Mesothelioma

Mesothelioma of the Tunica Vaginalis Complicated by Chyluria

2010-04-07T02:19:00.001-07:00

An 83-year-old man was admitted to our hospital with fatigue,
dyspnea, and a cough that had been producing brown sputum for 3
weeks. He had no fever and no signs of heart failure. Seventeen years
ago he stopped smoking. His medical history revealed hypertension
and pleural drainage for a right-sided pneumothorax in 1990 after
introduction of a central venous catheter before laparotomy for repair
of an aneurysm of the abdominal aorta. Six months before admission
the patient was examined by an urologist because of scrotal enlargement.
Ultrasonography showed a tumor of 3 1.5 cm with solid and
cystic compartments, suggestive of a malignancy of the right epididymis.
An inguinal orchiectomy was performed demonstrating a paratesticulair
tumor. Testis and funiculus were embedded in a solid
tumor, microscopically consisting of desmoplastic stroma with nests
of large epithelioid cells with poor intercellular cohesion, resulting in
pseudolumens. The tumor cells were immunohistochemically characterized
as mesothelial (cytokeratin 7, calretinin, and thrombomodulin
positive; cytokeratin 20 and CEA negative). He had no
history of exposure to asbestos. Staging included a computed tomography
(CT) scan of the abdomen, which was normal and a radiograph
of the chest that showed some pleural thickening on the right, at the
same location where once the pleural drain was introduced but no
pleural effusion. Although strictly a pleural mesothelioma could not
be excluded, the abnormality on the chest radiograph was considered
to be scar tissue. As there were no therapeutic consequences the patient
was observed in the outpatient clinic on a frequent basis. On
physical examination the patient appeared ill and dyspneic with a
respiratory rate of 20 breaths/min. His body temperature was 37.3 °C,
his pulse was 90 beats/min, and his blood pressure was 175/90mmHg.
There were no palpable lymph nodes. Auscultation of the lungs revealed
reduced breath sounds on the right lung, wheezing on both
lungs, and inspiratory crackles on the left side. The abdomen was soft
with no masses and no tenderness. The extremities showed moderate
edema.Theerythrocyte sedimentation rate was 109mm/h,the hematocrit
40%, white cell count 16 109 and theCreactive protein was 102
mg/L. The bloodgas analysis showed pH 7.40, pC02 23 mmHg, PO2
44 mmHg, HCO3-14 mmol/L, base excess 9.0 mmol/L, and O2
saturation 84%. Chest radiography showed bilateral pleural effusion,
more prominent on the right side. There were widespread areas of
consolidation in the right apex and bilateral at the base of both lungs.
There was right-sided pleural thickening unchanged compared with
previous radiographic examinations of the chest. The trans-thoracic
echocardiogram was normal.Adiagnosis of double-sided pneumonia
was made. Cultures of blood and sputum were taken but had negative
results and intravenous treatment was started with antibiotics and
corticosteroids. Unfortunately the patient did not respond well: he
became progressively dyspneic and hypoxic and was transferred to the
intensive care unit for mechanical ventilation. On physical examination,
there were signs of venous-collateral flow on the left side of the
chest. Aspiration of the right pleural cavity showed a milky-white
fluid, which contained triglyceriden (12.7 mmol/L) and albumin
(28 g/L), typical for chylous, but no tumor cells or microorganisms.
Bronchoscopic examination was negative. Shortly after admission the
liver enzymes increased and the patient developed chyluria (Fig 1).The
CT scan of the chest showed double-sided pleural effusion with consolidations
and mediastinal lymphadenopathy. The CT scan of the
abdomen showed enlarged lymph nodes in the retroperitoneum and
some ascites while the hepatic portal vein was patent. Ultrasonographic
guided fine needle aspirates (Fig 2; 400) from retroperitoneal
lymph nodes and liver yielded cellular smears with clusters and
dissociated large histiocytoid-epithelioid cells, calretinin positive (inset),
CD68negative, and therefore consistent with spread of malignant
mesothelioma. The patient’s condition deteriorated and he subsequently
died. Autopsy was denied by the family.
Mesotheliomas are tumors that arise from the mesothelial lining
cells of the pleura, peritoneum, pericardium or tunica vaginalis.1 Approximately
85% arise in the pleura, approximately 9% in the peritoneum,
and less then 5% in the pericardium or the tunica vaginalis
testis.2 Exposure to asbestos or asbestos-containing material is a wellknown
risk factor for its development, irrespective of the location of
the mesothelioma.1,3 Approximately 50% to 70% of the mesotheliomas
are associated with known asbestos exposure.4 To the best of our
knowledge, we describe for the first time the development of chyluria
Fig 1.
Fig 2.
Diagnosis in Oncology
www.jco.org 5329
Copyright © 2006 by the American Society of Clinical Oncology. All rights reserved.
Downloaded from jco.ascopubs.org on January 6, 2010 . For personal use only. No other uses without permission.
as a result of lymph node metastases from a malignant mesothelioma
of the tunica vaginalis testis. Since its original description in 1957,
fewer than 80 cases of mesothelioma of the tunica vaginalis have been
reported.3 The major symptom is enlargement of the scrotum, which
may develop within several months.2,3 Ultrasound of the scrotum can
aid in the diagnosis, but time sampling is mandatory.2 There are three
histologic types: epithelial, sarcomatous, and mixed. The most frequent
occurring epithelial type has a predominant tubulopapillary
growth pattern. The histologic type combined with a positive cytokeratin
5, calretinin, immunohistochemic staining establish the definitive
diagnosis.2,3 Once the diagnosis is performed, staging should include
CTscans of the chest and abdomen.2 For localized testicular mesotheliomas,
first-line therapy should be radical orchiectomy. Although
primary treatment may not be curative, local recurrence is reduced
compared with hydrocele wall resection.2,3 In one review, 14.9% of
patients had disseminated disease, mostly with lymph node metastases.
2 Another review recommended inguinal lymphadenectomy
to reduce local and distant metastases.3 Active drugs for pleural
and peritoneal mesothelioma include cisplatin and permetrexed,
which might also be effective for treatment of tunica vaginalis
mesothelioma. Our patient developed mediastinal and abdominal
lymph node and liver metastases. The nodal spread caused obstruction
in lymph flow, leading to chylothorax and chyluria. Chyluria
results from chyle (lymph and triglyceride in an emulsion) in
the urine due to obstruction between intestinal lymphatics and
(or) thoracic duct leading to rupture of renal lymphatics into renal
tubules. The differential diagnosis includes filariasis, tuberculosis,
pyogenic infections, and malignant disease, especially Kaposi’s
sarcoma. In 1990, a case report described a 42-year-old woman
with chylous ascites, caused by lymph node metastases from a
pleural mestothelioma.5 We believe our patient developed lymph
node metastases from the malignant mesothelioma of the tunica
vaginalis.
Editor’s Note
Mesothelioma of the tunica vaginalis is rare enough, but chyluria
(white urine) is very unusual. Other abnormal colors of urine include
orange (bilirubin pigments), red (hematuria, heme pigment, or adriamycin
excretion), black (melanin from metastatic melanoma), brown
(rectovesicle fistula), blue or blue-green (methemoglobinuria or mitoxantrone
excretion), and probably rare other colors.
Marjan J. van Apeldoorn, Cees Rustemeijer, and
Bert J. Voerman
Department of Internal Medicine, Ziekenhuis Amstelland, Amstelveen,
the Netherlands
Johannes Peterse
Department of Pathology, Netherlands Cancer Institute Anthony van Leeuwen
Hospital, Amsterdam, the Netherlands
© 2006 by American Society of Clinical Oncology
REFERENCES
1. Hassan R, Alexander R: Nonpleural mesotheliomas: Mesothelioma of the
peritoneum, tunica vaginalis, and pericardium. Hematol Oncol Clin North Am
19:1067-1087, 2005
2. Plas E, Riedl C, Pfluger H: Malignant mesothelioma of the tunica vaginalis
testis. Cancer 83:2437-2446, 1998
3. Spiess P, Tuziak T, Kassouf W, et al: Malignant mesotheliomas of the tunica
vaginalis. Urology 66:397-401, 2005
4. Antman K, Hassan R, Eisner M, et al: Update on malignant mesothelioma.
Oncology 19:1301-1316, 2005
5. Scully R, Mark E, McNeely W, et al: Case records of the Massachusetts
General Hospital. N Engl J Med 323:659-667, 1990
DOI: 10.1200/JCO.2006.07.6596
■ ■ ■
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Pneumocystis Carinii Pneumonia During
Dose-Dense Chemotherapy for
Breast Cancer
A52-year-old premenopausalwomanwith aT2N1invasive ductal
carcinoma of the right breast presented with fever and neutropenia.
Two months before admission, she began chemotherapy with doxorubicin,
60 mg/m2, and cyclophosphamide, 600 mg/m2, given every 2
weeks, with pegfilgrastim support. She received antiemetics with each
cycle that included 3 days of dexamethasone at 4 milligrams given
twice daily. She received three cycles without difficulty, and before the
fourth cycle, experienced a fever to 101.3°F accompanied by a nonproductive
cough. She had no evidence of neutropenia, and her fevers
resolved spontaneously, so she was treated with her fourth cycle. Three
days after receiving her fourth cycle, she developed a fever, was evaluated
as an outpatient, found to have a normal neutrophil count, and
was discharged to home. A dry cough persisted, and 9 days after her
fourth cycle of chemotherapy, she presented to an outside hospital
with a fever and an absolute neutrophil count of 800/mm3. An initial
chest x-ray was normal, and she was admitted and started on empiric
ceftazidime, then cefipime, and then gatifloxacin and azithromycin,
due to persistant fevers. A follow-up chest x-ray revealed infiltrates
involving the left upper lobe, right upper lobe, and right lower lobe.
Eighteen days after her fourth cycle of chemotherapy, she was transferred
to our hospital for further evaluation. On admission, she was
started on broad spectrum antibiotics with ceftazidime, vancomycin,
and levoquin. A computed tomography scan of the chest revealed
extensive air space opacification with air bronchograms and septal
thickening (Fig 1). Nasal swabs were negative for adenovirus, influenza
A and B, and respiratory syncytial virus, urine was negative for
Legionella antigen, and serum was negative for parainfluenza antigen
and Mycoplasma. An HIV antibody was negative, and a CD4 count
was 485 mm3. She underwent bronchoscopy and bronchial alveolar
Fig

Mesothelioma among Workers in Asbestiform Fiber-bearing Talc Mines in New York State

2010-04-07T02:18:00.000-07:00

MINDY J. HULL¹, JERROLD L. ABRAHAM¹* and BRUCE W. CASE²

¹State University of New York, Upstate Medical University, Pathology, Syracuse, NY 13210, USA; ²School of Environment, McGill University, Montreal, Canada

Asbestos-related disease among talc miners and millers in a group of mines in two counties of northern New York State has been noted and disputed since the 1930s. One of the two counties was identified as among the 10 in the USA with the highest mesothelioma mortality up to 1981 for both men and women. Eight talc miners had been identified in previous studies as having mesothelioma. In the current study we: (i) report five new cases of mesothelioma among talc workers; (ii) present the results of and demonstrate the similarity between lung fiber burden analyses for selected cases and controls; and (iii) update mesothelioma mortality in this district using demographic and cause of death cancer information from 1950 to 1997. Our results indicate that New York talc exposure is associated with mesothelioma, and deserves further public health attention.

