DOI: 10.1148/rg.271065105
RadioGraphics 2007;27:259-264
© RSNA, 2007
Best Cases from the AFIP
Malignant Mesothelioma1
Sean M. Tyszko, MD,
Gary D. Marano, MD,
Robert J. Tallaksen, MD and
Kymberly A. Gyure, MD
1 From the Departments of Radiology (S.M.T., G.D.M., R.J.T.) and Pathology (K.A.G.), West Virginia University, 1 Medical Center Dr, Room 2278, Box 9235, Morgantown, WV 26506. Received May 25, 2006; revision requested June 14 and received June 27; accepted June 28. All authors have no financial relationships to disclose.
Address correspondence to S.M.T. (e-mail: styszko{at}hsc.wvu.edu).
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History
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A 58-year-old man who had worked on asbestos-lined furnaces 40 years ago presented to his physician with a history of multiple episodes of exertional dyspnea over the past year. Over the past 6 months, the patient had three pleural effusions drained on the left side with unremarkable results at cytologic analysis. He also reported weight loss of about 10 lb (4.5 kg) over the previous 4–6 months. Physical examination demonstrated decreased breath sounds on the left side with dullness to percussion. Laboratory data were unremarkable.
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Imaging Findings
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Initial chest radiography and chest computed tomography (CT) demonstrated circumferential, lobulated pleural thickening involving the left lung with associated left lung volume loss (Figs 1, 2). Whole-body integrated positron emission tomography (PET)–CT demonstrated circumferential pleural thickening surrounding the entire left lung with significant hypermetabolic glucose activity consistent with tumor. PET-CT also showed hypermetabolic tumor foci invading the pulmonary parenchyma. No evidence of chest wall or mediastinal invasion was seen and no distant metastases were identified (Fig 3).
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Figure 2. Axial contrast-enhanced CT scan shows circumferential, lobulated pleural thickening encasing the left lung. Tumor tissue is also seen abutting the mediastinum and pericardium.
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Figure 3a. Anterior (a) and posterior (b) coronal fused PET-CT images show the hypermetabolic tumor encasing the left lung and infiltrating into the lung parenchyma and along the fissure. The tumor is also seen to contact but not invade the diaphragm and pericardium.
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Figure 3b. Anterior (a) and posterior (b) coronal fused PET-CT images show the hypermetabolic tumor encasing the left lung and infiltrating into the lung parenchyma and along the fissure. The tumor is also seen to contact but not invade the diaphragm and pericardium.
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Pathologic Evaluation
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A complete left extrapleural pneumonectomy was performed including resection of half of the pericardium and diaphragm. The pathologic specimen was received en bloc and demonstrated a firm, gray-white, lobulated tumor measuring approximately 2.5 cm in thickness involving the entire pleural surface, which was adherent to the pericardium and diaphragm. There were multiple similar-appearing intrapulmonary masses measuring up to 7.2 cm in greatest dimension. The bronchial and vascular channels were focally surrounded by but not grossly involved by the tumor (Fig 4).
Histologic examination revealed malignant mesothelioma, epithelioid type, which was characterized by sheets of cells with prominent nucleoli and eosinophilic cytoplasm arranged in a focally papillary architecture (Fig 5). There was no evidence of vascular or lymphatic invasion, and regional lymph nodes were negative for disease.
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Figure 5. High-power photomicrograph (hematoxylin-eosin stain) shows the focally papillary architecture of the tumor, which is composed of large cells with eosinophilic cytoplasm and prominent nucleoli.
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Discussion
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Mesothelioma of the thorax is a malignant neoplasm that involves the parietal pleura to a greater extent than the visceral pleura (1). There is a significantly increased risk of developing this disease in those individuals with prior exposure to asbestos. The lifetime risk of developing mesothelioma in heavily exposed individuals is as high as 10%. There is a long latent period of approximately 35–40 years for the development of asbestos-related mesothelioma (1). However, there has been no evidence to suggest smoking plays any role in the development of mesothelioma. This is in contrast to the significantly increased risk for development of adenocarcinoma in those patients who both smoke and have been exposed to asbestos (2).
