastic astrocytoma glioblastoma multiforme

#ependymal tumors
--myxopapillary and well-differentiated ependymoma anaplastic ependymoma ependymoblastoma
#oligodendroglial tumors
--well-differentiated oligodendroglioma anaplastic oligodendroglioma
#mixed tumors
--mixed astrocytoma-ependymoma mixed astrocytoma-oligodendroglioma mixed astrocytoma-ependymoma-oligodendroglioma
#medulloblastoma

Nonglial tumors:

#pineal parenchymal tumors
--pineocytoma pineoblastoma astrocytoma (see above)
#germ cell tumors
--germinoma embryonal carcinoma choriocarcinoma teratoma
#craniopharyngioma meningiomas
--meningioma malignant meningiomas
----anaplastic meningioma hemangiopericytoma papillary meningioma
#choroid plexus tumors
--choroid plexus papilloma anaplastic choroid plexus papilloma

References:

1. Kleihues P, Burger PC, Scheithauer BW, et al.: Histological typing of tumours of the central nervous system. Berlin: Springer-Verlag, 2nd ed., 1993.

Stage Information

Brain tumors are classified on the basis of tumor cell type and histologic grade. For some tumors, location and metastatic spread within the cerebrospinal fluid are also used in classification.1

Cerebral Astrocytic Gliomas

Gliomas constitute the most common primary central nervous system (CNS) tumors. Of the gliomas, astrocytomas of variable malignancy are the most prevalent. Cerebral astrocytomas are subdivided into categories (grades) based on the degree of tumor anaplasia and the presence or absence of necrosis.

Noninfiltrating astrocytomas

These astrocytomas are relatively slow-growing tumors such as juvenile pilocytic and subependymal astrocytomas, which occur most frequently in children but can occur in adults.

Well-differentiated mildly and moderately anaplastic astrocytomas

These tumors are more infiltrative than the juvenile pilocytic and subependymal astrocytomas but are still relatively slow-growing tumors.

Anaplastic astrocytomas

These tumors are highly anaplastic with obvious vascular abnormalities. This grade III astrocytoma grows more rapidly than the more differentiated astrocytomas.

Glioblastoma multiforme

This grade IV astrocytoma is a poorly differentiated, rapidly growing tumor that occurs most often in adults.

Brain Stem Gliomas

Brain stem gliomas are usually diagnosed on clinical evidence because diagnosis by biopsy might be hazardous. Tumors that diffusely enlarge the brain stem carry a worse prognosis than those that are more focal. Higher grades of malignancy (see above) carry poorer prognoses as well.

Cerebellar Astrocytomas

Although the majority of these tumors are of lower grade and frequently are curable, they vary in grade of malignancy. The higher grade lesions carry a worse prognosis, but prognosis is generally better than for their cerebral counterparts.

Ependymal Tumors

Ependymal tumors are considered to arise from ependymal cells that line the ventricles and from ependymal rests. They vary in grade of malignancy.

Well-differentiated ependymomas

These tumors include myxopapillary ependymoma and well-differentiated ependymoma, and are often curable.

Anaplastic ependymomas

These tumors have more features of anaplasia and appear mitotically more active than the myxopapillary or well-differentiated ependymomas. Although previously considered to do worse than the well-differentiated ependymoma, conflicting evidence suggests that patients treated with surgery and radiation therapy might do nearly as well.

Ependymoblastomas

These are generally tumors of childhood and are considered by some to be primitive neuroectodermal tumors. They are rare.

Oligodendroglial Tumors

Oligodendroglial tumors are gliomas that arise from the oligodendroglia. They vary in grade of malignancy, and prognosis is related to grade.

Well-differentiated oligodendrogliomas

These tumors are usually slow-growing and well circumscribed.

Anaplastic oligodendrogliomas

These tumors are comparable to the highly anaplastic gliomas in prognosis.

Mixed Gliomas

Mixed gliomas can occur with combinations of generally 2, but sometimes 3, different cell types: astrocytoma, ependymoma, and/or oligodendroglioma. Survival statistics are inexact for this group because the cell types and grade of the most malignant-appearing cells influence prognosis. In general, these tumors carry a prognosis that is between the prognoses of well-differentiated and anaplastic astrocytomas.

Medulloblastoma

Medulloblastoma is a rapidly growing tumor arising in the posterior fossa and is found almost exclusively in children and young adults. It has the tendency to spread from the brain to the spinal axis. Prognosis is dependent on the staging following surgical resection.

Pineal Region Tumors

Pineal parenchymal tumors vary in histology and grade of malignancy relative to patient age at occurrence. They can vary from the slow-growing pineocytoma to the more malignant and faster growing pineoblastoma. Astrocytomas can also grow in this location (see above), as can a variety of primary germ cell tumors: germinoma, embryonal carcinoma, choriocarcinoma, and teratoma. These uncommon tumors vary in prognosis. The absence of biopsy specimens in many series make the prognosis for each tumor type difficult to evaluate.

Craniopharyngiomas

Craniopharyngioma is a tumor that arises from the remains of a structure found in the developing embryo in the region of the pituitary gland. This tumor causes symptoms and signs by pressing on vital areas of the brain and the optic nerves; it also causes internal hydrocephalus by obstructing the foramen of Monro in children.

Meningiomas

Meningiomas arise from the meninges surrounding the brain and spinal cord and are generally slow-growing. There are other variants that constitute a group called malignant meningioma and include malignant meningioma, hemangiopericytoma, papillary meningioma, and meningeal sarcoma. Malignant meningiomas are more likely than other meningiomas to metastasize within the craniospinal axis.

Meningiomas

Meningioma is usually curable with surgery if the initial resection is complete. The shape of the tumor is a prognostic factor and should be considered in planning surgery. Incomplete resection associated with lobulated and mushrooming patterns of tumor growth is associated with a higher risk of recurrence.2

Malignant meningiomas

The prognosis for patients with malignant meningioma is worse than for patients with the more well-differentiated meningiomas.

Choroid Plexus Tumors

Choroid plexus tumors are rare tumors arising from choroid plexus epithelial cells. The more benign form is choroid plexus papilloma; the more malignant form is called anaplastic choroid plexus papilloma. These latter tumors are most likely to spread within the craniospinal axis.

References:

1. Levin VA, Leibel SA, Gutin PH: Neoplasms of the central nervous system. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 2022-2082.

2. Nakasu S, Nakasu Y, Nakajima M, et al.: Preoperative identification of meningiomas that are highly likely to recur. Journal of Neurosurgery 90(3): 455-462, 1999.

Treatment Option Overview

Surgical removal of brain tumors is recommended for most types and in most locations and should be as complete as possible within the constraints of preservation of neurologic function.1 An exception to this role for surgery is for deep-seated tumors, such as pontine gliomas, which are diagnosed on clinical evidence and are treated without initial surgery approximately 50% of the time. In the majority of cases, however, diagnosis by biopsy is preferred. Stereotaxic biopsy can be used for lesions that are difficult to reach and resect.

Radiation therapy has a major role in the treatment of most tumor types and can increase the cure rate or prolong disease-free survival. Radiation therapy may also be useful in the treatment of recurrences in patients treated initially with surgery alone.

Chemotherapy may prolong survival in some tumor types and has been reported to lengthen disease-free survival in patients with gliomas, medulloblastoma, and some germ cell tumors.2 Local chemotherapy with a nitrosourea applied to a polymer placed directly in the brain during surgery has been shown to be a safe modality and is under clinical evaluation.1,3

Patients who have brain tumors that are either infrequently curable or unresectable should be considered candidates for clinical trials that evaluate radiosensitizers, hyperthermia, or interstitial brachytherapy used in conjunction with external-beam radiation therapy to improve local control of the tumor or for studies that evaluate new drugs and biological response modifiers.

References:

1. Brem H, Piantadosi S, Burger PC, et al.: Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 345(8956): 1008-1012, 1995.

2. Cokgor I, Friedman HS, Friedman AH: Chemotherapy for adults with malignant glioma. Cancer Investigation 17(4): 264-272, 1999.

Brem H, Ewend MG, Piantadosi S, et al.: The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase I trial. Journal of Neuro-Oncology 26(2): 111-123, 1995.

3. Levin VA, Leibel SA, Gutin PH: Neoplasms of the central nervous system. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 2022-2082.

Adult Noninfiltrating Astrocytoma

Juvenile pilocytic and subependymal astrocytomas 1

Noninfiltrating astrocytic tumors are often curable.

Treatment options:

Standard:

1. Surgery alone if totally resectable.
2. Surgery followed by radiation therapy to known or suspected residual tumor.2

Under clinical evaluation:

At recurrence following surgery, patients should be considered for reoperation and radiation therapy if not previously given. Patients who have received radiation therapy should be considered candidates for nitrosourea-based chemotherapies and for clinical trials that evaluate new drugs and biological response modifiers.

References:

1. Wallner KE, Gonzales MF, Edwards MS, et al.: Treatment results of juvenile pilocytic astrocytoma. Journal of Neurosurgery 69(2): 171-176, 1988.

2. Shaw EG, Daumas-Duport C, Scheithauer BW, et al.: Radiation therapy in the management of low-grade supratentorial astrocytomas. Journal of Neurosurgery 70(6): 853-861, 1989.

Adult Well-Differentiated Mildly and Moderately Anaplastic Astrocytoma

Well-differentiated mildly and moderately anaplastic astrocytomas are less often curable.

Treatment options:

Standard:

Surgery plus radiation therapy, although some controversy exists and some physicians treat these patients with surgery alone if the patient is younger than 35 years of age and the tumor does not contrast-enhance on a computed tomographic scan.1

Under clinical evaluation:

Clinical trials in progress are evaluating the effect of adding drugs to local therapy, for example, radiation therapy with or without chemotherapy for incompletely resected well-differentiated mildly and moderately anaplastic astrocytomas. Other trials are evaluating the effect of deferring irradiation until the time of tumor progression and of high-dose versus low-dose irradiation.

References:

1. Shaw EG, Daumas-Duport C, Scheithauer BW, et al.: Radiation therapy in the management of low-grade supratentorial astrocytomas. Journal of Neurosurgery 70(6): 853-861, 1989.

Adult Anaplastic Astrocytoma

For anaplastic astrocytomas of higher grade, the cure rate is low with standard local treatment.1 These patients are appropriate candidates for clinical trials designed to improve local control by adding newer forms of treatment to standard treatment.

Treatment options:

Standard:

1. Surgery plus radiation therapy.
2. Surgery plus radiation therapy and chemotherapy.2-6

Under clinical evaluation:

Patients with brain tumors that are either infrequently curable or unresectable should be considered candidates for clinical trials that evaluate hyperfractionated irradiation, accelerated fraction radiation, stereotactic radiosurgery, radiosensitizers, hyperthermia, interstitial brachytherapy, or intraoperative radiation therapy used in conjunction with external-beam radiation therapy to improve local control of the tumor and/or for studies that evaluate new drugs and biological response modifiers following radiation therapy.7-11 Cooperative group trials that evaluate chemoradiotherapy administered with either hyperfractionated irradiation or a combination of brachytherapy and external-beam irradiation are now in progress. Carmustine (BCNU) impregnated polymer may be implanted during surgery.12,13

References:

1. Nelson DF, Nelson JS, Davis DR, et al.: Survival and prognosis of patients with astrocytoma with atypical or anaplastic features. Journal of Neuro-Oncology 3(2): 99-103, 1985.

2. Rodriguez L, Levin V: Does chemotherapy benefit the patient with a central nervous system glioma? Oncology (Huntington NY) 1(9): 29-36, 1987.

3. Chang CH, Horton J, Schoenfeld D, et al.: Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas: a joint Radiation Therapy Oncology and Eastern Cooperative Oncology Group Study. Cancer 52(6): 997-1007, 1983.

4. Levin VA, Silver P, Hannigan J, et al.: Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. International Journal of Radiation Oncology, Biology, Physics 18(2): 321-324, 1990.

5. Friedman HS, Kerby T, Calvert H: Temozolomide and treatment of malignant glioma. Clinical Cancer Research 6(7): 2585-2597, 2000.

6. Prados MD, Levin V: Biology and treatment of malignant glioma. Seminars in Oncology 27(3 suppl 6): 1-10, 2000.

7. Nelson DF, Urtasun RC, Saunders WM, et al.: Recent and current investigations of radiation therapy of malignant gliomas. Seminars in Oncology 13(1): 46-55, 1986.

8. Levin VA: Chemotherapy of primary brain tumors. Neurologic Clinics 3(4): 855-866, 1985.

9. Shapiro WR: Therapy of adult malignant brain tumors: what have the clinical trials taught us? Seminars in Oncology 13(1): 38-45, 1986.

10. Loeffler JS, Alexander E, Shea WM, et al.: Radiosurgery as part of the initial management of patients with malignant gliomas. Journal of Clinical Oncology 10(9): 1379-1385, 1992.

11. Yung WK, Prados MD, et al., for the Temodal Brain Tumor Group: Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Journal of Clinical Oncology 17(9): 2762-2771, 1999.

12. Brem H, Piantadosi S, Burger PC, et al.: Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 345(8956): 1008-1012, 1995.

13. Brem H, Ewend MG, Piantadosi S, et al.: The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase I trial. Journal of Neuro-Oncology 26(2): 111-123, 1995.

Adult Glioblastoma Multiforme

For glioblastoma multiforme, the cure rate is very low with standard local treatment. These patients are appropriate candidates for clinical trials designed to improve local control by adding newer forms of treatment to standard treatment.

Treatment options:

Standard:

1. Surgery plus radiation therapy and chemotherapy.1-3
2. Surgery plus radiation therapy.4

Under clinical evaluation:

Patients with brain tumors that are either infrequently curable or unresectable should be considered candidates for clinical trials that evaluate hyperfractionated irradiation, accelerated fraction irradiation, stereotactic radiosurgery, radiosensitizers, hyperthermia, interstitial brachytherapy, or intraoperative radiation therapy used in conjunction with external-beam radiation therapy to improve local control of the tumor and/or for studies that evaluate new drugs and biological response modifiers following radiation therapy.5-8 Cooperative group studies that evaluate hyperfractionated irradiation and interstitial brachytherapy are in progress.9 Carmustine (BCNU) impregnated polymer may be implanted during surgery.10,11

References:

1. Shapiro WR: Therapy of adult malignant brain tumors: what have the clinical trials taught us? Seminars in Oncology 13(1): 38-45, 1986.

2. Rodriguez L, Levin V: Does chemotherapy benefit the patient with a central nervous system glioma? Oncology (Huntington NY) 1(9): 29-36, 1987.

3. Prados MD, Levin V: Biology and treatment of malignant glioma. Seminars in Oncology 27(3 suppl 6): 1-10, 2000.

4. Friedman HS, Kerby T, Calvert H: Temozolomide and treatment of malignant glioma. Clinical Cancer Research 6(7): 2585-2597, 2000.

5. Leibel SA, Gutin PH, Sneed PK, et al.: Interstitial irradiation for the treatment of primary and metastatic brain tumors. Cancer: Principles and Practice of Oncology Updates 3(7): 1-11, 1989.

6. Nelson DF, Urtasun RC, Saunders WM, et al.: Recent and current investigations of radiation therapy of malignant gliomas. Seminars in Oncology 13(1): 46-55, 1986.

7. Loeffler JS, Alexander E, Shea WM, et al.: Radiosurgery as part of the initial management of patients with malignant gliomas. Journal of Clinical Oncology 10(9): 1379-1385, 1992.

8. Fontanesi J, Clark WC, Weir A, et al.: Interstitial iodine 125 and concomitant cisplatin followed by hyperfractionated external beam irradiation for malignant supratentorial glioma. American Journal of Clinical Oncology 16(5): 412-417, 1993.

9. Scharfen CO, Sneed PK, Wara WM, et al.: High activity iodine-125 interstitial implant for gliomas. International Journal of Radiation Oncology, Biology, Physics 24(1): 583-591, 1992.

10. Brem H, Piantadosi S, Burger PC, et al.: Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 345(8956): 1008-1012, 1995.

11. Brem H, Ewend MG, Piantadosi S, et al.: The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase I trial. Journal of Neuro-Oncology 26(2): 111-123, 1995.

Adult Brain Stem Glioma

Brain stem gliomas have a relatively poor prognosis that is correlated with histology (when biopsies are performed), location, and extent of tumor. The overall median survival time of patients in studies has been 44 to 74 weeks.1-5 The best results have been attained with hyperfractionated radiation therapy.5

Treatment options:

Standard:

Radiation therapy.1-5

Under clinical evaluation:

At recurrence, patients should be considered for clinical trials that evaluate new drugs and biological response modifiers.6,7

References:

1. Greenberger JS, Cassady JR, Levene MB: Radiation therapy of thalamic, midbrain and brain stem gliomas. Radiology 122(2): 463-468, 1977.

2. Levin VA, Edwards MS, Wara WM, et al.: 5-Fluorouracil and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) followed by hydroxyurea, misonidazole and irradiation for brain stem gliomas: a pilot study of the Brain Tumor Research Center and the Children's Cancer Study Group. Neurosurgery 14(6): 679-681, 1984.

3. Allen JC, Bloom J, Ertel I, et al.: Brain tumors in children: current cooperative and institutional chemotherapy trials in newly diagnosed and recurrent disease. Seminars in Oncology 13(1): 110-122, 1986.

4. Eifel PJ, Cassady JR, Belli JA: Radiation therapy of tumors of the brainstem and midbrain in children: experience of the Joint Center for Radiation Therapy and Children's Hospital Medical Center (1971-1981). International Journal of Radiation Oncology, Biology, Physics 13(6): 847-852, 1987.

5. Shrieve DC, Wara WM, Edwards MS, et al.: Hyperfractionated radiation therapy for gliomas of the brainstem in children and in adults. International Journal of Radiation Oncology, Biology, Physics 24(1): 599-610, 1992.

6. Fulton DS, Levin VA, Wara WM, et al.: Chemotherapy of pediatric brain-stem tumors. Journal of Neurosurgery 54(6): 721-725, 1981.

7. Rodriguez LA, Prados M, Fulton D, et al.: Treatment of recurrent brain stem gliomas and other central nervous system tumors with 5-fluorouracil, CCNU, hydroxyurea, and 6-mercaptopurine. Neurosurgery 22(4): 691-693, 1988.

Adult Well-Differentiated Ependymoma

Myxopapillary ependymoma and well-differentiated ependymoma

These ependymomas are often curable.

Treatment options:

Standard:

1. Surgery alone if totally resectable.
2. Surgery followed by radiation therapy to known or suspected residual tumor.1,2

Under clinical evaluation:

At recurrence following surgery, patients should be considered for reoperation and radiation therapy if not previously used. Patients who have received radiation therapy should be considered candidates for nitrosourea-based chemotherapies and for clinical trials that evaluate new drugs and biological response modifiers.

References:

1. Wallner KE, Wara WM, Sheline GE, et al.: Intracranial ependymomas: results of treatment with partial or whole brain irradiation without spinal irradiation. International Journal of Radiation Oncology, Biology, Physics 12(11): 1937-1941, 1986.

2. Shaw EG, Evans RG, Scheithauer BW, et al.: Postoperative radiotherapy of intracranial ependymoma in pediatric and adult patients. International Journal of Radiation Oncology, Biology, Physics 13(10): 1457-1462, 1987.

Adult Malignant Ependymoma

Anaplastic ependymoma and ependymoblastoma

Malignant ependymomas have variable prognoses that depend on location and extent of disease. Frequently, but not invariably, anaplastic ependymomas have a worse prognosis than well-differentiated ependymomas. The rare ependymoblastoma has a much worse prognosis.

Treatment options:

Standard:

Surgery plus radiation therapy.1,2

Under clinical evaluation:

Adjuvant chemotherapy before, during, and after radiation are treatment options being evaluated. At recurrence, patients should be considered candidates for nitrosourea-based chemotherapies and for clinical trials that evaluate new drugs and biological response modifiers.

References:

1. Wallner KE, Wara WM, Sheline GE, et al.: Intracranial ependymomas: results of treatment with partial or whole brain irradiation without spinal irradiation. International Journal of Radiation Oncology, Biology, Physics 12(11): 1937-1941, 1986.

2. Shaw EG, Evans RG, Scheithauer BW, et al.: Postoperative radiotherapy of intracranial ependymoma in pediatric and adult patients. International Journal of Radiation Oncology, Biology, Physics 13(10): 1457-1462, 1987.

Adult Well-Differentiated Oligodendroglioma

These tumors behave very similarly to the well-differentiated mildly and moderately anaplastic astrocytomas.

Treatment options:

Standard:

Surgery plus radiation therapy; however, some controversy exists. Some physicians treat these patients with surgery alone if the patient is younger than 45 years of age and the tumor is not contrast-enhanced on a computed tomographic scan.1

Under clinical evaluation:

Clinical trials in progress are evaluating the effect of adding drugs to local therapy, e.g., radiation therapy with or without chemotherapy for incompletely resected well-differentiated mildly or moderately anaplastic astrocytomas.

References:

1. Salazar OM, Castro-Vita H, Van Houtte P, et al.: Improved survival in cases of intracranial ependymoma after radiation therapy: late report and recommendations. Journal of Neurosurgery 59(4): 652-659, 1983.

Adult Anaplastic Oligodendroglioma

For anaplastic oligodendrogliomas of higher grade, the cure rate is low with standard local treatment.1 Such patients are appropriate candidates for clinical trials designed to improve local control by adding newer forms of treatment.

Treatment options:

Standard:

1. Surgery plus radiation therapy.2-5
2. Surgery plus radiation therapy plus chemotherapy.6

Under clinical evaluation:

Patients with brain tumors that are either infrequently curable or unresectable should be considered candidates for clinical trials that evaluate interstitial brachytherapy, radiosensitizers, hyperthermia, or intraoperative radiation therapy in conjunction with external-beam radiation therapy to improve local control of the tumor and/or for studies that evaluate new drugs and biological response modifiers following radiation therapy.

References:

1. Kyritsis AP, Yung WK, Bruner J, et al.: The treatment of anaplastic oligodendrogliomas and mixed gliomas. Neurosurgery 32(3): 365-371, 1993.

2. Bullard DE, Rawlings CE, Phillips BW, et al.: Oligodendroglioma: an analysis of the value of radiation therapy. Cancer 60(9): 2179-2188, 1987.

3. Burger PC, Rawlings CE, Cox EB, et al.: Clinicopathologic correlations in the oligodendroglioma. Cancer 59(7): 1345-1352, 1987.

4. Lindegaard KF, Mork SJ, Eide GE, et al.: Statistical analysis of clinicopathological features, radiotherapy, and survival in 170 cases of oligodendroglioma. Journal of Neurosurgery 67(2): 224-230, 1987.

5. Wallner KE, Gonzales M, Sheline GE: Treatment of oligodendrogliomas with or without postoperative irradiation. Journal of Neurosurgery 68(5): 684-688, 1988.

6. Cairncross JG, Macdonald DR: Successful chemotherapy for recurrent malignant oligodendroglioma. Annals of Neurology 23(4): 360-364, 1988.

Mixed Gliomas

Mixed astrocytoma-ependymoma, mixed astrocytoma-oligodendroglioma, and mixed astrocytoma-ependymoma-oligodendroglioma

These mixed glial tumors have a prognosis similar to that for anaplastic astrocytomas and can be treated as such.

Treatment options:1

Standard:

1. Surgery plus radiation therapy.2
2. Surgery plus radiation therapy plus chemotherapy.

Under clinical evaluation:

Patients with brain tumors that are either infrequently curable or unresectable should be considered candidates for clinical trials that evaluate interstitial brachytherapy, radiosensitizers, hyperthermia, or intraoperative radiation therapy in conjunction with external-beam radiation therapy to improve local control of the tumor and/or for studies that evaluate new drugs and biological response modifiers following radiation therapy.

References:

1. Kyritsis AP, Yung WK, Bruner J, et al.: The treatment of anaplastic oligodendrogliomas and mixed gliomas. Neurosurgery 32(3): 365-371, 1993.

2. Shaw EG, Daumas-Duport C, Scheithauer BW, et al.: Radiation therapy in the management of low-grade supratentorial astrocytomas. Journal of Neurosurgery 70(6): 853-861, 1989.

Adult Medulloblastoma

Treatment options:

Standard:

Surgery plus craniospinal irradiation for good-risk patients.1,2

Under clinical evaluation:

For poor-risk patients, in addition to surgery plus craniospinal irradiation, various chemotherapy programs are being evaluated.3

References:

1. Levin VA, Vestnys PS, Edwards MS, et al.: Improvement in survival produced by sequential therapies in the treatment of recurrent medulloblastoma. Cancer 51(8): 1364-1370, 1983.

2. Carrie C, Lasset C, Alapetite C, et al.: Multivariate analysis of prognostic factors in adult patients with medulloblastoma: retrospective study of 156 patients. Cancer 74(8): 2352-2360, 1994.

3. Allen JC, Bloom J, Ertel I, et al.: Brain tumors in children: current cooperative and institutional chemotherapy trials in newly diagnosed and recurrent disease. Seminars in Oncology 13(1): 110-122, 1986.

Adult Pineal Parenchymal Tumor

Pineocytoma and pineoblastoma

These diverse tumors require special consideration. Pineocytomas are slow growing and carry variable prognoses for cure. Pineoblastomas are more rapidly growing and have a worse prognosis.

Pineal astrocytoma

Depending on the degree of anaplasia, pineal astrocytomas vary in prognosis. Higher grades have a worse prognosis.

Treatment options:

Standard:

1. Surgery plus radiation therapy for pineocytoma and lower grades of astrocytoma.1,2
2. Surgery plus radiation therapy and chemotherapy for pineoblastoma and higher grades of astrocytoma.1,2

Under clinical evaluation:

Patients with brain tumors that are either infrequently curable or unresectable should be considered candidates for clinical trials that evaluate radiosensitizers, hyperthermia, or intraoperative radiation therapy in conjunction with external-beam radiation therapy to improve local control of the tumor and/or for studies that evaluate new drugs and biological response modifiers following radiation therapy.

References:

1. Stein BM, Fetell MR: Therapeutic modalities for pineal region tumors. Clinical Neurosurgery 32: 445-455, 1985.

2. Rich TA, Cassady JR, Strand RD, et al.: Radiation therapy for pineal and suprasellar germ cell tumors. Cancer 55(5): 932-940, 1985.

