Lepidic intrapulmonary growth of malignant mesothelioma presenting as recurrent hydropneumothorax

CASE STUDIES d e v a s c u l a r i z e d wall o f a n a l l o g r a f t r e n a l v e i n p o o r l y s u p p o r t s the ingrowth of granulation tissue neovascular elements into the thrombus. The exact age of the thrombus in this case cannot be determined, but the patient's surgical history indicates an age o f t 0 d a y s o r less. It is p l a u s i b l e t h a t e n d o t h e l i a l hy-perplasia c o n t r i b u t e d to r e n a l i s c h e m i a b y e n h a n c i n g t h r o m b o s i s . I n s u m m a r y , we p r e s e n t t h e first r e p o r t o f I P E H i n a n a l l o g r a f t vessel, a n d we f i n d its d e v e l o p m e n t in a s s o c i a t i o n w i t h a t h r o m b u s to b e f u r t h e r e v i d e n c e t h a t I P E H r e p r e s e n t s a n u n c o m m o n e x p r e s s i o n o f t h r o m b u s o r g a n i z a t i o n . Its r a p i d d e v e l o p m e n t , i n t h a t t h e t h r o m b u s was n o m o r e t h a n 10 d a y s old, c o n t r a s t s w i t h t h e u s u a l i n d o l e n t clinical p r e s e n t a t i o n o f I P E H b u t f u r t h e r i n d i c a t e s its r e a c t i v e n a t u r e .

REFERENCES 1. Masson P: Hemangio-endotheliome vegetant intravascnlaire. Bull Soc Anat Paris 93:517-523, 1923 2. Kuo T-T, Sayers CP, Rosai J: Masson's "vegetant intravascular hemangioendothelioma:" A lesion often mistaken for angiosarcoma. Cancer 38:12271236, 1976 3, Salver WR, Salyer DC: Intravascular angiomatosis: Development and distinction from angiosarcoma. Cancer 36:995-1001, 1975 4. Cozzuno C, Guarino M, Dodero P, et al: Intravascular endothelial proliferations in children. Am J Clin Pathol 71:247-252, 1979 5. Hashimoto H, Dalmm'u Y, Enjoji M: Intravascular papillary endothelial hyperplasia: A clinicopathologic study of 91 cases. Pan J Dermatopatbol 5:539545, 1983 6. Barr RJ, Graham JH, Sherwin LA: Intravascular papillary endothelial hyperplasia: A benign lesion mimicking angiosarcoma. Arch Dermatol 114:723726, 1978 7. Clearkin KP, Enzinger FM: lntravascular papillary endothelial hyperplasia. Arch Pathol Lab Med 100:441444, 1976 8. Stout AP, Lattes R: Tumors of the soft tissue. Atlas of Tumor Pathology, 2nd series. Washington, DC, Armed Forces Institute of Pathology, 1967, pp 147-149 9. Kreutner A, Smith RM, Trefny FA: Intravascular papillary endothelial