Evidence has also implicated simian virus 40, a DNA virus that blocks tumor suppressor genes, as a cofactor in the causation of malignant mesothelioma (3). Simian virus 40 DNA sequences have been found in brain and bone tumors, lymphomas, and malignant mesotheliomas (4). Currently, the involvement of simian virus 40 in the pathogenesis of malignant mesothelioma is controversial, and investigation into its role continues.
The typical patient with mesothelioma presents with symptoms of chest pain, dyspnea, and recurrent pleural effusions (5) and has a history of significant asbestos exposure. Other common presenting signs and symptoms include weight loss, fatigue, and cough (5). Classic physical examination findings include dullness to percussion and decreased breath sounds.
Plain radiographic and CT findings alone are nonspecific, but in the presence of a long history of asbestos exposure they can be highly suggestive of malignant mesothelioma. Plain chest radiography is usually the first-line radiologic examination and may demonstrate circumferential pleural thickening, pleural effusions, and lung nodules or masses (6). Circumferential pleural thickening is suggestive of but not specific for mesothelioma and can be seen in other disease entities such as adenocarcinomas, lymphoma, thymoma, asbestos-related benign pleural disease, and infections (1).
CT demonstrates similar nonspecific findings; however, with a history of significant asbestos exposure, a diagnosis of mesothelioma can be suggested. In addition to the previously mentioned findings, CT can also be useful in demonstrating invasion of the tumor into the mediastinum, chest wall, diaphragm, and pericardium, which aids in disease staging and treatment planning. Chest wall invasion may manifest as obscured fat planes, invasion of intercostal muscles, infiltration or separation of ribs by tumor, or bone destruction. Invasion into the mediastinum including vital structures such as the heart, great vessels, esophagus, and trachea may appear as obliteration of fat planes or as direct tumor invasion (7).
Magnetic resonance (MR) imaging is another imaging modality that is not used routinely in patients with mesothelioma; however, it can provide valuable information and help in treatment planning. MR imaging provides excellent soft-tissue contrast and can prove beneficial in evaluating for invasion of tumor into the adjacent structures. The tumor typically shows increased signal intensity on T1-weighted images and similar to increased signal intensity on T2-weighted images relative to muscle. Also, owing to the superior soft-tissue resolution compared with CT alone, invasion into surrounding tissues can be better detected (7). The ability to provide direct imaging in all three planes (axial, coronal, and sagittal) also improves the ability to detect tumor invasion into the diaphragm and chest wall. This can potentially alter the patient’s stage of disease and possibly surgical and chemotherapeutic options. However, there are limitations of MR imaging, as there can be a relatively high false-positive and false-negative rate in predicting surgical resectability of the tumor (1).
Integrated PET-CT is not routinely performed in patients suspected of having mesothelioma. However, PET-CT has been shown to demonstrate more extensive disease involvement than that shown with other imaging modalities and is particularly useful in identifying occult distant metastases (8). When used with CT fusion, PET is able to show more extensive disease involvement by demonstrating direct tumor invasion into adjacent structures, which appears as invasion of hypermetabolic tumor into mediastinal or chest wall structures. This provides valuable information to the surgeons and oncologists in determining the stage of disease and in treatment planning. The ability to provide imaging in all three planes (axial, coronal, and sagittal) also aids in demonstrating the extent of disease and in determining resectability.
Although imaging remains the mainstay for noninvasive diagnosis and staging of malignant mesothelioma, several serum and genetic markers as well as pathologic immunomarkers have emerged for assisting in making the diagnosis (9). Serum mesothelin-related protein is a soluble form of mesothelin found to be elevated in 84% of patients with malignant mesothelioma and in less than 2% with other pulmonary or pleural diseases (10). This is best used as an adjunct to cyto-pathologic and histopathologic examination in diagnosis of malignant mesothelioma. Levels of serum mesothelin-related protein are seen to increase with progression of disease and decrease with regression or resection of the tumor, which could play a factor in monitoring response to treatment (10). CA-125, CA-15-5, and hyaluronic acid are also under investigation as possible serum markers for malignant mesothelioma (9).