Adult Central Nervous System Germ Cell Tumor

Germinoma, embryonal carcinoma, choriocarcinoma, and teratoma

The prognosis and treatment of germ cell tumors depends on the histology, location, presence and amount of biological markers, and surgical resectability.1,2

References:

1. Edwards MS, Hudgins RJ, Wilson CB, et al.: Pineal region tumors in children. Journal of Neurosurgery 68(5): 689-697, 1988.

2. Lindstadt D, Wara WM, Edwards MS, et al.: Radiotherapy of primary intracranial germinomas: the case against routine craniospinal irradiation. International Journal of Radiation Oncology, Biology, Physics 15(2): 291-297, 1988.

Adult Craniopharyngioma

Craniopharyngioma is often curable.

Treatment options:

Standard:

1. Surgery alone if totally resectable.1
2. Debulking surgery plus radiation therapy if unresectable.2

References:

1. Baskin DS, Wilson CB: Surgical management of craniopharyngiomas: a review of 74 cases. Journal of Neurosurgery 65(1): 22-27, 1986.

2. Rajan B, Ashley S, Gorman C, et al.: Craniopharyngioma - long-term results following limited surgery and radiotherapy. Radiotherapy and Oncology 26(1): 1-10, 1993.

Adult Meningioma

Meningioma is usually curable when resectable.

Treatment options:

Standard:

1. Surgery.1
2. Surgery plus radiation therapy (in selected cases, such as for patients with known or suspected residual disease or with recurrence after previous surgery).2-4

References:

1. Black PM: Meningiomas. Neurosurgery 32(4): 643-657, 1993.

2. Wara WM, Sheline GE, Newman H, et al.: Radiation therapy of meningiomas. American Journal of Roentgenology, Radium Therapy and Nuclear Medicine 123(3): 453-458, 1975.

3. Barbaro NM, Gutin PH, Wilson CB, et al.: Radiation therapy in the treatment of partially resected meningiomas. Neurosurgery 20(4): 525-528, 1987.

4. Taylor BW, Marcus RB, Friedman WA, et al.: The meningioma controversy: postoperative radiation therapy. International Journal of Radiation Oncology, Biology, Physics 15(2): 299-304, 1988.

Adult Malignant Meningioma

Malignant meningioma, hemangiopericytoma, and papillary meningioma

The prognosis for patients with malignant meningioma is worse than for the more well-differentiated meningiomas because complete resections are less common and the proliferative capacity is greater.1,2

Treatment options:

Standard:

Surgery plus radiation therapy.

Under clinical evaluation:

Patients with brain tumors that are either infrequently curable or unresectable should be considered candidates for clinical trials that evaluate interstitial brachytherapy, radiosensitizers, hyperthermia, or intraoperative radiation therapy in conjunction with external-beam radiation therapy to improve local control of the tumor and/or for studies that evaluate new drugs and biological response modifiers following radiation therapy.

References:

1. Alvarez F, Roda JM, Perez-Romero M, et al.: Malignant and atypical meningiomas: a reappraisal of clinical, histological, and computed tomographic features. Neurosurgery 20(5): 688-694, 1987.

2. Perry A, Scheithauer BW, Stafford SL, et al.: "Malgnancy" in meningiomas: a clinicopathologic study of 116 patients, with grading implications. Cancer 85(9): 2046-2056, 1999.

Recurrent Adult Brain Tumor

Treatment options:

Standard:

1. Surgery alone or in conjunction with chemotherapy.1-3
2. Radiation therapy if not previously used, alone or with chemotherapy.
3. Interstitial irradiation.4

Under clinical evaluation:

Numerous clinical trials (particularly phase II trials) are evaluating the use of newer drugs in the treatment of brain tumors. Carmustine (BCNU) impregnated polymer may be implanted during surgery.5,6

References:

1. Salcman M, Kaplan RS, Ducker TB, et al.: Effect of age and reoperation on survival in the combined modality treatment of malignant astrocytoma. Neurosurgery 10(4): 454-463, 1982.

2. Rodriguez L, Levin V: Does chemotherapy benefit the patient with a central nervous system glioma? Oncology (Huntington NY) 1(9): 29-36, 1987.

3. Young B, Oldfield EH, Markesbery WR, et al.: Reoperation for glioblastoma. Journal of Neurosurgery 55(6): 917-921, 1981.

4. Leibel SA, Gutin PH, Sneed PK, et al.: Interstitial irradiation for the treatment of primary and metastatic brain tumors. Cancer: Principles and Practice of Oncology Updates 3(7): 1-11, 1989.

5. Brem H, Piantadosi S, Burger PC, et al.: Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 345(8956): 1008-1012, 1995.

6. Brem H, Ewend MG, Piantadosi S, et al.: The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase I trial. Journal of Neuro-Oncology 26(2): 111-123, 1995.

Bladder Cancer

2008-07-23T08:22:00.002-07:00

Table of Contents

General Information
Cellular Classification
Stage Information
TNM definitions
AJCC stage groupings
Stage 0a
Stage 0is
Stage I
Stage II
Stage III
Stage IV
Treatment Option Overview
Stage 0 Bladder Cancer
Tis or Ta, N0, M0
Stage I Bladder Cancer
T1, N0, M0
Stage II Bladder Cancer
T2a, N0, M0 or T2b, N0, M0
Stage III Bladder Cancer
T3a, N0, M0 or T3b, N0, M0 or T4a, N0, M0
Stage IV Bladder Cancer
T4b, N0, M0, any T, N1-N3, M0, or any T, any N, M1
Recurrent Bladder Cancer

General Information

Approximately 70% to 80% of patients with newly diagnosed bladder cancer will present with superficial bladder tumors (i.e., stage Ta, Tis, or T1). Those who do present with superficial, noninvasive bladder cancer are often curable, and those with deeply invasive disease can sometimes be cured by surgery, irradiation, or a combination of modalities that include chemotherapy. Studies have demonstrated that some patients with distant metastases have achieved long-term complete response following treatment with combination chemotherapy regimens. There are clinical trials suitable for patients with all stages of bladder cancer; whenever possible, patients should be included in clinical trials designed to improve on standard therapy.

The major prognostic factors in carcinoma of the bladder are the depth of invasion into the bladder wall and the degree of differentiation of the tumor. Most superficial tumors are well differentiated. Patients in whom superficial tumors are less differentiated, large, multiple, or associated with carcinoma in situ (Tis) in other areas of the bladder mucosa are at greatest risk for recurrence and the development of invasive cancer. Such patients may be considered to have the entire urothelial surface at risk for the development of cancer. Tis may exist for variable durations. Adverse prognostic features associated with a greater risk of disease progression include the presence of multiple aneuploid cell lines, nuclear p53 overexpression, and expression of the Lewis-x blood group antigen.1-4 Patients with Tis who have a complete response to bacillus Calmette-Guerin have approximately a 20% risk of disease progression at 5 years; patients with incomplete response have approximately a 95% risk of disease progression.1 Several treatment methods (i.e., transurethral surgery, intravesical medications, and cystectomy) have been used in the management of patients with superficial tumors, and each method can be associated with 5-year survival in 55% to 80% of patients treated.1,2,5

Invasive tumors that are confined to the bladder muscle on pathologic staging after radical cystectomy are associated with approximately a 75% 5-year progression-free survival rate. Patients with more deeply invasive tumors (which are also usually less well differentiated) experience 5-year survival rates of 20% to 40% following radical cystectomy. When the patient presents with locally extensive tumor that invades pelvic viscera or with metastases to lymph nodes or distant sites, 5-year survival is uncommon, but considerable symptomatic palliation can still be achieved.6

Expression of the tumor suppressor gene p53 also has been associated with an adverse prognosis for patients with invasive bladder cancer. A retrospective study of 243 patients treated by radical cystectomy found that the presence of nuclear p53 was an independent predictor for recurrence among patients with stage T1, T2, or T3 tumors.7 Another retrospective study showed p53 expression to be of prognostic value when considered with stage or labeling index.8

References:

1. Hudson MA, Herr HW: Carcinoma in situ of the bladder. Journal of Urology 153(3, Part 1): 564-572, 1995.

2. Torti FM, Lum BL: The biology and treatment of superficial bladder cancer. Journal of Clinical Oncology 2(5): 505-531, 1984.

3. Lacombe L, Dalbagni G, Zhang ZF, et al: Overexpression of p53 protein in a high-risk population of patients with superficial bladder cancer before and after bacillus Calmette-Guerin therapy: correlation to clinical outcome. Journal of Clinical Oncology 14(10): 2646-2652, 1996.

4. Stein JP, Grossfeld GD, Ginsberg DA, et al.: Prognostic markers in bladder cancer: a contemporary review of the literature. Journal of Urology 160(3 pt 1): 645-659, 1998.

5. Witjes JA, Caris CT, Mungan NA, et al.: Results of a randomized phase III trial of sequential intravesical therapy with mitomycin C and bacillus Calmette-Guerin versus mitomycin C alone in patients with superficial bladder cancer. Journal of Urology 160(5): 1668-1672, 1998.

6. Thrasher JB, Crawford ED: Current management of invasive and metastatic transitional cell carcinoma of the bladder. Journal of Urology 149(5): 957-972, 1993.

7. Esrig D, Elmajian D, Groshen S, et al.: Accumulation of nuclear p53 and tumor progression in bladder cancer. New England Journal of Medicine 331(19): 1259-1264, 1994.

8. Lipponen PK: Over-expression of p53 nuclear oncoprotein in transitional-cell bladder cancer and its prognostic value. International Journal of Cancer 53: 365-370, 1993.

Cellular Classification

More than 90% of bladder carcinomas are transitional cell carcinomas derived from the uroepithelium. About 6% to 8% are squamous cell carcinomas, and 2% are adenocarcinomas.1 Adenocarcinomas may be either of urachal origin or of nonurachal origin; the latter type is generally thought to arise from metaplasia of chronically irritated transitional epithelium.2 Pathologic grade, which is based on cellular atypia, nuclear abnormalities, and the number of mitotic figures, is of great prognostic importance.

References:

1. Mostofi FK, Davis CJ, Sesterhenn IA: Pathology of tumors of the urinary tract. In: Skinner DG, Lieskovsky G, Eds.: Diagnosis and Management of Genitourinary Cancer. Philadelphia, WB Saunders, 1988, pp 83-117.

2. Wilson TG, Pritchett TR, Lieskovsky G, et al.: Primary adenocarcinoma of bladder. Urology 38(3): 223-226, 1991.

Stage Information

The clinical staging of carcinoma of the bladder is determined by the depth of invasion of the bladder wall by the tumor. This determination requires a cystoscopic examination that includes a biopsy, and examination under anesthesia to assess the size and mobility of palpable masses, the degree of induration of the bladder wall, and the presence of extravesical extension or invasion of adjacent organs. Clinical staging, even when computed tomographic and/or magnetic resonance imaging scans and other imaging modalities are used, often underestimates the extent of tumor, particularly in cancers that are less differentiated and more deeply invasive.1-3

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define bladder cancer.4

TNM definitions

Primary tumor (T)

The suffix "m" should be added to the appropriate T category to indicate multiple lesions. The suffix "is" may be added to any T to indicate the presence of associated carcinoma in situ.

TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Ta: Noninvasive papillary carcinoma Tis: Carcinoma in situ: "flat tumor" T1: Tumor invades subepithelial connective tissue T2: Tumor invades muscle
T2a: Tumor invades superficial muscle (inner half) T2b: Tumor invades deep muscle (outer half)
T3: Tumor invades perivesical tissue
T3a: microscopically T3b: macroscopically (extravesical mass)
T4: Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, or abdominal wall.
T4a: Tumor invades the prostate, uterus, vagina T4b: Tumor invades the pelvic wall, abdominal wall

Regional lymph nodes (N)

Regional lymph nodes are those within the true pelvis; all others are distant lymph nodes.

NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Metastasis in a single lymph node, 2 cm or less in greatest dimension N2: Metastasis in a single lymph node, more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, none more than 5 cm in greatest dimension N3: Metastasis in a lymph node more than 5 cm in greatest dimension

Distant metastasis (M)

MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis

AJCC stage groupings

Stage 0a

Ta, N0, M0

Stage 0is

Tis, N0, M0

Stage I

T1, N0, M0

Stage II

T2a, N0, M0 T2b, N0, M0

Stage III

T3a, N0, M0 T3b, N0, M0 T4a, N0, M0

Stage IV

T4b, N0, M0 Any T, N1, M0 Any T, N2, M0 Any T, N3, M0 Any T, Any N, M1

An older, less frequently used, staging system was derived by comparing clinical estimates of stage with the pathologic stage of radical cystectomy specimens.2,3 To better ensure uniform staging and reporting of clinical results, the use of the modern TNM classification described above is recommended.

References:

1. National Institutes of Health: National Institutes of Health Consensus Development Conference: magnetic resonance imaging. JAMA: Journal of the American Medical Association 259(14): 2132-2138, 1988.

2. Marshall VF: The relationship of the preoperative estimate to the pathologic demonstration of the extent of vesical neoplasms. Journal of Urology 68(4): 714-723, 1952.

3. Skinner DG: Current state of classification and staging of bladder cancer. Cancer Research 37(8, Part II): 2838-2842, 1977.

4. Urinary bladder. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 241-246.

Treatment Option Overview

Prolonged survival in most patients with superficial cancers is achieved by transurethral resection (TUR) with or without intravesical chemotherapy. However, cure is not possible for the majority of patients with deeply invasive tumors and for most patients with regional or distant metastases. In North America, the standard treatment of patients with invasive bladder cancers is radical cystectomy and urinary diversion. Other treatment approaches include TUR and segmental resection with or without radiation therapy, combined chemotherapy-radiation therapy, or either followed by salvage cystectomy, when needed, for local failure. Therefore, many newly diagnosed bladder cancer patients are candidates for participation in a clinical trial. Clinical trials include studies of chemoprevention of superficial disease, adjuvant chemotherapy for advanced local or regional disease, preservation of bladder function with chemotherapy-radiation therapy, and development of more effective systemic therapy and methods of palliation for metastatic tumors.1-6

Reconstructive techniques that fashion low-pressure storage reservoirs from the reconfigured small and large bowel eliminate the need for external drainage devices and, in some male patients, allow voiding per urethra. These techniques are designed to improve the quality of life for patients who require cystectomy.7

References:

1. Thrasher JB, Crawford ED: Current management of invasive and metastatic transitional cell carcinoma of the bladder. Journal of Urology 149(5): 957-972, 1993.

2. Housset M, Maulard C, Chretien Y, et al.: Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study. Journal of Clinical Oncology 11(11): 2150-2157, 1993.

3. Kachnic LA, Kaufman DS, Heney NM, et al.: Bladder preservation by combined modality therapy for invasive bladder cancer. Journal of Clinical Oncology 15(3): 1022-1029, 1997.

4. Lamm DL, Riggs DR, Shriver JS, et al.: Megadose vitamins in bladder cancer: a double-blind clinical trial. Journal of Urology 151(1): 21-26, 1994.

5. Raghavan D, Huben R: Management of bladder cancer. Current Problems in Cancer 19(1): 1-64, 1995.

6. Sauer R, Birkenhake S, Kuhn R, et al.: Efficacy of radiochemotherapy with platin derivatives compared to radiotherapy alone in organ-sparing treatment of bladder cancer. International Journal of Radiation Oncology, Biology, Physics 40(1): 121-127, 1998.

7. Hautmann RE, Miller K, Steiner U, et al.: The ileal neobladder: 6 years of experience with more than 200 patients. Journal of Urology 150(1): 40-45, 1993.

Stage 0 Bladder Cancer

Tis or Ta, N0, M0

Stage 0 bladder tumors can be cured by a variety of forms of treatment, even though the tendency for new tumor formation is high. In a series of patients with Ta or T1 tumors who were followed for a minimum of 20 years or until death, the risk of bladder cancer recurrence following initial resection was 80%.1 Patients at greatest risk of recurrent disease are those whose tumors are large, poorly differentiated, multiple, or associated with nuclear p53 overexpression. In addition, patients with carcinoma in situ (Tis) or dysplasia of grossly uninvolved bladder epithelium are at greater risk of recurrence and progression.1-3

Transurethral resection (TUR) and fulguration are the most common and conservative forms of management. Careful surveillance of subsequent bladder tumor progression is important. One retrospective series addressed the value of performing a second TUR within 2 to 6 weeks of the first.4[Level of evidence: 3iiDiii] A second TUR performed on 38 patients with Tis or Ta disease found that 9 patients (24%) had lamina propria invasion (T1) and 3 patients (8%) had muscle invasion (T2). Such information may change the definitive management options in these individuals. Patients who require more aggressive forms of treatment are those with extensive multifocal recurrent disease and/or other unfavorable prognostic features. Segmental cystectomy is applicable to only a small minority of patients because of the tendency of bladder carcinoma to involve multiple regions of the bladder mucosa and to occur in areas that cannot be segmentally resected.

Intravesical therapy with thiotepa, mitomycin, doxorubicin, or bacillus Calmette-Guerin (BCG) is most often used in patients with multiple tumors or recurrent tumors or as a prophylactic measure in high-risk patients after TUR. Administration of intravesical BCG plus subcutaneous BCG following TUR was compared with TUR alone in patients with Ta and T1 lesions. Treatment with BCG delayed progression to muscle-invasive and/or metastatic disease, improved bladder preservation, and decreased the risk of death from bladder cancer.5,6 Another randomized study of patients with superficial bladder cancer also reports a decrease in tumor recurrence in patients given intravesical and percutaneous BCG compared with controls.7 Two nonconsecutive 6-week treatment courses with BCG may be necessary to obtain optimal response.8 Patients with a T1 tumor at the 3-month evaluation after a 6-week course of BCG and patients with Tis that persists after a second 6-week BCG course have a high likelihood of developing muscle-invasive disease and should be considered for cystectomy.8-10 A randomized study that compared intravesical and subcutaneous BCG with intravesical doxorubicin showed better response rates and freedom from recurrence with the BCG regimen for recurrent papillary tumors as well as for Tis.11 A randomized trial from the Swedish-Norwegian Bladder Cancer Group compared 2 years of intravesical treatment with mitomycin C versus BCG. However, no difference was observed in tumor progression or overall survival between the two arms at 5 years.12[Level of evidence: 1iiD] Although BCG may not prolong overall survival for Tis disease, it appears to afford complete response rates of about 70%, thereby decreasing the need for salvage cystectomy.13 Studies show that intravesical BCG delays tumor recurrence and tumor progression.6,14 Preliminary results from a prospective randomized trial suggest that maintenance BCG, when given to patients who are disease-free after a 6-week induction course, improves survival.15 One study that compared mitomycin with interferon alfa-2b showed an improved outcome with mitomycin, although interferon was better tolerated.16

Treatment options:

Standard:

1. TUR with fulguration.17
2. TUR with fulguration followed by intravesical BCG. BCG is the treatment of choice for Tis.5,7,9,13,14
3. TUR with fulguration followed by intravesical chemotherapy.2,11,17
4. Segmental cystectomy (rarely indicated).17
5. Radical cystectomy in selected patients with extensive or refractory superficial tumor.17,18

Under clinical evaluation:

1. Photodynamic therapy after intravenous hematoporphyrin derivative appears capable of completely eradicating tumors in one half of the treated patients who were in a small study with minimal follow-up.19 Further evaluation of this technique is needed.
2. Intravesical interferon alfa-2a has shown activity against papillary tumors and Tis both as primary treatment and as secondary treatment after failure of other intravesical agents.20
3. Use of chemoprevention agents after treatment to prevent recurrence.21

References:

1. Holmang S, Hedelin H, Anderstrom C, et al.: The relationship among multiple recurrences, progression and prognosis of patients with stages Ta and T1 transitional cell cancer of the bladder followed for at least 20 years. Journal of Urology 153(6): 1823-1827, 1995.

2. Igawa M, Urakami S, Shirakawa H, et al.: Intravesical instillation of epirubicin: effect on tumour recurrence in patients with dysplastic epithelium after transurethral resection of superficial bladder tumour. British Journal of Urology 77(3): 358-362, 1996.

3. Lacombe L, Dalbagni G, Zhang ZF, et al: Overexpression of p53 protein in a high-risk population of patients with superficial bladder cancer before and after bacillus Calmette-Guerin therapy: correlation to clinical outcome. Journal of Clinical Oncology 14(10): 2646-2652, 1996.

4. Herr HW: The value of second transurethral resection in evaluating patients with bladder tumors. Journal of Urology 162(1): 74-76, 1999.

5. Herr HW, Schwalb DM, Zhang ZF, et al.: Intravesical Bacillus Calmette-Guerin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. Journal of Clinical Oncology 13(6): 1404-1408, 1995.

6. Lamm DL, Griffith JG: Intravesical therapy: does it affect the natural history of superficial bladder cancer? Seminars in Urology 10(1): 39-44, 1992.

7. Sarosdy MF, Lamm DL: Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. Journal of Urology 142(3): 719-722, 1989.

8. Coplen DE, Marcus MD, Myers JA, et al.: Long-term follow-up of patients treated with 1 or 2, 6-week courses of intravesical bacillus Calmette-Guerin: analysis of possible predictors of response free of tumor. Journal of Urology 144(3): 652-657, 1990.

9. Catalona WJ, Hudson MA, Gillen DP, et al.: Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. Journal of Urology 137(2): 220-224, 1987.

10. Herr HW: Progression of stage T1 bladder tumors after intravesical bacillus Calmette-Guerin. Journal of Urology 145(1): 40-44, 1991.

11. Lamm DL, Blumenstein BA, Crawford ED, et al.: A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional-cell carcinoma of the bladder. New England Journal of Medicine 325(17): 1205-1209, 1991.

12. Malmstrom PU, Wijkstrom H, Lundholm C, et al.: 5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. Journal of Urology 161(4): 1124-1127, 1999.

13. De Jager R, Guinan P, Lamm D, et al.: Long-term complete remission in bladder carcinoma in situ with intravesical TICE bacillus Calmette Guerin: overview analysis of six phase II clinical trials. Urology 38(6): 507-513, 1991.

14. Herr HW, Wartinger DD, Fair WR, et al.: Bacillus Calmette-Guerin therapy for superficial bladder cancer: a 10-year followup. Journal of Urology 147(4): 1020-1023, 1992.

15. Lamm DL, Crawford ED, Blumenstein B, et al.: Maintenance BCG immunotherapy of superficial bladder cancer: a randomized prospective Southwest Oncology Group study. Proceedings of the American Society of Clinical Oncology 11: A-627, 203, 1992.

16. Boccardo F, Cannata D, Rubagotti A, et al.: Prophylaxis of superficial bladder cancer with mitomycin or interferon alfa-2b: results of a multicentric Italian study. Journal of Clinical Oncology 12(1): 7-13, 1994.

17. Soloway MS: The management of superficial bladder cancer. In: Javadpour N, Ed.: Principles and Management of Urologic Cancer. Baltimore: Williams and Wilkins, 2nd ed., 1983, pp 446-466.

18. Amling CL, Thrasher JB, Frazier HA, et al.: Radical cystectomy for stages TA, TIS, and T1 transitional cell carcinoma of the bladder. Journal of Urology 151(1): 31-36, 1994.

19. Prout GR, Lin CW, Benson RC, et al.: Photodynamic therapy with hematoporphyrin derivative in the treatment of superficial transitional-cell carcinoma of the bladder. New England Journal of Medicine 317(20): 1251-1255, 1987.

20. Torti FM, Shortliffe LD, Williams RD, et al.: Alpha-interferon in superficial bladder cancer: a Northern California Oncology Group study. Journal of Clinical Oncology 6(3): 476-483, 1988.

21. Lamm DL, Riggs DR, Shriver JS, et al.: Megadose vitamins in bladder cancer: a double-blind clinical trial. Journal of Urology 151(1): 21-26, 1994.

Stage I Bladder Cancer

T1, N0, M0

Stage I bladder tumors can be cured by a variety of forms of treatment, even though the tendency for new tumor formation is high. In a series of patients with Ta or T1 tumors who were followed for a minimum of 20 years or until death, the risk of bladder recurrence following initial resection was 80%.1 Patients at greatest risk of recurrent disease are those whose tumors are large, poorly differentiated, multiple, or associated with nuclear p53 overexpression.2 In addition, patients with carcinoma in situ (Tis) or dysplasia of grossly uninvolved bladder epithelium are at greater risk of recurrence and progression.1,3,4

Transurethral resection (TUR) and fulguration are the most common and conservative forms of management. Careful surveillance of subsequent bladder tumor progression is important. One retrospective series addressed the value of performing a second TUR within 2 to 6 weeks of the first.5[Level of evidence: 3iiDiii] A second TUR performed on 58 patients with T1 disease found that 14 patients (24%) had residual (T1) disease and 16 patients (28%) had muscle invasion (T2). Such information may change the definitive management options in these individuals. Patients who require more aggressive forms of treatment are those with extensive multifocal recurrent disease and/or other unfavorable prognostic features. Segmental cystectomy is applicable to only a small minority of patients because of the tendency of bladder carcinoma to involve multiple regions of the bladder mucosa and to occur in areas that cannot be segmentally resected.