hyperplasia: Light and electron microscopic observations of a case. Cancer 42:2304-2310, 1978 10. Albrecht S, Kahn HJ: IInmunocheniistry of intravascular papillary endothelial h)?erplasia. J Cutan Pathol 17:16-21, 1990 11. Salyer WR, Salyer DC, Hutchins GM: Local arterial wall injury caused by thromboemboli. Am J Pathol 75:285-300, 1974 12. Pins MR, Rosenthal DI, Springfield DS, et al: Florid extravascular papillary endothelial hyperplasia (Masson's pseudoangiosarcoma) presenting as a soft tissue sarcoma. Arch Pathol Lab Med 1993 117:259-263, 1993 13. Park JY, Chung-Park M, Snow N: Intravascular papiIlary endothelial hyperplasia of superior vena cava: A rare cause of the superior vena cava syndrome. Thorax 46:272-273, 1991 14. PyeJK: A case of Masson's vegetant intravascular haemangioendothelioma presenting in a large neck vein. Clin Oncol 9:57-59, 1983 15. Eichorn JH, Rosenberg AE: Intravascular papillary endothelial hyperplasia involving the synovium. Arch Pathol Lab Med 112:647-650, 1988 16. Garber BB, Prestipino AJ, Pollack HM, et al: Masson's tumor of the kidney: A new renal lesion. J Urol 143:344-346, 1990 17. Barua R, Munday RN: Intravascular angiomatosis in female urethral mass: Masson intravascular hemangioendothelioma. Urology 21:191-193, 1983 18. Eusebi V, Fanti A, Fedeli F, et al: Masson's intravascular vegetant hemangioendothefioma. Tumori 66:489-498, 1980 19. Garmer JC, Hashida Y, O'Gorman M, et al: Endothelial proliferation in paroxysmal nocturnal hemoglobinuria. Pediatr Patho[ 8:313-320, 1988 20. Dunphy CH, Sotelo-Avila C, Luisiri A, et al: Paroxysmal nocturnal hemoglobinuria associated with venous thrombosis and papillary endothelial hyperplasia presenting as ulcerated duodenal mass. Arch Pathol Lab Med 118:837-840, 1994 91. Miyamoto H, Nagatani T, Mohfi S, et al: Intravascular papillary endothelial hyperplasia. Clin Exp Dermatol 13:411-415, 1988 22. Kuo T, Gomez LG: Papillary endothelial proliferation in cystic lynrphangiomas. Arch Pathol Lab Med 103:306-308, 1979 23. Axiotis CA, Merino MJ, pan K, et al: Papillary endothelial hKperplasia in the thyroid following fine-needle aspiration. Arch Pathol Lab Med. I15:240242, 1991 24. RosalJ, Akerman LR: Intravenous atypical vascular proliferation, Arch Dermatol 109:714-717, 1974 25. Enzinger FM, Weiss SW (eds): Soft Tissue Tumors, 3rd ed, St. Louis, MO, Mosby, 1995, pp 647~548 26. Stewart M, Smoger BR: Multiple lesions ofintravascular papillary endothelial hyperplasia (Masson's lesions). Arch Pathol Lab Med 118:315-316, 1994 27. Salyer WR, Page DL, Hntchins GM: The development of cardiac my-xomas and papillary endocardial lesions from mural thrombus. Am Heart J 89:417, 1975

LEPIDIC INTRAPULMONARY GROWTH OF MALIGNANT MESOTHELIOMA PRESENTING AS RECURRENT HYDROPNEUMOTHORAX HONG W u , MD, PhD, GREGORYTINO, MD, FRANKH. GAMMON, MD, LARRYR. KAISER, MD, AND GIUSEPPE G. PIETRA, MD

We report a case of malignant mesothelioma with u n u s u a l clinical and histological findings. The patient presented with recurrent hydropneumothorax and minimal pleural thickening on chest computed tomography (CT). Histologically, the pleura was involved by the malignant mesothelioma, albeit to a limited degree. Unexpectedly, the lung parenchyma from two different lobes showed focal nests of mesothelioma ceils filling the alveolar spaces and growing on the luminal surface of the alveolar septa, closely resembling the multicentric growth pattern of bronchioloalveolar adenocarcinoma. Immunohistochemical a n d ultrastrnctural studies confirmed that the pulmonary lesions were an extension of the malignant mesothelioma. This

case illustrates clinically, the importance of a high index of suspicion for malignancy in older patients with unexplained recurrent hydropneumothorax; and histologically the potential of malignant mesothelioma to invade the lung at an early stage of growth. HUM PATrlOL 27:989--992. Copyright © 1996 by W.B. Saunders Company Key words: malignant mesothelioma, bronchioloalveolar carcinoma, hydropneumothorax. Abbreviaflogs: CT, computed tomography; PPD, purified protein derivative; HEENT, head, eyes, ears, nose, and throat; CEA, carcinoembryonic antigen; EMA, epithelial membrane antigen.