Keywords: mesothelioma; talc; pathology; epidemiology; mortality; scanning electron microscopy; asbestos

BACKGROUND

In 1878 talc mining introduced an economic boon to the rural agricultural counties of St Lawrence and Jefferson in northern New York State. The hub of this industry was Gouverneur, home of several talc mines, at least one of which is still operational. We believe that occupational exposure to dust from the talc mines and mills caused the mesothelioma excess in these counties. We support this by examining the similarity between the lung fiber burden of talc miners with and without mesothelioma, and determining the presence or absence of retained fibers indicative of commercial amphibole asbestos exposure. There are at least eight histologically confirmed cases of mesothelioma among New York State talc miners and millers reported as of 1986, and increased pleural mesothelioma mortality in Jefferson County. Here we report five new mesothelioma cases and epidemiological data to determine if this trend continues.

In the 1930s Merewether (1930) and others begin to describe asbestos exposure and its role in fibrotic lung disease. Pathology related to talc exposure also was being investigated, with a reported range of lung findings from nodular, silicosis-like to diffuse,

*Author to whom correspondence should be addressed. Department of Pathology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.

asbestos-like patterns (Porro et al., 1942). By 1943, Siegal and co-workers were studying New York State talc miners and millers (Siegal et al., 1943). They described the mined talc ‘of a fibrous variety…with it is found tremolite…a similar appearing mineral occurring in a fibrous or asbestiform state which… changes over to talc’. Midget impinger concentrations of particles ranged from 6 to 5000 million particles per cubic foot (mpcf) in mining and from 20 to 215 mpcf in milling. They found evidence of marked pulmonary fibrosis on chest roentgenograms in 32, all of whom had a >10 yr exposure history, out of a total of 221 talc workers. This established a clear relationship between lung fibrosis and duration of talc exposure. Fourteen of these workers also had pleural plaques, providing the first documentation of ‘talc plaques’. In 1967 Kleinfeld et al. documented 9/220 talc workers with lung cancer; this represented a >4-fold excess. In addition, the first pleural ‘fibrosarcoma’ and peritoneal mesothelioma in talc miners were described in this cohort. Vianna et al. (1981) conducted an incidence study of all histologically confirmed mesos in New York State between 1973 and 1978. They found that Jefferson County had a mesothelioma rate twice that of the rest of the state. A total of six cases of mesothelioma (four male, two female) occurred in talc miners. Enterline and Henderson (1987) also concluded a mesothelioma excess in Jefferson County after looking at national mesothelioma incidence by county from 1968 to 1981. They observed four cases in

132

Mesothelioma in asbestiform fiber-bearing talc mines Table 1. Diagnosis and immunohistochemical results (where applicable) of three mesothelioma cases

Description of pleural mesothelioma Immunohistochemistry

Case 1 Biphasic, diffuse Pan-cytokeratin (+++), calretinin (+++) Case 2 Sarcomatous Cytokeratin (+++), calretinin (–) Case 3 Epithelial, with rare biphasic areas CEA (–), alcian blue (+ cellular), mucicarmine (+ rare focal) Case 4 Diagnosis of mesothelioma made by New York State

Worker’s Compensation Board. No tissue available Case 5 Diagnosis of mesothelioma made by death certificate. No tissue available

(+++) strongly positive; (+) weakly positive; (–) negative. Table 2. Pertinent data from New York talc miners diagnosed with malignant mesothelioma

Case Birth Death Smoking Relevant occupation(s) in the talc industry^bFirst year on Job duration history^ajob (yr)

1 1931 1989 10 Mucker, driller, Hardinge operator 1952 22 2 1937 1990 0 Packed talc into trucks 1955 4 3 1912 1984 0 Mechanical engineer—helped construct two talc mines Unknown 2 4 1923 1981 Unknown Unspecified employment at a single talc company 1953 22 5 1925 1994 Unknown Roustabout, foreman, packhouse worker 1949 25

^aIn pack-yr (no. of packs per day × no. of yr smoking). ^bIncludes all known dusty jobs (talc or otherwise).

females (0.6 expected), and seven cases in males (1.4 expected). This gave Jefferson County the second and sixth highest mortality rates from mesothelioma for females and males, respectively, in the USA.

METHODS AND RESULTS

Subjects

The SUNY Upstate Medical University serves the catchment area of Jefferson and St Lawrence counties. From 1984 to 1987, 36 biopsy and/or autopsy samples were recovered from talc workers with lung disease. Hospitalization, employment and (when applicable) death information were collected. From the 36 miners, five mesothelioma cases were documented. For three of these, the diagnosis of mesothelioma was histologically and immunohistochemically confirmed using hematoxylin & eosin, alcian blue, mucicarmine, calretinin, carcinoembryonic antigen (CEA) and cytokeratin staining (see Table 1). Case 1 is described in detail as a representative clinical course of mesothelioma. Table 2 contains demographic data for the five mesothelioma cases.

Observed and expected pleural mesothelioma mortality in mining counties

Calculations of mortality were performed at the University of Pittsburgh using the same protocol as that described by Enterline and Henderson (1987). Observed and expected values were updated to include the most recent years available (overall, from 1968 to 1997). Figure 1a,b presents the mesothelioma mortality for males and females, respectively.

Lung-retained particulate and fiber analysis

Lung parenchyma from two mesothelioma cases and eight non-mesothelioma cases was available for analysis. The non-fibrous inorganic particulate lung

M. J. Hull, J. L. Abraham and B. W. Case

burden was measured using morphometric in situ analysis of tissue sections (Abraham and Burnett, 1983). For fiber analysis, lung tissue was digested with sodium hypochlorite and the residue collected on polycarbonate filters for analysis of asbestos bodies by light microscopy or fibers by scanning electron microscopy/energy dispersive X-ray spectroscopy (Abraham et al., 1991). The analytical results are displayed in Table 3. For fibers >1 µm, length, width and chemistry were recorded. Log normalized lengths and widths of the fibers found in the mesothelioma cases and the non-mesothelioma cases were compared using Student’s t-test (Analyze-It Software, Ltd). Significance was defined as P < 0.05. Finding no difference between dimensions of each fiber type would support similar dust exposure between miners with and without mesothelioma.

Case 1 illustrates a representative medical history. This was a 43-yr-old, 5′8″, 190 lb, white, hypertensive male, with a 10 pack-yr smoking history who presented in 1974 with ‘hardness of breathing’ for 4–5 yr. He reported nocturnal wheezing, persistent anterior chest pressure, chronic cough (1 oz daily sputum), occasional hemoptysis, and difficulty walking ~200 m. He had a 22 yr talc dust exposure history, working at times as a mucker, driller and Hardinge™ operator at two New York talc mines. He had optional access to a respirator that proved too cumbersome to work with. Both his father (now deceased) and brother had been diagnosed with talc pneumoconiosis. His physical examination showed a symmetrical chest wall with an increased anteroposterior dimension and diminished inspiratory expansion. Auscultation revealed harsh inspiratory and expiratory bilateral diffuse rhonchi and fine scattered expiratory wheezing. A chest X-ray showed bilateral prominence of mediastinal/cardiac shadows and increased reticular pulmonary markings, particularly over the lower lung zones. He had markedly restricted ventilatory function on spirometry, with FVC = 3.3 l (75% predicted), FEV₁= 2.5 l (74% predicted) and V = 60 l/min (39% predicted). Like

max

his brother and father, he was diagnosed with talc pneumoconiosis. His disease progressed, and in <2 yr he was placed on permanent total disability. He died at age 58, 15 yr after presentation. The post-mortem revealed a biphasic diffuse pleural mesothelioma encasing the left lung, which had not been suspected during life. It is noteworthy that ‘congestive heart failure’ was the only listed cause of death—there was no mention of mesothelioma on the death certificate.

DISCUSSION AND CONCLUSIONS

We have found a continued trend of increased mesothelioma mortality at 5–10 times the background rate in Jefferson County from 1982 to 1997, with five new male cases (two expected) and three new female cases (0.5 expected). We also show that increasing talc exposure duration is associated with an increase in lung burden of both fibrous and non-fibrous talc. Asbestos bodies were also seen in elevated concentration in most men with >10 yr exposure who had not been diagnosed with mesothelioma. The concentrations of each fiber type from mesothelioma and non-mesothelioma cases were similar, except for a high tremolite concentration in case 2. There was no significant difference found between non-mesothelioma and mesothelioma miners with regard to length and width of the tremolite and talc fibers (Tables 4 and 5), supporting our hypothesis that they were exposed to dust with similar

Table 3. Lung-retained particulate analyses of mesothelioma and non-mesothelioma cases

Mesotheliomas Non-mesotheliomas

1		2	A	B	C	D	E	F	G	H
Age at death	58	52	49	58	60	63	66	71	71	76
Years of talc mining	22	4	21	21	18	30	23	25	2	10
Diagnosisa	ATM	ATM	ATSC	ATS	ATP	ATSP	ATPC	ATP	Nl	Pn
Asbestos bodiesb	350	93	200	10	980	890	417	4850	1	10
Asbestos fibersc
Anthophyllite	5	n/d	12	85	64	4	14	n/d	0.04	0.4
Tremolite/actinolite	2	1110	1	105	7	17	31	43	0.07	0.9
Chrysotile	5	21	7	188	10	21	9	19	0.18	2.6
Talc (fibrous)c	46	96	24	716	4 7	157	195	233	0.1	3.1
Talc (non-fibrous)d	37	146	511	60	n/a	139	n/a	51	1	1
Silicad	7	n/d	15	10	n/a	68	n/a	n/d	1	1

n/a, not available; n/d, not detected. ^aNl, normal; Pn, pneumonia; A, asbestosis; T, talcosis; S, silicosis; P, pleural plaques; M, mesothelioma; C, lung cancer. ^bThousands of bodies/gram dry lung. ^cMillions of fibers/gram dry lung. ^dMillions of non-fibrous particles/ml lung.