Intravesical therapy with thiotepa, mitomycin, doxorubicin, or BCG (bacillus Calmette-Guerin) is most often used in patients with multiple tumors or recurrent tumors or as a prophylactic measure in high-risk patients after TUR. Administration of intravesical BCG combined with subcutaneous BCG following TUR was compared with TUR alone in patients with Ta and T1 lesions. Treatment with BCG delayed progression to muscle-invasive and/or metastatic disease, improved bladder preservation, and decreased the risk of death from bladder cancer.6 Another randomized study in patients with superficial bladder cancer also reports a decrease in tumor recurrence in patients given intravesical and percutaneous BCG compared with controls.7 Two nonconsecutive 6-week courses with BCG may be necessary to obtain optimal response.8 Patients with a T1 tumor at the 3-month evaluation after a 6-week course of BCG and patients with Tis that persists after a second 6-week BCG course have a high likelihood of developing muscle-invasive disease and should be considered for cystectomy.8-10 A randomized study that compared intravesical and subcutaneous BCG to intravesical doxorubicin showed better response rates and freedom from recurrence with the BCG regimen for recurrent papillary tumors as well as for Tis.11 Preliminary results of one study have shown a possible survival benefit with maintenance BCG after a 6-week induction course.12 Another study that compared alternating mitomycin and BCG with BCG alone, both given for 24 months, found that the efficacy was equal, but that the side effects of the combined regimen were slightly less.13[Level of evidence: 1iiDii] A similar trial comparing sequential mitomycin and BCG to mitomycin alone also found no major differences in toxic effects or efficacy.14[Level of evidence: 1iiDii] A randomized trial from the Swedish-Norwegian Bladder Cancer Group compared 2 years of intravesical treatment with mitomycin C versus BCG for patients at high risk for recurrence or progression. At 5 years, a significant improvement was noted in disease-free survival with BCG (p=0.04); however, no difference was observed in tumor progression or overall survival between the two arms.15

Treatment options:

Standard:

1. TUR with fulguration.16,17
2. TUR with fulguration followed by intravesical BCG.6,7,9,10,13
3. TUR with fulguration followed by intravesical chemotherapy.3,13
4. Segmental cystectomy (rarely indicated).16
5. Radical cystectomy in selected patients with extensive or refractory superficial tumor.18
6. Interstitial implantation of radioisotopes with or without external-beam irradiation.19,20

Under clinical evaluation:

1. Use of chemoprevention agents after treatment to prevent recurrence.21
2. Intravesical therapies.

References:

1 Holmang S, Hedelin H, Anderstrom C, et al.: The relationship among multiple recurrences, progression and prognosis of patients with stages Ta and T1 transitional cell cancer of the bladder followed for at least 20 years. Journal of Urology 153(6): 1823-1827, 1995.

2. Smits G, Schaafsma E, Kiemeney L, et al.: Microstaging of pT1 transitional cell carcinoma of the bladder: identification of subgroups with distinct risks of progression. Urology 52(6): 1009-1014, 1998.

3. Igawa M, Urakami S, Shirakawa H, et al.: Intravesical instillation of epirubicin: effect on tumour recurrence in patients with dysplastic epithelium after transurethral resection of superficial bladder tumour. British Journal of Urology 77(3): 358-362, 1996.

4. Lacombe L, Dalbagni G, Zhang ZF, et al: Overexpression of p53 protein in a high-risk population of patients with superficial bladder cancer before and after bacillus Calmette-Guerin therapy: correlation to clinical outcome. Journal of Clinical Oncology 14(10): 2646-2652, 1996.

5. Herr HW: The value of second transurethral resection in evaluating patients with bladder tumors. Journal of Urology 162(1): 74-76, 1999.

6. Herr HW, Schwalb DM, Zhang ZF, et al.: Intravesical Bacillus Calmette-Guerin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. Journal of Clinical Oncology 13(6): 1404-1408, 1995.

7. Sarosdy MF, Lamm DL: Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. Journal of Urology 142(3): 719-722, 1989.

8. Coplen DE, Marcus MD, Myers JA, et al.: Long-term follow-up of patients treated with 1 or 2, 6-week courses of intravesical bacillus Calmette-Guerin: analysis of possible predictors of response free of tumor. Journal of Urology 144(3): 652-657, 1990.

9. Catalona WJ, Hudson MA, Gillen DP, et al.: Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. Journal of Urology 137(2): 220-224, 1987.

10. Herr HW: Progression of stage T1 bladder tumors after intravesical bacillus Calmette-Guerin. Journal of Urology 145(1): 40-44, 1991.

11. Lamm DL, Blumenstein BA, Crawford ED, et al.: A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional-cell carcinoma of the bladder. New England Journal of Medicine 325(17): 1205-1209, 1991.

12. Lamm DL, Crawford ED, Blumenstein B, et al.: Maintenance BCG immunotherapy of superficial bladder cancer: a randomized prospective Southwest Oncology Group study. Proceedings of the American Society of Clinical Oncology 11: A-627, 203, 1992.

13. Rintala E, Jauhiainen K, Kaasinen E, et al.: Alternating mitomycin C and bacillus Calmette-Guerin instillation prophylaxis for recurrent papillary (stages Ta to T1) superficial bladder cancer. Journal of Urology 156(1): 56-60, 1996.

14. Witjes JA, Caris CT, Mungan NA, et al.: Results of a randomized phase III trial of sequential intravesical therapy with mitomycin C and bacillus Calmette-Guerin versus mitomycin C alone in patients with superficial bladder cancer. Journal of Urology 160(5): 1668-1672, 1998.

15. Malmstrom PU, Wijkstrom H, Lundholm C, et al.: 5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. Journal of Urology 161(4): 1124-1127, 1999.

16. Soloway MS: The management of superficial bladder cancer. In: Javadpour N, Ed.: Principles and Management of Urologic Cancer. Baltimore: Williams and Wilkins, 2nd ed., 1983, pp 446-466.

17. Herr HW, Reuter VE: Evaluation of new resectoscope loop for transurethral resection of bladder tumors. Journal of Urology 159(6): 2067-2068, 1998.

18. Amling CL, Thrasher JB, Frazier HA, et al.: Radical cystectomy for stages TA, TIS, and T1 transitional cell carcinoma of the bladder. Journal of Urology 151(1): 31-36, 1994.

19. Goffinet DR, Schneider MJ, Glatstein EJ, et al.: Bladder cancer: results of radiation therapy in 384 patients. Radiology 117(1): 149-153, 1975.

20. Vanderwerf-Messing B, Hop WC: Carcinoma of the urinary bladder, category T1 NX M0 treated either by radium implant or by transurethral resection only. International Journal of Radiation Oncology, Biology, Physics 7(3): 299-303, 1981.

21. Lamm DL, Riggs DR, Shriver JS, et al.: Megadose vitamins in bladder cancer: a double-blind clinical trial. Journal of Urology 151(1): 21-26, 1994.

Stage II Bladder Cancer

T2a, N0, M0 or T2b, N0, M0

Stage II bladder cancer may be controlled in some cases by transurethral resection (TUR), but often more aggressive forms of treatment are dictated by recurrent tumor or by the large size, multiple foci, or undifferentiated grade of the neoplasm. Segmental cystectomy is appropriate only in very selected patients. Radical cystectomy is considered standard treatment. In some reports, bladder-sparing radiation therapy with salvage cystectomy when indicated yields similar therapeutic results to those of radical cystectomy and can be delivered to patients who are not candidates for surgery. In some studies, one half or more of patients who had bladder-preserving therapy (initial TUR of as much tumor as possible with chemotherapy and concomitant radiation therapy) were disease-free 3 to 4 years after treatment;1-3 radical cystectomy was reserved for patients who did not achieve a complete response. Single institution studies report that disease-specific survival is worse for patients with hydronephrosis on the initial intravenous pyelogram, and therefore, such patients should not be considered as candidates for this approach.1,3,4 Choice of treatment is affected by a patient's overall medical condition and consideration of the adverse effects of therapy. Radical cystectomy includes removal of the bladder, perivesical tissues, prostate, and seminal vesicles in men and the uterus, tubes, ovaries, anterior vaginal wall, and urethra in women and may or may not be accompanied by pelvic lymph node dissection.5 Studies suggest that radical cystectomy with preservation of sexual function can be performed in some men and that new forms of urinary diversion can obviate the need for an external urinary appliance.6-9 In a retrospective analysis from a single institution, elderly patients (70 years of age or older) in good general health were found to have similar clinical and functional results following radical cystectomy when compared to younger patients.10 The only prospective, randomized trial reported to date did not show any survival advantage for preoperative radiation therapy and radical cystectomy compared with radical cystectomy alone.11 Treatment with concurrent chemotherapy and radiation therapy has been associated with improved rates of local control compared with historical series of patients treated with radiation therapy alone. The only prospective, randomized comparison of radiation therapy and chemoradiotherapy reported an improved rate of local control when cisplatin was given in conjunction with radiation therapy.12

Treatment options:

Standard:

1. Radical cystectomy with or without pelvic lymph node dissection.13
2. External-beam irradiation (nonsurgical candidates and selected cases).14-16
3. Interstitial implantation of radioisotopes before or after external-beam irradiation.17
4. TUR with fulguration (in selected patients).
5. Segmental cystectomy (in selected patients).13

Under clinical evaluation:

Multiple clinical trials are evaluating the potential of chemotherapy administered prior to cystectomy, following cystectomy, or in conjunction with external-beam radiation therapy to improve local tumor control, prevent distant metastases, or allow preservation of the bladder.1-3,18-22 The combination regimen methotrexate, vinblastine, doxorubicin, and cisplatin produced a pathologic complete response in approximately 20% of patients treated prior to definitive surgery.20 However, there is no evidence to date that the use of neoadjuvant cisplatin or cisplatin-based regimens will improve the survival of patients with locally advanced bladder cancer.23[Level of evidence: 1iiA];24[Level of evidence: 1iiA] In a bladder-sparing clinical trial of external radiation therapy with chemotherapy, initial results from the Radiation Therapy Oncology Group have shown that 2 cycles of neoadjuvant methotrexate, cisplatin, and vinblastine do not improve down staging to a complete response, patient survival, or freedom from metastatic disease over radiation and concurrent cisplatin alone.3[Level of evidence: 1iiA]

References:

1. Kachnic LA, Kaufman DS, Heney NM, et al.: Bladder preservation by combined modality therapy for invasive bladder cancer. Journal of Clinical Oncology 15(3): 1022-1029, 1997.

2. Housset M, Maulard C, Chretien Y, et al.: Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study. Journal of Clinical Oncology 11(11): 2150-2157, 1993.

3. Shipley WU, Winter KA, Kaufman DS, et al.: Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: inital results of Radiation Therapy Oncology Group 89-03. Journal of Clinical Oncology 16(11): 3576-3583, 1998.

4. Matos T, Cufer T, Cervek J, et al.: Prognostic factors in invasive bladder carcinoma treated by combined modality protocol (organ-sparing approach). International Journal of Radiation Oncology, Biology, Physics 46(2): 403-409, 2000.

5. Olsson CA: Management of invasive carcinoma of the bladder. In: deKernion JB, Paulson DF, Eds.: Genitourinary Cancer Management. Philadelphia: Lea and Febiger, 1987, pp 59-94.

6. Brendler CB, Steinberg GD, Marshall FF, et al.: Local recurrence and survival following nerve-sparing radical cystoprostatectomy. Journal of Urology 144(5): 1137-1141, 1990.

7. Skinner DG, Boyd SD, Lieskovsky G: Clinical experience with the Kock continent ileal reservoir for urinary diversion. Journal of Urology 132(6): 1101-1107, 1984.

8. Fowler JE: Continent urinary reservoirs and bladder substitutes in the adult: part I. Monographs in Urology 8(2): 1987.

9. Fowler JE: Continent urinary reservoirs and bladder substitutes in the adult: part II. Monographs in Urology 8(3): 1987.

10. Figueroa AJ, Stein JP, Dickinson M, et al.: Radical cystectomy for elderly patients with bladder carcinoma: an updated experience with 404 patients. Cancer 83(1): 141-147, 1998.

11. Smith JA, Crawford ED, Blumenstein B, et al.: A randomized prospective trial of pre-operative irradiation plus radical cystectomy versus surgery alone for transitional cell carcinoma of the bladder: a Southwest Oncology Group study. Journal of Urology 139(4, Part 2): 266A, 1988.

12. Coppin CM, Gospodarowicz MK, James K, et al.: Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. Journal of Clinical Oncology 14(11): 2901-2907, 1996.

13. Richie JP: Surgery for invasive bladder cancer. Hematology/Oncology Clinics of North America 6(1): 129-145, 1992.

14. Gospodarowicz MK, Hawkins NV, Rawlings GA, et al.: Radical radiotherapy for muscle invasive transitional cell carcinoma of the bladder: failure analysis. Journal of Urology 142(6): 1448-1454, 1989.

15. Yu WS, Sagerman RH, Chung CT, et al.: Bladder carcinoma: experience with radical and preoperative radiotherapy in 421 patients. Cancer 56(6): 1293-1299, 1985.

16. Jahnson S, Pedersen J, Westman G: Bladder carcinoma - a 20-year review of radical irradiation therapy. Radiotherapy and Oncology 22(2): 111-117, 1991.

17. van der Werf-Messing BH, van Putten WL: Carcinoma of the urinary bladder category T2,3 NX M0 treated by 40 Gy external irradiation followed by cesium-137 implant at reduced dose (50%). International Journal of Radiation Oncology, Biology, Physics 16(2): 369-371, 1989.

18. Tester W, Porter A, Asbell S, et al.: Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12. International Journal of Radiation Oncology, Biology, Physics 25(5): 783-790, 1993.

19. Natale RB, Southwest Oncology Group: NCI HIGH PRIORITY CLINICAL TRIAL --- Phase III Randomized Comparison of Cystectomy Alone vs Neoadjuvant MVAC (MTX/VBL/DOX/CDDP) plus Cystectomy in Patients with Locally Advanced Transitional Cell Carcinoma of the Bladder (Summary Last Modified 09/98), SWOG-8710, clinical trial, closed, 07/01/1998.

20. Scher H, Herr H, Sternberg C, et al.: Neo-adjuvant chemotherapy for invasive bladder cancer: experience with the M-VAC regimen. British Journal of Urology 64(3): 250-256, 1989.

21. Skinner DG, Daniels JR, Russell CA, et al.: The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. Journal of Urology 145(3): 459-467, 1991.

22. Tester W, Caplan R, Heaney J, et al.: Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. Journal of Clinical Oncology 14(1): 119-126, 1996.

23. Does neoadjuvant cisplatin-based chemotherapy improve the survival of patients with locally advanced bladder cancer: a meta-analysis of individual patient data from randomized clinical trials. Advanced Bladder Cancer Overview Collaboration. British Journal of Urology 75(2): 206-213, 1995.

24. International Collaboration of Trialists: Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. Lancet 354(9178): 533-540, 1999.

Stage III Bladder Cancer

T3a, N0, M0 or T3b, N0, M0 or T4a, N0, M0

A few highly selected patients with stage III bladder cancer may be suitable for segmental cystectomy or interstitial irradiation. The relatively high frequency of extensive intramural tumor spread and lymph node involvement make radical cystectomy and external-beam irradiation more logical forms of treatment in most patients. Because of the relatively poor results of either of these modalities when used alone, preoperative irradiation followed by radical cystectomy has been widely used during the past decade. This combined modality treatment appears to reduce the rate of local recurrence and is associated with especially good results in patients whose resected bladders contain no pathologic evidence of cancer. However, similar results achieved with radical cystectomy alone in some series have brought this issue under scrutiny. The only prospective, randomized trial reported to date did not show any survival advantage for preoperative radiation therapy and radical cystectomy compared with radical cystectomy alone.1 Studies suggest that radical cystectomy with preservation of sexual function can be performed in some men and that new forms of urinary diversion can obviate the need for an external urinary appliance.2-5

In the United States, external-beam irradiation has been generally reserved for patients who are poor medical candidates for radical cystectomy. However, selected patients have been treated with transurethral resection (TUR) and definitive radiation therapy, with salvage cystectomy reserved for those whose treatment fails.6,7 One series suggests that patients treated with preoperative radiation therapy and immediate cystectomy had an outcome similar to those treated with radical irradiation alone, with salvage cystectomy reserved for local recurrence.6 In combined modality studies, one half or more of patients who had bladder-preserving therapy were disease-free 3 to 4 years after treatment,8-11 with salvage cystectomy reserved for patients who did not achieve a complete response. Some investigators think that the prognosis is worse for patients with hydronephrosis on the initial intravenous pyelogram, and therefore, they are not candidates for this approach.8,11

Because the frequency of distant metastases is becoming apparent with improved local control of advanced bladder cancer, systemic preoperative or postoperative adjuvant chemotherapy is now under evaluation in clinical trials. Treatment with concurrent chemotherapy and radiation therapy has been associated with improved rates of local control compared with radiation therapy alone. The only prospective, randomized trial reported to date resulted in an improved rate of local control when cisplatin was given in conjunction with radiation therapy.12

All patients with this stage should be considered candidates for clinical trials.

Treatment options:

Standard:

1. Radical cystectomy.1
2. External-beam irradiation.13-15
3. External-beam irradiation with interstitial implantation of radioisotopes.16
4. Segmental cystectomy (in highly selected cases).17
5. Combined external-beam irradiation and chemotherapy.8-12

Under clinical evaluation:

Multiple trials are evaluating the potential of chemotherapy administered prior to cystectomy, following cystectomy, or in conjunction with external-beam radiation therapy to improve local tumor control, prevent distant metastases, or allow preservation of the bladder.8-11,18-24 The combination regimen methotrexate, vinblastine, doxorubicin, and cisplatin produced a pathologic complete response in approximately 20% of patients treated prior to definitive surgery.25 Results from two clinical studies suggest that a combined modality treatment with neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) followed by radiation therapy and concurrent cisplatin can result in high rates of tumor clearance and can allow bladder preservation in some patients.8,11,21 However, there is no evidence to date that the use of neoadjuvant cisplatin or cisplatin-based regimens will improve the survival of patients with locally advanced bladder cancer.26[Level of evidence: 1iiA];27[Level of evidence: 1iiA] In a bladder-sparing clinical trial of external radiation therapy with chemotherapy, initial results from the Radiation Therapy Oncology Group have shown that 2 cycles of neoadjuvant MCV do not improve down staging to a complete response, patient survival, or freedom from metastatic disease over radiation and concurrent cisplatin alone.11[Level of evidence: 1iiA]

References:

1. Smith JA, Crawford ED, Blumenstein B, et al.: A randomized prospective trial of pre-operative irradiation plus radical cystectomy versus surgery alone for transitional cell carcinoma of the bladder: a Southwest Oncology Group study. Journal of Urology 139(4, Part 2): 266A, 1988.

2. Brendler CB, Steinberg GD, Marshall FF, et al.: Local recurrence and survival following nerve-sparing radical cystoprostatectomy. Journal of Urology 144(5): 1137-1141, 1990.

3. Skinner DG, Boyd SD, Lieskovsky G: Clinical experience with the Kock continent ileal reservoir for urinary diversion. Journal of Urology 132(6): 1101-1107, 1984.

4. Fowler JE: Continent urinary reservoirs and bladder substitutes in the adult: part I. Monographs in Urology 8(2): 1987.

5. Fowler JE: Continent urinary reservoirs and bladder substitutes in the adult: part II. Monographs in Urology 8(3): 1987.

6. Sell A, Jakobsen A, Nerstrom B, et al.: Treatment of advanced bladder cancer category T2 T3 and T4a: a randomized multicenter study of preoperative irradiation and cystectomy versus radical irradiation and early salvage cystectomy for residual tumor: DAVECA protocol 8201. Scandinavian Journal of Urology and Nephrology 138(Suppl): 193-201, 1991.

7. Jenkins BJ, Caulfield MJ, Fowler CG, et al.: Reappraisal of the role of radical radiotherapy and salvage cystectomy in the treatment of invasive (T2/T3) bladder cancer. Journal of Urology 62(4): 343-346, 1988.

8. Kachnic LA, Kaufman DS, Heney NM, et al.: Bladder preservation by combined modality therapy for invasive bladder cancer. Journal of Clinical Oncology 15(3): 1022-1029, 1997.

9. Housset M, Maulard C, Chretien Y, et al.: Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study. Journal of Clinical Oncology 11(11): 2150-2157, 1993.

10. Tester W, Porter A, Asbell S, et al.: Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12. International Journal of Radiation Oncology, Biology, Physics 25(5): 783-790, 1993.

11. Shipley WU, Winter KA, Kaufman DS, et al.: Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: inital results of Radiation Therapy Oncology Group 89-03. Journal of Clinical Oncology 16(11): 3576-3583, 1998.

12. Coppin CM, Gospodarowicz MK, James K, et al.: Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. Journal of Clinical Oncology 14(11): 2901-2907, 1996.

13. Gospodarowicz MK, Hawkins NV, Rawlings GA, et al.: Radical radiotherapy for muscle invasive transitional cell carcinoma of the bladder: failure analysis. Journal of Urology 142(6): 1448-1454, 1989.

14. Yu WS, Sagerman RH, Chung CT, et al.: Bladder carcinoma: experience with radical and preoperative radiotherapy in 421 patients. Cancer 56(6): 1293-1299, 1985.

15. Jahnson S, Pedersen J, Westman G: Bladder carcinoma - a 20-year review of radical irradiation therapy. Radiotherapy and Oncology 22(2): 111-117, 1991.

16. van der Werf-Messing BH, van Putten WL: Carcinoma of the urinary bladder category T2,3 NX M0 treated by 40 Gy external irradiation followed by cesium-137 implant at reduced dose (50%). International Journal of Radiation Oncology, Biology, Physics 16(2): 369-371, 1989.

17. Skinner DG: Current perspectives in the management of high-grade invasive bladder cancer. Cancer 45(7): 1866-1874, 1980.

18. Logothetis CJ, Johnson DE, Chong C, et al.: Adjuvant chemotherapy of bladder cancer: a preliminary report. Journal of Urology 139(6): 1207-1211, 1988.

19. Natale RB, Southwest Oncology Group: NCI HIGH PRIORITY CLINICAL TRIAL --- Phase III Randomized Comparison of Cystectomy Alone vs Neoadjuvant MVAC (MTX/VBL/DOX/CDDP) plus Cystectomy in Patients with Locally Advanced Transitional Cell Carcinoma of the Bladder (Summary Last Modified 09/98), SWOG-8710, clinical trial, closed, 07/01/1998.

20. Skinner DG, Daniels JR, Russell CA, et al.: The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. Journal of Urology 145(3): 459-467, 1991.

21. Tester W, Caplan R, Heaney J, et al.: Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. Journal of Clinical Oncology 14(1): 119-126, 1996.

22. Fleming GF, University of Chicago Cancer Research Center: Phase I Study of Concomitant Chemoradiotherapy with Vinorelbine and Paclitaxel in Patients with Advanced Pelvic Malignancies (Summary Last Modified 10/1998), UCCRC-8270, clinical trial, closed, 07/17/2000.

23. Kaufman DS, Radiation Therapy Oncology Group: Phase I/II Study of Radiotherapy With Concurrent Paclitaxel and Cisplatin Followed By Selective Bladder Preservation or Radical Cystectomy and Adjuvant Chemotherapy in Patients With Stage II or III Muscle Invasive Carcinoma of the Bladder Treated With Transurethral Tumor Resection (Summary Last Modified 08/2001), RTOG-9906, clinical trial, active, 09/13/1999.

24. Bolla M, EORTC Radiotherapy Group: Phase II Study of Accelerated External Radiotherapy with Concurrent Fluorouracil and Cisplatin Following Transurethral Resection in Patients with Stage II or III Muscle Invasive Transitional Cell Carcinoma of the Bladder (Summary Last Modified 09/2001), EORTC-22971, clinical trial, closed, 07/11/2001.

25. Scher H, Herr H, Sternberg C, et al.: Neo-adjuvant chemotherapy for invasive bladder cancer: experience with the M-VAC regimen. British Journal of Urology 64(3): 250-256, 1989.

26. Does neoadjuvant cisplatin-based chemotherapy improve the survival of patients with locally advanced bladder cancer: a meta-analysis of individual patient data from randomized clinical trials. Advanced Bladder Cancer Overview Collaboration. British Journal of Urology 75(2): 206-213, 1995.

27. International Collaboration of Trialists: Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. Lancet 354(9178): 533-540, 1999.

Stage IV Bladder Cancer

T4b, N0, M0, any T, N1-N3, M0, or any T, any N, M1

Currently, only a small fraction of patients with stage IV bladder carcinoma can be cured. The potential for cure is restricted to patients with stage IV disease with involvement of pelvic organs by direct extension or small volume metastases to regional lymph nodes.1 These patients can receive radical cystectomy with or without preoperative irradiation.2[Level of evidence: 1iiA] Studies suggest that radical cystectomy with preservation of sexual function can be performed in some men and that new forms of urinary diversion can obviate the need for an external urinary appliance.3-5 The prognosis of patients with T4 tumors is generally poor with either radical cystectomy or radiation therapy.

Prognosis is so poor in patients with stage IV disease that consideration of entry into a clinical trial is appropriate. The focus of care for many stage IV patients is on palliation of symptoms from bladder tumor that is often massive. Urinary diversion may be indicated, not only for palliation of urinary symptoms, but also for preservation of renal function in candidates for chemotherapy. Combination chemotherapy regimens that include methotrexate, cisplatin, and vinblastine, with or without doxorubicin are encouraging and have induced some pathological complete responses.6,7 A prospective, randomized trial of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) compared with cisplatin, cyclophosphamide, and doxorubicin demonstrated improved response and median survival rates with the former regimen.8 Results from a randomized trial that compared M-VAC to single-agent cisplatin in advanced bladder cancer show a significant advantage with M-VAC in both response rate and median survival.9 The (outpatient) regimen of paclitaxel and carboplatin has been shown to be active and well tolerated. Partial responses in the range of 50% have been reported in phase II trials.10,11[Level of evidence: 3iiiDiii] Phase III trials further evaluating the role of this regimen are in progress.12 Gemcitabine has shown activity in phase II trials of patients with metastatic bladder cancer.13 Phase III trials comparing the gemcitabine/cisplatin combination with the M-VAC regimen are also in progress. Patients should be encouraged to participate in clinical trials whenever possible.

Treatment options:

For T4b, N0, M0 or any T, N1-N3, M0 patients:

Standard:

1. Radical cystectomy alone (in node-negative patients).14
2. External-beam irradiation.15
3. Urinary diversion or cystectomy for palliation.
4. Chemotherapy as an adjunct to local treatment.16-20

Under clinical evaluation:

Multiple trials are evaluating the potential of chemotherapy administered prior to cystectomy, following cystectomy, or in conjunction with external-beam radiation therapy to improve local tumor control, prevent distant metastases, or allow preservation of the bladder.14,16-19,21,22

For any T, any N, M1 patients:

Standard:

1. Chemotherapy alone or as an adjunct to local treatment.6,7
2. External-beam irradiation (palliative).
3. Urinary diversion or cystectomy for palliation.

Under clinical evaluation:

Other chemotherapy regimens appear active in the treatment of metastatic disease. Chemotherapy agents that have shown activity in metastatic bladder cancer include paclitaxel, ifosfamide, gallium nitrate, and gemcitabine.23,24

References:

1. Vieweg J, Gschwend JE, Herr HW, et al.: The impact of primary stage on survival in patients with lymph node positive bladder cancer. Journal of Urology 161(1): 72-76, 1999.