The clinical and pathological diagnosis of early pleural mesothelioma is often very difficult because of the nonspecificity of the symptoms and the histological overlap between malignant mesothelioma and benign reactive mesothelial proliferation or other malignant tumors. ] The distinction be-

t w e e n m a l i g n a n t m e s o t h e l i o m a a n d p e r i p h e r a l p u l m o n a r y adenocarcinomas can be especially problematic. 2 We report h e r e a c a s e o f m a l i g n a n t m e s o t h e l i o m a w i t h a n u n u s u a l clinical a n d h i s t o p a t h o l o g i c p r e s e n t a t i o n . Clinically, t h e t u m o r p r e s e n t e d as r e c u r r e n t h y d r o p n e u m o t h o r a x and minimal p l e u r a l t h i c k e n i n g o n c h e s t c o m p u t e d t o m o g r a p h y ( C T ) . Histopathologically, there was intxapulmonary extension wtth an unique pattern of lepidic growth of malignant mesothelial cells a l o n g t h e a l v e o l a r s e p t a s i m u l a t i n g a b r o n c h i o l o a l v e o l a r carcinoma of the lung.

From the Division of Anatomic Pathology, D e p a r t m e n t of Pathology a n d Laboratory Medicine, P u l m o n a r y a n d Critical Care Division, D e p a r t m e n t of Medicine, Division of Thoracic Surgery, D e p a r t m e n t of Surgery, Hospital of University of Pennsylvania, Philadelphia, PA. Address correspondence a n d reprint requests to H o n g Wu, MD, PhD, D e p a r t m e n t of Pathology a n d Laboratory Medicine, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104. Copyright © 1996 by W.B. Saunders C o m p a n y 0046-8177/96/2709-002955.00/0

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CLINICAL HISTORY A 69-year-old w h i t e m a n , e x - s m o k e r , w a s a d m i t t e d f o r evaluation of right hydropneumothorax associated with progressive d y s p n e a o n e x e r t i o n .

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It was well known that he was without underlying lung disease until 4 months before admission when he sustained a soft tissue injury to the right lateral chest after a fall at home. He did not seek medical attention. Several weeks later, he noted onset of progressive dyspnea on exertion without accompanying systemic or respiratory complaints. A chest radiograph obtained elsewhere revealed a right hydropneumothorax. A chest CT scan confirmed this finding as well as minimal pleural thickening in the right upper lobe. A chest thoracostomy tube was placed; fluid chemistries were consistent with a sterile exudate. Cytological examination revealed mononuclear inflammatory cells and atypical mesothelial cells. Routine, fungal and mycobacterial stains and cultures were unrevealing. A purified protein derivative (PPD) was negative. The patient improved symptomatically, and the chest tube was removed after resolution of the air leak. The management plan included close radiographic and clinical follow-up. He remained otherwise asymptomatic until 2 to 3 weeks before admission when he again noted dyspnea on exertion. He denied fevers, pleuritic chest pain or other localizing complaints. A chest radiograph revealed recurrent right hydropneumothorax. His medical history was remarkable for coronary artery disease, and a murmur of aortic regurgitation. He had a 60 to 70 pack-year history of cigarette smoking, which he discontinued several years before admission. He was a retired engineer, and had worked for many years as a naval officer on submarines, where he may have been exposed to asbestos. There was no history of alcohol, illicit drug use, or other toxic exposures. Physical examination revealed a mildly tachypneic, but otherwise well-appearing man; his blood pressure was 140/ 72, pulse was 80, and a respiratory rate of 24. Oxyhemoglobin saturation at rest on room air was 86%. There were no skin rashes or palpable lymphadenopathy. Head, eyes, ears, nose, and throat (HEENT) exam was unremarkable. There was no subcutaneous emphysema, tracheal deviation, or stridor. The left lung field was clear; diminished breath sounds with dull-

FIGURE 2. At higher magnification lepidic growth of malignant mesothelial cells along the alveolar septa, mimicking bronchioloalveolar carcinoma, is clearly observed (HematoxyIin-eosin stain; original magnification x l00).