Mesothelioma in asbestiform fiber-bearing talc mines

Table 4. Dimensional analysis for lung fibers in two New York State talc miners with immunohistochemically diagnosed malignant mesothelioma

Fiber type	na	Width (µm)			Length (µm)			ARb
		Xc	Min	Max	X	Min	Max
Actinolite	1	0.20	–	–	4.6	–	–	23
Anthophyllite	6	0.15	0.06	0.30	10.6	3.9	30.2	90
Chrysotile	5	0.05	0.03	0.06	4.1	1.9	6.1	93
Tremolite	38	0.22	0.10	0.40	4.5	1.7	10.6	26
Talc	54	0.20	0.05	1.00	5.3	1.4	53.0	43

^aNumber of fibers measured. ^bMean aspect ratio = length × width^{^–¹}. ^cGeometric mean.

Table 5. Dimensional analysis for lung fibers in eight New York State talc miners with pulmonary disease other than mesothelioma

Fiber type	na	Width (µm)			Length (µm)			ARb
		X	Min	Max	X	Min	Max
Actinolite	7	0.18	0.12	0.25	3.4	2.5	5.4	20
Anthophyllite	85	0.24	0.05	1.60	7.7	1.6	146.0	56
Chrysotile	33	0.08	0.04	0.40	7.4	2.1	36.1	133
Tremolite	51	0.34	0.04	1.00	5.3	1.5	17.0	24
Talc	284	0.33	0.06	2.80	6.4	1.3	219.0	30

^aNumber of fibers measured. ^bMean aspect ratio = length × width^{^–¹}.

^cGeometric mean.

fiber dimensions. Finally, in all of the 10 cases analyzed, only a single commercial amphibole fiber was found.

New York talc miners are exposed to a mixture of platy talc, silica and fibrous minerals, resulting in a disease process much more complex than pure talcosis. The asbestiform fibers in the New York talc miners’ lungs are a mixture of talc, tremolite and related mineral series. Our results indicate that mesos continue to occur at high rates in counties where New York talc mining occurs. Furthermore, New York talc miners without evidence of commercial amphibole asbestos exposure develop mesos. Talc miners with mesos have lung fiber burdens similar to those without, indicating comparable exposures. Increased public health attention to the risks of exposure to New York talc is indicated.

Acknowledgements—M.J.H. was a Post Sophomore Fellow in Pathology during part of this work. Supported by Department of Pathology, SUNY Upstate Medical University.

REFERENCES

Abraham JL, Burnett BR. (1983) Quantitative analysis of inorganic particulate burden in situ in tissue sections. Scanning Electron Microsc (Part 2); 681–96.

Abraham JL, Burnett BR, Hunt A. (1991) Development and use of a pneumoconiosis database of pulmonary inorganic particulate burden in over 400 lungs. Scanning Microsc; 5: 95–104.

Enterline P, Henderson B. (1987) Geographic patterns for pleural mesothelioma deaths in the United States, 1968–81. J Natl Cancer Inst; 79: 31–7.

Kleinfeld M, Messite J, Kooyman O, Zaki MH. (1967) Mortality among talc miners and millers in New York State. Arch Environ Health; 14: 666–7.

Merewether ERA. (1930) Occurrence of pulmonary fibrosis and other pulmonary affections in asbestos workers. J Ind Hyg; 12: 198.

Porro FW, Patton JR, Hobbs AA. (1942) Pneumoconiosis in the talc industry. Am J Roentgen; 42: 507–24.

Siegal W, Smith AR, Greenburg L. (1943) The dust hazard in tremolite talc mining, including roentgenological findings in talc workers. Am J Roentgen; 49: 11–29.

Vianna NJ, Maslowsky J, Robert S, Spellman G, Patton B. (1981) Malignant mesothelioma; epidemiologic patterns in New York State. NY State J Med; 81: 735

MESOTHELIOMA INCIDENCE AND COMMUNITY ASBESTOS EXPOSURE

2010-04-07T02:14:00.000-07:00

AUGUST 1995
ABSTRACT

The purpose of this study was to evaluate the incidence of mesothelioma among persons
living in an area that had been the location of an asbestos manufacturing plant between 1912 and
1980. Two study designs were used: standardized incidence ratios and a case-control format.
Only vital record data were used in this project.
Cases were the 110 diagnosed mesotheliomas among residents in Somerset County
reported to the population-based New Jersey State Cancer Registry from 1979 through 1987.
Cases were removed from the analysis when their "usual employment" was reported as being at
the asbestos plant, as evidenced through union lists or occupational information from either the
Cancer Registry or mortality records.
Standardized Incidence Ratios (SIR) were computed for total Manville residents, and for
males and females separately. Average annual New Jersey mesothelioma rates, 1979-1986, were
used to generate the expected number of mesothelioma cases. The SIR for the total Manville
population was 14.9 (95% Confidence Interval [C.I.]: 9.1-23.1). Female Manville residents had a
mesothelioma SIR of 29.7 (95% C.I.: 11.9-61.3). Male Manville residents had a mesothelioma
SIR of 11.4 (95% C.I.: 6.1-19.5). Total and male Somerset County mesothelioma incidence were
slightly elevated compared to the State rates.
Controls for the case-control study design included the 1,016 selected cancers deemed
unrelated to asbestos exposure. The controls were also residents of Somerset County at time of
diagnosis and diagnosed during the same time period as the cases. Using logistic regression
analysis, explanatory variables included town of residence, age at diagnoses, and year of
diagnoses stratified by sex. For males, residence in Manville had an odds ratio of 6.4 (95% C.I.:
3.0-13.5) compared with residence in other county locations. For females, the odds ratio for
residence in Manville was 31.7 (95% C.I.: 8.7-116.1).
These record-based approaches demonstrate a strong relationship between past asbestos
exposure from living in Manville and eventual development of mesothelioma. The use of such
study designs may be helpful in evaluating hazards of known occupational carcinogens found in
community settings.

AGE-ADJUSTED SEER CANCER INCIDENCE RATESa, 1980-2003

2010-01-06T05:24:00.000-08:00

AGE-ADJUSTED SEER CANCER INCIDENCE RATESa, 1980-2003

AGE ADJUSTED SEER INCIDENCEa RATES BY YEAR, RACE AND SEX

Mesothelioma: Mesothelioma lawyer and asbestos attorney guide in these States:

2010-01-06T05:09:00.000-08:00

Mesothelioma: Mesothelioma lawyer and asbestos attorney guide in these States:

Mesothelioma lawyer and asbestos attorney guide in these States:

2010-01-06T03:01:00.000-08:00

Mesothelioma is one of the deadliest forms of cancer known today - an incurable disease that claims the lives of thousands of victims in the United States each year.
While medical science continues to develop miraculous technology that prolongs many of the lives ravaged by this insidious condition, a cure for mesothelioma is still out of reach and the prognosis is always fatal. Tragically, there is usually little time left after a mesothelioma diagnosis, and physicians are left with few options except to help alleviate physical suffering and ensure that a victim's final days are as comfortable and pain-free as possible.
Within this site you'll find facts and information about mesothelioma that includes:

• What is Mesothelioma? Facts on Pleural , Peritoneal , and Pericardial mesothelioma.

• What is Asbestos? Asbestos in the home and workplace.

• Mesothelioma Symptoms.

• Mesothelioma Treatment and Treatment Options.

• Lung Cancer - Facts on causes, growth, metastasis, and lung cancer cell types.

• Mesothelioma Diagnosis - methods and tests for mesothelioma.

• Asbestosis - Facts, indications and symptoms of this non-cancer condition.

Proving the link between one's illness and their asbestos exposure is a difficult and time-consuming responsibility. This is why the guidance of an experienced
Mesothelioma lawyer
is critical in helping victims and their families seek and receive financial compensation for their profound suffering. People can be exposed to asbestos in their home, workplace, many workers in older factories, ore mines, and shipyards were at risk of asbestos exposure.
Other types of workers exposed to asbestos includes:

• US Military and Navy personnel

• Engineers

• Construction workers such as pipefitters and steel workers

• Auto mechanics -working on brakes containing asbestos

• Insulation workers

• Asbestos textile workers

• Demolition workers

Mesothelioma Cancer:
Cancer can attack any system or organ in the body, and very often shows few external symptoms until it is too late. Another lethal aspect of cancer derives from the nature of cancerous cells to spread to healthy surrounding tissues by means of the circulatory or lymphatic systems. This combination of factors has made cancers like mesothelioma the single greatest threat to health around the globe.
Mesothelioma is a particularly destructive cancer, for decades pass between exposure to the asbestos and appearance of cancerous symptoms. Further complicating mesothelioma treatment is the malignant nature of the cancer, for once symptoms surface, current therapeutic treatments are usually no longer effective and post-diagnosis survival rates typically range from four months to a year.
Even though mesothelioma is a rather rare condition, there are a number of professions that exposed people to this deadly and incurable disease. Many people who worked in or around military installations, or in the automotive, construction, or chemical industries now exhibit the first signs of mesothelioma. Asbestos was used for decades as insulation or in building materials, which potentially exposed millions of workers to this deadly cancer. Most doctors and medical experts agree that there will be tens of thousands of new cases of mesothelioma in the years to come.
Facts about Asbestos and Mesothelioma:
There is only one known cause of mesothelioma: exposure to asbestos.
Asbestos is a naturally occurring mineral used for centuries in insulation, clothing, and fire-resistant materials. Ancients praised this versatile material, but also decried the lethal nature of the small fibers easily inhaled by anyone who used it. It was not until the 20th century that X-Rays, computed axial tomography (CAT) scans, and magnetic resonance imagery (MRI) revealed the extensive damage caused by these microscopic fibers. Even though advances are made every day in modern times, medical science is still only beginning to provide adequate treatment for mesothelioma.
Asbestos Exposure Facts.
Responsibility for deadly asbestos exposure is primarily due to the proliferation of asbestos related materials combined with the negligence of the injury to properly warn their employees and consumers about the dangers of their products. For years the asbestos industry concealed or minimized the potential dangers their products posed in the name of profits, fearing lawsuits and diminished demand would ruin their businesses. Ultimately, this deception and negligence virtually destroyed the industry and nearly bankrupted several prominent insurance companies responsible for protecting asbestos companies against potential lawsuits.
If you are suffering from mesothelioma, or have lost a loved one to the disease, you may have the right to receive reparations from the asbestos industry that failed to adequately warn consumers of the grave risks associated with their product. A knowledgeable and understanding mesothelioma lawyer will help you fight for justice and the financial compensation to offset those spiraling medical expenses and to provide financial security for your family's future. Don't hesitate though, because the law limits how much time you have to file your claim - contact a mesothelioma lawyer today.
Mesothelioma Lawyers Legal Guide
When you are faced with something as devastating as a Mesothelioma diagnosis, you have a right to seek answers about why you weren't forewarned of the dangers of asbestos, and you have the right to seek reparations for you and your family. If you are a grieving family member or executor of the will of a person who has died from asbestos-related disease or mesothelioma, you may be eligible to file a claim as well. Legal details are understandably the last thing that someone wants to confront after the initial shock of an asbestos-related illness. However, taking advantage of your legal rights can create the necessary funds to finance aggressive treatment, pay off huge medical bills incurred during diagnosis, and provide financial security for your family for years to come.
Mesothelioma Litigation Lawsuit
A good Mesothelioma attorney understands the unique complexities involved in this kind of litigation lawsuit, including asbestos product identification, specific asbestos-related medical issues, and specific time constraints that narrow the window of opportunity to file a claim. It's important to find the right Mesothelioma lawyer before your state's statutes of limitations expire, leaving you and your family grieving and empty-handed. There's no time to wait - contact our mesothelioma lawyers today for a free case review.