2. International Collaboration of Trialists: Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. Lancet 354(9178): 533-540, 1999.

3. Brendler CB, Steinberg GD, Marshall FF, et al.: Local recurrence and survival following nerve-sparing radical cystoprostatectomy. Journal of Urology 144(5): 1137-1141, 1990.

4. Skinner DG, Boyd SD, Lieskovsky G: Clinical experience with the Kock continent ileal reservoir for urinary diversion. Journal of Urology 132(6): 1101-1107, 1984.

5. Richie JP: Surgery for invasive bladder cancer. Hematology/Oncology Clinics of North America 6(1): 129-145, 1992.

6. Sternberg CN, Yagoda A, Scher HI, et al.: Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Cancer 64(12): 2448-2458, 1989.

7. Harker WG, Meyers FJ, Freiha FS, et al.: Cisplatin, methotrexate, and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract, a Northern California Oncology Group study. Journal of Clinical Oncology 3(11): 1463-1470, 1985.

8. Logothetis CJ, Dexeus FH, Finn L, et al.: A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. Journal of Clinical Oncology 8(6): 1050-1055, 1990.

9. Loehrer PJ, Einhorn LH, Elson PJ, et al.: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. Journal of Clinical Oncology 10(7): 1066-1073, 1992.

10. Vaughn DJ, Malkowicz SB, Zoltick B, et al.: Paclitaxel plus carboplatin in advanced carcinoma of the urothelium: an active and tolerable outpatient regimen. Journal of Clinical Oncology 16(1): 255-260, 1998.

11. Redman BG, Smith DC, Flaherty L, et al.: Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma. Journal of Clinical Oncology 16(5): 1844-1848, 1998.

12. Roth BJ, Eastern Cooperative Oncology Group: Phase III Randomized Study of Methotrexate, Vinblastine, Doxorubicin, and Cisplatin (M-VAC) Versus Carboplatin and Paclitaxel in Patients With Advanced Carcinoma of the Urothelium (Summary Last Modified 09/2001), E-4897, clinical trial, closed, 06/13/2001.

13. Bajorin DF: Paclitaxel in the treatment of advanced urothelial cancer. Oncology 14(1): 43-50,52,57, 2000.

14. Thrasher JB, Crawford ED: Current management of invasive and metastatic transitional cell carcinoma of the bladder. Journal of Urology 149(5): 957-972, 1993.

15. Jahnson S, Pedersen J, Westman G: Bladder carcinoma - a 20-year review of radical irradiation therapy. Radiotherapy and Oncology 22(2): 111-117, 1991.

16. Kachnic LA, Kaufman DS, Heney NM, et al.: Bladder preservation by combined modality therapy for invasive bladder cancer. Journal of Clinical Oncology 15(3): 1022-1029, 1997.

17. Tester W, Porter A, Asbell S, et al.: Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12. International Journal of Radiation Oncology, Biology, Physics 25(5): 783-790, 1993.

18. Logothetis CJ, Johnson DE, Chong C, et al.: Adjuvant chemotherapy of bladder cancer: a preliminary report. Journal of Urology 139(6): 1207-1211, 1988.

19. Skinner DG, Daniels JR, Russell CA, et al.: The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. Journal of Urology 145(3): 459-467, 1991.

20. Scher HI: Chemotherapy for invasive bladder cancer: neoadjuvant versus adjuvant. Seminars in Oncology 17(5): 555-565, 1990.

21. Housset M, Maulard C, Chretien Y, et al.: Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study. Journal of Clinical Oncology 11(11): 2150-2157, 1993.

22. Shipley WU, Winter KA, Kaufman DS, et al.: Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: inital results of Radiation Therapy Oncology Group 89-03. Journal of Clinical Oncology 16(11): 3576-3583, 1998.

23. Raghavan D, Huben R: Management of bladder cancer. Current Problems in Cancer 19(1): 1-64, 1995.

24. Vogelzang NJ, Stadler WM: Gemcitabine and other new chemotherapeutic agents for the treatment of metastatic bladder cancer. Urology 53(2): 243-250, 1999.

Recurrent Bladder Cancer

The prognosis for any patient with progressive or recurrent invasive bladder cancer is generally poor. Management of recurrence depends on prior therapy, sites of recurrence, and individual patient considerations. Treatment of new superficial or locally invasive tumors that develop in the setting of previous conservative therapy for superficial bladder neoplasia has been discussed earlier in this summary. Recurrent or progressive disease in distant sites or after definitive local therapy has an extremely poor prognosis, and clinical trials should be considered whenever possible.

In patients with recurrent transitional cell carcinoma, combination chemotherapy has produced high response rates with occasional complete responses seen.1,2 Results from a randomized trial that compared M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) to single-agent cisplatin in advanced bladder cancer show a significant advantage with M-VAC in both response rate and median survival.3 The overall response rate with M- VAC in this cooperative group trial was 39%.3 Other chemotherapy agents that have shown activity in metastatic bladder cancer include: paclitaxel, ifosfamide, gallium nitrate, and gemcitabine. Ifosfamide and gallium have shown limited activity in patients previously treated with cisplatin.4-10

References:

1. Sternberg CN, Yagoda A, Scher HI, et al.: Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Cancer 64(12): 2448-2458, 1989.

2. Harker WG, Meyers FJ, Freiha FS, et al.: Cisplatin, methotrexate, and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract, a Northern California Oncology Group study. Journal of Clinical Oncology 3(11): 1463-1470, 1985.

3. Loehrer PJ, Einhorn LH, Elson PJ, et al.: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. Journal of Clinical Oncology 10(7): 1066-1073, 1992.

4. Roth BJ: Preliminary experience with paclitaxel in advanced bladder cancer. Seminars in Oncology 22(3, Suppl 6): 1-5, 1995.

5. Witte RS, Elson P, Bono B, et al.: Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. Journal of Clinical Oncology 15(2): 589-593, 1997.

6. Einhorn LH, Roth BJ, Ansari R, et al.: Phase II trial of vinblastine, ifosfamide, and gallium combination chemotherapy in metastatic urothelial carcinoma. Journal of Clinical Oncology 12(11): 2271-2276, 1994.

7. Pollera CF, Ceribelli A, Crecco M, et al.: Weekly gemcitabine in advanced bladder cancer: a preliminary report from a phase I study. Annals of Oncology 5(2): 182-184, 1994.

8. Seidman AD, Scher HI, Heinemann MH, et al.: Continuous infusion gallium nitrate for patients with advanced refractory urothelial tract tumors. Cancer 68(12): 2561-2565, 1991.

9. Roth BJ: Ifosfamide in the treatment of bladder cancer. Seminars in Oncology 23(3, Suppl 6): 50-55, 1996.

10.Bajorin DF: Paclitaxel in the treatment of advanced urothelial cancer. Oncology 14(1): 43-50,52,57, 2000.

Anal Cancer

2008-07-23T07:45:00.000-07:00

Table of Contents

General Information
Cellular Classification
Stage Information
TNM definitions
Stage 0
Stage I
Stage II
Stage IIIA
Stage IIIB
Stage IV
Treatment Option Overview
HIV and anal cancer
Stage 0 Anal Cancer
Stage I Anal Cancer
Stage II Anal Cancer
Stage IIIA Anal Cancer
Stage IIIB Anal Cancer
Stage IV Anal Cancer
Recurrent Anal Cancer

General Information

Anal cancer is an often curable disease. The 3 major prognostic factors are site (anal canal versus perianal skin), size (primary tumors less than 2 centimeters in size have a better prognosis), and differentiation (well-differentiated tumors are more favorable than poorly differentiated tumors).

Anal cancer is an uncommon malignancy, accounting for only a small percentage (4%) of all cancers of the lower alimentary tract. Clinical trials have evaluated the roles of chemotherapy, radiation therapy, and surgery in the treatment of this disease.1,2
Overall, the risk of anal cancer is rising, with data suggesting that individuals with human papillomavirus and male homosexuals, in particular, are at increased risk of anal cancer.3-5

References:

1. Martenson JA, Lipsitz SR, Lefkopoulou M, et al.: Results of combined modality therapy for patients with anal cancer (E7283): an Eastern Cooperative Oncology Group study. Cancer 76(10): 1731-1736, 1995.

2. Fuchshuber PR, Rodriguez-Bigas M, Weber T, et al.: Anal canal and perianal epidermoid cancers. Journal of the American College of Surgeons 185(5): 494-505, 1997.

3. Daling JR, Weiss NS, Hislop TG, et al.: Sexual practices, sexually transmitted diseases, and the incidence of anal cancer. New England Journal of Medicine 317(16): 973-977, 1987.

4. Palefsky JM, Holly EA, Gonzales J, et al.: Detection of human papillomarvirus DNA in anal intraepithelial neoplasia and anal cancer. Cancer Research 51(3): 1014-1019, 1991.

5. Ryan DP, Compton CC, Mayer RJ: Carcinoma of the anal canal. New England Journal of Medicine 342(11): 792-800, 2000.

Cellular Classification

Squamous cell (epidermoid) carcinomas make up the majority of all primary cancers of the anus. The important subset of cloacogenic (basaloid transitional cell) tumors constitute the remainder. These two histologic variants are associated with human papillomavirus infection.1 Adenocarcinomas from anal glands or fistulae formation and melanomas are rare. Treatment of anal melanoma is not included in this summary.

References:

1. Palefsky JM, Holly EA, Gonzales J, et al.: Detection of human papillomarvirus DNA in anal intraepithelial neoplasia and anal cancer. Cancer Research 51(3): 1014-1019, 1991.

Stage Information

The anal canal extends from the rectum to the perianal skin and is lined by a mucous membrane that covers the internal sphincter. The following is a staging system for anal canal cancer that has been described by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer.1,2 Tumors of the anal margin (below the anal verge and involving the perianal hair-bearing skin) are classified with skin tumors.

TNM definitions

Primary tumor (T)

TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ T1: Tumor 2 cm or less in greatest dimension T2: Tumor more than 2 cm but not more than 5 cm in greatest dimension T3: Tumor more than 5 cm in greatest dimension T4: Tumor of any size that invades adjacent organ(s), e.g., vagina, urethra, bladder (involvement of the sphincter muscle(s) alone is not classified as T4)

Regional lymph nodes (N)

NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Metastasis in perirectal lymph node(s) N2: Metastasis in unilateral internal iliac and/or inguinal lymph node(s) N3: Metastasis in perirectal and inguinal lymph nodes and/or bilateral internal iliac and/or inguinal lymph nodes

Distant metastasis (M)

MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis

Stage 0

Stage 0 anal cancer is carcinoma in situ. Rarely diagnosed, it is a very early cancer that has not spread below the limiting membrane of the first layer of anal tissue. Stage 0 anal cancer corresponds to the following TNM grouping:

Tis, N0, M0

Stage I

Stage I anal cancer is cancer that is 2 centimeters or less in greatest dimension and that has not spread anywhere else. There is no sphincter involvement. Stage I anal cancer corresponds to the following TNM grouping:

T1, N0, M0

Stage II

Stage II anal cancer is cancer that is more than 2 centimeters and that does not involve adjacent organs or lymph nodes. Stage II anal cancer corresponds to the following TNM groupings:

T2, N0, M0 T3, N0, M0

Stage IIIA

Stage IIIA anal cancer is cancer that has spread to perirectal lymph nodes or to adjacent organs. Stage IIIA anal cancer corresponds to the following TNM groupings:

T1, N1, M0 T2, N1, M0 T3, N1, M0 T4, N0, M0

Stage IIIB

Stage IIIB anal cancer is cancer that has spread to internal iliac and/or inguinal nodes (unilateral or bilateral) or has spread to both adjacent organs and perirectal lymph nodes. Stage IIIB anal cancer corresponds to the following TNM groupings:

T4, N1, M0 Any T, N2, M0 Any T, N3, M0

Stage IV

Stage IV anal cancer is cancer that has spread to distant lymph nodes within the abdomen or to other organs in the body. Stage IV anal cancer corresponds to the following TNM groupings:

Any T, Any N, M1

References:

1. Anal canal. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 91-95.

2. Anal canal. In: Sobin LH, Wittekind C, eds.: TNM: Classification of Malignant Tumours. New York, NY: Wiley-Liss, Inc., 5th ed., 1997, pp 70-73.

Treatment Option Overview

Abdominoperineal resection leading to permanent colostomy was previously thought to be required for all but small anal cancers below the dentate line, with approximately 70% of patients surviving 5 or more years in single institutions,1 but such surgery is no longer the treatment of choice.2,3 Radiation therapy alone may lead to a 5-year survival rate in excess of 70%, although high doses (6,000 cGy or greater) may yield necrosis or fibrosis.4 Chemotherapy concurrent with lower-dose radiation therapy has a 5-year survival rate in excess of 70% with low levels of acute and chronic morbidity, and few patients require surgery for dermal or sphincter toxic effects.5-10 The optimal dose of radiation with concurrent chemotherapy to optimize local control and minimize sphincter toxic effects is under evaluation but appears to be in the 45 Gy to 60 Gy range.11,12 Analysis of an intergroup trial that compared radiation therapy plus fluorouracil/mitomycin with radiation therapy plus fluorouracil alone in patients with anal cancer has shown improved results (lower colostomy rates and higher colostomy-free and disease-free survival) with the addition of mitomycin.13 Radiation with continuous infusion of fluorouracil plus cisplatin is also under evaluation.14,15 Standard salvage therapy for those patients with either gross or microscopic residual disease following chemoradiotherapy has been abdominoperineal resection. Alternately, patients may be treated with additional salvage chemoradiotherapy in the form of fluorouracil, cisplatin, and a radiation boost to potentially avoid permanent colostomy.13

Because of the small number of cases, information that can only come from patient participation in well-designed clinical trials is needed to improve the management of anal cancer. Patients with stages II, III, and IV disease should be considered candidates for clinical trials.

HIV and anal cancer

The tolerance of patients with human immunodeficiency virus (HIV) and anal carcinoma to standard fluorouracil/mitomycin chemoradiation is not well defined.16,17 Patients with pretreatment CD4 counts of less than 200 may have increased acute and late toxic effects;18 chemoradiation doses may require modification in this subset of patients.

References:

1. Boman BM, Moertel CG, O'Connell MJ, et al.: Carcinoma of the anal canal: a clinical and pathologic study of 188 cases. Cancer 54(1): 114-125, 1984.

2. Stearns MW, Quan SH: Epidermoid carcinoma of the anorectum. Surgery, Gynecology and Obstetrics 131(5): 953-957, 1970.

3. Cummings BJ: The role of radiation therapy with 5-fluorouracil in anal canal cancer. Seminars in Radiation Oncology 7(4): 306-312, 1997.

4. Cantril ST, Green JP, Schall GL, et al.: Primary radiation therapy in the treatment of anal carcinoma. International Journal of Radiation Oncology, Biology, Physics 9(9): 1271-1278, 1983.

5. Leichman L, Nigro N, Vaitkevicius VK, et al.: Cancer of the anal canal: model for preoperative adjuvant combined modality therapy. American Journal of Medicine 78(2): 211-215, 1985.

6. Sischy B: The use of radiation therapy combined with chemotherapy in the management of squamous cell carcinoma of the anus and marginally resectable adenocarcinoma of the rectum. International Journal of Radiation Oncology, Biology, Physics 11(9): 1587-1593, 1985.

7. Sischy B, Doggett RL, Krall JM, et al.: Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314. Journal of the National Cancer Institute 81(11): 850-856, 1989.

8. Cummings BJ: Anal cancer. International Journal of Radiation Oncology, Biology, Physics 19(5): 1309-1315, 1990.

9. Zucali R, Doci R, Bombelli L: Combined chemotherapy-radiotherapy of anal cancer. International Journal of Radiation Oncology, Biology, Physics 19(5): 1221-1223, 1990.

10. Fuchshuber PR, Rodriguez-Bigas M, Weber T, et al.: Anal canal and perianal epidermoid cancers. Journal of the American College of Surgeons 185(5): 494-505, 1997.

11. Fung CY, Willett CG, Efird JT, et al.: Chemoradiotherapy for anal carcinoma: what is the optimal radiation dose? Radiation Oncology Investigations 2(3): 152-156, 1994.

12. John M, Pajak T, Flam M, et al.: Dose escalation in chemoradiation for anal cancer: preliminary results of RTOG 92-08. Cancer Journal from Scientific American 2(4): 205-211, 1996.

13. Flam M, John M, Pajak TF, et al.: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. Journal of Clinical Oncology 14(9): 2527-2539, 1996.

14. Rich TA, Ajani JA, Morrison WH, et al.: Chemoradiation therapy for anal cancer: radiation plus continuous infusion of 5-fluorouracil with or without cisplatin. Radiotherapy and Oncology 27(3): 209-215, 1993.

15. Ajani JA, Radiation Therapy Oncology Group: Phase III Randomized Study of Fluorouracil and Mitomycin With Concurrent Radiotherapy Versus Fluorouracil and Cisplatin With Concurrent Radiotherapy in Patients With Anal Canal Carcinoma (Summary Last Modified 09/2001), RTOG-9811, clinical trial, active, 10/31/1998.

16. Holland JM, Swift PS: Tolerance of patients with human immunodeficiency virus and anal carcinoma to treatment with combined chemotherapy and radiation therapy. Radiology 193(1): 251-254, 1994.

17. Peddada AV, Smith DE, Rao AR, et al.: Chemotherapy and low-dose radiotherapy in the treatment of HIV-infected patients with carcinoma of the anal canal. International Journal of Radiation Oncology, Biology, Physics 37(5):1101-1105, 1997.

18. Hoffman R, Krieg R, Klencke B: Outcome and treatment tolerance for HIV-positive patients with anal cancer based on pretreatment CD4 count. International Journal of Radiation Oncology, Biology, Physics 42(1 suppl): A-80, 164, 1998.

Stage 0 Anal Cancer

Treatment options:

Surgical resection is used for treatment of lesions of the perianal area not involving the anal sphincter (approach depends on the location of the lesion in the anal canal).

Stage I Anal Cancer

Stage I anal cancer was formerly treated with abdominoperineal resection. Current sphincter-sparing therapies include wide local excision for small tumors of the perianal skin or anal margin, or definitive chemoradiation (fluorouracil and mitomycin) for cancers of the anal canal. Salvage chemoradiotherapy (fluorouracil and cisplatin plus a radiation boost) may avoid permanent colostomy in patients with residual tumor following initial nonoperative therapy.1 Radical resection is reserved for patients with incomplete responses or recurrent disease. Therefore, continued surveillance with rectal examination every 3 months for the first 2 years and endoscopy/biopsy when indicated after completion of sphincter-preserving therapy is important.

Treatment options:

1. Small tumors of the perianal skin or anal margin not involving the anal sphincter may be adequately treated with local resection.2
2. All other stage I cancers of the anal canal that involve the anal sphincter or are too large for complete local excision are treated with external beam radiation therapy with or without chemotherapy.1,3-8 Chemotherapy with fluorouracil and mitomycin combined with primary radiation therapy appears to be more effective than radiation therapy alone.9 The optimal dose of radiation with concurrent chemotherapy is under evaluation.10-12 Selected tumors are also suitable for interstitial irradiation.4
3. Radical resection is reserved for residual or recurrent cancer in the anal canal after nonoperative therapy.
4. Alternately, salvage chemotherapy with fluorouracil and cisplatin combined with a radiation boost may avoid a permanent colostomy in selected patients with small amounts of residual tumor following initial nonoperative therapy.1
5. Interstitial iridium-192 after external-beam radiation may convert some patients with residual disease into complete responders.13

References:

1. Flam M, John M, Pajak TF, et al.: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. Journal of Clinical Oncology 14(9): 2527-2539, 1996.

2. Enker WE, Heilwell M, Janov AJ, et al.: Improved survival in epidermoid carcinoma of the anus in association with preoperative multidisciplinary therapy. Archives of Surgery 121(12): 1386-1390, 1986.

3. Papillon J, Mayer M, Montbarbon JF, et al.: A new approach to the management of epidermoid carcinoma of the anal canal. Cancer 51(10): 1830-1837, 1983.

4. Cummings B, Keane T, Thomas G, et al.: Results and toxicity of the treatment of anal canal carcinoma by radiation therapy or radiation therapy and chemotherapy. Cancer 54(10): 2062-2068, 1984.

5. Leichman L, Nigro N, Vaitkevicius VK, et al.: Cancer of the anal canal: model for preoperative adjuvant combined modality therapy. American Journal of Medicine 78(2): 211-215, 1985.

6. James RD, Pointon RS, Martin S: Local radiotherapy in the management of squamous carcinoma of the anus. British Journal of Surgery 72(4): 282-285, 1985.

7. Sischy B: The use of radiation therapy combined with chemotherapy in the management of squamous cell carcinoma of the anus and marginally resectable adenocarcinoma of the rectum. International Journal of Radiation Oncology, Biology, Physics 11(9): 1587-1593, 1985.

8. Sischy B, Doggett RL, Krall JM, et al.: Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314. Journal of the National Cancer Institute 81(11): 850-856, 1989.

9. UKCCCR Anal Cancer Trial Working Party: Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet 348(9034): 1049-1054, 1996.

10. Fung CY, Willett CG, Efird JT, et al.: Chemoradiotherapy for anal carcinoma: what is the optimal radiation dose? Radiation Oncology Investigations 2(3): 152-156, 1994.

11. John M, Pajak T, Flam M, et al.: Dose escalation in chemoradiation for anal cancer: preliminary results of RTOG 92-08. Cancer Journal from Scientific American 2(4): 205-211, 1996.

12. Ajani JA, Radiation Therapy Oncology Group: Phase III Randomized Study of Fluorouracil and Mitomycin With Concurrent Radiotherapy Versus Fluorouracil and Cisplatin With Concurrent Radiotherapy in Patients With Anal Canal Carcinoma (Summary Last Modified 09/2001), RTOG-9811, clinical trial, active, 10/31/1998.

13. Sandhu AP, Symonds RP, Robertson AG, et al.: Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience. International Journal of Radiation Oncology, Biology, Physics 40(3): 575-581, 1998.

Stage II Anal Cancer

Stage II anal cancer was formerly treated with abdominoperineal resection. Current sphincter-sparing therapies include wide local excision for small tumors of the perianal skin or anal margin, or definitive chemoradiation (fluorouracil and mitomycin) for cancers of the anal canal. Salvage chemotherapy (fluorouracil with cisplatin plus a radiation boost) may avoid permanent colostomy in patients with residual tumor following initial nonoperative therapy. Radical resection is reserved for patients with incomplete responses or recurrent disease. Therefore, continued surveillance with rectal examination every 3 months for the first 2 years and endoscopy/biopsy when indicated after completion of sphincter-preserving therapy is important.

Treatment options:

1. Small tumors of the perianal skin or anal margin not involving the anal sphincter may be adequately treated with local resection.1
2. All other stage II cancers of the anal canal that involve the anal sphincter or are too large for complete local excision are treated with external beam radiation therapy plus chemotherapy.2-8 Chemotherapy with fluorouracil and mitomycin combined with primary radiation therapy appears to be more effective than radiation therapy alone.9 The optimal dose of radiation with concurrent chemotherapy is under evaluation.10-12 Selected tumors are also suitable for interstitial irradiation.3,13
3. Radical resection is reserved for continued residual or recurrent cancer in the anal canal after nonoperative therapy.
4. Alternately, salvage chemotherapy with fluorouracil and cisplatin combined with a radiation boost may avoid a permanent colostomy in selected patients with small amounts of residual tumor following initial nonoperative therapy.8

References:

1. Enker WE, Heilwell M, Janov AJ, et al.: Improved survival in epidermoid carcinoma of the anus in association with preoperative multidisciplinary therapy. Archives of Surgery 121(12): 1386-1390, 1986.

2. Papillon J, Mayer M, Montbarbon JF, et al.: A new approach to the management of epidermoid carcinoma of the anal canal. Cancer 51(10): 1830-1837, 1983.

3. Cummings B, Keane T, Thomas G, et al.: Results and toxicity of the treatment of anal canal carcinoma by radiation therapy or radiation therapy and chemotherapy. Cancer 54(10): 2062-2068, 1984.

4. Leichman L, Nigro N, Vaitkevicius VK, et al.: Cancer of the anal canal: model for preoperative adjuvant combined modality therapy. American Journal of Medicine 78(2): 211-215, 1985.

5. James RD, Pointon RS, Martin S: Local radiotherapy in the management of squamous carcinoma of the anus. British Journal of Surgery 72(4): 282-285, 1985.

6. Sischy B: The use of radiation therapy combined with chemotherapy in the management of squamous cell carcinoma of the anus and marginally resectable adenocarcinoma of the rectum. International Journal of Radiation Oncology, Biology, Physics 11(9): 1587-1593, 1985.

7. Sischy B, Doggett RL, Krall JM, et al.: Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314. Journal of the National Cancer Institute 81(11): 850-856, 1989.

8. Flam M, John M, Pajak TF, et al.: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. Journal of Clinical Oncology 14(9): 2527-2539, 1996.

9. UKCCCR Anal Cancer Trial Working Party: Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet 348(9034): 1049-1054, 1996.

10. Fung CY, Willett CG, Efird JT, et al.: Chemoradiotherapy for anal carcinoma: what is the optimal radiation dose? Radiation Oncology Investigations 2(3): 152-156, 1994.

11. John M, Pajak T, Flam M, et al.: Dose escalation in chemoradiation for anal cancer: preliminary results of RTOG 92-08. Cancer Journal from Scientific American 2(4): 205-211, 1996.

12. Ajani JA, Radiation Therapy Oncology Group: Phase III Randomized Study of Fluorouracil and Mitomycin With Concurrent Radiotherapy Versus Fluorouracil and Cisplatin With Concurrent Radiotherapy in Patients With Anal Canal Carcinoma (Summary Last Modified 09/2001), RTOG-9811, clinical trial, active, 10/31/1998.

13. Sandhu AP, Symonds RP, Robertson AG, et al.: Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience. International Journal of Radiation Oncology, Biology, Physics 40(3): 575-581, 1998.

Stage IIIA Anal Cancer

Stage IIIA anal cancer presents clinically as stage II in most instances and is determined to be IIIA by clinically evident perirectal nodal disease or adjacent organ involvement. Endorectal or endoanal ultrasound may aid in pretreatment staging.

Treatment options:

1. Treatment as for stage I and II disease, using radiation therapy plus chemotherapy.1
2. Abdominoperitoneal resection combined with resection of femoral, inguinal, abductor, and iliac lymph nodes, followed by postoperative radiation therapy.

