Correspondence

Malignant Mesothelioma

N Engl J Med 2006; 354:305-307January 19, 2006

Article

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

5 References

1. 1

   Robinson BWS, Lake RA. Advances in malignant mesothelioma. N Engl J Med 2005;353:1591-1603
   Full Text | Web of Science | Medline

2. 2

   Churg A, Colby TV, Cagle P, et al. The separation of benign and malignant mesothelial proliferations. Am J Surg Pathol 2000;24:1183-1200
   CrossRef | Web of Science | Medline

3. 3

   Dabbs DJ. Immunocytology. In: Dabbs J, ed. Diagnostic immunohistochemistry. New York: Churchill Livingstone, 2002:625-39.
   

4. 4

   King JA, Tucker JA. Evaluation of membranous staining of mesothelioma. Cell Vis 1998;5:24-27
   Medline

5. 5

   Moran CA, Wick MR, Suster S. The role of immunohistochemistry in the diagnosis of malignant mesothelioma. Semin Diagn Pathol 2000;17:178-183
   Web of Science | Medline

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.1 This gain was consistent across all subgroups analyzed2 and appeared to be independent of second-line chemotherapy.3 Moreover, pemetrexed-based 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

3 References

1. 1

   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
   CrossRef | Web of Science | Medline

2. 2

   Hazarika M, White RM Jr, Booth BP, et al. Pemetrexed in malignant pleural mesothelioma. Clin Cancer Res 2005;11:982-992
   Web of Science | Medline

3. 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;16:923-927
   CrossRef | Web of Science | Medline

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 polymerase-chain-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

4 References

1. 1

   MacLachlan DS. SV40 in human tumors: new documents shed light on the apparent controversy. Anticancer Res 2002;22:3495-3499
   Web of Science | Medline

2. 2

   Lopez-Rios 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;364:1157-1166
   CrossRef | Web of Science | Medline

3. 3

   Manfredi JJ, Dong J, Liu WJ, et al. Evidence against a role for SV40 in human mesothelioma. Cancer Res 2005;65:2602-2609
   CrossRef | Web of Science | Medline

4. 4

   Shah KV. Causality of mesothelioma: SV40 question. Thorac Surg Clin 2004;14:497-504
   CrossRef | Medline

Author/Editor Response

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 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 quality-of-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

4 References

1. 1

   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;32:156-159
   CrossRef | Web of Science | Medline

2. 2

   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;189:251-257
   CrossRef | Web of Science | Medline

3. 3

   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;43:231-238
   CrossRef | Web of Science | Medline

4. 4

   Lake RA, Robinson BW. Immunotherapy and chemotherapy -- a practical partnership. Nat Rev Cancer 2005;5:397-405
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Derrick Nguyen, Sang-Joon Lee, Edward Libby, Claire Verschraegen. (2008) Rate of Thromboembolic Events in Mesothelioma. The Annals of Thoracic Surgery 85:3, 1032-1038
   CrossRef