Mesothelioma lawyer and asbestos attorney guide in these States:

Alabama (AL), Alaska (AK), Arizona (AZ), Arkansas (AR), California (CA), Colorado (CO), Connecticut (CT), Delaware (DE), Florida (FL), Georgia (GA), Hawaii (HI), Idaho (ID), Illinois (IL), Indiana (IN), Iowa (IA), Kansas (KS), Kentucky (KY), Louisiana (LA), Maine (ME), Maryland (MD), Massachusetts (MA), Michigan (MI), Minnesota (MN), Mississippi (MS), Missouri (MO), Montana (MT), Nebraska (NE), Nevada (NV), New Hampshire (NH), New Jersey (NJ), New Mexico (NM), New York (NY), North Carolina (NC), North Dakota (ND), Ohio(OH), Oklahoma (OK), Oregon (OR), Pennsylvania (PA), Rhode Island (RI), South Carolina (SC), South Dakota (SD), Tennessee (TN), Texas (TX), Utah (UT), Vermont (VT), Virginia (VI), Washington (WA), Washington DC (DC), West Virginia (WV), Wisconsin (WI), Wyoming (WY).

Malignant Pleural Mesothelioma: A Comprehensive Review

2010-01-06T02:55:00.000-08:00

Roohi Ismail-Khan, MD, Lary A. Robinson, MD, Charles C Williams, Jr, MD, Christopher R. Garrett, MD, Gerold Bepler, MD, PhD, and George R. Simon, MD

Background: The incidence of malignant mesothelioma continues to increase, but the disease remains difficult to detect early and treat effectively. Methods: The authors review the pathogenesis, incidence, clinical presentation, diagnosis, pathology, and both standard and experimental treatments for mesothelioma. Results: When possible, surgery (video-assisted thoracoscopy, pleurectomy/decortication, or extrapleural pneumonectomy) is utilized. Effects on underlying structures limit application of radiation therapy, but some systemic agents are beginning to enhance survival. Conclusions: The disease is expected to increase in incidence till 2020, so awareness of this entity as a possible diagnosis should be heightened. In patients with advanced disease, several newer antitumor agents are already showing a capability of extending survival so it is not unreasonable to expect further progress in this area.

From the Division of Thoracic Oncology & Experimental Therapeutics at the H. Lee Moffitt Cancer Center & Research Institute,
Tampa, Florida.

Submitted April 20, 2006; accepted July 10, 2006.
Address correspondence to George R.Simon, MD,Thoracic Oncology
Program, H. Lee Moffitt Cancer Center & Research Institute, 12902

Magnolia Drive, MRC-4W, Tampa, FL 33612. E-mail: simongr@
moffitt. usf.edu
Dr Simon receives honoraria from Eli Lilly and Co and Genentech,

Inc. No significant relationship exists between the other authors
and the companies/organizations whose products or services may
be referenced in this article.

Abbreviations used in this paper: MPM = malignant pleural mesothelioma, CT = computed tomography, VATS = video-assisted thoracoscopy, P/D = pleurectomy/decortication, EPP = extrapleural pneumonectomy.

Introduction

Mesothelioma is an uncommon neoplasm arising from the mesothelial cells lining the pleura. Rarely, pleural mesothelioma is localized, benign, and readily resect-able for cure. A variant of localized pleural mesothelioma is a fibrous tumor of the pleura that probably arises from a different layer of cells in the pleura, and it also is usually completely resectable. For the purposes of this review, only the more common and aggressive diffuse malignant pleural mesothelioma (MPM) will be discussed. MPM is usually associated with history of chronic asbestos exposure. Despite its relatively rare incidence, there is a great interest in this disease as it has spawned many legal battles and consequently has led to the elimination of asbestos in all the industrial sectors, particularly in shipping and construction.

Incidence

In the United States, MPM occurs in approximately 2,500 persons per year, with nearly 200 individuals diagnosed in Florida annually, and 19% are women.¹Almost 72,000 cases are expected to occur in the United States in the next 20 years. In Western Europe, 5,000 patients die of the disease each year. Worldwide, the incidence is increasing and it is expected to peak in the year 2020.²Nevertheless, most physicians will encounter MPM only a few times in their careers. Historically, the untreated median survival has only been 6 months, which explains the palliative approach taken by the oncologists treating patients with MPM.

Malignant mesothelioma was first recognized in 1870,³but the link between asbestos and MPM was not discovered until 1960 in South Africa when the first convincing evidence of a link between malignant mesothelioma and both occupational and incidental asbestos exposure was reported.^2,4It was not until the second half of the 20th century that mesotheliomas and lung cancer were considered separate entities.²Due to the extraordinary fire-resistant properties of asbestos, this substance was widely used in the United States and Europe in an uncontrolled fashion, mostly in the shipbuilding and construction industries, between the 1940s and 1979 when the US government curtailed its use. During that time, an estimated 40% of the entire workforce, or about 27 million individuals, were exposed to asbestos. Although its industrial use was largely eliminated, asbestos is still present in countless buildings where it was commonly used as insulation and a fire retardant. Manmade and natural disasters that destroy these building could therefore still expose millions to asbestos. An estimated 10 million New Yorkers were possibly exposed to this carcinogen during the World Trade Center disaster on September 11, 2001, where dust laden with asbestos filled the air.

Pathogenesis

Of the two basic types of asbestos, the larger amphibole fibers are the most carcinogenic. Their greater biopersistence and higher iron content catalyze the production of reactive oxygen radicals. When inhaled, the fibers are too large to be phagocytized by pulmonary macrophages, and over the years they burrow back into the serosal surfaces of the pleura, pericardium, and peritoneum. Asbestos may lead to a variety of other conditions such as benign pleural plaques, diffuse pleural thickening, benign pleuritis with effusion, and asbestosis. However, it is unknown why MPM occurs in the relatively few individuals within the large total population exposed to asbestos. Only 2% to 10% of individuals with heavy, prolonged asbestos exposure develop MPM. Conversely, up to 80% of MPM patients have a history of asbestos exposure.⁴

Due to the lack of asbestos exposure in some patients with MPM as well as its failure to produce the neoplasm in all exposed individuals, investigators have been looking for other etiologies or cofactors for MPM. Genetic predisposition for MPM may play a strong role, such that even minimal or apparently inconsequential asbestos exposure may lead to tumor development. An intriguing and controversial putative cofactor linked to MPM development is exposure to the tumorigenic simian vacuolating virus 40 (SV40), one of over 40 viruses that infected Macacus monkey kidney cells that were used to prepare early batches of live polio vaccine. SV40 viral gene sequences have been demonstrated in a variety of malignancies including certain brain cancers, sarcomas of bone, non-Hodgkin’s lymphoma, and in over 50% of epithelial MPM.^5,6Of the estimated 62% of the 92 million US residents who received the potentially SV40-contaminated Salk polio vaccine for the 8 years it was used (1955–1963), at least one fifth may have received live, infectious SV40containing vaccine. Despite numerous and quite compelling studies of the possible role and malignant transformation capacity of SV40 virus in vitro and in animal studies of MPM,⁵epidemiologic studies of age-specific trends in the US incidence of MPM are not consistent with an etiologic effect of exposure to SV40-contaminated polio virus.⁷Although testing for SV40 was done rigorously, not all cohorts born after 1963 were SV40free. A major eastern European manufacturer used a procedure to deactivate SV40 that did not fully inactivate SV40 in oral poliovirus vaccine; these SV40-contaminated vaccines were produced from the early 1960s to about 1978 and were used throughout the world.⁸This remains a highly controversial aspect of MPM etiology and pathogenesis.

Clinical Presentation

The initial clinical presentation for most patients with MPM is progressive dyspnea and/or steady chest wall pain.⁴Dyspnea is usually the result of a large pleural effusion, and the nonpleuritic chest pain is generally caused by significant chest wall invasion. There also may be a dry cough, weight loss, fever, fatigue, or night sweats. The disease is more commonly found unilaterally (95%) located in the right chest (60%),and it occurs predominantly in men, usually presenting in the 6th through 8th decades. Eighty percent of patients will have a definite asbestos exposure history, often with a 20- to 50-year latency between asbestos exposure and development of the malignancy. The symptoms of MPM may be insidious and nonspecific such that the time from initial presentation until diagnosis is often 3 to 6 months. Common prior occupational exposures include pipefitters, plumbers, steamfitters, heavy construction or shipbuilding industry workers, and those working aboard ships, especially in the boiler room.

Diagnosis

The physical examination and chest radiographs will demonstrate a large pleural effusion in 80% to 95% of patients with MPM.⁵Conversely, 10% to 29% have little or no fluid. As the disease advances, there tends to be less pleural fluid present. Initially, the fluid is free flowing and layers out on decubitus chest radiographs, which may be similar in appearance to the effusion seen in heart failure, early empyema, and other benign causes. Later, as MPM progresses, the effusion becomes loculated. Localized chest pain and a palpable chest wall mass indicate chest wall invasion and nonresectability.

Computed chest tomography (CT) with contrast is a much more sensitive examination. CT scans will show the pleural effusion, the size of the lymph nodes in the hilum and mediastinum, and the presence of pleural masses, especially as the tumor tends to form a rind of tissue that encases the lung and often extending into the fissures and along the mediastinal pleura and diaphragm. Although chest wall invasion and trans-diaphragmatic spread of tumor may be visible or suspected on chest CT scans, magnetic resonance imaging (MRI) of the chest with contrast, which includes coronal and sagittal views, is more sensitive in illustrating this and is especially important when a potentially curative surgery is being considered for the patient. Fig 1 illustrates some of the findings typically seen on imaging studies in MPM. Positron emission tomography (PET) may offer some additional information in the staging of MPM since it reliably detects contralateral chest involvement and extrathoracic metastases such as supraclavicular nodal disease. In some cases, it may be difficult to differentiate the primary tumor from N2 mediastinal lymph node involvement because of their close anatomic proximity.

