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Malignant Mesothelioma: Natural History, Pathologic Features and Future Therapies
The American Journal of Medicine (2007) 120, e7-e9
CLINICAL COMMUNICATION TO THE EDITOR Malignant Mesothelioma: Natural History, Pathologic Features and Future Therapies To the Editor: A 75-year-old-man presented with a chronic history of progressive dyspnea and chest pain previously evaluated on multiple opportunities to exclude acute ischemic heart events. His occupational history revealed 15 years working as a spray painter at a shipyard. Physical examination was remarkable for slight peripheral soft edema. Posteroanterior (PA) chest radiograph (Figure 1A) and computed tomography (CT) scan of the chest (Figure 1B) demonstrate bilateral pleural calcifications (C). Initial sequential pleural biopsies revealed inflammatory changes with severe mesothelial atypia. Subsequent morphological and immunohistochemistry studies of progressive pleural thickening were consistent with malignant mesothelioma. Chest radiographs (Figure 2A) and CT scan of the chest (Figure 2B) confirmed rapidly developing left pleural masses (T) in addition to the established thickening and calcifications. The patient underwent a left intrapericardial extrapleural pneumonectomy and continues to recover after surgery.
DISCUSSION Malignant mesothelioma is a highly aggressive neoplasm that originates in the serosal surface of the pleura and results from previous exposure to asbestos fibers and less commonly to simian virus 40.1,2 Asbestos is a common component of insulation, ceiling and roofing vinyls, cement, and automotive brake materials.3 An important characteristic of mesotheliomas is their ability to exhibit a broad range of cytomorphologic features and to grow in a wide variety of histologic patterns. When presenting with a tubular or papillary pattern (Figure 3) they can be confused with adenocarcinomas, whereas a sarcomatoid morphology can often be confused with sarcomatoid carcinomas or sarcomas composed of spindle cells or having pleomorphic features. Of the various ancillary techniques that have been employed in the differential diagnosis of mesotheliomas, immunohistochemistry has been recognized as the most useful, especially Requests for reprints should be addressed to Luis H. Camacho, MD, Phase I Program, Clinical Center for Targeted Therapies, Division of Cancer Medicine, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX 77030. E-mail address: [email protected]
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved.
Figure 1 (A) Posteroanterior chest radiograph representing typical pleural calcifications (C). (B) CT scan of the thorax with contrast demonstrating pleural calcifications typical of asbestos exposure.
when distinguishing epithelioid mesotheliomas from carcinomas involving the serosal membranes. Epithelioid pleural mesotheliomas must be distinguished from peripheral adenocarcinomas of the lung involving the pleura and from metastatic adenocarcinomas arising from a distant organ,
e8 for example, the kidney. In the peritoneum, malignant mesotheliomas may resemble papillary peritoneal serous carcinomas or metastatic serous carcinomas of the ovary. A specific tumor marker for mesotheliomas has not yet been recognized; therefore, the immunohistochemical diagnosis of this tumor largely depends on the use of panels of markers that are frequently expressed in mesotheliomas (positive mesothelioma markers) combined with those that are commonly expressed in adenocarcinomas (negative mesothelioma markers) (Figure 4). In general, calretinin, keratin 5/6, WT1, and podoplanin are considered to be the best positive mesothelioma markers and CEA, MOC-31, B72.3, and Ber-EP4 the best negative markers for distinguishing between epithelioid mesotheliomas and adenocarcinomas.4 Because TTF-1, estrogen receptors, and RCC Ma are frequently expressed in lung adenocarcinomas, serous carcinomas, and renal cell carcinomas, respectively, but not in me-
The American Journal of Medicine, Vol 120, No 7, July 2007
Figure 3 Light microscopy showing the prominent tubulopapillary architecture of the tumor.
Figure 4 Immunohistochemical preparation showing strong nuclear and cytoplasmic positivity for calretinin.
sotheliomas, immunostaining for these markers can be useful in providing additional information regarding the site of origin of the carcinoma involving the serosal membrane.4-7 There is no current standard treatment for diffuse malignant mesothelioma, but surgery may improve the survival of patients with limited disease. Recent characterization of molecular abnormalities includes deletions in 9p21, where critical cell cycle regulators such as p16INK4A and p15INK4B and the p53 regulator p14ARF reside. Other defects described involve the insulin growth factor (IGF) and bcl-2 pathways.8 The identification of these molecular defects may be critical for future targeted anticancer therapies. Luis H. Camacho, MD, MPH Ana Mora-Bowen, MS
Figure 2 (A) Posteroanterior chest radiograph representing typical pleural calcifications (C) and a newly developed pleural mass in the left apex (T). (B) CT scan of the thorax with contrast demonstrating pleural calcifications (C) typical of asbestos exposure and a newly evidenced left upper lobe mass (T).
