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Pulmonary Adenocarcinoma Simulating Malignant Mesothelioma Ping Tang, MD, PhD; Sheel K Vatsia, MD; Saul Teichberg, PhD; Ellen Kahn, MD Adenocarcinoma of the lung with pleural involvement REPORT OF A CASE frequently resembles pleural epithelioid mesothelioma clinically as well as macro- and microscopically. Special stains, immunohistochemical studies, and electron micro scopic studies are needed to differentiate these 2 tumors. A 75-year-old male retired biology teacher with a history of hypertension, transient ischemic attack, and depression and a re mote history of smoking presented with dry cough, respiratory distress, and weight loss of several months' duration. A chest We report a case of pleural involvement by adenocarci radiograph showed left side pleural effusion. The patient under noma, mimicking in the hematoxylin-eosin stain an epithe lioid mesothelioma, correctly identified only after immu nohistochemical and electron microscopic examinations. (Arch Pathol Lab Med. 2001;125:1598-1600) went thoracentesis. Cytology of the pleural fluid was positive for malignant cells, with a differential diagnosis of epithelioid me sothelioma versus adenocarcinoma. Subsequently, the patient un derwent partial pleurectomy. The pleurectomy specimen was characterized by fragments of fibrous connective tissue lined by mesothelial cells with focal papillary area. Normal mesothelium There is general agreement that the microscopic char was found in continuity with hyperplastic stratified and papillary acteristics of an adenocarcinoma involving the pleura structure without invasion of the underlying fibrous connective and an epithelioid mesothelioma overlap in the hematox- tissue. The cells were cuboidal in the hyperplastic and papillary ylin-eosin-stained slide. Additional studies such as elec tron microscopy and immunohistochemical stains are needed for proper identification.1 We describe a pleural areas, with an increased nucleocytoplasmic ratio, round bland nuclei with low mitotic activity, and inconspicuous nucleoli (Fig ure 1). Thus, a diagnosis of malignant mesothelioma, epithelioid type was rendered. However, additional clinical inflammation tumor with ''typical'' features of mesothelioma in the he- challenged the diagnosis of epithelioid mesothelioma. The patient matoxylin-eosin stain slide that with further studies was had a 4.4-cm perihilar mass; furthermore, the patient also had a reclassified as adenocarcinoma. probable brain mass (2 small enhancing lesions evaluated by magnetic resonance imaging), bony metastasis (multiple areas of increasing uptake evaluated by bone scan) and a 3-cm lesion in Accepted for publication June 8, 2001. From the Departments of Pathology (DrsTang, Teichberg, and Kahn) and Surgery (Dr Vatsia), North Shore University Hospital-New York University School of Medicine, Manhasset, NY. Reprints: Ellen Kahn, MD, Department of Pathology, North Shore University Hospital, 300 Community Dr, Manhasset, NY 1 1030. the right kidney (based on computed tomographic scan). All this additional clinical information favored a diagnosis of adenocar cinoma rather than malignant mesothelioma. Subsequent studies of this tumor showed that it stained positive for Leu M1, CK7, D-PAS, and alcian blue (hyaluronidase resistant) and negative for calretinin, carcinoembryonic antigen, and CK20 (Figure 2). Elec- Figure 1. A, Transition between normal mesothelium and hyperplastic stratified and papillary structures without invasion ofthe underlying fibrous connective tissue (hematoxylin-eosin, original magnification X125). B, Higher magnification shows the papillary structure restricted to the pleural surface (hematoxylin-eosin, original magnification X250). 