Pleural fluid cytology may yield a definitive diagnosis of MPM in 20% to 33% of patients. A blind core

Fig 1. — Typical radiographic appearance of pleural mesothelioma. (A) Chest CT showing (small arrow) borderline enlarged right paratracheal lymph node in right-sided mesothelioma (large arrow). (B) Axial T2-weighted MR image at the same level showing (arrow) enhancement (white) of this lymph node, which was found to contain metastatic mesothelioma on mediastinoscopy. (C) Coronal T2-weighted MR image of same patient showing enhancing right-sided pleural tumor with arrow showing the sharp line of the diaphragm indicating no definite tumor invasion. (D) Axial T2-weighted MR image at the level of the heart showing (arrow) typical thick pleural tumor and some fluid pockets in right-sided MPM. Images provided courtesy of OncoView: Current Opinions in Thoracic Oncology, a publication of the Moffitt Cancer Center’s Thoracic Oncology Program. February 2005;2(1). www.MoffittCancerCenter.org.

October 2006, Vol. 13, No. 4 Cancer Control 257

needle biopsy of the pleura modestly improves the yield. A CT-guided core needle biopsy of one of the pleural masses is more sensitive (87%) in making a diagnosis. Diagnostic accuracy of greater than 95% is possible using video-assisted thoracoscopy (VATS), which allows directed pleural biopsy and drainage of the effusion after breaking up loculations. Intrapleural talc, which yields the highest pleurodesis rate in MPM, can then be instilled to prevent reaccumulation of the effusion. One disadvantage of VATS in mesothelioma is the possible seeding of tumor along the surgical incisions and chest tube tracts, which ultimately results in tumor growth in the chest wall in up to 20% of patients.⁹

In addition to standard histology, special immunohistochemical stains of the biopsy tissue may be necessary to make a definitive diagnosis of MPM because of its histomorphologic similarities to adenocarcinoma. Mesothelioma is characterized by staining for calretinin in 88% and vimentin in 50% of patients. However, adenocarcinoma usually lacks these markers and instead stains positive for carcinoembryonic antigen (84%), CD15 (77%) and Ber-EP-4 (82%). A complete array of immunostains must be performed to make a reliable diagnosis. Electron microscopy, although more costly, may be needed in equivocal cases to make the distinction between the two neoplasms.

Adequate tumor tissue not only allows a definitive diagnosis but also helps to determine which of the histologic subtypes is present. Epithelial mesothelioma is the most common, is found in approximately 50% of cases, and has the best prognosis. The more aggressive sarcomatoid type is seen in 16%, and the mixed type is seen in 34%.

Recently, investigators in Australia have discovered a new serum marker called soluble mesothelin-related protein (SMRP) in 84% of patients with mesothelioma.¹⁰This protein, which is detected with a simple blood test, may offer not only a useful diagnostic test for MPM, but also a means of monitoring treatment responses. It could also be a method for screening at-risk individuals. SMRP is elevated in only 2% of patients with other pleural diseases. A commercial SMRP tumor marker assay test kit should be available soon.

In a recently published study, serum osteopontin levels were found to be significantly higher in patients with pleural mesothelioma than in patients with exposure to asbestos or those patients who have fibrosis alone.¹¹Immunohistochemical analysis revealed osteopontin staining of the tumor cells in 36 of 38 samples of pleural mesothelioma. This indicates that osteopontin levels may help us in the near future in early diagnoses of patients who have a known history of asbestos exposure.

Despite the ready availability of multiple diagnostic techniques with this neoplasm, a definitive diagnosis of MPM is often delayed due to a low clinical suspicion for this disease. Hence the clinician must have a high index of suspicion, especially in a patient with a history of asbestos exposure who has a pleural effusion or atypical noncardiac chest pain to ensure that a timely diagnosis is made.

Staging

As with all malignancies, proper staging is crucial in MPM for rational treatment planning. Over the years, many staging systems have been proposed. The most widely accepted is the TNM-type system of the International Mesothelioma Interest Group (IMIG).¹²The IMIG system is the most comprehensive classification, albeit somewhat more detailed. A brief explanation of the classification follows:

Stage I includes lymph node-negative patients with minimal tumor confined to the parietal pleura (stage Ia) or with minimal visceral pleural involvement (stage Ib).

Stage II includes lymph node-negative patients with confluent superficial tumor on all pleural surfaces or involvement of the diaphragmatic muscle or lung parenchyma. Stage I and II patients have potentially resect-able tumor.

Stage III is the most common presenting stage and includes patients with metastasis to hilar (N1) or ipsilateral mediastinal (N2) lymph nodes, or those with extension of tumor into the soft tissues of the chest wall, the endothoracic fascia, mediastinal fat or pericardium (T3 tumor).

Stage IV includes patients who have locally advanced tumor invading the spine or ribs, the chest wall extensively, transdiaphragmatic spread, or contralateral pleural spread. Patients with stage IV disease also may have contralateral or supraclavicular lymph node involvement (N3) or distant metastases.

Treatment

MPM does not have one widely accepted treatment modality since none reliably results in cure. Moreover, there is a striking lack of randomized, clinical trials comparing treatment regimens in this disease, due in part to the relatively low incidence of this neoplasm. Clinical series generally are either at best phase II trials of one treatment regimen or retrospective reviews of a small number of patients treated over a long period of time. Despite these shortcomings, significant improvements in therapy for MPM offer a ray of hope in this aggressive malignancy.

Surgery

Complete surgical resection is theoretically the most effective treatment. However, with the usual diffuse spread of MPM throughout the hemithorax, complete resection of this neoplasm with histologically negative margins is rarely achieved. Hence, the term cytoreduction was coined to describe the type of resection usually employed in MPM, which results in removal of the vast bulk of the tumor, but generally at least microscopic tumor is left behind.

Three surgical procedures may be used with MPM for palliation and/or treatment: (1) VATS talc pleurodesis,

(2) pleurectomy/decortication (P/D), or (3) extrapleural pneumonectomy (EPP). There are no randomized studies comparing these techniques, and results are generally found in retrospective series that often used different staging systems, further confounding comparisons.

Video-Assisted Thoracoscopy

VATS plays an important role in MPM by permitting directed biopsy to obtain diagnostic tissue. Then at the same procedure, the effusion is drained, loculations are lysed, and pleurodesis is accomplished usually with aerosolized talc. Although no cytoreduction of tumor is performed, this technique is effective in creating a pleurodesis that relieves the dyspnea caused by the commonly seen effusion in this disease. However, this procedure does not prevent the occasional patient from undergoing subsequent EPP. VATS pleurodesis by itself does not prolong survival, but it is preferred in patients with comorbidities or advanced-stage disease, who then may undergo systemic chemotherapy.

Pleurectomy/Decortication

One therapeutic surgical option that is intended to cytoreduce actual tumor burden is P/D. This procedure is performed through an open thoracotomy and consists of removing the parietal pleura including the portion over the mediastinum, pericardium, and diaphragm (often requiring removal of part of the diaphragm) and stripping off of the visceral pleura to decorticate the lung. Compared with EPP, this procedure poses some-

Table 1. — Patient Selection Criteria for EPP

ECOG performance status 0–1.

Stage I or II (rarely stage III) mesothelioma
(International Mesothelioma Interest Group staging system).
No prior coronary bypass surgery.
Cardiac ejection fraction >45%, and no significant cardiac

arrhythmias or dysfunction.
Adequate pulmonary function to tolerate a pneumonectomy.
No significant renal or liver disease or other comorbidities.
Minimal or no chest wall pain.
Epithelial subtype mesothelioma.
No prior pleurectomy (but VATS talc pleurodesis does not

disqualify the patient).

what less physiologic stress on the patient since it leaves the lung in place, and it has a slightly lower operative mortality rate of 1.5% to 5%.¹²Common disadvantages of P/D are the large postoperative air leak, empyema, hemorrhage, the frequent inability to remove all of the tumor from lung fissures, impairment or lack of diaphragmatic (or phrenic nerve) function, and the obvious limitation on any postoperative radiotherapy because the lung is still present. Macroscopic tumor is left in the chest at the end of the procedure almost 80% of the time.¹³By itself, P/D provides good palliation and prevents return of a symptomatic effusion, but there is usually a high locoregional recurrence (80% to 90%),¹⁴and generally it is not considered a potentially curative procedure.

Extrapleural Pneumonectomy

The most aggressive surgical procedure is EPP, which involves en bloc resection of the parietal and visceral pleura along with the involved lung, mediastinal lymph nodes, diaphragm, and pericardium. The diaphragm and pericardium are then reconstructed with Gortex or Marlex mesh. Although this procedure has a profound physiologic impact on the patient since the lung is removed, it may be performed in experienced centers with less than a 5% mortality.^12,15This is the most complete cytoreductive procedure and essentially the only procedure with which long-term survivorship is seen.

Selection of the appropriate subset of patients for EPP is crucial. Table 1 lists the patient selection criteria used at our institution for EPP. Aside from the obvious selection criteria listed, prior coronary bypass grafting usually precludes performing an EPP since at least one bypass graft on either side is usually located out in the pleural cavity encased by tumor, and the tumor cannot be separated from the graft. Patients with nonepithelial-type mesothelioma have an aggressive tumor that EPP does not control. Chest wall pain usually is found where there is unresectable tumor deeply invading the chest wall. Prior pleurectomy generally precludes the technical performance of EPP since any potential resection planes are obliterated and only an incomplete resection is possible. In the patient population seen at our institution, only approximately 10% to 15% of all MPM patients seen may qualify for EPP. In view of the documented lack of survival benefit of cytoreductive surgery in patients with metastases to often normal-sized mediastinal nodes in MPM,¹⁴we favor routine mediastinoscopy in all patients considered for EPP.

Radiotherapy

Unlike most tumors, MPM grows as a diffuse sheet of tumor throughout the pleural cavity, enveloping the lung. As a result, it is difficult to deliver to the entire neoplasm the radiotherapy needed to be tumoricidal (>60Gy) because of the limitations on dose to the underlying structures (lung 20 Gy, liver 30 Gy, spinal cord 45 Gy, heart 45 Gy, and esophagus 45–50 Gy). Radiation pneumonitis, myelitis, and hepatitis have been well described in early series attempting primary treatment with whole chest radiotherapy. Some recent reports have shown promise for the use of the more complex technique of intensity-modulated radiotherapy (IMRT) to treat the unresected tumor.¹⁶This conformal technique requires three-dimensional treatment planning that delivers a homogeneous dose to the tumor with good protection of organs at risk.

Currently, radiotherapy in MPM is used effectively to treat localized chest wall recurrences such as those

Fig 2. — Kaplan-Meier estimates of overall survival time for all patients (A) and for fully supplemented patients (B). From Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636-2644. Reprinted with permission from the American Society of Clinical Oncology.

Fig 3. — Kaplan-Meier estimates of time to progressive disease for all patients (A) and for fully supplemented patients (B). From Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636-2644. Reprinted with permission from the American Society of Clinical Oncology.