Phase I Program, Division of Cancer Medicine The University of Texas M. D. Anderson Cancer Center Houston
Reginald Munden, MD Department of Diagnostic Radiology The University of Texas M. D. Anderson Cancer Center Houston
Clinical Communication to the Editor
e9 W. Roy Smythe, MD
Department of Surgery Texas A&M University Health Science Center Temple
Nelson G. Ordoñez, MD Department of Pathology The University of Texas M. D. Anderson Cancer Center Houston
doi:10.1016/j.amjmed.2006.05.057
References 1. Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet. 2005;366:397-408. 2. De Luca A, Baldi A, Esposito V, et al. The retinoblastoma gene family pRb/p105, p107, pRb2/p130 and simian virus-40 large T-antigen in human mesotheliomas. Nat Med. 1997;3:913-916.
3. Britton M. The epidemiology of mesothelioma. Semin Oncol. 2002;29: 18-25. 4. Ordonez NG. Immunohistochemical diagnosis of epithelioid mesothelioma: an update. Arch Pathol Lab Med. 2005;129:14071414. 5. Ordonez NG. Value of thyroid transcription factor-1, E-cadherin, BG8, WT1, and CD44S immunostaining in distinguishing epithelial pleural mesothelioma from pulmonary and nonpulmonary adenocarcinoma. Am J Surg Pathol. 2000;24:598-606. 6. Ordonez NG. The diagnostic utility of immunohistochemistry in distinguishing between mesothelioma and renal cell carcinoma: a comparative study. Hum Pathol. 2004;35:697-710. 7. Ordonez NG. Value of estrogen and progesterone receptor immunostaining in distinguishing between peritoneal mesotheliomas and serous carcinomas. Hum Pathol. 2005;36:1163-1167. 8. Whitson BA, Kratzke RA. Molecular pathways in malignant pleural mesothelioma. Cancer Lett. 2006;239:183-189.
CLINICAL COMMUNICATION TO THE EDITOR Malignant Mesothelioma: Natural History, Pathologic Features and Future Therapies To the Editor: A 75-year-old-man presented with a chronic history of progressive dyspnea and chest pain previously evaluated on multiple opportunities to exclude acute ischemic heart events. His occupational history revealed 15 years working as a spray painter at a shipyard. Physical examination was remarkable for slight peripheral soft edema. Posteroanterior (PA) chest radiograph (Figure 1A) and computed tomography (CT) scan of the chest (Figure 1B) demonstrate bilateral pleural calcifications (C). Initial sequential pleural biopsies revealed inflammatory changes with severe mesothelial atypia. Subsequent morphological and immunohistochemistry studies of progressive pleural thickening were consistent with malignant mesothelioma. Chest radiographs (Figure 2A) and CT scan of the chest (Figure 2B) confirmed rapidly developing left pleural masses (T) in addition to the established thickening and calcifications. The patient underwent a left intrapericardial extrapleural pneumonectomy and continues to recover after surgery.
DISCUSSION Malignant mesothelioma is a highly aggressive neoplasm that originates in the serosal surface of the pleura and results from previous exposure to asbestos fibers and less commonly to simian virus 40.1,2 Asbestos is a common component of insulation, ceiling and roofing vinyls, cement, and automotive brake materials.3 An important characteristic of mesotheliomas is their ability to exhibit a broad range of cytomorphologic features and to grow in a wide variety of histologic patterns. When presenting with a tubular or papillary pattern (Figure 3) they can be confused with adenocarcinomas, whereas a sarcomatoid morphology can often be confused with sarcomatoid carcinomas or sarcomas composed of spindle cells or having pleomorphic features. Of the various ancillary techniques that have been employed in the differential diagnosis of mesotheliomas, immunohistochemistry has been recognized as the most useful, especially Requests for reprints should be addressed to Luis H. Camacho, MD, Phase I Program, Clinical Center for Targeted Therapies, Division of Cancer Medicine, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX 77030. E-mail address: [email protected]
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved.