References:

1. Sischy B, Doggett RL, Krall JM, et al.: Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314. Journal of the National Cancer Institute 81(11): 850-856, 1989.

Stage IIIB Anal Cancer

The presence of inguinal nodes that are involved with metastatic disease (unilateral or bilateral) is a poor prognostic sign, although cure of this stage of disease is possible. Because of the poor prognosis associated with this stage, patients should be included in clinical trials whenever possible.

Treatment options:

Radiation therapy plus chemotherapy (as described for stage II) with surgical resection of residual disease at the primary site (local resection or abdominoperineal resection) and unilateral or bilateral superficial and deep inguinal node dissection for residual or recurrent tumor.

Stage IV Anal Cancer

Patients in this stage should be considered candidates for clinical trials. There is no standard chemotherapy for patients with metastatic disease. Palliation of symptoms from the primary lesion is of major importance.

Treatment options:

1. Palliative surgery. 2. Palliative irradiation. 3. Palliative combined chemotherapy and radiation therapy. 4. Clinical trials.

Recurrent Anal Cancer

Local recurrences after treatment with either radiation therapy and chemotherapy or surgery as the primary treatment can be effectively controlled in a substantial number of patients by using the alternate treatment (surgical resection after radiation and vice versa).1 Clinical trials are exploring the use of radiation therapy with chemotherapy and/or radiosensitizers to improve local control.

References:

1. Longo WE, Vernava AM, Wade TP, et al.: Recurrent squamous cell carcinoma of the anal canal: predictors of initial treatment failure and results of salvage therapy. Annals of Surgery 220(1): 40-49, 1994.

AIDS-Related Lymphoma

2008-07-23T05:38:00.000-07:00

Table of Contents

General Information
HIV-Associated Hodgkin's Disease
Cellular Classification
Stage Information
Staging Classification System
Stage I
Stage II
Stage III
Stage IV
Treatment Option Overview
AIDS-Related Peripheral/Systemic Lymphoma
AIDS-Related Primary Central Nervous System Lymphoma

General Information

The acquired immunodeficiency syndrome (AIDS) was first described in 1981, and the first definitions included certain opportunistic infections, Kaposi's sarcoma, and central nervous system (CNS) lymphomas. In 1984, a multicentered study described the clinical spectrum of non-Hodgkin's lymphomas in the populations at risk for AIDS.1 In 1985 and 1987, the Centers for Disease Control (CDC) revised the definition of AIDS to include human immunodeficiency virus (HIV)-infected patients who had aggressive B-cell non-Hodgkin's lymphoma. The incidence of non-Hodgkin's lymphoma has increased in an almost parallel course with the AIDS epidemic and accounts for 2% to 3% of newly diagnosed AIDS cases.2 Pathologically, AIDS-related lymphomas are comprised of a narrow spectrum of histologic types consisting almost exclusively of B-cell tumors of aggressive type. These include diffuse large cell lymphoma; B-immunoblastic; and small non-cleaved, either Burkitt's or Burkitt's like. The HIV-associated lymphomas can be categorized into: 1) primary central nervous system lymphoma (PCNSL), which represents 20% of all NHL cases in AIDS patients; 2) systemic lymphoma; and 3) primary effusion lymphoma, also called body cavity-based lymphoma (BCBL). The latter has been associated with co-infection by the 1994 discovery of human herpes virus type-8 (HHV-8).3,4 All of these lymphomas differ from non-HIV-related lymphomas in their molecular characteristics, presumed mechanism of pathogenesis, treatment, and clinical outcome. All 3 pathologic types are equally distributed and represent aggressive disease. In addition, there appears to be a marked increase in the incidence of lymphoma in patients with previously diagnosed AIDS or AIDS-related complex that, because these are secondary diagnoses, are not included in the CDC statistics.5 Reports from the National Cancer Institute have estimated the probability of developing a high-grade non-Hodgkin's B-cell lymphoma in this group of patients to be as high as 19.4% by 36 months after starting antiretroviral therapy.6 Other reports suggest a relatively constant rate of risk for the development of non-Hodgkin's lymphoma of 1.6% to 2.0% per year in a population with AIDS or AIDS-related complex.6-8 The diagnosis of AIDS precedes the onset of non-Hodgkin's lymphoma in approximately 57% of the patients, but in 30%, the diagnosis of AIDS is made at the time of the diagnosis of non-Hodgkin's lymphoma and HIV positivity.9 The geographic distribution of these lymphomas is also similar to the geographic spread of AIDS. Unlike Kaposi's sarcoma, that has a predilection for homosexual men and appears to be on the decline in incidence, all risk groups appear to have an excess number of non-Hodgkin's lymphomas; these risk groups include intravenous drug users and children of HIV-positive individuals.

In general, the clinical setting and response to treatment of patients with AIDS-related lymphoma is very different from the non-HIV patients with lymphoma. The HIV-infected individual with aggressive lymphoma usually presents with advanced-stage disease that is frequently extranodal.5 The clinical course is more aggressive, and the disease is both more extensive and less responsive to chemotherapy. Immunodeficiency and cytopenias, common in these patients at the time of initial presentation, are exacerbated by the administration of chemotherapy. Therefore, treatment of the malignancy increases the risk of opportunistic infections that, in turn, further compromise the delivery of adequate treatment.

Prognoses of patients with AIDS-related lymphoma have been associated with stage (extent of disease, extranodal involvement, and bone marrow involvement), severity of the underlying immunodeficiency (measured by CD4 lymphocyte count in peripheral blood), performance status, and prior AIDS diagnosis (history of opportunistic infection or Kaposi's sarcoma). Patients with AIDS-related primary CNS lymphoma appear to have more severe underlying HIV-related disease than do patients with systemic lymphoma. In one report, this severity was evidenced by patients with primary CNS lymphoma having a higher incidence of a prior AIDS diagnoses (73% versus 37%), lower median number of CD4 lymphocytes (30/dL versus 189/dL), and a worse median survival time (2.5 months versus 6.0 months).10 This same report showed that patients with poor risk factors (defined as Karnofsky performance status less than 70%, history of prior AIDS diagnosis, and bone marrow involvement) had a median survival time of 4.0 months compared with a good-prognosis group without any of these risk factors, who had a median survival time of 11.3 months. In another report, prognostic factors were evaluated in a group of 192 patients with newly diagnosed AIDS-related lymphoma who were randomized to receive either low-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) or standard-dose m-BACOD with granulocyte-macrophage colony-stimulating factor.11 There were no differences between these two treatments in terms of efficacy for disease-free survival, median survival, or risk-ratio for death.11[Level of evidence: 1iiA] On multivariate analysis, factors associated with decreased survival included age older than 35 years, history of intravenous drug use, stage III or IV disease, and CD4 counts of less than 100 cells per cubic millimeter. The median survival rates were 46 weeks for patients with 1 or no risk factors, 44 weeks for patients with 2 risk factors, and 18 weeks for patients with 3 or more risk factors.

HIV-Associated Hodgkin's Disease

Since 1984, several series of cases of Hodgkin's disease occurring in patients at risk for AIDS have been reviewed.12 However, Hodgkin's disease is still not part of the CDC definition of AIDS because there has been no clear demonstration of its increased incidence in conjunction with HIV, as is the case for aggressive non-Hodgkin's lymphoma. The CDC, in conjunction with the San Francisco Department of Public Health, has reported a cohort study in which HIV-infected men had an excess risk that was attributable to the HIV infection of 19.3 cases of Hodgkin's disease per 100,000 person-years and 224.9 cases of non-Hodgkin's lymphoma per 100,000 person-years. Although an excess incidence of Hodgkin's disease was found in HIV-infected homosexual men in this report, additional epidemiologic studies will be needed before the CDC will reconsider Hodgkin's disease as an HIV-associated malignancy.13

HIV-associated Hodgkin's disease presents in an aggressive fashion, often with extranodal or bone marrow involvement.12 A distinctive feature of HIV-associated Hodgkin's disease is the lower frequency of mediastinal adenopathy compared to non-HIV-associated Hodgkin's disease. Most patients in these series had either mixed cellularity or lymphocyte-depleted Hodgkin's disease, B symptoms, and a median CD4 lymphocyte count of 300/dL or less. Median survival time ranges from 8 to 20 months, which is much poorer than the survival expected in patients with non-HIV-associated Hodgkin's disease. Potential causes of decreased survival include early death from other AIDS-related diseases, decreased efficacy of standard therapies, and/or increased toxic effects of treatment.

References:

1. Ziegler JL, Beckstead JA, Volberding PA, et al.: Non-Hodgkin's lymphoma in 90 homosexual men: relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. New England Journal of Medicine 311(9): 565-570, 1984.

2. Rabkin CS, Yellin F: Cancer incidence in a population with a high prevalence of infection with human immunodeficiency virus type 1. Journal of the National Cancer Institute 86(22): 1711-1716, 1994.

3. Nador RG, Cesarman E, Knowles DM, et al.: Herpes-like DNA sequences in a body-cavity-based lymphoma in an HIV-negative patient. New England Journal of Medicine 333(14): 943, 1995.

4. Nador RG, Cesarman E, Chadburn A, et al.: Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood 88(2): 645-656, 1996.

5. Cote TR, Biggar RJ, Rosenberg PS, et al.: Non-Hodgkin's lymphoma among people with AIDS: incidence, presentation and public health burden. International Journal of Cancer 73(5): 645-650, 1997.

6. Pluda JM, Yarchoan R, Jaffe ES, et al.: Development of non-Hodgkin lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on long-term antiretroviral therapy. Annals of Internal Medicine 113(4): 276-282, 1990.

7. Gail MH, Pluda JM, Rabkin CS, et al.: Projections of the incidence of non-Hodgkin's lymphoma related to acquired immunodeficiency syndrome. Journal of the National Cancer Institute 83(10): 695-701, 1991.

8. Pluda JM, Venzon DJ, Tosato G, et al.: Parameters affecting the development of non-Hodgkin's lymphoma in patients with severe human immunodeficiency virus infection receiving antiretroviral therapy. Journal of Clinical Oncology 11(6): 1099-1107, 1993.

9. Knowles DM, Chamulak GA, Subar M, et al.: Lymphoid neoplasia associated with the acquired immunodeficiency syndrome (AIDS): the New York University Medical Center experience with 105 patients. Annals of Internal Medicine 108(5): 744-753, 1988.

10 Levine AM, Sullivan-Halley J, Pike MC, et al.: Human immunodeficiency virus-related lymphoma: prognostic factors predictive of survival. Cancer 68(11): 2466-2472, 1991.

11. Kaplan LD, Straus DJ, Testa MA, et al.: Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human immunodeficiency virus infection. New England Journal of Medicine 336(23): 1641-1648, 1997.

12. Spina M, Vaccher E, Nasti G, et al.: Human immunodeficiency virus-associated Hodgkin's disease. Seminars in Oncology 27(4): 480-488, 2000.

13. Hessol NA, Katz MH, Liu JY, et al.: Increased incidence of Hodgkin disease in homosexual men with HIV infection. Annals of Internal Medicine 117(4): 309-311, 1992.

Cellular Classification

Pathologically, AIDS-related lymphomas are comprised of a narrow spectrum of histologic types consisting almost exclusively of B-cell tumors of aggressive type. These include diffuse large-cell, B-immunoblastic, and small non-cleaved, either Burkitt's or Burkitt's like. All 3 pathologic types are equally distributed and represent aggressive disease.

AIDS-related lymphomas, although usually of B-cell origin as demonstrated by immunoglobulin heavy-chain gene rearrangement studies, have also been shown to be oligoclonal and polyclonal as well as monoclonal in origin. Although HIV does not appear to have a direct etiologic role, HIV infection does lead to an altered immunologic milieu. HIV generally infects T-lymphocytes whose loss of regulation function leads to hypergammaglobulinemia and polyclonal B-cell hyperplasia. B cells are not the target of HIV infection. Instead, Epstein-Barr virus (EBV) is thought to be at least a cofactor in the etiology of some of these lymphomas. The EBV genome has been detected in varying numbers of patients with AIDS-related lymphomas; molecular analysis suggests that the cells were infected before clonal proliferation began.1 EBV is detected in 30% of patients with small, non-cleaved and in 80% of patients with diffuse large cell lymphomas. The rare primary effusion lymphoma consistently harbors HHV-8, and frequently contains EBV. Other genetic lesions commonly detected in AIDS-related lymphomas are not seen.2 HIV-related T-cell lymphomas have also been identified and appear to be associated with EBV infection.3

References:

1. Neri A, Barriga F, Inghirami G, et al.: Epstein-Barr virus infection precedes clonal expansion in Burkitt's and acquired immunodeficiency syndrome-associated lymphoma. Blood 77(5): 1092-1095, 1991.

2. Gaidano G, Carbone A, Dalla-Favera R: Genetic basis of acquired immunodeficiency syndrome-related lymphomagenesis. Journal of the National Cancer Institute Monographs 23: 95-100, 1998.

3. Thomas JA, Cotter F, Hanby AM, et al.: Epstein-Barr Virus-related oral T-cell lymphoma associated with Human Immunodeficiency Virus immunosuppression. Blood 81(12): 3350-3356, 1993.

Stage Information

Although stage is important in selecting the treatment of patients with non-Hodgkin's lymphoma who do not have acquired immunodeficiency syndrome (AIDS), the majority of patients with AIDS-related lymphomas have far advanced disease. In general, the staging system used is the Ann Arbor system, which is identical to that used for non-AIDS-related non-Hodgkin's lymphomas.

Staging Classification System

Stages I, II, III, and IV non-Hodgkin's disease can be subclassified into A and B categories: B for those with well-defined generalized symptoms and A for those without. The B designation is given to patients with any of the following symptoms:

unexplained loss of more than 10% of body weight in the 6 months before diagnosis
unexplained fever with temperatures higher than 38 degrees C
drenching night sweats

The designation "E" is used when extranodal lymphoid malignancies arise in tissues away from the major lymphatic aggregates. If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed. Sites are identified by the following notation:

N = nodes---H = liver-----L = lung---M = marrow

S = spleen---P = pleura---O = bone---D = skin

Stage I

Stage I non-Hodgkin's lymphoma means involvement of a single lymph node region (I), or localized involvement of a single extralymphatic organ or site (IE).1,2

Stage II

Stage II non-Hodgkin's lymphoma means involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ or site and its regional lymph nodes with or without other lymph node regions on the same side of the diaphragm (IIE).1,2

Stage III

Stage III non-Hodgkin's lymphoma means involvement of lymph node regions on both sides of the diaphragm (III) that may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE), involvement of the spleen (IIIS), or both (IIIS+E).1,2

Stage IV

Stage IV non-Hodgkin's lymphoma means disseminated (multifocal) involvement of one or more extralymphatic organs with or without associated lymph node involvement or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement.1,2

A number of factors that are important for determining prognosis are not included in the staging system for non-Hodgkin's lymphomas. All of these factors should be considered when selecting treatment. Prognosis is related to the severity of the underlying immune deficiency (CD4 lymphocyte count), the presence or history of opportunistic infections (prior AIDS-defining illness), bone marrow involvement, performance status, and presence of extranodal disease.3 Typically, AIDS-related lymphomas are widespread with extranodal disease at the time of presentation. The most common extranodal sites are the gastrointestinal (GI) tract, central nervous system, bone marrow, and liver. In one series, the largest group of patients had both extranodal and nodal disease (43%), but one third of the patients presented with extranodal disease only.4 In a second series, 87% of the patients had extranodal disease at presentation.5 Two thirds of patients have stage IV disease at diagnosis. In addition, unusual presentations include involvement of the rectum, heart, pericardium, pulmonary parenchyma, bile ducts, mouth, and subcutaneous and soft tissues. The clinical features of AIDS-related lymphomas correlate with histopathology. The majority of patients with small noncleaved cell (Burkitt's) lymphomas present with stage IV disease, mostly because of bone marrow involvement. This compares with approximately a 40% stage IV presentation by those with immunoblastic and large cell lymphomas. A particular prevalence for GI involvement has been noted in patients who have immunoblastic and large-noncleaved cell lymphoma types.6 While high-risk behavior should be looked for in every patient, HIV testing should probably be done for any patient who has Burkitt's lymphoma or the atypical presentation of extranodal lymphoma that involves rare sites, i.e., rectum, GI tract, bone, or orbit. Similarly, malignant lymphoma should be considered in any HIV-infected patient who has progressive lymphadenopathy, tumors at any site, central nervous system symptoms, or unexplained wasting, fever, or abdominal pain.

References:

1. Non-Hodgkin's lymphoma. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 289-294.

2. The Non-Hodgkin's Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. Cancer 49(10): 2112-2135, 1982.

3. Levine AM: Acquired immunodeficiency syndrome-related lymphoma: clinical aspects. Seminars in Oncology 27(4): 442-453, 2000.

4. Kaplan LD, Abrams DI, Feigal E, et al.: AIDS-associated non-Hodgkin's lymphoma in San Francisco. JAMA: Journal of the American Medical Association 261(5): 719-724, 1989.

5. Knowles DM, Chamulak GA, Subar M, et al.: Lymphoid neoplasia associated with the acquired immunodeficiency syndrome (AIDS): the New York University Medical Center experience with 105 patients. Annals of Internal Medicine 108(5): 744-753, 1988.

6. Raphael BG, Knowles DM: Acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma. Seminars in Oncology 17(3): 361-366, 1990.

Treatment Option Overview

The treatment of acquired immunodeficiency syndrome (AIDS)-related lymphomas presents the challenge of integrating therapy appropriate for the stage and histologic subset of malignant lymphoma with the limitations imposed by HIV infection, to date an incurable illness.1 In addition to antitumor therapy, essential components of an optimal non-Hodgkin's lymphoma treatment strategy include antiretroviral therapy, prophylaxis for opportunistic infections, and rapid recognition and treatment of intercurrent infections. Patients with HIV positivity and underlying immunodeficiency have poor bone marrow reserve, thereby compromising the potential for drug dose intensity. There is a risk of intercurrent opportunistic infection, which may also lead to a decrease in drug delivery. Furthermore, chemotherapy itself compromises the immune system thus increasing the likelihood of opportunistic infection. In general, response rates are lower than for a non-HIV population. Complete responses occur but tend to be of shorter duration with frequent relapses. The question is whether the curative potential of high-dose chemotherapy is so compromised by the treatment-related morbidity and mortality that low-dose chemotherapy should be used. Most studies have used a lower dose intensity, and delays in treatment have been common. Several investigators have attempted to use intensive chemotherapy regimens, with a median overall survival time for treated patients of approximately 6 to 9 months.2-5 The patients with the more favorable prognoses and prolonged survival tend to have CD4 lymphocyte counts greater than 100/microliter, less disease (stage I or II), no systemic symptoms, good performance status, and no central nervous system or bone marrow involvement. The optimal dose intensity of chemotherapy in these patients is under clinical evaluation. In a randomized prospective trial, 198 HIV-seropositive patients with previously untreated, aggressive lymphoma received standard-dose therapy with methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) plus granulocyte-macrophage colony-stimulating factor (GM-CSF) or reduced-dose m-BACOD with GM-CSF only if needed.6 There were no differences in complete response rates, disease-free survival, or overall survival (median survival was 8 months).6[Level of evidence: 1A] Reduced doses of m-BACOD caused fewer hematologic toxic effects and days of hospitalization with no loss of efficacy. Outside the context of a clinical trial, low-dose chemotherapy should be considered for most patients with HIV infection and a CD4 lymphocyte count under 200. Although m-BACOD was used in the randomized trial, many clinicians now employ half-dose CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone).7 Patients with HIV and CD4 lymphocyte counts over 200 may tolerate full-dose chemotherapy with fewer complications; it is unclear whether efficacy in this group of patients would be compromised with low-dose therapy.

References:

1. Levine AM: Acquired immunodeficiency syndrome-related lymphoma: clinical aspects. Seminars in Oncology 27(4): 442-453, 2000.

2. Gisselbrecht C, Oksenhendler E, Tirelli U, et al.: Human immunodeficiency virus-related lymphoma treatment with intensive combination chemotherapy. American Journal of Medicine 95(2): 188-196, 1993.

3. Remick SC, McSharry JJ, Wolf BC, et al.: Novel oral combination chemotherapy in the treatment of intermediate-grade and high-grade AIDS-related non-Hodgkin's lymphoma. Journal of Clinical Oncology 11(9): 1691-1702, 1993.

4. Sparano JA, Wiernik PH, Strack M, et al.: Infusional cyclophosphamide, doxorubicin, and etoposide in human immunodeficiency virus- and human T-cell leukemia virus type I-related non-Hodgkin's lymphoma: a highly active regimen. Blood 81(10): 2810-2815, 1993.

5. Sparano JA, Wiernik PH, Strack M, et al.: Infusional cyclophosphamide, doxorubicin and etoposide in HIV-related non-Hodgkin's lymphoma: a follow-up report of a highly active regimen. Leukemia and Lymphoma 14(3-4): 263-271, 1994.

6. Kaplan LD, Straus DJ, Testa MA, et al.: Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human immunodeficiency virus infection. New England Journal of Medicine 336(23): 1641-1648, 1997.

7. Ratner L, AIDS Associated Malignancies Clinical Trials Consortium: Phase II Pilot Study of Combination Chemotherapy Modified Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone and Combination Antiviral Therapy in the Treatment of AIDS-Related Non-Hodgkin's Lymphoma (Summary Last Modified 04/2001), AMC-005, clinical trial, completed, 04/01/2000.

AIDS-Related Peripheral/Systemic Lymphoma

As noted above, the treatment of acquired immunodeficiency syndrome (AIDS)-related lymphomas involves overcoming several problems. These are all aggressive lymphomas, which by definition are diffuse large cell/immunoblastic lymphoma or small noncleaved cell lymphoma. These lymphomas frequently involve the bone marrow and central nervous system and therefore are usually in an advanced stage. In addition, the immunodeficiency of AIDS and the leukopenia that is commonly seen with HIV infection makes the use of immunosuppressive chemotherapy difficult.

A large number of retrospective studies and several prospective studies have been reported to use regimens such as the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and the combination of intermediate-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD), as commonly used with non-AIDS aggressive lymphomas.1-4 In general, these studies have combined the various histologic subsets of AIDS-related systemic peripheral lymphomas. Unlike the non-HIV-related lymphomas, investigators have treated diffuse large cell/immunoblastic lymphoma as they have small noncleaved cell lymphoma. These studies have shown that complete remissions are possible, although the responses are often of short duration and relapses are frequent. The patients who go into remission are more likely to have less disease, no bone marrow or central nervous system (CNS) involvement, no prior AIDS-defining illness, and a better performance status. Patients at risk for subsequent CNS involvement include those with bone marrow involvement or those with Epstein-Barr virus identified in the primary tumor or in the cerebrospinal fluid (by polymerase chain reaction).5-7 Intrathecal chemotherapy is usually considered for these patients at higher risk for CNS involvement. Overall complete responses have been seen in approximately 50% of patients. The complete response rate and survival time is greater in patients with diffuse large cell lymphoma. Whether patients with small noncleaved cell and immunoblastic lymphoma have a worse prognosis is unclear and varies from one series to another.8 The most appropriate treatment regimen for patients with AIDS-related lymphoma is not known. Delays in therapy and dose reductions are often necessary, and some investigators have advocated using lower-dose chemotherapeutic regimens. Since myelosuppression and opportunistic infections are the predominant toxic effects, effort has focused on combining combination chemotherapy with colony stimulating factors and antiretroviral therapy. Less myelosuppression was seen when a 96 hour infusion of cyclophosphamide, doxorubicin, and etoposide (CDE) was combined with filgrastim (G-CSF) and didanosine (ddI).9

References:

1. Kaplan LD, Abrams DI, Feigal E, et al.: AIDS-associated non-Hodgkin's lymphoma in San Francisco. JAMA: Journal of the American Medical Association 261(5): 719-724, 1989.

2. Levine AM, Wernz JC, Kaplan L, et al.: Low-dose chemotherapy with central nervous system prophylaxis and zidovudine maintenance in AIDS-related lymphoma: a prospective multi-institutional trial. JAMA: Journal of the American Medical Association 266(1): 84-88, 1991.

3. Kaplan LD, Kahn JO, Crowe S, et al.: Clinical and virologic effects of recombinant human granulocyte-macrophage colony stimulating factor in patients receiving chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma: results of a randomized trial. Journal of Clinical Oncology 9(6): 929-940, 1991.

4. Levine AM: Acquired immunodeficiency syndrome-related lymphoma: clinical aspects. Seminars in Oncology 27(4): 442-453, 2000.

5. Gill PS, Levine AM, Krailo M, et al.: Aids-related malignant lymphoma: results of prospective treatment trials. Journal of Clinical Oncology 5(9): 1322-1328, 1987.

6. Cingolani A, Gastaldi R, Fassone L, et al.: Epstein-Barr virus infection is predictive of CNS involvement in systemic AIDS-related non-Hodgkin's lymphomas. Journal of Clinical Oncology 18(19): 3325-3330, 2000.

7. Scadden DT: Epstein-Barr virus, the CNS, and AIDS-related lymphomas: as close as flame to smoke. Journal of Clinical Oncology 18(19): 3323-3324, 2000.

8. Pedersen C, Gerstoft J, Lundgren JD, et al.: HIV-associated lymphoma: histopathology and association with Epstein-Barr virus genome related to clinical, immunological and prognostic features. European Journal of Cancer 27(11): 1416-1423, 1991.

9. Sparano JA, Wiernik PH, Hu X, et al.: Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide plus didanosine and filgrastim in patients with human immunodeficiency virus-associated non-Hodgkin's lymphoma. Journal of Clinical Oncology 14(11): 3026-3035, 1996.