1598 Arch Pathol Lab Med--Vol 125, December 2001 Pulmonary Adenocarcinoma Simulating Malignant Mesothelioma--Tang et al Figure 2. Immunohistochemistry studies ofthe tumor cells. A, Leu Ml positive. B, CK7positive. C, Calretinin negative. D, CK20 negative (original magnification X200). Procedure Special stains Alcian blue Colloidal iron Mucicarmine Periodic acid-Schiff Immunohistochemistry Calretinin Cytokeratin 5/6 Thrombomodulin HBME-1 CD44S N-cadherin MOC13 BG-8 Carcinoembryonic antigen Leu-M1(CD15) E-cadherin Ber-EP-4 B72.3 Electron microscopy Microvilli Lumenlike structures Comparison of Mesothelioma and Adenocarcinoma Mesothelioma Adenocarcinoma + (hyaluronidase-sensitive) + (hyaluronidase-sensitive) - + + + + + + - + (hyaluronidase-resistant) + (hyaluronidase-resistant) + + + + + + + + + Long, slender - Short, sparse + Arch Pathol Lab Med--Vol 125, December 2001 Pulmonary Adenocarcinoma Simulating Malignant Mesothelioma--Tang et al 1599 Figure 3. Electron micrograph of the apical region of several tumor cells, which form a ductlike space with its lumen covered by short, widely spaced microvilli. L indicates lumen; N, nucleus (original mag nification X10400). tron microscopic study showed tumor cells with short, widely spaced microvilli and some cells forming ductlike lumen and api cal junction complex (Figure 3). All of these studies supported a diagnosis of adenocarcinoma. COMMENT The differential diagnosis between malignant mesothe lioma of pleura and adenocarcinoma of lung with pleural involvement is problematic.2 Their clinical features fre quently overlap. They both occur in older adults, who pre sent with chest pain, pleural effusion, and respiratory dis tress. Pleural thickening with a nodular mass within lung parenchyma and prominent hilar lymphadenopathy favors a diagnosis of adenocarcinoma with pleural involvement.3 Macroscopically, malignant mesothelioma usually pre sents as multiple grayish tan nodules in a diffusely thick ened pleura. However, this presentation is also commonly seen in primary lung adenocarcinoma with prominent pleural involvement. Microscopically, both tumors can form papillary structures. The tumor cells in an epitheli oid mesothelioma are usually more uniform, cuboidal, and less crowded than the tumor cells in adenocarcinoma, which are more pleomorphic, columnar, and crowded with nuclear molding. However, even with these guide lines, it is often difficult to differentiate malignant meso thelioma from adenocarcinoma in hematoxylin-eosinstained slides. Electromicroscopic studies and immunohistochemical studies, however, allow correct differentiation of mesothe lioma from adenocarcinoma (Table).4-7 The lesion described in our case, with microscopic fea tures typical of an epithelioid mesothelioma in the hematoxylin-eosin stain, stained negative for calretinin, was resistant to hyaluronidase in the colloidal iron stain, stained positive for Leu-M1, and had short villi and lu minal and apical junctional complex on electron micro scopic studies diagnostic of adenocarcinoma. In summary, special stains, including immunohistochemical studies and electron microscopy, are essential for the differential diagnosis of malignant mesothelioma and adenocarcinoma even when ''typical'' features of meso thelioma are noted in hematoxylin-eosin-stained slides. We thank Ms Lisa Moskowitz and Ms Eleonore Boss for per forming the immunohistochemistry studies. References 1. Moskal TL, Urschel JD, Anderson TM, Antkowiak JG, Takita H. Malignant pleural mesothelioma: a problematic review. Surg Oncol. 1999;7:5-12. 2. Koss MN, Fleming M, Przygodzki RM, Sherrod A, Travis W, Hochholzer L. Adenocarcinoma simulating mesothelioma: a clinicopathological and immuno histochemical study of 29 cases. Ann Diagn Pathol. 1998;2:93-102. 3. Crondin SC, Sugarbaker DJ. Malignant mesothelioma of the pleural space. Oncology. 1999;13:919-92 6. 4. Riera JR, Astengo-Osuna C, Longmate JA, Battifora H. The immunohisto chemical diagnostic panel for epithelial mesothelioma: a reevaluation after heatinduced epitope retrieval. Am J Surg Pathol. 1997;21:1409-1419. 5. Ordonez NG. The immunohistochemical diagnosis of epithelial mesotheli oma. Hum Pathol. 1 999;30:313-323. 6. Cury PM, Butcher DN, Fisher C, Corrin B, Nicholson AG. Value of mesothelium-associated antibodies thrombomodulin, cytokeratin 5/6, calretinin, and CD44H in distinguishing epithelioid pleural mesothelioma from adenocarcinoma metastatic to the pleura. Mod Pathol. 2000;13:107-112. 7. Chan JKC. Advances in immunohistochemistry: impact on surgical pathol ogy practice. Semin Diagn Pathol. 2000;17:170-177. 1600 Arch Pathol Lab Med--Vol 125, December 2001 Pulmonary Adenocarcinoma Simulating Malignant Mesothelioma--Tang et al