Pre-Chemo 3 Cycles Chemo

Fig 4. — Effect of chemotherapy (3 cycles of cisplatin/pemetrexed) on T2N2 epithelial pleural mesothelioma. Chest CT at level of cardiac ventricles. Images provided courtesy of OncoView: Current Opinions in Thoracic Oncology, a publication of the Moffitt Cancer Center’s Thoracic Oncology Program. February 2005;2(1). www.MoffittCancerCenter.org.

seen occasionally in a chest tube tract or surgical wound tumor implantation. Some groups employ hemithoracic adjuvant radiotherapy, after EPP, for treatment of the entire resected hemithorax or for treatment of known residual localized unresected tumor. Although adjuvant radiotherapy along with chemotherapy is used by some groups after radical EPP, there are no randomized studies that show that radiotherapy adds any value to just adjuvant chemotherapy alone in the setting of a fully resected tumor.

Chemotherapy

The role of chemotherapy in MPM is now established beyond any ambiguity. The recently reported phase III trial of cisplatin plus pemetrexed¹⁷demonstrated a statistically significant survival advantage (12.1 months) for the combination vs cisplatin alone (9.3 months) in all eligible patients. The study was initially started without vitamin supplementation. Vitamin supplementation was initiated after chemotherapy-related deaths occurred in the pemetrexed arm. Fig 2 shows the overall survival curves of all patients and for those patients in whom full vitamin supplementation was instituted. Fig 3 shows the Kaplan-Meier estimates of time to progressive disease for all patients and for fully supplemented patients.

Additionally, there was statistically significant improvement in response rate for the doublet (41% vs 17%; P<.0001), improvement in lung function by the sixth cycle (P = .006), improvement in dyspnea by the sixth cycle (P = .004), and improvement in pain by the fourth cycle (P = .017). Based on these data, cisplatin in combination with pemetrexed is the currently accepted first-line treatment for MPM.¹⁷Fig 4 depicts a chest CT of a patient treated with cisplatin and pemetrexed at our institution who continues to be progression-free 3 years after the initial diagnosis.

Other drugs have also shown activity in MPM. Table 2 outlines the single-agent efficacy of agents active in MPM, and Table 3 outlines studies using the most popular cisplatin combinations. Data from studies using some of the newer agents are presented in Table 4,showing that response rates with some of these targeted agents have been singularly disappointing.

Patients with MPM have some of the highest vascular endothelial growth factor (VEGF) levels compared to most solid tumors. Bevacizumab is a recombinant humanized monoclonal antibody to VEGF. Compounds targeting VEGF have demonstrated promise in MPM and therefore are being evaluated in several clinical trials.⁹

Currently, a multicenter, double-blind, placebo-controlled, randomized trial¹⁸is looking at bevacizumab in

Table 2. — Response Rate of Mesothelioma to
Available Chemotherapeutic Agents

Drug	Total No.	No. of	Response
	of Patients	Studies	Rate
Doxorubicin	69	2	12%
Liposomal doxorubicin	109	3	5%
Epirubicin	69	2	12%
Gemcitabine	60	3	12%
Cisplatin	73	3	18%
Carboplatin	88	3	11%
Vinorelbine	29	1	24%
Paclitaxel	60	2	5%
Ifosfamide	83	3	8%
Docetaxel	41	2	15%
Methotrexate	78	3	41%
Trimetrexate	52	1	12%
Edatrexate	20	1	25%
Edatrexate/leucovorin	40	1	16%
Pemetrexed	64	1	14%

Table 3. — Malignant Pleural Mesothelioma Treated With Combination Chemotherapy

Regimen	No. of	% Responders	Survival Range
	Studies	(Range)	(Mos)
Doxorubicin + cisplatin	5	14–46	8.8–2.3
Cisplatin + gemcitabine	4	9–48	10–10.3
			40%–53% (1-yr)

combination with gemcitabine and cisplatin. The safety analysis done so far does not show any significant increase in toxicities in the bevacizumab arm. Response and survival data are anxiously awaited. As pemetrexed and cisplatin demonstrated a survival advantage over cisplatin alone, we are currently conducting a phase II trial where bevacizumab is being added to cisplatin and pemetrexed.

There are no standard second-line treatment options for the treatment of advanced MPM. Typically, one of the agents listed in Table 1 is used as a second-line treatment. The most commonly used second-line treatments are gemcitabine, vinorelbine, doxorubicin, and irinotecan (CPT-11). Ranpirnase (Onconase), an antitumor ribonuclease, is a novel agent under active investigation in the second-line treatment of MPM. Used as a single agent at 480 μg/m²intravenously week-ly,ranpirnase demonstrated prolonged periods of stable disease in phase II trials and a potential survival benefit, compared with doxorubicin, in a small unpublished phase III trial.^19,20In all clinical studies, it has generally demonstrated a favorable safety profile except for easily controlled allergic reactions and dose modifications for renal impairment. At present, a phase III trial of doxorubicin with or without ranpirnase is nearing completion in patients with MPM without prior chemotherapy or one prior chemotherapy regimen. Results of this trial are anxiously awaited.

Multimodality Therapy

Due to the failure of any single modality of treatment to significantly affect long-term survival, a variety of combinations of therapy, usually involving cytoreductive surgery (P/D or EPP),have been used to treat MPM. Unfortunately, most reports are retrospective case series so results are difficult to compare objectively.

The most well-known and largest series comes from the Brigham and Women’s Hospital, involving EPP followed by chemoradiation.¹⁵In 137 patients treated in a 17-year period beginning in 1980,the mortality rate of EPP was 3.8% (morbidity 50%), with adjuvant chemotherapy using varying regimens given beginning 4 to 6 weeks after surgery, then followed by hemithoracic radiation (30 to 40 Gy). The median survival was 19 months, and 2-year and 5-year survival rates were 38% and 15%,respectively. In the subset with epithelial histology and negative nodes with complete resection, the 5-year survival rate was 46%. Locoregional recurrence was the predominant mode of failure in most patients despite intensive local treatment with surgery and radiotherapy.

Nevertheless, other series with EPP and systemic chemotherapy or EPP and adjuvant radiotherapy have shown median survivals similar to the Brigham series, also with better results occurring in the subset of node-negative epithelial tumors. With complete macroscopic tumor resection, there are no convincing data to suggest that employing two adjuvant modalities (with the increased toxicity) improves results more than using one.¹²

Phase I reports of other multimodality approaches include radical P/D with intraoperative radiotherapy and conformal radiotherapy and, in some patients, adjuvant chemotherapy. In a small, highly selected series of 32 patients, there was a 6.3% mortality rate and an 18month median survival; most treatment failures were locoregional.^21,22

Cytoreductive surgery with intraoperative photo-dynamic therapy (PDT) has been studied in several centers. The use of intraoperative intrapleural chemotherapy has been reported in several small series including hyperthermic (40–41^oC) perfusion,most with cisplatin. This modality appears feasible, albeit with significantly increased morbidity, but currently there is no documented survival benefit of this technique.^12,15,22

Table 4. — Recent Phase II Trials of New Agents in Mesothelioma

Chemotherapy/Group	No. Patients	Response Rate	Survival
	(Yr Published)	(%)	(mos)
Imatinib/Chicago	17 (2004)	0	12+ (all with prior chemotherapy)
Erlotinib/SWOG	64 (2004)	0	7.0
Gefitinib/CALGB	43 (2003)	2	5.0
Capecitabine/CALGB	26 (2004)	4	4.9
Thalidomide/Amsterdam	31 (2001)	0	N/A
Vatalanib(PTK 787)/CALGB	40 (ongoing)	N/A	N/A
262 Cancer Control			October 2006, Vol. 13, No. 4

Conclusions

Malignant mesothelioma continues to be a difficult disease to treat. Maintaining a high index of suspicion may result in an earlier diagnosis and a more successful treatment outcome. The overall outlook for the treatment of this disease has improved with the emergence of newer therapies. Several new agents are currently under active investigation and hold promise to further improve treatment outcomes. Results of currently ongoing clinical trials are anxiously awaited. In fact, survival for patients with MPM is now generally greater than for patients with advanced non-small cell lung cancer.

As with any rare disease, referral of the patient to a center with extensive experience and expertise in this disease is recommended to enhance the probability of accruing such patients to clinical trials.

References

Work-Related Lung Disease Surveillance Report 2002. NIOSH Publication No. 2003-111. National Institute for Occupational Safety and Health. Section 7. Malignant Mesothelioma. Available at http://www.cdc.gov/niosh/ docs/2003-111/2003-111.html. Accessed on September 7, 2006.
Robinson BW, Lake RA. Advances in malignant mesothelioma. N Engl J Med. 2005;353:1591-1603.
Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J Ind Med. 1960;17:260-271.
Cugell DW, Kamp DW. Asbestos and the pleura: a review. Chest. 2004;125:1103-1117.
Carbone M, Pass HI, Miele L, et al. New developments about the association of SV40 with human mesothelioma. Oncogene. 2003;22:51735180.
Barbanti-Brodano G, Sabbioni S, Martini F, et al. Simian virus 40 infection in humans and association with human diseases: results and hypotheses. Virology. 2004;318:1-9.
Strickler HD, Goedert JJ, Devesa SS, et al. Trends in U.S. pleural mesothelioma incidence rates following simian virus 40 contamination of early poliovirus vaccines. J Natl Cancer Inst. 2003;95:38-45.
Cutrone R, Lednicky J, Dunn G, et al. Some oral poliovirus vaccines were contaminated with infectious SV40 after 1961. Cancer Res. 2005;65: 10273-10279.
Zellos LS, Sugarbaker DJ. Multimodality treatment of diffuse malignant pleural mesothelioma. Semin Oncol. 2002;29:41-50.
Robinson BW, Creaney J, Lake R, et al. Mesothelin-family proteins and the diagnosis of mesothelioma. Lancet. 2003;362:1612-1616.
Pass HI, Lott D, Lonardo F, et al. Asbestos exposure, pleural mesothelioma, and serum osteopontin levels. N Engl J Med. 2005;353:1564-1573.
van Ruth S, Baas P, Zoetmulder FA. Surgical treatment of malignant pleural mesothelioma: a review. Chest. 2003;123:551-561.
Rusch VW. Pleurectomy/decortication in the setting of multimodality treatment for diffuse malignant pleural mesothelioma. Semin Thorac Cardiovasc Surg. 1997;9:367-372.
Stewart DJ, Martin-Ucar A, Pilling JE, et al. The effect of extent of local resection on patterns of disease progression in malignant mesothelioma. Ann Thorac Surg. 2004;78:245-252.
Zellos LS, Sugarbaker DJ. Multimodality treatment of diffuse malignant pleural mesothelioma. Semin Oncol. 2002;29:41-50.
Zierhut D, Gutwein S, Munter MW, et al. Radiation therapy of mesothelioma: the Heidelberg experience and future aspects. Lung Cancer. 2004; 45(suppl 1):S85-S91.
Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636-2644.
Kindler HL, Karrison T, Lu C, et al. A multicenter, double-blind, placebo-controlled randomized phase II trial of gemcitabine/cisplatin (GC) plus bevacizumab (B) or placebo in patients (pts) with malignant mesothelioma (MM). Proc Annu Meet Am Soc Clin Oncol. 2005;23:7019. Abstract.
Mikulski SM, Costanzi JJ, Vogelzang NJ, et al. Phase II trial of a single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma. J Clin Oncol. 2002;20:274-281.
Pavlakis N, Vogelzang NJ. Ranpirnase--an antitumour ribonuclease: its potential role in malignant mesothelioma. Expert Opin Biol Ther. 2006;6: 391-399.