AIDS-Related Primary Central Nervous System Lymphoma

Until the 1980s, primary central nervous system (CNS) lymphoma was a rare disease. There has been a dramatic increase in primary CNS lymphoma in association with acquired immunodeficiency syndrome (AIDS).1 Primary CNS lymphoma accounts for approximately 0.6% of initial AIDS diagnoses and is the second most frequent CNS mass lesion in adults with AIDS. As with other AIDS-related lymphomas, these are usually aggressive B-cell neoplasms, either diffuse large cell or diffuse immunoblastic non-Hodgkin's lymphoma. However, unlike AIDS-related systemic lymphomas in which 30% to 50% of tumors are associated with Epstein-Barr virus (EBV), AIDS-related primary CNS lymphoma has been reported to have a 100% association with EBV.2 This percentage indicates a pathogenetic role for EBV in this disease. These patients usually have evidence of far advanced AIDS, are severely debilitated, and present with focal neurologic symptoms such as seizures and paralysis. Computed tomographic scans show contrast-enhancing mass lesions that may not always be distinguished from other CNS diseases, such as toxoplasmosis, that occur in AIDS patients.3 Magnetic resonance imaging studies using gadolinium contrast may be a more useful initial diagnostic tool in differentiating lymphoma from cerebral toxoplasmosis or progressive multifocal leukoencephalopathy. Lymphoma tends to present with large lesions, which are enhanced by gadolinium. In cerebral toxoplasmosis, ring enhancement is very common, lesions tend to be smaller, and multiple lesions are seen.4-6 Use of positron emission scanning has demonstrated an improved ability to distinguish primary central nervous system lymphoma (PCNSL) from toxoplasmosis.7,8 PSNCL has an increased uptake while toxoplasmosis lesions are metabolically inactive. Antibodies against toxoplasmosis may also be very useful, since the vast majority of cerebral toxoplasmosis occur as a consequence of reactivity of a previous infection. If the IgG titer is less than 1:4, the disease is unlikely to be toxoplasmotic. A lumbar puncture may be useful to detect the up to 23% of patients with malignant cells in their cerebral spinal fluid (CSF). Evaluating the CSF for EBV DNA may be a useful lymphoma-specific tool since EBV is present in all patients with PCNSL. Despite all of these evaluations, however, the majority of patients with PCNSL require a pathologic diagnosis.9-11 Diagnosis is made by biopsy. Primary CNS lymphoma is often identified as a terminal manifestation of AIDS or on postmortem examination.

Radiation therapy alone has usually been used in this group of patients. With doses in the 3500 to 4000 cGy range, median duration of survival has been only 72 to 119 days.3,12,13 Survival is longer in younger patients with better performance status and absence of opportunistic infection.14 Most patients respond to treatment by showing partial improvement in neurologic symptoms. Autopsies have revealed that these patients die of opportunistic infections as well as tumor progression. Treatment of these patients is also complicated by other AIDS-related CNS infections, including subacute AIDS encephalitis, cytomegalovirus encephalitis, and toxoplasmosis encephalitis.

References:

1. Ziegler JL, Beckstead JA, Volberding PA, et al.: Non-Hodgkin's lymphoma in 90 homosexual men: relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. New England Journal of Medicine 311(9): 565-570, 1984.

2. MacMahon EM, Glass JD, Hayward SD, et al.: Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 338(8773): 969-973, 1991.

3. Goldstein JD, Dickson DW, Moser FG, et al.: Primary central nervous system lymphoma in acquired immune deficiency syndrome: a clinical and pathologic study with results of treatment with radiation. Cancer 67(11): 2756-2765, 1991.

4. Nyberg DA, Federle MP: AIDS-related Kaposi sarcoma and lymphomas. Seminars in Roentgenology 22(1): 54-65, 1987.

5. Fine HA, Mayer RJ: Primary central nervous system lymphoma. Annals of Internal Medicine 119(11): 1093-1104, 1993.

6. Ciricillo SF, Rosenblum ML: Use of CT and MR imaging to distinguish intracranial lesions and to define the need for biopsy in AIDS patients. Journal of Neurosurgery 73(5): 720-724, 1990.

7. Hoffman JM, Waskin HA, Schifter T, et al.: FDG-PET in differentiating lymphoma from nonmalignant central nervous system lesions in patients with AIDS. Journal of Nuclear Medicine 34(4): 567-575, 1993.

8. Pierce MA, Johnson MD, Maciunas RJ, et al.: Evaluating contrast-enhancing brain lesions in patients with AIDS by using positron emission tomography. Annals of Internal Medicine 123(8): 594-598, 1995.

9. Cinque P, Brytting M, Vago L, et al.: Epstein-Barr virus DNA in cerebrospinal fluid from patients with AIDS-related primary lymphoma of the central nervous system. Lancet 342(8868): 398-401, 1993.

10. Cingolani A, De Luca A, Larocca LM, et al.: Minimally invasive diagnosis of acquired immunodeficiency syndrome-related primary central nervous system lymphoma. Journal of the National Cancer Institute 90(5): 364-369, 1998.

11. Yarchoan R, Jaffe ES, Little R: Diagnosing central nervous system lymphoma in the setting of AIDS: a step forward. Journal of the National Cancer Institute 90(5): 346-347, 1998.

12. Baumgartner JE, Rachlin JR, Beckstead JH, et al.: Primary central nervous system lymphomas: natural history and response to radiation therapy in 55 patients with acquired immunodeficiency syndrome. Journal of Neurosurgery 73(2): 206-211, 1990.

13. Remick SC, Diamond C, Migliozzi JA, et al.: Primary central nervous system lymphoma in patients with and without the acquired immune deficiency syndrome: a retrospective analysis and review of the literature. Medicine 69(6): 345-360, 1990.

14. Corn BW, Donahue BR, Rosenstock JG, et al.: Performance status and age as independent predictors of survival among AIDS patients with primary CNS lymphoma: a multivariate analysis of a multi-institutional experience. Cancer Journal from Scientific American 3(1): 52-56, 1997.

Adrenocortical Carcinoma

2008-07-21T05:51:00.000-07:00

Table of Contents

General Information
Cellular Classification
Stage Information
TNM definitions
Stage I
Stage II
Stage III
Stage IV
Treatment Option Overview
Stage I Adrenocortical Carcinoma
Stage II Adrenocortical Carcinoma
Stage III Adrenocortical Carcinoma
Stage IV Adrenocortical Carcinoma
Recurrent Adrenocortical Carcinoma

General Information

Adrenocortical carcinoma is a rare tumor afflicting only one to two persons per one million population. It usually occurs in adults, and the median age at diagnosis is 44 years. Although potentially curable at early stages, only 30% of these malignancies are confined to the adrenal gland at the time of diagnosis.1

Approximately 60% of patients present with symptoms related to excessive hormone secretion, but hormone testing reveals that 60%-80% of tumors are functioning.2,3 Nonfunctioning carcinomas may be heralded by symptoms of local invasion by tumor or by metastases. Initial evaluation should include, in addition to appropriate endocrine studies, computed tomography and/or magnetic resonance imaging of the abdomen. Selective angiography and adrenal venography may be helpful for smaller lesions and for distinguishing tumors of the adrenal gland from tumors of the upper pole of the kidney. The detection of metastatic lesions may allow effective palliation of both functioning and nonfunctioning lesions.

Adrenal carcinoma may be curable if treated at an early stage. Radical surgical excision is the treatment of choice for localized malignancies and remains the only method by which long-term disease-free survival may be achieved. Overall 5-year survival for tumors resected for cure is approximately 40%. Retrospective studies have identified two important prognostic factors: completeness of resection and stage of disease. Patients without evidence of invasion into local tissues or spread to lymph nodes have an improved prognosis.4 The role of DNA ploidy as a prognostic indicator is controversial, with some 5 studies showing correlation between aneuploidy and prognosis, and other studies 4,6 showing no correlation.

The most common sites of metastases are the peritoneum, lung, liver, and bone. Palliation of metastatic functioning tumors may be achieved by resection of both the primary tumor and metastatic lesions. Unresectable or widely disseminated tumors may be palliated by antihormonal therapy with mitotane, systemic chemotherapy, or (for localized lesions) radiation therapy. However, survival for patients with stage IV tumors is usually less than 9 months unless a complete remission is achieved.3,7-9 To date, there is no convincing evidence that systemic therapy will improve the survival duration of patients with adrenal cancer.

References:

1. Norton JA: Adrenal tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 1659-1677.

2. Icard P, Chapuis Y, Andreassian B, et al.: Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112(6): 972-979, 1992.

3. Luton JP, Cerdas S, Billaud L, et al.: Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. New England Journal of Medicine 322(17): 1195-1201, 1990.

4. Lee JE, Berger DH, El-Naggar AK, et al.: Surgical management, DNA content, and patient survival in adrenal cortical carcinoma. Surgery 118(6): 1090-1098, 1995.

5. Camuto P, Schinella R, Gilchrist K, et al.: Adrenal cortical carcinoma: flow cytometric study of 22 cases, an ECOG study. Urology 37(4): 380-384, 1991.

6. Haak HR, Cornelisse CJ, Hermans J, et al.: Nuclear DNA content and morphological characteristics in the prognosis of adrenocortical carcinoma. British Journal of Cancer 68(1): 151-155, 1993.

7. Brennan MF: Adrenocortical carcinoma. CA: A Cancer Journal for Clinicians 37(6): 348-365, 1987.

8. Cohn K, Gottesman L, Brennan M: Adrenocortical carcinoma. Surgery 100(6): 1170-1177, 1986.

9. Wooten MD, King DK: Adrenal cortical carcinoma: epidemiology and treatment with mitotane and a review of the literature. Cancer 72(11): 3145-3155, 1993.

Cellular Classification

Adrenocortical carcinoma can be classified as follows:

Differentiated: Functioning tumors are usually differentiated.

Anaplastic: Production of hormones by anaplastic tumors is rare.

Hormonal: Approximately 60% of adrenocortical carcinomas produce hormones. The associated clinical syndromes include the following:1-3

hypercortisolism (Cushing's syndrome)
adrenogenital syndrome
virilization
feminization
precocious puberty
hyperaldosteronism
primary hyperaldosteronism (Conn's syndrome)

References:

1. Javadpour N, Woltering EA, Brennan MF: Adrenal neoplasms. Current Problems in Surgery 17(1): 5-52, 1980.

2. Nader S, Hickey RC, Sellin RV, et al.: Adrenal cortical carcinoma: a study of 77 cases. Cancer 52(4): 707-711, 1983.

3. Norton JA: Adrenal tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 1659-1677.

Stage Information

The stage of adrenocortical carcinoma is determined by the size of the primary tumor, the degree of local invasion, and whether it has spread to regional lymph nodes or distant sites.1-4 Proper staging should include computed tomography (CT) of the abdomen. Magnetic resonance imaging (MRI) may add specificity to CT evaluation of an adrenal mass.5 In-phase and out-of-phase T1-weighted imaging may be the most effective noninvasive method to differentiate benign from malignant adrenal masses. MRI can also often clearly demonstrate any evidence of extracapsular tumor invasion, extension into the vena cava, or metastases. Patency of surrounding vessels can often be demonstrated with gadolinium-enhanced sequences or flip-angle techniques.6 Vena caval contrast studies and angiography may provide additional staging information and allow for more complete preoperative assessment. Review of published data from 608 patients revealed the following stage distribution at diagnosis: 3% stage I, 29% stage II, 20% stage III, and 49% stage IV.7

Stages are defined by TNM classification.8

TNM definitions

Primary tumor (T)

T1: Primary tumor no more than 5 cm in size; no local invasion T2: Primary tumor greater than 5 cm in size; no invasion T3: Primary tumor of any size, locally invading to but not involving
adjacent organs
T4: Tumor any size, locally invading adjacent organs

Nodal involvement (N)

N0: No regional positive nodes N1: Positive regional nodes

Distant metastasis (M)

MX: Minimum requirements to assess the presence of distant metastasis cannot be met
M0: No (known) distant metastasis M1: Distant metastasis present

Stage I

Stage I adrenocortical carcinoma is defined by the following TNM grouping:

T1, N0, M0

Stage II

Stage II adrenocortical carcinoma is defined by the following TNM grouping:

T2, N0, M0

Stage III

Stage III adrenocortical carcinoma is defined by the following TNM groupings:

T3, N0, M0 T1 or T2, N1, M0

Stage IV

Stage IV adrenocortical carcinoma is defined by the following TNM groupings:

T3 or T4, N1, M0 any T, any N, M1

References:

1. Cerfolio RJ, Vaughan ED, Brennan TG, et al.: Accuracy of computed tomography in predicting adrenal tumor size. Surgery, Gynecology and Obstetrics 176(4): 307-309, 1993.

2. Brennan MF: Adrenocortical carcinoma. CA: A Cancer Journal for Clinicians 37(6): 348-365, 1987.

3. Cohn K, Gottesman L, Brennan M: Adrenocortical carcinoma. Surgery 100(6): 1170-1177, 1986.

4. Nader S, Hickey RC, Sellin RV, et al.: Adrenal cortical carcinoma: a study of 77 cases. Cancer 52(4): 707-711, 1983.

5. Doppman JL, Reinig JW, Dwyer AJ, et al.: Differentiation of adrenal masses by magnetic resonance imaging. Surgery 102(6): 1018-1025, 1987.

6. Brown ED, Semelka RC: Magnetic resonance imaging of the adrenal gland and kidney. Topics in Magnetic Resonance Imaging 7(2): 90-101, 1995.

7. Wooten MD, King DK: Adrenal cortical carcinoma: epidemiology and treatment with mitotane and a review of the literature. Cancer 72(11): 3145-3155, 1993.

8. Henley DJ, Van Heerden JA, Grant CS, et al.: Adrenal cortical carcinoma: a continuing challenge. Surgery 94(6): 926-931, 1983.

Treatment Option Overview

Stage I Adrenocortical Carcinoma

Standard treatment options:

Complete surgical removal of the tumor is the treatment of choice for patients with stage I adrenocortical carcinomas. The long-term survival with nonfunctioning tumors is comparable to that with functioning tumors. Removal of regional lymph nodes that are not clinically enlarged is not indicated.1-5

Treatment options under clinical evaluation:

Adjuvant radiation or chemotherapy with mitotane has not been proven to be of value in improving survival.5,6

References:

1. Javadpour N, Woltering EA, Brennan MF: Adrenal neoplasms. Current Problems in Surgery 17(1): 5-52, 1980.

2. Brennan MF: Adrenocortical carcinoma. CA: A Cancer Journal for Clinicians 37(6): 348-365, 1987.

3. Cohn K, Gottesman L, Brennan M: Adrenocortical carcinoma. Surgery 100(6): 1170-1177, 1986.

4. Icard P, Chapuis Y, Andreassian B, et al.: Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112(6): 972-979, 1992.

5. Luton JP, Cerdas S, Billaud L, et al.: Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. New England Journal of Medicine 322(17): 1195-1201, 1990.

6. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, et al.: Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 71(10): 3119-3123, 1993.

Stage II Adrenocortical Carcinoma

Standard treatment options:

Complete surgical removal of the tumor is the treatment of choice for patients with stage II adrenocortical carcinomas. The long-term survival with nonfunctioning tumors is comparable to that with functioning tumors. Removal of regional lymph nodes that are not clinically enlarged is not indicated.1-5

Treatment options under clinical evaluation:

Adjuvant radiation or chemotherapy with mitotane has not been proven to be of value in improving survival.5,6

References:

1. Javadpour N, Woltering EA, Brennan MF: Adrenal neoplasms. Current Problems in Surgery 17(1): 5-52, 1980.

2. Brennan MF: Adrenocortical carcinoma. CA: A Cancer Journal for Clinicians 37(6): 348-365, 1987.

3. Cohn K, Gottesman L, Brennan M: Adrenocortical carcinoma. Surgery 100(6): 1170-1177, 1986.

4. Icard P, Chapuis Y, Andreassian B, et al.: Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112(6): 972-979, 1992.

5. Luton JP, Cerdas S, Billaud L, et al.: Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. New England Journal of Medicine 322(17): 1195-1201, 1990.

6. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, et al.: Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 71(10): 3119-3123, 1993.

Stage III Adrenocortical Carcinoma

Standard treatment options:

Complete surgical removal of the tumor, with or without regional lymph node dissection. The treatment of patients who have tumors with local invasion, but without clinically enlarged regional lymph nodes, is complete surgical removal as for stage I and stage II tumors. For those with enlarged regional lymph nodes, a lymph node dissection should be included in the procedure. These patients are at high risk for disease recurrence and should be considered for enrollment in a clinical trial.

Treatment options under clinical evaluation:

1. Clinical trials are appropriate for newly diagnosed patients when possible.

2. Radiation therapy: 4,200-5,000 rads given for a period of 4 weeks to localized but unresectable tumors.1

3. For patients unable to undergo complete resection, mitotane in doses up to 10-12 grams per day can be considered. This antitumor drug produces useful clinical responses that average 10 months in duration in about 30% of patients with measurable metastases. Responses in patients who achieve complete remission can be durable. Approximately 80% of treated patients with functioning tumors will show substantial diminution in hormone production. The drug is not usually used unless either radiologically evaluable metastases are present or the residual tumor is producing measurable levels of hormone.2,3 There does not appear to be a role for mitotane as adjuvant therapy if the patient has undergone complete resection of the tumor.3,4

References:

1. Percarpio B, Knowlton AH: Radiation therapy of adrenocortical carcinoma. Acta Radiologica 15(4): 288-292, 1976.

2. Lubitz JA, Freeman L, Okun R: Mitotane use in inoperable adrenal cortical carcinoma. JAMA: Journal of the American Medical Association 223(10): 1109-1112, 1973.

3. Luton JP, Cerdas S, Billaud L, et al.: Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. New England Journal of Medicine 322(17): 1195-1201, 1990.

4. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, et al.: Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 71(10): 3119-3123, 1993.

Stage IV Adrenocortical Carcinoma

Temporary palliation of disseminated adrenocortical carcinomas can sometimes be achieved with the chemotherapeutic agent mitotane. Although measurable partial remissions are unusual and are reported in only 19%-34% of cases, excellent palliation of hormone symptoms is commonly observed.1 Prolonged treatment with mitotane, however, is often limited by gastrointestinal and neurologic toxicity. Local recurrences and selected sites of metastatic disease can sometimes be palliated surgically.2

Clinical trials are appropriate and should be considered whenever possible, especially phase I and II trials that evaluate newer chemotherapeutic and biologic agents.3-6 Palliative chemotherapy with cisplatin-based regimens has produced short-term objective responses in approximately 30% of patients treated.4,5,7,8 One study reported that doxorubicin produced objective responses in 3 of 16 patients with poorly-differentiated, non-hormone-producing tumors but no responses in 15 patients whose disease did not respond to mitotane.3

Standard treatment options:

1. Chemotherapy with mitotane.1

2. Radiation therapy to bone metastases.9

3. Surgical removal of localized metastases, particularly those that are functioning.2

Treatment options under clinical evaluation:

Cisplatin has been reported to produce beneficial effects in some selected patients with metastatic disease.7,8,10

References:

1. Lubitz JA, Freeman L, Okun R: Mitotane use in inoperable adrenal cortical carcinoma. JAMA: Journal of the American Medical Association 223(10): 1109-1112, 1973.

2. Pommier RF, Brennan MF: An eleven-year experience with adrenocortical carcinoma. Surgery 112(6): 963-971, 1992.

3. Decker RA, Elson P, Hogan TF, et al.: Eastern Cooperative Oncology Group study 1879: mitotane and adriamycin in patients with advanced adrenocortical carcinoma. Surgery 110: 1006-1013, 1991.

4. Bukowski RM, Wolfe M, Levine HS, et al.: Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study. Journal of Clinical Oncology 11(1): 161-165, 1993.

5. Hesketh PJ, McCaffrey RP, Finkel HE, et al.: Cisplatin-based treatment of adrenocortical carcinoma. Cancer Treatment Reports 71(2): 222-224, 1987.

6. Schlumberger M, Ostronoff M, Bellaiche M, et al.: 5-fluorouracil, doxorubicin, and cisplatin regimen in adrenal cortical carcinoma. Cancer 61(8): 1492-1494, 1988.

7. Tattersall MH, Lander H, Bain B, et al: Cis-platinum treatment of metastatic adrenal carcinoma. Medical Journal of Australia 1(9): 419-421, 1980.

8. Chun HG, Yagoda A, Kemeny N, et al.: Cisplatin for adrenal cortical carcinoma. Cancer Treatment Reports 67(5): 513-514, 1983.

9. Percarpio B, Knowlton AH: Radiation therapy of adrenocortical carcinoma. Acta Radiologica 15(4): 288-292, 1976.

10. Haq MM, Legha SS, Samaan NA, et al.: Cytotoxic chemotherapy in adrenal cortical carcinoma. Cancer Treatment Reports 64(8-9): 909-913, 1980.

Recurrent Adrenocortical Carcinoma

The question and selection of further treatment of adrenocortical carcinoma depends on many factors, including previous treatment and site of recurrence as well as individual patient considerations. Local recurrence and selected sites of metastatic disease can sometimes be palliated by surgery. Although none of these patients can be considered curable, palliation of hormonal symptoms and occasional 5-year survivals can be achieved.1,2 Substantial morbidity, however, is associated with resection of these recurrent tumors.2 Clinical trials are appropriate and should be considered whenever possible, especially phase I and II trials that evaluate newer chemotherapeutic and biological agents.3-6

References:

1. Pommier RF, Brennan MF: An eleven-year experience with adrenocortical carcinoma. Surgery 112(6): 963-971, 1992.

2. Jensen JC, Pass HI, Sindelar WF, et al.: Recurrent or metastatic disease in select patients with adrenocortical carcinoma: aggressive resection vs chemotherapy. Archives of Surgery 126(4): 457-461, 1991.

3. Decker RA, Elson P, Hogan TF, et al.: Eastern Cooperative Oncology Group study 1879: mitotane and adriamycin in patients with advanced adrenocortical carcinoma. Surgery 110: 1006-1013, 1991.

4. Bukowski RM, Wolfe M, Levine HS, et al.: Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study. Journal of Clinical Oncology 11(1): 161-165, 1993.

5. Hesketh PJ, McCaffrey RP, Finkel HE, et al.: Cisplatin-based treatment of adrenocortical carcinoma. Cancer Treatment Reports 71(2): 222-224, 1987.

6. Schlumberger M, Ostronoff M, Bellaiche M, et al.: 5-fluorouracil, doxorubicin, and cisplatin regimen in adrenal cortical carcinoma. Cancer 61(8): 1492-1494, 1988.

Unusual Cancers of Childhood

2008-07-20T09:37:00.000-07:00

Table of Contents

Description
HEAD AND NECK CANCERS
Nasopharyngeal Carcinoma
Thyroid Tumors
Oral Cancers
Salivary Gland Cancers
Laryngeal Carcinoma
THORACIC CANCERS
Breast Cancer
Bronchial Adenomas/Carcinoids
Pleuropulmonary Blastoma
Esophageal Tumors
Thymomas
Tumors of the Heart
Mesothelioma
ABDOMINAL CANCERS
Carcinoma of the Adrenal Cortex
Renal Cell Carcinoma
Carcinoma of the Stomach
Cancer of the Pancreas
Colorectal Carcinoma
Carcinoid Tumors
GENITAL/URINARY TUMORS
Carcinoma of the Bladder
Ovarian Cancer
OTHER RARE CHILDHOOD CANCERS
Multiple Endocrine Neoplasia Syndrome
Skin Cancer (Melanoma, Basal Cell and Squamous Cell Carcinoma)
Clear Cell Sarcoma of Tendon Sheaths
Cancer of Unknown Primary Site

Description

GENERAL INFORMATION

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others in order to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.1 At these pediatric cancer centers, there are clinical trials available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Much of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI.

The tumors discussed in this summary are diverse; the discussion is arranged in descending anatomic order, from infrequent tumors of the head and neck to rare tumors of the urogenital tract and skin. All of these cancers are rare enough that most pediatric hospitals might see fewer than two in a year. Most of these tumors are more frequent in adults with cancer; thus, much of the information about these tumors may also be sought through sources relevant to adults with cancer.

HEAD AND NECK CANCERS

Head and neck cancers include nasopharyngeal carcinoma, thyroid tumors, mouth cancer, salivary gland cancer, and laryngeal carcinoma. The prognosis, diagnosis, classification, and treatment of these head and neck cancers are discussed below.

Nasopharyngeal Carcinoma

Nasopharyngeal cancer arises in the lining of the nasal cavity and pharynx.2 This tumor accounts for about one-third of all cancers of the upper airways. The incidence of this tumor is approximately one in 100,000 persons under the age of 20 in the United States.3 There is a higher frequency of this tumor in North Africa and Southeast Asia.

Nasopharyngeal carcinoma occurs in association with Epstein-Barr virus (EBV), the virus associated with infectious mononucleosis. The virus can be detected in biopsy specimens of these cancers, and tumor cells can have EBV antigens on their cell surface. Three histologic subtypes are recognized by the World Health Organization. Type 1 is squamous cell carcinoma, type 2 is nonkeratinizing carcinoma, and type 3 is undifferentiated carcinoma.

This cancer most frequently spreads to lymph nodes in the neck, which may alert the patient, parent, or physician to the presence of this tumor. The tumor may also spread to the nose, mouth, and pharynx, causing snoring, epistaxis, obstruction of the eustachian tubes, or hearing loss; it may also invade the base of the skull, causing cranial nerve palsy or difficulty with movements of the jaw (trismus). Distant metastatic sites may include the bones, the lungs, and the liver. The location of the primary tumor can be made by direct inspection of the nasopharynx. A diagnosis can be made from a biopsy of the primary tumor or of enlarged lymph nodes of the neck. Nasopharyngeal carcinomas must be distinguished from all other cancers that can present with enlarged lymph nodes and from other types of cancer in the head and neck area. Thus, diseases such as thyroid cancer, rhabdomyosarcoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, and Burkitt's lymphoma must be considered, as should benign conditions such as nasal angiofibroma (which presents with epistaxis) and infections draining into the lymph nodes of the neck.

Diagnostic tests should determine the extent of the primary tumor and whether there are metastases. Visualization of the nasopharynx by an ear-nose-throat specialist using a mirror, examination by a neurologist, and magnetic resonance imaging (MRI) of the head and neck can be used to determine the extent of the primary tumor. Evaluation of the chest and abdomen by computed tomography (CT) and bone scan should also be performed to determine whether there is metastatic disease. The levels of EBV and antibody to EBV should also be measured.2,4

Tumor staging is done by the tumor-node-metastasis (TNM) classification system of the American Joint Committee on Cancer. Various reports have indicated an overall survival rate of at least 75% for patients with early stage disease; there is a lower survival rate for patients with higher stage disease.5 No factors other than extent of tumor have correlated with prognosis.