ness to percussion, and decreased tactile fremitus were present on the right. Cardiac examination showed a regular rate, and a m u r m u r of aortic regurgitation. The abdomen was normal; no clubbing, cyanosis, or edema was present. Chest radiograph revealed a large right hydropneumothorax without mediastinal shift. A contrast-enhanced CT scan again confirmed the hydropneumothorax associated with atelectasis of the right middle and lower lobes. Slight pleural thickening and fibrous adhesions was present but there was not a dominant pleural-based mass. No other abnormalities were present. The patient was initially treated with supplemental oxygen and general supportive care. He then underwent a diagnostic right video thoracoscopy. A large amount of turbid pleural fluid was present. The visceral pleural surface was covered by thin fibrinous exudate; small, whitish nodular densities were observed on the visceral pleura of the upper and lower lobes. A biopsy was performed on the pleura, as well as right upper and lower lobes. PATHOLOGICAL FINDINGS

FIGURE 1. Wedge biopsy of the right upper lobe showing nodular growth of malignant mesothelioma on the visceral pleura (arrow) and underlying alveolar spaces filled with tumor cells (Hematoxylin-eosin stain; original magnification ×40). 990

Cytological examination of the pleural fluid revealed atypical mesothelial cells in a background of typical mesothelial and mononuclear inflammatory cells. Biopsies of the pleura showed a malignant mesothelioma forming small nodules on the pleural surface and infiltrating the pleural connective tissue. The predominant growth pattern was that of papillary-tubular structures lined by atypical mesothelial cells with "glassy" cytoplasm, round nuclei with fine chromatin and prominent single nucleoli. Occasional tumor cells showed prominent cytoplasmic vacuoles. Macroscopic examination of the wedge resection specimens of the right upper and lower lobes showed minimal thickening of the visceral pleura and multiple small, ill-defined nodules within the lung parenchyma. Histological sections of the right upper lobe wedge revealed thickened, fibrotic pleura with dilated vessels and proliferation of mesothelioma cells similar to the ones described previously

CASE STUDIES

(Fig 1). More striking pathological changes were noted within the lung parenchyma, which showed minimally thickened alveolar septa lined with cuboidal to columnar cells with eosinophilic, slightly "glassy" cytoplasm, large round nuclei with fine chromatin and a single, distinct nucleolus (Fig 2). In other fields, the tumor cells filled the alveolar spaces and were admixed with alveolar macrophages and lymphocytes (Fig 1). In contrast to the right upper lobe wedge, tile lower lobe wedge exhibited more prominent pleural proliferation of mesothelial cells forming short tubulo-papillary structures. The lung parenchyma revealed only a small area of lepidic growth of tumor cells similar to the ones described above. Asbestos bodies were not identified in either lung specimens. Both the pleural and pulmonary tumor cells showed the characteristic histochemical and immunohistochemical reactions of mesothelial cells. The cytoplasmic vacuoles were positive for acidic mucosubstance by the colloidal iron stain sensitive to hyaluronidase digestion, and negative for neutral mucosubstance by the mucicarmine stain. The tumor cells were positive for cytokeratin (AE1/3, Boehringer Manheim Diagnostics, Indianapolis, IN), negative for CEA (BectonDickinson, Mountain View, CA), LeuM1 (DAKO Corp, Carpenteria, CA) and showed peripheral membranous staining for EMA (DAKO Corp) (Fig 3). By electron microscopy the tumor cells were characterized by numerous slender surface microvilli, perinuclear bundles of cytoskeletal filaments, and well-developed desmosomes (Fig 4 and 5).

DISCUSSION Malignant m e s o t h e l i o m a is an u n c o m m o n t u m o r of the mesothelial cells. T h e incidence of the disease is higher a m o n g older m e n with asbestos exposure. ~-4 Although in a high percentage of cases, a history of asbestos exposure is not elicited. 5-6 T h e most c o m m o n presentation of malignant mesothelioma is chest pain, dyspnea, and pleural effusion. A handful of cases have b e e n r e p o r t e d in which the

FIGURE 3. Immunohistochemical staining of the lung biopsy showing faint membranous staining pattern with EMA of the mesothelial cells growing on the alveolar septa (Original magnification x400).