Sugarbaker DJ, Flores RM, Jaklitsch MT, et al. Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg. 1999;117:54-65.
Lee TT, Everett DL, Shu HK, et al. Radical pleurectomy/decortication and intraoperative radiotherapy followed by conformal radiation with or without chemotherapy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2002;124:1183-1189.

Malignant Mesothelioma

2010-01-06T02:47:00.001-08:00

To the Editor: In their review article, Robinson and Lake (Oct. 13 issue)¹ write that membranous immunoreactivity of malignant cells in effusions with epithelial membrane antigen (EMA) is highly suggestive of malignant mesothelioma. If this were true, then the cytologic diagnosis of mesothelioma would be far less challenging than is the case in current practice. Not all malignant mesotheliomas are EMA-positive.² Moreover, reactive mesothelial cells may demonstrate membranous staining with EMA, albeit in only 3 to 4 percent of cases.³ Finally, some adenocarcinomas (14 percent) may also have a membranous EMA staining pattern.⁴ The experience of several experts in the field shows why EMA is not helpful in individual cases.⁵ Hence, we share the sentiments of the United States–Canadian Mesothelioma Reference Panel that no immunomarker allows for the separation of benign mesothelioma from malignant mesothelioma.²

Liron Pantanowitz, M.D. Christopher N. Otis, M.D.

Baystate Medical Center Springfield, MA 01199 lpantanowitz@hotmail.com

Robinson BWS, Lake RA. Advances in malignant mesothelioma. N Engl J Med 2005;353:1591-603.
Churg A, Colby TV, Cagle P, et al. The separation of benign and malignant mesothelial proliferations. Am J Surg Pathol 2000; 24:1183-200.
Dabbs DJ. Immunocytology. In: Dabbs J, ed. Diagnostic immunohistochemistry. New York: Churchill Livingstone, 2002:625-39.
King JA, Tucker JA. Evaluation of membranous staining of mesothelioma. Cell Vis 1998;5:24-7.
Moran CA, Wick MR, Suster S. The role of immunohistochemistry in the diagnosis of malignant mesothelioma. Semin Diagn Pathol 2000;17:178-83.

n engl j med 354;3 www.nejm.org january 19, 2006

The new england journal of medicine

To the Editor: We think that the role of chemotherapy, specifically pemetrexed, was insufficiently considered by Robinson and Lake. In our opinion, pemetrexed is the most important therapeutic advance for this devastating disease to date. In the largest randomized trial conducted among patients with malignant mesothelioma, patients treated with pemetrexed plus cisplatin had a survival benefit of 2.8 months, with a reduction in the relative risk of death of 23 percent, as compared with patients who received cisplatin alone.¹This gain was consistent across all subgroups analyzed² and appeared to be independent of second-line chemotherapy.³ Moreover, pemetrexedbased treatment was associated with a statistically significant improvement in lung function.²

On the basis of these findings, pemetrexed (in combination with cisplatin) is the first treatment for unresectable malignant mesothelioma that has received regulatory approval.² Given the probable rise in the worldwide incidence of this disease during the next few years, the impact of such chemotherapy will be very relevant.

Alberto Muñoz, M.D.
Ramón Barceló, Ph.D.
Guillermo López-Vivanco, Ph.D.

Hospital de Cruces 48903 Barakaldo, Spain amunoz@hcru.osakidetza.net

Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636-44.
Hazarika M, White RM Jr, Booth BP, et al. Pemetrexed in malignant pleural mesothelioma. Clin Cancer Res 2005;11:982

92.

3. Manegold C, Symanowsky J, Gatzemeier U, et al. Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma. Ann Oncol 2005;16:923-7.

To the Editor: Although Robinson and Lake acknowledge that the role of simian virus 40 (SV40) in the pathogenesis of mesothelioma is controversial, one reference that was provided for this statement was written by an attorney for plaintiffs who claim that their cancer was caused by vaccines contaminated with SV40.¹ During the past two years, several studies have raised serious questions about the various lines of evidence presented for this proposed link between SV40 and human cancer. The finding that unsuspected SV40 sequences in common laboratory plasmids can lead to false positive results on polymerasechain-reaction (PCR) assays for SV40 DNA has cast doubt on the reliability of published PCR-based data on SV40 in human cancers.² The reported detection of SV40 antigens in human tumors and cell lines by immunohistochemical analysis and Western blotting appears to be irreproducible.^2,3 These new data, together with abundant epidemiologic and serologic data that are inconsistent with a link between SV40 and human cancer,⁴ argue strongly for a more cautious perspective on this important issue.

Fernando López-Ríos, M.D., Ph.D.

Hospital Universitario 12 de Octubre 28041 Madrid, Spain

Marc Ladanyi, M.D.

Memorial Sloan-Kettering Cancer Center New York, NY 10021

MacLachlan DS. SV40 in human tumors: new documents shed light on the apparent controversy. Anticancer Res 2002;22: 3495-9.
López-Ríos F, Illei PB, Rusch V, Ladanyi M. Evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive PCR results owing to presence of SV40 sequences in common laboratory plasmids. Lancet 2004;364:1157-66.
Manfredi JJ, Dong J, Liu WJ, et al. Evidence against a role for SV40 in human mesothelioma. Cancer Res 2005;65:2602-9.
Shah KV. Causality of mesothelioma: SV40 question. Thorac Surg Clin 2004;14:497-504.

The authors reply: EMA is very useful in the cytologic evaluation of individual cases of suspected cancer involving the pleura, whether the cancer is mesothelioma or adenocarcinoma. However, there are caveats about the interpretation of a particular case as “positive.” First, the staining must be strong and seen in a majority of the cells in question, and the antibody clone that is used must be carefully chosen (e.g., E29 rather than Mc5). EMA antibody should always be used as part of a panel of antibodies to help identify mesothelial or glandular cell types, and the observer must be an experienced cytopathologist. We see about 50 cases of mesothelioma per year that are identified in effusions; to our knowledge, during the past 20 years, the approach we describe has not resulted in a single false positive diagnosis of malignant mesothelioma. Of course, some cases of mesothelioma are EMA-negative, but a clearly positive result remains a very useful indicator. This view is shared by other experienced cytopathology groups.^1-3

We agree with Muñoz et al. about the value

n engl j med 354;3 www.nejm.org january 19, 2006

correspondence

of chemotherapy, and our article describes how the field of chemotherapy for mesothelioma has moved from “poor response rates” to “several new therapies that appear to be useful.” Both of the regimens described (pemetrexed or gemcitabine plus cisplatin) provide symptomatic and qualityof-life benefits, as well as improved survival and objective response rates. The challenge now is to work out how to improve on these therapies and combine them with other novel approaches to provide biologically useful synergies and explore the biologic basis underlying nonresponding tumors.⁴

We also agree with López-Ríos and Ladanyi that the role of SV40 in the pathogenesis of mesothelioma is controversial. There are strong data from accomplished research groups supporting both the notion that SV40 plays a role in the pathogenesis of mesothelioma and the notion that it does not. Our choice of references was made to illustrate the position of skeptics toward the view that SV40 plays an important role in the pathogenesis of mesothelioma and to inform readers that the SV40 controversy extends beyond the realm of science and into the world of law.

Bruce W.S. Robinson, M.D.

University of Western Australia Perth 6009, Australia bwsrobin@cyllene.uwa.edu.au

Richard A. Lake, Ph.D.

Sir Charles Gairdner Hospital Perth 6009, Australia

Saad RS, Cho P, Liu YL, Silverman JF. The value of epithelial membrane antigen expression in separating benign mesothelial proliferation from malignant mesothelioma: a comparative study. Diagn Cytopathol 2005;32:156-9.
Cury PM, Butcher DN, Corrin B, Nicholson AG. The use of histological and immunohistochemical markers to distinguish pleural malignant mesothelioma and in situ mesothelioma from reactive mesothelial hyperplasia and reactive pleural fibrosis. J Pathol 1999;189:251-7.
Attanoos RL, Griffin A, Gibbs AR. The use of immunohistochemistry in distinguishing reactive from neoplastic mesothelium: a novel use for desmin and comparative evaluation with epithelial membrane antigen, p53, platelet-derived growth factor-receptor, P-glycoprotein and Bcl-2. Histopathology 2003;43: 231-8.
Lake RA, Robinson BW. Immunotherapy and chemotherapy

— a practical partnership. Nat Rev Cancer 2005;5:397-405.

Immunologic Tolerance to Intravenously Injected Insulin

To the Editor: Rosalyn Yalow, the inventor of radioimmunoassay, found that insulin treatments led to the production of antibodies against insulin.¹ Initially, this phenomenon was thought to be due to slight immunogenicity induced by the refining of preparations or the difference in amino acid sequences between species. However, even today, when genetically engineered preparations of human insulin are used, anti–human insulin IgG subclasses still are frequently detected in patients treated with insulin. Why therapeutically used insulin molecules, despite having exactly the same primary structure as endogenous insulin, are immunogenic has not been fully clarified.

We describe the induction of immunologic tolerance with the use of intravenously injected insulin in a severely insulin-allergic patient with diabetes. In April 2003, a 24-year-old man with a three-year history of poorly controlled type 1 diabetes and with insulin allergy was referred to our institution. Skin tests performed with all forms of commercially available insulin and insulin analogues were positive, but skin tests were negative for solvent and additives. Attempted desensitization with the subcutaneous administration of insulin, with continuous subcutaneous injection of insulin lispro, or with oral antiallergic agents did not prevent frequent life-threatening allergic symptoms (e.g., systemic urticaria, shock, and dyspnea), especially after bolus injections with meals. However, when no allergic reactions were observed after intravenous injection of 0.05 U of regular insulin per patient, we gradually increased the dose.