Genetic markers are also being investigated as an aid in diagnosis of mesothelioma. A preliminary study comparing 16 mesothelioma tumors with four normal pleural samples showed a coordinated up-regulation of the expression of genes associated with energy, protein translation, and cytoskeletal remodeling pathways (11). Genetic markers have also proved useful in differentiating mesothelioma from adenocarcinoma, often a diagnostic challenge pathologically, by measuring the expression levels of the three pairs of genes encoding for calretinin and TTF-1 (12).
Pathologically, several immunohistochemical markers have proved useful in differentiating mesothelioma from other pleural diseases. Malignant mesothelioma is characterized by the presence of staining for epithelial membrane antigen, calretinin, Wilms tumor 1 antigen, cytokeratin 5/6, HBME-1 (an anti–mesothelial cell antibody), or mesothelin (>85% of epithelioid-type mesotheliomas are positive for mesothelin) and the absence of staining for antigens such as carcinoem-bryonic antigen; thyroid transcription factor 1; the tumor glycoproteins B72.3, MOC-31, and Ber-EP4; and the epithelial glycoprotein BG8. Although other tumors can also stain positive for mesothelioma markers (eg, ovarian carcinoma stains for mesothelin and Wilms tumor 1 antigen), use of the clinical and imaging features as well as the pathologic data can typically suggest the diagnosis (9).
The prognosis in patients with malignant mesothelioma is extremely poor, with a median survival time of 12 months (9). Factors that worsen the prognosis include extensive disease, poor performance status, elevated white blood cell counts, anemia, thrombocytosis, sarcomatoid histologic findings, high standardized uptake value ratios at PET, and evidence of simian virus 40 in the tumor (13). Few patients survive past 2 years even with stage I disease. Standard treatment options include surgical resection and chemotherapy, although newer treatments such as radiation therapy, immunotherapy, and gene therapy are being used in conjunction with the standard therapies (9).
Currently, two surgical treatment options are available: pleurectomy and extrapleural pneumonectomy. Pleurectomy is typically a palliative procedure aimed at relieving chest wall pain and alleviating recurrent pleural effusions by stripping off the parietal and visceral pleura. Incomplete resection is often seen along the mediastinal and diaphragmatic pleura. Extrapleural pneumonectomy is en bloc resection of the pleura, lung, hemi-diaphragm, and ipsilateral pericardium to remove all evident disease. This is indicated for tumors with no involvement of the mediastinal lymph nodes or distant metastases. No difference in overall long-term survival is seen with surgery alone, but the disease-free survival period is improved (1). Improved survival rates have been seen with surgery performed in combination with chemotherapy, radiation therapy, immunotherapy, or other treatments (7).
Initial response rates to single-agent chemotherapy were poor (<15%–20%) (14), and recommendations for chemotherapy were typically saved for palliative treatment. However, recent multicenter trials have shown improved response rates to newer combination therapeutic regimens. Pemetrexed is a protein inhibitor that, in a phase III study of 448 patients, demonstrated an overall longer median survival time when combined with cisplatin (12.1 months) than for cisplatin alone (9.3 months) (15). Gemcitabine in combination with cisplatin also showed objective response rates of 48% and 33% in two studies as well as symptomatic improvement and quality-of-life benefits (16). Other therapies including radiation therapy, gene therapy, and immunotherapy have yet to show evidence to warrant widespread use; however, they have been beneficial when used in conjunction with surgery and chemotherapy (9).