Treatment combines the use of surgery, radiation therapy, and chemotherapy.6 Nasopharyngeal carcinoma generally has spread to the bones of the skull and to lymph nodes in the neck at the time of diagnosis; thus, the principal role of surgery is to obtain adequate diagnostic material from a biopsy of the involved lymph node or the primary site. Combined modality therapy with radiation and chemotherapy appears to be the most effective treatment for this tumor.7,8 Chemotherapy approaches include neoadjuvant and/or adjuvant therapy with cisplatin, 5-fluorouracil, and methotrexate. Radiation dose to the tumor should be greater than 60 Gy. An overall survival rate of 78% has been reported with this approach.9,10

Thyroid Tumors

Tumors of the thyroid are classified as adenomas or carcinomas.11 Adenomas are benign growths that may cause enlargement of all or part of the gland, which extends to both sides of the neck and can be quite large. Some of these tumors may secrete hormones. Transformation to a malignant carcinoma may occur in some cells, which then may grow and spread to lymph nodes in the neck or to the lungs.

Most thyroid carcinomas occur in girls. Although rare, these cancers represent about 1.5% of all tumors seen in the pediatric age group. There is an excessive frequency of thyroid adenoma and carcinoma in patients who previously received irradiation to the neck.12 Thyroid cancer may be associated with the development of other types of malignant tumors, such as the multiple endocrine neoplasia (MEN) syndromes. Thyroid carcinomas are differentiated tumors, meaning that they tend to grow slowly and are not highly malignant. Thyroid radionuclide scans do not demonstrate the uptake of radioisotope into the area of the suspected neoplasm.

Various histologies account for the general diagnostic category of carcinoma of the thyroid.13 Papillary carcinoma represents 60% to 75% of these tumors,14 follicular carcinoma 10% to 20%, medullary carcinoma 5% to 10%, and anaplastic carcinoma less than 1%. Follicular carcinomas may be sporadic or familial. Follicular carcinoma and papillary carcinoma generally have a benign course, with an approximately 80% 10-year survival rate. Fifty percent of medullary thyroid carcinomas, which may be familial, have hematogenous metastases at diagnosis.15 Follicular carcinoma may also have a high incidence of metastases, whereas papillary carcinomas often have multicentric origin. Patients with medullary carcinoma of the thyroid have a guarded prognosis, unless they have very small tumors ("microcarcinoma," defined as less than 1.0 cm in diameter), which carry a good prognosis.16

Surgery is the treatment required for all thyroid neoplasms. Total thyroidectomy is recommended for medullary cancer, and the resected parathyroid glands generally are autotransplanted to other sites such as the forearm.17 A more conservative approach is recommended for papillary carcinoma, with lymph node dissection leading to near total thyroidectomy. Over the 4 to 6 weeks following surgery, patients may develop hypothyroidism. A radioactive iodine scan is performed to search for residual neoplasm in the functioning thyroid tissue. After the thyroid scan, radioactive iodine (I-131) treatment is given at a dose of 100 to 150 mCu, and the patient is kept in a safe area overnight or until the kidney clears virtually all of the radioactive component. In the postoperative period, hormone replacement therapy must be given to compensate for the lost thyroid hormone.18 I-131 is usually successful in suppressing thyroid function, after which the patient is treated with synthetic thyroid hormones for life. Periodic evaluations are required to determine whether there is metastatic disease involving the lungs. Lifelong follow-up is necessary.19 Thyroglobulin levels, T4, and TSH levels should be evaluated periodically to determine whether replacement hormone is appropriately dosed. Patients with thyroid cancer generally have an excellent survival with relatively few side effects.19 Recurrence is common, however, and is seen more often in children younger than 10 years old.20 Even patients with tumor that has spread to the lungs may expect to have no decrease in life span after appropriate treatment.

Oral Cancers

Cancer of the mouth in children or in adolescents is extremely rare.3 This cancer primarily occurs in adults older than 50 years who have used tobacco for many years; however, it can occur in survivors of other childhood tumors who have had radiation therapy to this area. Evidence suggests that oral cancer at younger ages primarily results from the use of smokeless tobacco products among preadolescent boys.17 Changes in the texture, color, and shape of the mucosal lining of the mouth have been seen, together with degenerative changes of the gingiva, in more than half of all teenagers who use smokeless tobacco.21 Precancerous lesions are common among children. Squamous cell carcinoma, the most frequent type of cancer in these sites, must be distinguished from benign tumors of the pharynx and neck, e.g., dermoid cysts, lipomas, myofibromas, cystic hygroma, and teratomas. Other tumors in this area may include ameloblastoma or adamantinoma, a rare tumor that may arise in the mandible or the maxilla, as well as in the long bones.22 The treatment of ameloblastoma is surgical resection, if possible. Ameloblastoma may be benign or malignant; pulmonary metastases may be discovered many years after treatment for this tumor.

Salivary Gland Cancers

Many salivary gland cancers arise in the parotid gland.23,24 About 15% of these tumors may arise in the submandibular glands or in the minor salivary glands under the tongue and jaw. These tumors are most frequently benign, but on very rare occasions, may be malignant. The malignant lesions include adenocarcinoma, undifferentiated carcinoma, acinic cell carcinomas, and mucoepidermoid carcinoma. These tumors may occur after radiation therapy is given for treatment of primary leukemia or solid tumors. Radical surgical removal is the treatment of choice, whenever possible, with additional use of radiation therapy and chemotherapy for high-grade tumors or tumors that have spread from their site of origin.25,26 Prognosis for patients with these tumors is generally good.27

Laryngeal Carcinoma

Benign and especially malignant tumors of the larynx are rare. Malignant tumors may be associated with benign tumors such as polyps and papillomas.28,29 These tumors may cause hoarseness, difficulty swallowing, and enlargement of the lymph nodes of the neck. Rhabdomyosarcoma is the most common malignant tumor of the larynx in the pediatric age group. Squamous cell carcinoma of the larynx should be managed in the same manner as in adults with carcinoma at this site, with surgery and radiation. Laser surgery may be the first type of treatment utilized for these lesions.

Papillomatosis of the larynx is a benign overgrowth of tissues lining the larynx, associated with the human papillomavirus.30 This condition is not cancerous and may be treated with interferon.31 These tumors can cause hoarseness because of their association with wart-like nodules on the vocal cords and may extend into the lung, producing significant morbidity. Malignant degeneration may occur, with development of cancer in the larynx.

THORACIC CANCERS

Thoracic cancers include breast cancer, bronchial adenomas, bronchial carcinoid tumors, pleuropulmonary blastoma, esophageal tumors, thymomas, tumors of the heart and mesothelioma. The prognosis, diagnosis, classification, and treatment of these thoracic cancers are discussed below.

Breast Cancer

Most tumors that involve the breast during childhood are benign, yet carcinomas have been reported in both males and females younger than 21 years.32-35 There is an increased lifetime risk of breast cancer in female survivors of Hodgkin's disease who were treated with radiation to the chest area.35 Carcinomas are more frequent than sarcomas. Mammograms should start at age 25 for any patient who has had radiation therapy to the chest. Treatment options include radiation, chemotherapy, and surgery for children and adolescents with breast cancer. Breast tumors may also occur as metastatic deposits from leukemia, rhabdomyosarcoma, or other sarcomas.

Bronchial Adenomas/Carcinoids

Bronchial adenomas, which are slow-growing neoplasms, are also called carcinoid tumors.36-38 Primary treatment of these tumors is surgical resection. For bronchial carcinoid tumors, nuclear scans may demonstrate uptake of radioactivity by the tumor or lymph nodes, suggesting metastatic spread. Neither chemotherapy nor radiation therapy is indicated for bronchial carcinoid, unless evidence of metastasis is documented.

Pleuropulmonary Blastoma

Pleuropulmonary blastoma is a rare and highly aggressive pulmonary malignancy in children. The tumor usually is located in lung periphery, but it may be extrapulmonary with involvement of the mediastinum, diaphragm, and/or pleura.39 The tumors may recur or metastasize, in spite of primary resection.40 Responses to chemotherapy have been reported with agents similar to those used for the treatment of rhabdomyosarcoma.41 Chemotherapeutic agents may include vincristine, cyclophosphamide, dactinomycin, and doxorubicin. Radiation, either external beam or p32, may be used when the tumor cannot be surgically removed. A family history of cancer in close relatives has been noted for many young patients affected by this tumor.42

Esophageal Tumors

Esophageal cancer is rare in the pediatric age group, although it is relatively common in older adults.43 Symptoms are related to difficulty in swallowing and associated weight loss. Most of these tumors are squamous cell carcinomas, although sarcomas can also arise in the esophagus. The most common benign tumor is leiomyoma. Diagnosis is made by histologic examination of biopsy tissue.

Treatment options for esophageal carcinoma include either external beam, intracavitary radiation therapy, or chemotherapy with the platinum derivatives, paclitaxel, and etoposide, agents commonly used to treat carcinomas. Prognosis generally is poor for this cancer, which rarely can be completely resected.

Thymomas

A cancer of the thymus is not considered a thymoma unless there are neoplastic changes of the epithelial cells that cover the organ.44 Other tumors that involve the thymus gland include lymphoma, germ cell tumors, carcinomas, carcinoid, and thymoma. Hodgkin's disease and non-Hodgkin's lymphoma may also involve the thymus and must be differentiated from true thymomas.

Thymomas are rare in adults and children.45 Various diseases and syndromes are associated with thymoma, including myasthenia gravis, polymyositis, systemic lupus erythematosus, rheumatoid arthritis, thyroiditis, and pure red cell aplasia.46 Endocrine (hormonal) disorders including hyperthyroidism, Addison's disease, and panhypopituitarism can also be associated with a diagnosis of thymoma.47

Thymomas are usually located in the front part of the chest, and are usually discovered during a routine chest x-ray. Symptoms can include cough, difficulty with swallowing, tightness of the chest, chest pain, and shortness of breath although nonspecific symptoms may occur. These tumors generally are slow-growing, but are potentially invasive, with metastases to distant organs or lymph nodes. Staging is related to invasiveness. Surgery is performed with the goal of a complete resection.

Radiation therapy is necessary for patients with invasive thymoma, whether or not there has been a complete resection.47 Chemotherapy is usually reserved for patients with advanced stage disease who have not responded to radiation therapy or corticosteroids. Agents that have been effective include doxorubicin, cisplatin and paclitaxel.47-49 The prognosis for patients with invasive thymoma usually is poor, although significantly higher rates of survival have been reported for patients with tumors that are not locally invasive. Thymic carcinoma, which microscopically resembles undifferentiated nasopharyngeal carcinoma, is associated with Epstein-Barr virus infection, as is nasopharyngeal carcinoma. This tumor is responsive to chemotherapy and is potentially curable.

Tumors of the Heart

The most common tumors of the heart are benign and include myxomas and neurofibromas, i.e., tumors of the nerves that innervate the muscles.50 Other tumors of the heart can include metastatic spread of rhabdomyosarcoma, melanoma, leukemia, and carcinoma of other sites. Primary tumors of the heart may include benign and malignant teratoma, rhabdomyosarcoma, hemangioma, and chondrosarcoma. Symptoms include abnormalities of heart rhythm, enlargement of the heart, fluid in the pericardial sac, and congestive heart failure. Successful treatment requires surgery, which may include transplantation, and chemotherapy appropriate for the type of cancer that is present.51

Mesothelioma

This tumor can involve the membranous coverings of the lung, the heart, or the abdominal organs.52 These tumors can spread over the surface of organs, without invading far into the underlying tissue, and may spread to regional or distant lymph nodes. Mesothelioma may develop after successful treatment of an earlier cancer, especially after treatment with radiation.53,54 In adults, these tumors have been associated with exposure to asbestos, which was used as building insulation.55 The amount of exposure required to develop cancer is unknown, and there is no information about the risk for children exposed to asbestos.

Benign and malignant mesotheliomas cannot be differentiated using histologic criteria. A poor prognosis is associated with lesions that are diffuse and invasive or for those that recur. In general, the course of the disease is slow, and long-term survival is common. Treatment with various chemotherapeutic agents used for carcinomas or sarcomas may result in partial responses. Pain is an infrequent symptom; however, radiation therapy may be used for palliation of pain.

Papillary serous carcinoma of the peritoneum is sometimes mistaken for mesothelioma.56 This tumor generally involves all surfaces lining the abdominal organs, including the surfaces of the ovary. Treatment includes surgical resection whenever possible and use of chemotherapy with agents such as cisplatin, carboplatin, and paclitaxel.

ABDOMINAL CANCERS

Abdominal cancers include adrenocortical tumors, renal cell carcinoma, carcinoma of the stomach, cancer of the pancreas, colorectal carcinoma, carcinoid tumors, and multiple endocrine neoplasia syndrome. The prognosis, diagnosis, classification, and treatment of these abdominal cancers are discussed below.

Carcinoma of the Adrenal Cortex

Adrenocortical tumors are classified as carcinomas and adenomas.57 Adrenocortical tumors may be hormonally active or inactive. Adenomas are generally benign, whereas adrenocortical carcinomas frequently secrete hormones and may cause the patient to develop masculine traits, irrespective of the patient's gender. Pediatric patients with adrenocortical carcinoma often have Li-Fraumeni syndrome, which is an inherited condition that predisposes family members to multiple cancers, including breast cancer, rhabdomyosarcoma, and osteosarcoma.58

These tumors spread locally to the lymph nodes and can also involve the kidneys, lungs, and bones. Surgical removal should be attempted but may not always be possible if the tumor has spread widely. Additional treatment may include the use of an artificial hormone that blocks the masculinizing effects of the tumor 59 or chemotherapy using cisplatin, 5-fluorouracil, and etoposide.60 The prognosis for patients who have small, completely resected tumors generally is excellent, but prognosis can be poor for patients who have large primary tumors or metastatic disease at diagnosis.61

Renal Cell Carcinoma

Renal cell carcinoma is the most common primary malignancy of the kidney in adults; however, it occurs rarely in children.62,63 The annual incidence rate is approximately 4 per 1 million children, compared to an incidence of Wilms' tumor of the kidney that is at least 29-fold higher. Renal cell carcinoma may be associated with von Hippel-Lindau disease, a hereditary condition in which blood vessels within the retina and cerebellum grow excessively.64 The gene for von Hippel-Lindau is on chromosome 3p14 and is a tumor-suppressor gene whose function is lost in patients with the syndrome. Renal cell carcinoma has also been associated with tuberous sclerosis, a hereditary disease characterized by benign fatty cysts in the kidney.65-67 Familial renal cell carcinoma has been associated with an inherited chromosome translocation involving chromosome 3.66 A high incidence of chromosome 3 abnormalities has also been demonstrated in nonfamilial renal tumors.

Renal cell carcinoma usually presents as an abdominal mass, and there may be discomfort, pain, and/or blood in the urine.65 The tumor can metastasize to the lungs, bones, liver, and lymph nodes and often has spread before the diagnosis is made. This tumor should be considered whenever a patient presents with a kidney mass and is older than 5 years of age.

The primary treatment includes total surgical removal of the kidney and associated lymph nodes. Consideration should also be given to treatment with irradiation, chemotherapy, or both. Treatment of metastatic disease is presently unsatisfactory but usually includes the use of immune system modulators such as interferon-alfa and interleukin-2.68 Rare spontaneous regression of pulmonary metastasis may occur with resection of the primary tumor.

Carcinoma of the Stomach

The frequency and death rate from stomach cancer has declined worldwide over the past 50 years with the introduction of food preservation practices such as refrigeration.69 The tumor must be distinguished from other conditions such as non-Hodgkin's lymphoma, malignant carcinoid, leiomyosarcoma, and various benign conditions or tumors of the stomach. Symptoms include vague upper abdominal pain, which can be associated with poor appetite, and weight loss. Many individuals become anemic but otherwise show no symptoms before the development of metastatic spread. Other symptoms may include nausea, vomiting, change in bowel habits, poor appetite, weakness, and Helicobacter pylori infection.70 Fiberoptic endoscopy can be used to visualize the tumor or to take a biopsy sample to ensure the correctness of diagnosis. Confirmation can also involve an x-ray examination of the upper gastrointestinal tract.

Treatment should include surgical excision with wide margins. For individuals who cannot have a complete surgical resection, radiation therapy may be used along with chemotherapeutic agents such as 5-fluorouracil and irinotecan.71 Other agents that may be of value are the nitrosoureas, with or without cisplatin, etoposide, doxorubicin or mitomycin C.

Prognosis depends on the extent of the disease at the time of diagnosis and the success of treatment that is appropriate for the clinical situation.72 Because of the rarity of stomach cancer in the pediatric age group, little information regarding the treatment outcomes of children exists.

Cancer of the Pancreas

Pancreatic tumors are rare in children and adolescents.3 Tumors included in the general category can arise at any site within the pancreas. Cancers of the pancreas may be classified as adenocarcinoma, squamous cell carcinoma, acinic cell carcinoma, liposarcoma, lymphoma, papillary-cystic carcinoma, pancreaticoblastoma, malignant insulinoma, glucagonoma, and gastrinoma.73 Most pancreatic tumors do not secrete hormones, although some tumors secrete insulin, which can lead to symptoms of weakness, fatigue, hypoglycemia, and coma.73 If tumor interferes with the normal function of the islet cells, patients may have watery diarrhea or abnormalities of salt balance. Both carcinoma of the pancreas and pancreaticoblastoma can produce active hormones and can be associated with abdominal mass, wasting, and pain.74-76 At times, there is obstruction of the head of the pancreas, which is associated with jaundice and gastrointestinal bleeding.

The diagnosis is usually established by biopsy, using laparotomy or a minimally invasive surgery (laparoscopy). A diagnosis can only be achieved after ruling out various benign and cancerous lesions. Treatment includes various surgical procedures to remove the pancreas and duodenum or removal of part of the pancreas. For pediatric patients, the effectiveness of radiation therapy is not known. Chemotherapy may be useful for treatment of localized or metastatic pancreatic carcinoma, although few cases have been successfully treated. Agents that may be of value include 5-fluorouracil, streptozotocin, mitomycin C, doxorubicin, carboplatin, gemcitabine, and irinotecan. Response rates and survival rates generally are not good.75,76

Colorectal Carcinoma

Carcinoma of the large bowel is rare in the pediatric age group, as it is seen in only 1 person per 1 million younger than 20 years in the United States annually.77 These tumors can occur anywhere in the colon or rectum and are often associated with a family cancer syndrome.78 There is an increasing risk of colorectal carcinoma in members of families with a family history of intestinal polyposis, which can lead to the development of multiple adenomatous polyps.79 Juvenile polyps are not associated with an increased incidence or risk of cancer.

Familial polyposis is inherited as a dominant trait, which confers a high degree of risk. Early diagnosis and surgical removal of the colon eliminate the risk of developing carcinomas of the large bowel.80 Some colorectal carcinomas in young people, however, may be associated with a mutation of the adenomatous polyposis coli (APC) gene, which also is associated with an increased risk of brain tumors and hepatoblastoma.81 The familial APC syndrome is caused by mutation of a gene on chromosome 5q, which normally suppresses proliferation of cells lining the intestine and later development of polyps.82 Another tumor suppressor gene on chromosome 18 is associated with progression of polyps to malignant form. Multiple colon carcinomas have also been associated with progression of polyps to a malignant form. Multiple colon carcinomas have been associated with neurofibromatosis type I (NF-1) and several other rarer syndromes.83

The histologic types of colorectal cancer include adenocarcinoma, mucinous or colloid adenocarcinomas, signet-ring adenocarcinoma, and scirrhous tumors. Most tumors in the pediatric age group are mucin-producing carcinomas,84 whereas only about 15% of adult lesions are of this histology. The tumors of younger patients with this histologic variant may be less responsive to chemotherapy. These tumors arise from the surface of the bowel, usually at the site of an adenomatous polyp. The tumor may extend into the muscle layer surrounding the bowel, or the tumor may perforate the bowel entirely and seed through the spaces around the bowel, including intra-abdominal fat, lymph nodes, liver, ovaries, and the surface of other loops of bowel. A high incidence of metastasis involving the pelvis, ovaries, or both may be present in girls.85

Colorectal carcinoma usually presents with symptoms related to the site of the tumor. Changes in bowel habits are associated with tumors of the rectum or lower colon. Tumors of the right colon may cause more subtle symptoms, but are often associated with an abdominal mass, weight loss, decreased appetite, and blood in the stool. Any tumor that causes complete obstruction of the large bowel can cause bowel perforation and spread of the tumor cells within the abdominal cavity.

Because of its rarity, colorectal carcinoma is rarely diagnosed in a pediatric patient; however, vague gastrointestinal symptoms should alert the physician to investigate this possibility. Diagnostic studies that may be of value include examination of the stool for blood, studies of liver and kidney function, measurement of carcinoembryonic antigen, and various medical imaging studies, including direct examination using colonoscopy to detect polyps in the large bowel. Other conventional radiographic studies include barium enema followed by CT of the chest and bone scans.84,85

Most patients present with evidence of metastatic disease, either as gross tumor or as microscopic deposits in lymph nodes, on the surface of the bowel, or on intra-abdominal organs. Complete surgical excision should be the primary aim of the surgeon, but in most instances this is impossible; removal of large portions of tumor provides little benefit for the individuals with extensive metastatic disease. Most patients with microscopic metastatic disease generally develop gross metastatic disease, and few individuals with metastatic disease at diagnosis become long-term survivors.

Current therapy includes the use of radiation for rectal and lower colon tumors, in conjunction with chemotherapy using 5-fluorouracil with leucovorin.86 Other agents that may be of value include irinotecan and oxaliplatin. No significant benefit has been determined for interferon-alfa given in conjunction with 5-fluorouracil/leucovorin.87

Carcinoid Tumors

These tumors, like bronchial adenomas, may be benign or malignant and can involve the lining of the lung or the large or small bowel.88,89 Most lung lesions are benign, however, some metastasize.90 It has become accepted practice to remove the entire right colon in patients with large carcinoid tumors of the appendix (greater than 2 cm in diameter) or with tumors that have spread to the nodes. Treatment of metastatic carcinoid tumors of the large bowel or stomach becomes more complicated and requires treatment similar to that given for colorectal carcinoma. The carcinoid syndrome of excessive excretion of somatostatin is characterized by flushing, labile blood pressure, and metastatic spread of the tumor to the liver.90 Symptoms may be lessened by giving somatostatin analogues, which are available in short- and long-acting forms.

GENITAL/URINARY TUMORS

Genital/urinary tumors include carcinoma of the bladder and ovarian cancer. The prognosis, diagnosis, classification, and treatment of these genital/urinary tumors are discussed below.

Carcinoma of the Bladder

Carcinoma of the bladder is extremely rare in children. The most common carcinoma to involve the bladder is transitional cell carcinoma, which generally presents with hematuria.91 The diagnosis and treatment of this tumor are the same for children, adolescents, and adults. Adolescents who develop this tumor are often prone to the development of other cancers, including other bladder cancers. Bladder cancer in adolescents may develop as a consequence of alkylating-agent chemotherapy given for other childhood tumors or leukemia.92,93 The association between cyclophosphamide and bladder cancer is the only established relationship between a specific anticancer drug and a solid tumor.92 One of the most important risk factors for bladder cancer in adults is cigarette smoking, which may be associated with up to 50% of these cancers in men and 33% in women.93

Ovarian Cancer

Most cancers that affect the ovaries are of germ cell origin, which are more common in children than adults, in whom adenocarcinomas are more frequently encountered. Ovarian carcinomas of nongerm-cell origin include tumors derived from malignant epithelial elements, including adenocarcinoma,94 cystadenocarcinoma, endometrioid tumors, clear cell tumors, and undifferentiated carcinomas. Treatment is stage related and may include radiation and chemotherapy with cisplatin, carboplatin, etoposide, topotecan, taxol, and other agents.

OTHER RARE CHILDHOOD CANCERS

Other rare childhood cancers include multiple endocrine neoplasia syndrome, skin cancer, clear cell sarcoma of tendon sheaths, and cancer of unknown primary site. The prognosis, diagnosis, classification, and treatment of these other rare childhood cancers are discussed below.

Multiple Endocrine Neoplasia Syndrome

These syndromes are familial disorders that are characterized by neoplastic changes in more than one endocrine organ.80 Changes may include hyperplasia, benign adenomas, and carcinomas. There are distinct genetic disorders with characteristic clinical presentations referred to as MEN-1, MEN-2a, and MEN-2b. An additional complex is referred to as the Carney complex, which is an association of multiple endocrine neoplasia associated with heart and skin tumors.95-97

The MEN-1 syndrome, also referred to as Werner's syndrome,98 may involve tumors of the pituitary gland, the parathyroid, adrenal, and gastric and pancreatic structures, which may secrete hormones such as insulin. The gene for this syndrome is located on chromosome 11q13. The MEN-2a syndrome (Sipple syndrome) is associated with medullary thyroid carcinoma, parathyroid hyperplasia, adenomas, and pheochromocytoma. The MEN-2b syndrome is associated with medullary thyroid carcinoma, parathyroid hyperplasia, adenomas, and pheochromocytoma, mucosal neuromas, and ganglioneuromas.99 Patients with the MEN-2b syndrome may have a slender body build, long and thin extremities, a high arch palate, and pectus excavatum or pes cavus. The face may be characterized by thick lips because of mucosal neuromas. Such patients can also be identified by performing a pentagastrin stimulation test or by genetic screening in families known to be affected. In this syndrome, medullary thyroid carcinoma may be particularly aggressive; therefore, the thyroid should be removed by age 5 or 6 years in affected individuals.100,101

The Carney complex includes the association of primary pigmented nodular adrenocortical disease with blue nevi of the skin and mucosa and a variety of additional endocrine or non-endocrine tumors. There may be myxomas of the skin or breast and tumors of peripheral nerve sheath origin.95-97 The outcome of patients with the MEN-1 syndrome is generally good provided adequate treatment can be obtained for parathyroid, pancreatic, and pituitary tumors. The outcome for patients with the MEN-2a syndrome is also generally good, yet the possibility exists for recurrence of medullary thyroid carcinoma and pheochromocytoma.100-102 For patients with the Carney complex, prognosis depends on the frequency of recurrences of cardiac and skin myxomas and other tumors.

Skin Cancer (Melanoma, Basal Cell and Squamous Cell Carcinoma)

Melanoma is thought to be the most common skin cancer in children, followed by basal cell and squamous cell carcinomas.103-107 The incidence of melanoma in children and adolescents represents approximately 1% of the new cases of melanoma that are diagnosed annually in this country. In all instances, melanoma in the pediatric population is similar to that of adults in relation to site of presentation, symptoms, description, spread, and prognosis.