Figure 1 (A) Posteroanterior chest radiograph representing typical pleural calcifications (C). (B) CT scan of the thorax with contrast demonstrating pleural calcifications typical of asbestos exposure.
when distinguishing epithelioid mesotheliomas from carcinomas involving the serosal membranes. Epithelioid pleural mesotheliomas must be distinguished from peripheral adenocarcinomas of the lung involving the pleura and from metastatic adenocarcinomas arising from a distant organ,
e8 for example, the kidney. In the peritoneum, malignant mesotheliomas may resemble papillary peritoneal serous carcinomas or metastatic serous carcinomas of the ovary. A specific tumor marker for mesotheliomas has not yet been recognized; therefore, the immunohistochemical diagnosis of this tumor largely depends on the use of panels of markers that are frequently expressed in mesotheliomas (positive mesothelioma markers) combined with those that are commonly expressed in adenocarcinomas (negative mesothelioma markers) (Figure 4). In general, calretinin, keratin 5/6, WT1, and podoplanin are considered to be the best positive mesothelioma markers and CEA, MOC-31, B72.3, and Ber-EP4 the best negative markers for distinguishing between epithelioid mesotheliomas and adenocarcinomas.4 Because TTF-1, estrogen receptors, and RCC Ma are frequently expressed in lung adenocarcinomas, serous carcinomas, and renal cell carcinomas, respectively, but not in me-
The American Journal of Medicine, Vol 120, No 7, July 2007
Figure 3 Light microscopy showing the prominent tubulopapillary architecture of the tumor.
Figure 4 Immunohistochemical preparation showing strong nuclear and cytoplasmic positivity for calretinin.
sotheliomas, immunostaining for these markers can be useful in providing additional information regarding the site of origin of the carcinoma involving the serosal membrane.4-7 There is no current standard treatment for diffuse malignant mesothelioma, but surgery may improve the survival of patients with limited disease. Recent characterization of molecular abnormalities includes deletions in 9p21, where critical cell cycle regulators such as p16INK4A and p15INK4B and the p53 regulator p14ARF reside. Other defects described involve the insulin growth factor (IGF) and bcl-2 pathways.8 The identification of these molecular defects may be critical for future targeted anticancer therapies. Luis H. Camacho, MD, MPH Ana Mora-Bowen, MS
Figure 2 (A) Posteroanterior chest radiograph representing typical pleural calcifications (C) and a newly developed pleural mass in the left apex (T). (B) CT scan of the thorax with contrast demonstrating pleural calcifications (C) typical of asbestos exposure and a newly evidenced left upper lobe mass (T).
Phase I Program, Division of Cancer Medicine The University of Texas M. D. Anderson Cancer Center Houston
Reginald Munden, MD Department of Diagnostic Radiology The University of Texas M. D. Anderson Cancer Center Houston
Clinical Communication to the Editor
e9 W. Roy Smythe, MD
Department of Surgery Texas A&M University Health Science Center Temple
Nelson G. Ordoñez, MD Department of Pathology The University of Texas M. D. Anderson Cancer Center Houston
doi:10.1016/j.amjmed.2006.05.057
References 1. Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet. 2005;366:397-408. 2. De Luca A, Baldi A, Esposito V, et al. The retinoblastoma gene family pRb/p105, p107, pRb2/p130 and simian virus-40 large T-antigen in human mesotheliomas. Nat Med. 1997;3:913-916.
3. Britton M. The epidemiology of mesothelioma. Semin Oncol. 2002;29: 18-25. 4. Ordonez NG. Immunohistochemical diagnosis of epithelioid mesothelioma: an update. Arch Pathol Lab Med. 2005;129:14071414. 5. Ordonez NG. Value of thyroid transcription factor-1, E-cadherin, BG8, WT1, and CD44S immunostaining in distinguishing epithelial pleural mesothelioma from pulmonary and nonpulmonary adenocarcinoma. Am J Surg Pathol. 2000;24:598-606. 6. Ordonez NG. The diagnostic utility of immunohistochemistry in distinguishing between mesothelioma and renal cell carcinoma: a comparative study. Hum Pathol. 2004;35:697-710. 7. Ordonez NG. Value of estrogen and progesterone receptor immunostaining in distinguishing between peritoneal mesotheliomas and serous carcinomas. Hum Pathol. 2005;36:1163-1167. 8. Whitson BA, Kratzke RA. Molecular pathways in malignant pleural mesothelioma. Cancer Lett. 2006;239:183-189.