We ultimately succeeded in administering all the required insulin intravenously with a portable parenteral-nutrition device (a central venous catheter, a subcutaneously embedded reservoir, and a portable infusion pump). All symptoms of an allergic reaction disappeared as soon as intravenous injection was begun. Oral antiallergic agents were no longer required. Within a year after the introduction of intravenously injected insulin, levels of anti–human insulin IgE returned to normal (decreasing from 2.51 to <0.34 U per milliliter), as did levels of anti–human insulin IgG

n engl j med 354;3 www.nejm.org january 19, 2006

MESOTHELIOMA INCIDENCE AND COMMUNITY ASBESTOS EXPOSURE

2010-01-06T02:40:00.001-08:00

MESOTHELIOMA INCIDENCE AND COMMUNITY ASBESTOS EXPOSURE
AUGUST 1995
ABSTRACT

The purpose of this study was to evaluate the incidence of mesothelioma among persons living in an area that had been the location of an asbestos manufacturing plant between 1912 and 1980. Two study designs were used: standardized incidence ratios and a case-control format. Only vital record data were used in this project.

Cases were the 110 diagnosed mesotheliomas among residents in Somerset County reported to the population-based New Jersey State Cancer Registry from 1979 through 1987. Cases were removed from the analysis when their "usual employment" was reported as being at the asbestos plant, as evidenced through union lists or occupational information from either the Cancer Registry or mortality records.

Standardized Incidence Ratios (SIR) were computed for total Manville residents, and for males and females separately. Average annual New Jersey mesothelioma rates, 1979-1986, were used to generate the expected number of mesothelioma cases. The SIR for the total Manville population was 14.9 (95% Confidence Interval [C.I.]: 9.1-23.1). Female Manville residents had a mesothelioma SIR of 29.7 (95% C.I.: 11.9-61.3). Male Manville residents had a mesothelioma SIR of 11.4 (95% C.I.: 6.1-19.5). Total and male Somerset County mesothelioma incidence were slightly elevated compared to the State rates.

Controls for the case-control study design included the 1,016 selected cancers deemed unrelated to asbestos exposure. The controls were also residents of Somerset County at time of diagnosis and diagnosed during the same time period as the cases. Using logistic regression analysis, explanatory variables included town of residence, age at diagnoses, and year of diagnoses stratified by sex. For males, residence in Manville had an odds ratio of 6.4 (95% C.I.: 3.0-13.5) compared with residence in other county locations. For females, the odds ratio for residence in Manville was 31.7 (95% C.I.: 8.7-116.1).

These record-based approaches demonstrate a strong relationship between past asbestos exposure from living in Manville and eventual development of mesothelioma. The use of such study designs may be helpful in evaluating hazards of known occupational carcinogens found in community settings.

Leptomeningeal Metastasis from Malignant Pleural Mesothelioma

2010-01-06T01:45:00.000-08:00

Leptomeningeal Metastasis from Malignant Pleural Mesothelioma

Boris D. Petrovic, Dusko B. Kozic, Robert R. Semnic, Mladen Prvulovic, Dragana Djilas-Ivanovic,
R. Nuri Sener, and Istvan Klem

eningeal metastasis from malignant mesothelioma is very rare; to our knowledge, only one imaging report exists in the literature. We present the case of widespread leptomeningeal lesions secondary to a malignant mesothelioma in a 61-year-old woman.

CNS involvement due to metastatic mesothelioma is very rare. The metastatic intracranial lesion may present as a solitary mass or as leptomeningeal infiltration (1–7). Leptomeningeal metastasis is extremely rare, and to our knowledge, only one report of the MR imaging findings of this condition exists in the literature (1). Herein, we believe we report the imaging findings in the second such reported case of this condition.

Case Report

Malignant mesothelioma of the right pleura in a 61-year-old woman was confirmed by pleurolysis and biopsy (Fig 1A and B). Although she responded well to chemotherapy, 1 year later she was admitted to the hospital because of vomiting, for which she received symptomatic therapy. A year thereafter, she was admitted again with confusion and ataxia, at which time T2weighted images revealed an impression of widened cerebellar sulci (Fig 2A). On postcontrast T1-weighted images, widespread leptomeningeal infiltrations were evident in the cerebellar and cerebral sulci. The lesions were more prominent in the cerebellar sulci compared with in the cerebral sulci. The third and lateral ventricles were dilated, which suggested development of acute hydrocephalus (Fig 2B and C). At that stage, findings of a chest radiograph and an abdominal sonogram were noted to be normal. Lumbar puncture revealed findings consistent with those of neoplastic infiltration.

The patient died 30 days after the MR imaging examination. At autopsy, mesothelioma with infiltration of the lower lobe of the right lung was evident. Metastases to the mediastenial lymph nodes and micrometastases to the liver were noted. Leptomeningeal infiltration was confirmed by histologic analysis revealing presence of sarcomatous cells (Fig 3).

Received November 6, 2003; accepted after revision November 20.

From the Department of Diagnostic Imaging, Institute of Oncology (B.D.P., D.B.K., R.R.S., M.P., D.D.-I.), and the Department of Pathology, Institute for Lung Diseases (I.K.), Sremska Kamenica, Serbia and Montenegro; and the Department of Radiology, Ege University Hospital (R.N.S.), Bornova, Izmir, Turkey.

Address correspondence to Professor R. Nuri Sener, Department of Radiology, Ege University Hospital, Bornova, Izmir, Turkey.

Discussion

It has been reported that hematogenous metastases of malignant mesothelioma usually involves the liver, adrenal glands, kidneys, and the contralateral lung. Metastatic spread to the CNS is rare. Most of these had been encountered as masses in the brain parenchyma (2–6), and one case was noted with orbital metastasis (7). Falconieri et al (2) reported three autopsy cases of malignant pleural mesothelioma with brain metastases and provided a review of 15 similar previously published reports. They noted that in two patients, the brain metastases were discovered incidentally at autopsy. In one patient, the brain metastasis was discovered ante mortem, when a CT scan suggested a primary tumor of the brain. With respect to the histopathologic findings, the tumors had spindle-shaped malignant cells, pseudopalisading, necrosis, and vascular buds suggestive of glioblastoma multiforme (2). Other authors also had the impression that the metastatic tumors of malignant mesothelioma in the brain mimicked the pattern of glioblastoma multiforme both histologically and radiologically (2–6). On the other hand, leptomeningeal involvement is very rare. The only imaging report is by Oksuzoglu et al (1), who used MR imaging. Their patient was a 44-year-old woman who presented clinically with convulsions, and the diagnosis of malignant mesothelioma was confirmed by biopsies of lymph nodes (1).

It is known that the causes of leptomeningeal metastasis include adenocarcinomas originating from the lung, stomach, breast, ovary, malignant melanoma, leukemia, lymphoma, and primary CNS malignancies. Clinically, these usually present as a low-grade meningitis syndrome. Our patient also presented with such a syndrome in that she had confusion and ataxia, which was an indication for a cranial MR imaging examination. This revealed leptomeningeal metastases with contrast enhancement, more prominent in the cerebellar sulci, and changes consistent with acute hydrocephalus, which likely accounted for ataxia and confusion.

Conclusion

This patient reveals that, although very rare, leptomeningeal metastases can be associated with malignant mesothelioma of the pleura. In the event that these patients present clinically with a low-grade meningitis syndrome, brain MR imaging should be performed with administration of intravenous paramagnetic contrast medium to uncover lesions in the leptomeninges.

1223
1224 PETROVIC AJNR: 25, August 2004

FIG 1. Mesothelioma.

A, Conventional radiograph of the chest, revealing the mesothelioma in the right pleura.

B, Positive Calretinin reaction of the mesothelioma (tumor biopsy obtained by pleuroscopy; X250 magnification)

FIG 2. Leptomeningeal metastasis. A, T2-weighted image, revealing widening of vermian sulci. B, Postcontrast T1-weighted image, revealing enhancement of the vermian sulci corresponding to leptomeningeal infiltration. Note

dilatation of temporal horns. C, Postcontrast T1-weighted image, revealing leptomeningeal enhancement in the frontal sulci. Lateral ventricular dilatation is noted.

References

Oksuzoglu B, Yalcin S, Erman M, Dagdelen S. Leptomeningeal infiltration of malignant mesothelioma. Med Oncol 2002;19:167–169
Falconieri G, Grandi G, DiBonito L, et al. Intracranial metastases from malignant pleural mesothelioma: report of three autopsy cases and review of the literature. Arch Pathol Lab Med

1991;115:591–595

Kitai R, Kabuto M, Kawano H, et al. Brain metastasis from malignant mesothelioma: case report. Neurol Med Chir (Tokyo) 1995;35:172–174
Kawai A, Nagasaka Y, Muraki M, et al. Brain metastasis in malignant pleural mesothelioma. Intern Med 1997;36:591–594
Schwechheimer K, Butzengeiger M. Brain metastases in malignant fibrous mesothelioma: case report and review of the literature. Acta Neuropathol (Berl) 1983;60:301–304
Kobayashi S, Ida M, Matsui O, et al. Lipomatous change in a brain metastasis from malignant pleural mesothelioma. Neuroradiology

2001;43:159–161

7. Kubota K, Furuse K, Kawahara M, et al. A case of malignant pleural mesothelioma with metastasis to the orbit. Jpn J Clin Oncol

1996;26:469–471

Mesothelioma

Mesothelioma of the Tunica Vaginalis Complicated by Chyluria

Mesothelioma among Workers in Asbestiform Fiber-bearing Talc Mines in New York State

MINDY J. HULL1, JERROLD L. ABRAHAM1* and BRUCE W. CASE2

BACKGROUND

METHODS AND RESULTS

DISCUSSION AND CONCLUSIONS

REFERENCES

MESOTHELIOMA INCIDENCE AND COMMUNITY ASBESTOS EXPOSURE

AGE-ADJUSTED SEER CANCER INCIDENCE RATESa, 1980-2003

Mesothelioma: Mesothelioma lawyer and asbestos attorney guide in these States:

Mesothelioma lawyer and asbestos attorney guide in these States:

Malignant Pleural Mesothelioma: A Comprehensive Review

Introduction

Incidence

Pathogenesis

Clinical Presentation

Diagnosis

Staging

Treatment

Surgery

Video-Assisted Thoracoscopy

Pleurectomy/Decortication

Extrapleural Pneumonectomy

Radiotherapy

Chemotherapy

Multimodality Therapy

Conclusions

References

Malignant Mesothelioma

Immunologic Tolerance to Intravenously Injected Insulin

MESOTHELIOMA INCIDENCE AND COMMUNITY ASBESTOS EXPOSURE

MESOTHELIOMA INCIDENCE AND COMMUNITY ASBESTOS EXPOSURE AUGUST 1995 ABSTRACT

Leptomeningeal Metastasis from Malignant Pleural Mesothelioma

Case Report

Discussion

Conclusion

References

MINDY J. HULL¹, JERROLD L. ABRAHAM¹* and BRUCE W. CASE²

MESOTHELIOMA INCIDENCE AND COMMUNITY ASBESTOS EXPOSURE
AUGUST 1995
ABSTRACT