The greatest cause of skin cancer of any type is exposure to the ultraviolet (UV) portion of sunlight.108-111 Other causes may be related to chemical carcinogenesis, radiation exposure, immunodeficiency, or immunosuppression. The person who is most likely to develop a melanoma is easily sunburned, has poor tanning ability, and generally has light hair, blue eyes, and pale skin. Worldwide, there is an increasing incidence of both melanoma and nonmelanoma skin cancers. Melanoma presents as a relatively flat, dark-colored lesion, which may enlarge, penetrate the skin, or metastasize.

Melanomas may be congenital.106 They are sometimes associated with large congenital black spots known as melanocytic nevi, which may cover the trunk and thigh. Melanomas can also develop in individuals with xeroderma pigmentosum, a rare recessive disorder characterized by extreme sensitivity to sunlight, keratosis, and various neurologic manifestations. Individuals with xeroderma pigmentosum may also develop other skin cancers, including squamous and basal cell carcinomas.107 Children with hereditary immunodeficiencies have an increased lifetime risk of developing melanoma.

Neurocutaneous melanosis is an unusual condition associated with large or multiple congenital nevi of the skin and melanin deposits within the central nervous system. These deposits may be detected by magnetic resonance imaging of the brain or spinal cord. Dysplastic nevi occur in about 5% of the U.S. population and are potential precursors of melanoma.107 Individuals with atypical moles, which include raised lesions (that may bleed) and various color hues (brown, tan, pink, black), are at an increased risk of having melanoma and of having children affected by these premalignant lesions.

Basal cell carcinomas generally appear as raised lumps or ulcerated lesions, usually in areas with previous sun exposure. These tumors may be multiple and exacerbated by radiation therapy as delivered for medulloblastoma.112,113 Squamous cell carcinomas are usually reddened lesions with varying degrees of scaling or crusting, and they have an appearance similar to eczema, infections, trauma, or psoriasis.114

Biopsy or excision is necessary to determine the diagnosis of any skin cancer. Diagnosis is necessary for decisions regarding additional treatment. Basal and squamous cell carcinomas are generally curable with surgery alone, but the treatment of melanoma requires greater consideration because of its potential for metastasis. Surgery for melanoma depends on the size, site, level of invasion, and metastatic extent or stage of the tumor.107 Wide excision with skin grafting may become necessary. It is currently recommended that surgical resection include a 2-cm-deep margin for melanoma lesions, with examination of the regional lymph nodes draining the site of the melanoma. This procedure may require the injection of a radioisotope, following its distribution, and then performing excision of the associated regional lymph nodes (sentinel node biopsy technique). This requires injection of a vital blue stain and radioisotope into the skin to characterize the pattern of lymph node drainage. Lymph node dissection is necessary if sentinel nodes are involved with the tumor; however, if there is no spread of the disease beyond the lymph nodes, adjuvant therapy with interferon alfa-2b alone may be recommended for a period of 1 year.107 For individuals with metastatic disease, a combination of cisplatin, vinblastine, imidazole carboxamide, interleukin-2, and interferon alfa-2b has been proposed.107 Prognosis for melanoma in children and adolescents is similar to that for adults with similar stage disease, with the prognosis depending on the tumor thickness and the extent of spread at the time of diagnosis.115,116 Survival decreases with greater depth of invasion and with metastases to lymph nodes.

Clear Cell Sarcoma of Tendon Sheaths

Malignant melanoma of soft parts has been described as "clear cell sarcoma of tendons and aponeuroses."117 Because of its association with tenosynovial structures and its derivation from neuroectoderm, malignant melanoma of soft parts shares a number of features with cutaneous melanoma, as has been shown by immunophenotyping and structural similarities. More than 95% of these tumors present in the extremities. Survival with this tumor has been correlated with tumor size and other microscopic features. Cytogenetic studies of these tumors have noted a specific chromosome abnormality. Treatment includes surgical removal, radiation therapy, and chemotherapy similar to that given for soft tissue sarcomas.

Cancer of Unknown Primary Site

These cancers present as a metastatic cancer for which a precise primary tumor site cannot be determined.118 As an example, lymph nodes at the base of the skull may enlarge in relationship to a tumor that may be on the face or the scalp but is not evident by physical examination or by radiographic imaging. Thus, modern imaging techniques may indicate the extent of the disease but not a primary site. Tumors such as adenocarcinoma, melanoma, and embryonal tumors such as rhabdomyosarcoma and neuroblastoma may have such a presentation.

For all patients who present with tumors from an unknown primary site, the treatment should be considered in relation to the pathology of the tumor and should be appropriate for the general type of cancer initiated, irrespective of the site or sites of involvement.118 Chemotherapy and radiation therapy treatments appropriate and relevant for the general category of carcinoma or sarcoma (depending upon the histologic findings, symptoms, and extent of tumor) should be initiated as early as possible.

References:

1. Sanders J, Glader B, Cairo M, et al.: Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99(1): 139-141, 1997.

2. Vasef MA, Ferlito A, Weiss LM: Nasopharyngeal carcinoma, with emphasis on its relationship to Epstein-Barr virus. Annals of Otology, Rhinology, and Laryngology 106(4): 348-356, 1997.

3. Young JL Jr, Miller RW: Incidence of malignant tumors in U.S. children. Journal of Pediatrics 86(2): 254-258, 1975.

4. Naegele RF, Champion J, Murphy S, et al.: Nasopharyngeal carcinoma in American children: Epstein-Barr virus-specific antibody titers and prognosis. International Journal of Cancer 29(2): 209-212, 1982.

5. Beahrs OH, Henson DE, Hutter RP, Myers MH, eds.: American Joint Committee on Cancer: Manual for Staging of Cancer. 5th ed., Philadelphia, Pa: JB Lippincott, 1997.

6. Martin WD, Shah KJ: Carcinoma of the nasopharynx in young patients. International Journal of Radiation Oncology, Biology, Physics 28(4): 991-999, 1994.

7. Al-Sarraf M, LeBlanc M, Giri PG, et al.: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. Journal of Clinical Oncology 16(4): 1310-1317, 1998.

8. Mertens R, Granzen B, Lassay L, et al.: Nasopharyngeal carcinoma in childhood and adolescence. Concept and preliminary results of the Cooperative GPOH study NPC-91. Cancer 80(5): 951-959, 1997.

9. Douglass EC, Fontanesi J, Ribeiro RC, et al.: Improved long-term disease-free survival in nasopharyngeal carcinoma (NPC) in childhood and adolescence: a multi-institution treatment protocol. Proceedings of the American Society of Clinical Oncology 15: A1470, 467, 1996.

10. Wolden SL, Steinherz PG, Kraus DH, et al.: Improved long-term survival with combined modality therapy for pediatric nasopharynx cancer. International Journal of Radiation Oncology, Biology, Physics 46(4): 859-864, 2000.

11. Geiger JD, Thompson NW: Thyroid tumors in children. Otolaryngologic Clinics of North America 29(4): 711-719, 1996.

12. Feinmesser R, Lubin E, Segal K, et al.: Carcinoma of the thyroid in children--a review. Journal of Pediatric Endocrinology and Metabolism 10(6): 561-568, 1997.

13. Flannery TK, Kirkland JL, Copeland KC, et al.: Papillary thyroid cancer: a pediatric perspective. Pediatrics 98(3 pt 1): 464-466, 1996.

14. Kaplan MM, Garnick MB, Gelber R, et al.: Risk factors for thyroid abnormalities after neck irradiation for childhood cancer. American Journal of Medicine 74(2): 272-280, 1983.

15. Hill CS, Ibanez ML, Samaan NA, et al.: Medullary (solid) carcinoma of the thyroid gland: an analysis of the M.D. Anderson Hospital experience with patients with the tumor, its special features, and its histogenesis. Medicine 52(2): 141-171, 1973.

16. Krueger JE, Maitra A, Albores-Saavedra J: Inherited medullary microcarcinoma of the thyroid: a study of 11 cases. American Journal of Surgical Pathology 24(6): 853-858, 2000.

17. Vassilopoulou-Sellin R: Childhood thyroid cancer outcome and mortality. Oncology Case Reports & Review 13(1): 1-7, 1998.

18. Yeh SD, La Quaglia MP: 131I therapy for pediatric thyroid cancer. Seminars in Pediatric Surgery 6(3): 128-133, 1997.

19. Vassilopoulou-Sellin R, Goepfert H, Raney B, et al.: Differentiated thyroid cancer in children and adolescents: clinical outcome and mortality after long-term follow-up. Head and Neck 20(6): 549-555, 1998.

20. Alessandri AJ, Goddard KJ, Blair GK, et al.: Age is the major determinant of recurrence in pediatric differentiated thyroid carcinoma. Medical and Pediatric Oncology 35(1): 41-46, 2000.

21. Stellman SD, Resnicow K: Tobacco smoking, cancer and social class. In: Kogevinas M, Pearce N, eds.: Social Inequalities and Cancer. Lyon, France: International Agency for Research on Cancer, IARC No. 138, 1997, pp 229-250.

22. Kahn MA: Ameloblastoma in young persons: a clinicopathologic analysis and etiologic investigation. Oral Surgery, Oral Medicine, and Oral Pathology 67(6): 706-715, 1989.

23. Johns ME, Goldsmith MM: Incidence, diagnosis, and classification of salivary gland tumors. Oncology (Huntington NY) 3(2): 47-62, 1989.

24. Kaste SC, Hedlund G, Pratt CB: Malignant parotid tumors in patients previously treated for childhood cancer: clinical and imaging findings in eight cases. American Journal of Roentgenology 162(3): 655-659, 1994.

25. Kamal SA, Othman EO: Diagnosis and treatment of parotid tumours. Journal of Laryngology and Otology 111(4): 316-321, 1997.

26. Rogers DA, Rao BN, Bowman L, et al.: Primary malignancy of the salivary gland in children. Journal of Pediatric Surgery 29(1): 44-47, 1994.

27. Bentz BG, Hughes CA, Ludemann JP, et al.: Masses of the salivary gland region in children. Archives of Otolaryngology, Head and Neck Surgery 126(12): 1435-1439, 2000.

28. McGuirt WF Jr., Little JP: Laryngeal cancer in children and adolescents. Otolaryngologic Clinics of North America 30(2): 207-214, 1997.

29. Bauman NM, Smith RJ: Recurrent respiratory papillomatosis. Pediatric Clinics of North America 43(6): 1385-1401, 1996.

30. Kashima HK, Mounts P, Shah K: Recurrent respiratory papillomatosis. Obstetrics and Gynecology Clinics of North America 23(3): 699-706, 1996.

31. Avidano MA, Singleton GT: Adjuvant drug strategies in the treatment of recurrent respiratory papillomatosis. Otolaryngology - Head and Neck Surgery 112(2): 197-202, 1995.

32. Serour F, Gilad A, Kopolovic J, et al.: Secretory breast cancer in childhood and adolescence: report of a case and review of the literature. Medical and Pediatric Oncology 20(4): 341-344, 1992.

33. Drukker BH: Breast disease: a primer on diagnosis and management. International Journal of Fertility 42(5): 278-287, 1997.

34. Rogers DA, Lobe TE, Rao BN, et al.: Breast malignancy in children. Journal of Pediatric Surgery 29(1): 48-51, 1994.

35. Kaste SC, Hudson MM, Jones DJ, et al.: Breast masses in women treated for childhood cancer. Cancer 82(4): 784-792, 1998.

36. Vadasz P, Palffy G, Egervary M, et al.: Diagnosis and treatment of bronchial carcinoid tumors: clinical and pathological review of 120 operated patients. European Journal of Cardio-thoracic Surgery 7(1): 8-11, 1993.

37. Kulke MH, Mayer RJ: Carcinoid tumors. New England Journal of Medicine 340(11): 858-868, 1999.

38. Oliaro A, Filosso PL, Donati G, et al.: Atypical bronchial carcinoids. Review of 46 patients. Journal of Cardiovascular Surgery 41(1): 131-135, 2000.

39. Indolfi P, Casale F, Carli M, et al.: Pleuropulmonary blastoma. Management and prognosis of 11 cases. Cancer 89(6): 1396-1401, 2000.

40. Wright JR Jr: Pleuropulmonary blastoma: a case report documenting transition from type I (cystic) to type III (solid). Cancer 88(12): 2853-2858, 2000.

41. Schmaltz C, Sauter S, Opitz O, et al.: Pleuro-pulmonary blastoma: a case report and review of the literature. Medical and Pediatric Oncology 25(6): 479-484, 1995.

42. Priest JR, Watterson J, Strong L, et al.: Pleuropulmonary blastoma: a marker for familial disease. Journal of Pediatrics 128(2): 220-224, 1996.

43. Gangopadhyay AN, Mohanty PK, Gopal SC, et al.: Adenocarcinoma of the esophagus in an 8-year-old boy. Journal of Pediatric Surgery 32(8): 1259-1260, 1997.

44. Verley JM, Hollmann KH: Thymoma. A comparative study of clinical stages, histologic features, and survival in 200 cases. Cancer 55(5): 1074-1086, 1985.

45. Furman WL, Buckley PJ, Green AA, et al.: Thymoma and myasthenia gravis in a 4-year-old child. Case report and review of the literature. Cancer 56(11): 2703-2706, 1985.

46. Souadjian JV, Enriques P, Silverstein MN, et al.: The spectrum of diseases associated with thymoma. Coincidence or syndrome? Archives of Internal Medicine 134(2): 374-379, 1974.

47. Cowen D, Richaud P, Mornex F, et al.: Thymoma: results of a multicentric retrospective series of 149 non-metastatic irradiated patients and review of the literature. Radiotherapy and Oncology 34(1): 9-16, 1995.

48. Carlson RW, Dorfman RF, Sikic BI: Successful treatment of metastatic thymic carcinoma with cisplatin, vinblastine, bleomycin, and etoposide chemotherapy. Cancer 66(10): 2092-2094, 1990.

49. Niehues T, Harms D, Jurgens H, et al.: Treatment of pediatric malignant thymoma: long-term remission in a 14-year-old boy with EBV-associated thymic carcinoma by aggressive, combined modality treatment. Medical and Pediatric Oncology 26(6): 419-424, 1996.

50. Chan HS, Sonley MJ, Moes CA, et al.: Primary and secondary tumors of childhood involving the heart, pericardium, and great vessels. A report of 75 cases and review of the literature. Cancer 56(4): 825-836, 1985.

51. Michler RE, Goldstein DJ: Treatment of cardiac tumors by orthotopic cardiac transplantation. Seminars in Oncology 24(5): 534-539, 1997.

52. Kelsey A: Mesothelioma in childhood. Pediatric Hematology and Oncology 11(5): 461-462, 1994.

53. Hofmann J, Mintzer D, Warhol MJ: Malignant mesothelioma following radiation therapy. American Journal of Medicine 97(4): 379-382, 1994.

54. Pappo AS, Santana VM, Furman WL, et al.: Post-irradiation malignant mesothelioma. Cancer 79(1): 192-193, 1997.

55. Hyers TM, Ohar JM, Crim C: Clinical controversies in asbestos-induced lung diseases. Seminars in Diagnostic Pathology 9(2): 97-101, 1992.

56. Wall JE, Mandrell BN, Jenkins JJ III, et al.: Effectiveness of paclitaxel in treating papillary serous carcinoma of the peritoneum in an adolescent. American Journal of Obstetrics and Gynecology 172(3): 1049-1052, 1995.

57. Abramson SJ: Adrenal neoplasms in children. Radiologic Clinics of North America 35(6): 1415-1453, 1997.

58. Li FP, Fraumeni JF Jr., Mulvihill JJ, et al.: A cancer family syndrome in twenty-four kindreds. Cancer Research 48(18): 5358-5362, 1988.

59. Bugg MF, Ribeiro RC, Roberson PK, et al.: Correlation of pathologic features with clinical outcome in pediatric adrenocortical neoplasia. A study of a Brazilian population. American Journal of Clinical Pathology 101(5): 625-629, 1994.

60. Sandrini R, Ribeiro RC, DeLacerda L: Childhood Adrenocortical tumors. Journal of Clinical Endocrinology and Metabolism 82(7): 2027-2031, 1997.

61. Mayer SK, Oligny LL, Deal C, et al.: Childhood adrenocortical tumors: case series and reevaluation of prognosis--a 24-year experience. Journal of Pediatric Surgery 32(6): 911-915, 1997.

62. Fiori E, Leone G, Gazzanelli S, et al.: Renal cell carcinoma in adolescents. A case report and review of the literature. Panminerva Medica 38(2): 121-128, 1996.

63. Carcao MD, Taylor GP, Greenberg ML, et al.: Renal-cell carcinoma in children: a different disorder from its adult counterpart? Medical and Pediatric Oncology 31(3): 153-158, 1998.

64. Bleggi-Torres LF, De Noranha L, Fillus NJ, et al.: Von Hippel-Lindau's disease: report of three cases and review of the literature. Arquivos de Neuro-Psiquiatria 53(4): 782-788, 1995.

65. Raney RB Jr., Palmer N, Sutow WW, et al.: Renal cell carcinoma in children. Medical and Pediatric Oncology 11(2): 91-98, 1983.

66. Wang N, Perkins KL: Involvement of band 3p14 in t(3;8) hereditary renal carcinoma. Cancer Genetics and Cytogenetics 11(4): 479-481, 1984.

67. Eble JN: Angiomyolipoma of kidney. Seminars in Diagnostic Pathology 15(1): 21-40, 1998.

68. Fyfe G, Fisher RI, Rosenberg SA, et al.: Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. Journal of Clinical Oncology 13(3): 688-696, 1995.

69. American Cancer Society: Cancer Facts and Figures-2000. Atlanta, Ga: American Cancer Society, 2000.

70. Rowland M, Drumm B: Helicobacter pylori infection and peptic ulcer disease in children. Current Opinion in Pediatrics 7(5): 553-559, 1995.

71. Ajani JA: Current status of therapy for advanced gastric carcinoma. Oncology (Huntington NY) 12(8 suppl 6): 99-102, 1998.

72. Schwartz MG, Sgaglione NA: Gastric carcinoma in the young: overview of the literature. The Mount Sinai Journal of Medicine 51(6): 720-723, 1984.

73. Vossen S, Goretzki PE, Goebel U, et al.: Therapeutic management of rare malignant pancreatic tumors in children. World Journal of Surgery 22(8): 879-882, 1998.

74. Schwartz MZ: Unusual peptide-secreting tumors in adolescents and children. Seminars in Pediatric Surgery 6(3): 141-146, 1997.

75. Murakami T, Ueki K, Kawakami H, et al.: Pancreatoblastoma: case report and review of treatment in the literature. Medical and Pediatric Oncology 27(3): 193-197, 1996.

76. Imamura A, Nakagawa A, Okuno M, et al.: Pancreatoblastoma in an adolescent girl: case report and review of 26 Japanese cases. European Journal of Surgery 164(4): 309-312, 1998.

77. Correa P, Haenszel W: The epidemiology of large-bowel cancer. Advances in Cancer Research 26: 1-141, 1978.

78. Sherlock P, Lipkin M, Winawer SJ: Predisposing factors in carcinoma of the colon. Advances in Internal Medicine 20: 121-150, 1975.

79. Lynch HT, Fusaro RM, Lynch JF: Cancer genetics in the new era of molecular biology. Annals of the New York Academy of Sciences 833: 1-28, 1997.

80. Dean PA: Hereditary intestinal polyposis syndromes. Revista de Gastroenterolgia de Mexico 61(2): 100-111, 1996.

81. Turcot J, Despres JP, St Pierre F: Malignant tumors of the central nervous system associated with familial polyposis of the colon: Report of two cases. Diseases of the Colon and Rectum 2: 465-468, 1959.

82. Vogelstein B, Fearon ER, Hamilton SR, et al.: Genetic alterations during colorectal-tumor development. New England Journal of Medicine 319(9): 525-532, 1988.

83. Pratt CB, Jane JA: Multiple colorectal carcinomas, polyposis coli, and neurofibromatosis, followed by multiple glioblastoma multiforme. Journal of the National Cancer Institute 83(12): 880-881, 1991.

84. Pratt CB, Rao BN, Merchant TE, et al.: Treatment of colorectal carcinoma in adolescents and young adults with surgery, 5-fluorouracil/leucovorin/interferon-alfa 2a and radiation therapy. Medical and Pediatric Oncology 32(6): 459-460, 1999.

85. Kauffman, WM, Jenkins JJ III, Helton K, et al.: Imaging features of ovarian metastases from colonic adenocarcioma in adolescents. Pediatric Radiology 25(4): 286-288, 1995.

86. Madajewicz S, Petrelli N, Rustum YM, et al.: Phase I-II trial of high-dose calcium leucovorin and 5-fluorouracil in advanced colorectal cancer. Cancer Research 44(10): 4667-4669, 1984.

87. Wolmark N, Bryant J, Smith R, et al.: Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. Journal of the National Cancer Institute 90(23): 1810-1816, 1998.

88. Modlin IM, Sandor A: An analysis of 8305 cases of carcinoid tumors. Cancer 79(4): 813-829, 1997.

89. Deans GT, Spence RA: Neoplastic lesions of the appendix. British Journal of Surgery 82(3): 299-306, 1995.

90. Tormey WP, FitzGerald RJ: The clinical and laboratory correlates of an increased urinary 5-hydroxyindoleacetic acid. Postgraduate Medical Journal 71(839): 542-545, 1995.

91. Hoenig DM, McRae S, Chen SC, et al.: Transitional cell carcinoma of the bladder in the pediatric patient. Journal of Urology 156(1): 203-205, 1996.

92. Johansson SL, Cohen SM: Epidemiology and etiology of bladder cancer. Seminars in Surgical Oncology 13(5): 291-298, 1997.

93. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer: Overall evaluations of carcinogenicity: an updating of IARC monographs, volumes 1 to 42. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Supplement 7. Lyon, France: International Agency for Research on Cancer, 1987.

94. Lovvorn HN III, Tucci LA, Stafford PW: Ovarian masses in the pediatric patient. AORN Journal 67(3): 568-576, 1998.

95. Carney JA, Go VL, Sizemore GW, et al.: Alimentary-tract ganglioneuromatosis: A major component of the syndrome of multiple endocrine neoplasia, type 2b. New England Journal of Medicine 295(23): 1287-1291, 1976.

96. Carney JA, Go VL, Gordon H, et al.: Familial pheochromocytoma and islet cell tumor of the pancreas. American Journal of Medicine 68(4): 515-521, 1980.

97. Carney JA, Young WF: Primary pigmented nodular adrenocortical disease and its associated conditions. Endocrinologist 2: 6-21, 1992.

98. Werner P: Endocrine adenomatosis and peptic ulcer in a large kindred: Inherited multiple tumors and mosaic pleiotropism in man. American Journal of Medicine 35(2): 205-212, 1963.

99. Skinner MA, DeBenedetti MK, Moley JF, et al.: Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. Journal of Pediatric Surgery 31(1): 177-182, 1996.

100. Lallier M, St-Vil D, Giroux M, et al.: Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome. Journal of Pediatric Surgery 33(6): 846-848, 1998.

101. Dralle H, Gim O, Simon D, et al.: Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. World Journal of Surgery 22(7): 744-751, 1998.

102. Skinner MA, Wells SA Jr: Medullary carcinoma of the thyroid gland and the MEN 2 syndromes. Seminars in Pediatric Surgery 6(3): 134-140, 1997.

103. Sasson M, Mallory SB: Malignant primary skin tumors in children. Current Opinion in Pediatrics 8(4): 372-377, 1996.

104. Barnhill RL: Childhood melanoma. Seminars in Diagnostic Pathology 15(3): 189-194, 1998.

105. Ruiz-Maldonado R, Orozco-Covarrubias ML: Malignant melanoma in children. A review. Archives of Dermatology 133(3): 363-371, 1997.

106. Pratt CB, Palmer MK, Thatcher N, et al.: Malignant melanoma in children and adolescents. Cancer 47(2): 392-397, 1981.

107. Ceballos PI, Ruiz-Maldonado R, Mihm MC Jr: Melanoma in children. New England Journal of Medicine 332(10): 656-662, 1995.

108. Pappo AS, Kaste SC, Rao BN, et al.: Childhood melanoma. In: Balch CM, Houghton AN, Sober AJ, et al., eds.: Cutaneous Melanoma. 3rd ed., St. Louis, Mo: Quality Medical Publishing Inc., 1998, pp 175-186.

109. Heffernan AE, O'Sullivan A: Pediatric sun exposure. Nurse Practitioner 23(7): 67-68, 71-78, 83-86, 1998.

110. Berg P, Lindelof B: Differences in malignant melanoma between children and adolescents. A 35-year epidemiological study. Archives of Dermatology 133(3): 295-297, 1997.

111. Elwood JM, Jopson J: Melanoma and sun exposure: An overview of published studies. International Journal of Cancer 73(2): 198-203, 1997.

112. Garcia-Silva J, Velasco-Benito JA, Pena-Penabad C, et al.: Basal cell carcinoma in a girl after cobalt irradiation to the cranium for acute lymphoblastic leukemia: case report and literature review. Pediatric Dermatology 13(1): 54-57, 1996.

113. Gorlin RJ: Nevoid basal cell carcinoma syndrome. Dermatologic Clinics 13(1): 113-125, 1995.

114. Kimonis VE, Goldstein AM, Pastakia B, et al.: Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. American Journal of Medical Genetics 69: 299-308, 1997.

115. Gibbs P, Moore A, Robinson W, et al.: Pediatric melanoma: are recent advances in the management of adult melanoma relevant to the pediatric population. Journal of Pediatric Hematology/Oncology 22(5): 428-432, 2000.

116. Conti EM, Cercato MC, Gatta G, et al.: Childhood melanoma in Europe since 1978: a population-based survival study. European Journal of Cancer 37(6): 780-784, 2001.

117. Hicks MJ, Saldivar VA, Chintagmapala MM, et al.: Malignant melanoma of soft parts involving the head and neck region: review of literature and case report. Ultrastructural Pathology 19(5): 395-400, 1995.

118. Kuttesch JF Jr, Parham DM, Kaste SC, et al.: Embryonal malignancies of unknown primary origin in children. Cancer 75(1): 115-121, 1995.