The patient presented in this case report underwent a successful extrapleural pneumonectomy with a relatively uneventful postoperative course. Three months after the surgery, he began experiencing left-sided chest pain, and repeat CT showed new pleural-based masses suspicious for recurrence of tumor. Six months after the surgery, the patient started receiving combination chemotherapy with pemetrexed and cisplatin but continued to show progression of his disease. Currently, he is receiving gemcitabine and cisplatin for palliation of his symptoms.
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Footnotes
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Editor’s Note.—Everyone who has taken the course in radiologic pathology at the Armed Forces Institute of Pathology (AFIP) remembers bringing beautifully illustrated cases for accession to the Institute. In recent years, the staff of the Department of Radiologic Pathology has judged the "best cases" by organ system, and recognition is given to the winners on the last day of the class. With each issue of RadioGraphics, one or more of these cases are published, written by the winning resident. Radiologic-pathologic correlation is emphasized, and the causes of the imaging signs of various diseases are illustrated.
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References
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- Miller BH, Rosado-de-Christenson ML, Mason AC, Fleming MV, White CC, Krasna MJ. Malignant pleural mesothelioma: radiologic-pathologic correlation. RadioGraphics 1996;16:613–644.[Abstract]
- Selikoff IJ, Hammond EC, Seidman H. Latency of asbestos disease among insulation workers in the United States and Canada. Cancer 1980;46: 2736–2740.[CrossRef][Medline]
- Carbone M, Pass HI, Rizzo P, et al. Simian virus 40–like DNA sequences in human pleural mesothelioma. Oncogene 1994;9:1781–1790.[Medline]
- Shivapurkar N, Harada K, Reddy J, et al. Presence of simian virus 40 DNA sequences in human lymphomas. Lancet 2002;359:851–852.[CrossRef][Medline]
- Lee YC, Light RW, Musk AW. Management of malignant pleural mesothelioma: a critical review. Curr Opin Pulm Med 2000;6:267–274.[CrossRef][Medline]
- Evans AL, Gleeson FV. Radiology in pleural disease: state of the art. Respirology 2004;9:300–312.[CrossRef][Medline]
- Wang ZJ, Reddy GP, Gotway MB, et al. Malignant pleural mesothelioma: evaluation with CT, MR imaging, and PET. RadioGraphics 2004;24: 105–119.[Abstract/Free Full Text]
- Truong MT, Marom EM, Erasmus JJ. Preoperative evaluation of patients with malignant pleural mesothelioma: role of integrated CT-PET imaging. J Thorac Imaging 2006;21(2):146–153.[CrossRef][Medline]
- Robinson BW, Lake RA. Advances in malignant mesothelioma. N Engl J Med 2005;353:1591–1603.[Free Full Text]
- Robinson BW, Creaney J, Lake RA, et al. Mesothelin-family proteins and diagnosis of mesothelioma. Lancet 2003;362:1612–1616.[CrossRef][Medline]
- Singhal S, Wiewrodt R, Malden LD, et al. Gene expression profiling of malignant mesothelioma. Clin Cancer Res 2003;9:3080–3097.[Abstract/Free Full Text]
- Gordon GJ, Jensen RV, Hsiao LL, et al. Translation of microarray data into clinically relevant cancer diagnostic tests using gene expression ratios in lung cancer and mesothelioma. Cancer Res 2002; 62:4963–4967.[Abstract/Free Full Text]
- O’Byrne KJ, Edwards JG, Waller DA. Clinico-pathological and biological prognostic factors in pleural malignant mesothelioma. Lung Cancer 2004;45(suppl 1):S45–S48.
- Janne PA. Chemotherapy for malignant pleural mesothelioma. Clin Lung Cancer 2003;5:98–106.[Medline]
- 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.[Abstract/Free Full Text]
- Nowak AK, Byrne MJ, Williamson R, et al. A multicentre phase II study of cisplatin and gemcitabine in malignant mesothelioma. Br J Cancer 2002;87:491–496.[CrossRef][Medline]
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History
Imaging Findings