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FIGURE 4. Representative electromicrophotograph of the pieural tumor cells showing long, slender surface microvilli (uranyl acetate-lead citrate, original magnification x7,500)

presenting symptom was spontaneous p n e u m o t h o r a x or r e c u r r e n t p n e u m o t h o r a c e s , 7-9 but how m a n y of these cases h a d also h y d r o p n e u m o t h o r a x is difficult to determine f r o m the clinical descriptions. In most of these r e p o r t e d cases, a diagnosis of malignancy was not suspected until histological examination. Based on the clinical and radiological features of this patient, the initial clinical impression was that of a traumatic hydrop n e u m o t h o r a x . However, because of a r e c u r r e n t hydrop n e u m o t h o r a x and the presence of atypical cells in the pleural cytology, a diagnostic and therapeutic thoracoscopic exploration and biopsy was u n d e r t a k e n to rule out malignancy, tuberculosis, or other infections. In this case, b o t h the atypical cells lining the alveolar septa and the pleural surface showed cytological, immunohistochemical, and ultrastructural features of malignant mesothelioma. However, at low-power, the lepidic growth pattern of the t u m o r cells along the alve-

FIGURE 5. Electromicrophotograph of the tumor cells growing on the alveolar septa showing long, slender surface microvilli (arrows), confirming their mesothelial origin, (Tissueretrieved from paraffin-embedded sections, uranyl acetate-lead citrate, original magnification x30,000).

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olar septa closely mimicked the histological appearance of a bronchioloalveolar carcinoma. 1° The concomitant presence of pleural lesions histologically characteristic of a malignant mesotheliolna, and a peripheral pulmonary lesion characteristic of a bronchioloalveolar adenocarcinoma, posed a diagnostic dilemma. It is wellknown that peripheral pulmonary adenocarcinomas can seed the pleura, giving a "pseudomesotheliomatous" appearanceY 1 Also, the possibility of coexisting malignant mesothelioma and pulmonary adenocarcinoma had to be considered. 12a3 The differential diagnosis was especially problematic in this case, because of the minimal extent of the pleural lesions. Additional studies were utilized. Both the pleural and lung specimens showed a lack of neutral mucin, negative carcinoembryonic antigen (CEA) or LeuM1 staining, membranous staining for epithelial membrane antigen (EMA), and ultrastructural features of mesothelial cells, confirming the pulmonary lesion as an extension of the malignant mesothelioma. In advanced cases of malignant mesothelioma there is often direct extension into the underlying lung parenchyma. However, the present case is unusual because the extension of the malignant mesothelial cells into the lung occurred with minimal pleural tumor burden. Furthermore, the lepidic pattern of growth of the tumor cells over the alveolar septa in two different lobes, closely mimicked multicentric growth of bronchioloalveolar adenocarcinoma. We have found only two other cases of diffuse intrapulmonary growth of malignant mesothelioma, with tumor cells extending into the lung in a lepidic growth pattern. In one case, radiological imaging studies showed both pleural thickening and right upper lobe densities. The diagnosis of pulmonary involvement was reached by sputum cytology.14The second case was reported as a clinicopathological exercise of a 61-year-old woman with pleural effusion and multiple pulmonary nodules, as well as pleural thickening

on chest radiograms. 15 In both of these cases, there was extensive pleural disease with pleural thickening shown by radiological studies and a diagnosis of mesothelioma was suspected preoperatively. 14-15The current case represents an early stage of the pleural and lung involvement by malignant mesothelioma. It shows the difficulties in diagnosing this disease in an early phase when new modalities of treatment might be attempted. Acknowledgment. The authors thank Ms. Minda for her excellent electron-microscopic skills and photography. REFERENCES 1. Skov BG, Lauritzen Atr, Hirsch F, et al: The histopathological diagnosis of malignant mesothelioma v. pulmonary adenocarcinoma: Reproducibility of the histopathological diagnosis. Histopathology 24:553-557, 1994 2. DessyE, Pietra GG: Pseudomesotheliomatous carcinoma of the lung. An immunohistochemical and ultrastructural study of three cases. Cancer 68:17471753, 1991 3. Wright WE, Sherwin RP, Dickson EA, et ah Malignant mesothelioma: Incidence, asbestus exposure, and reclassification of histopathology. BrJ Industrial Med 41:39-45, 1984 4. Hillerdal G: Malignant mesothelioma 1982: Review of 4,710 published cases. BrJ Dis Chest 77:321-343, 1983 5. Pelnar PV: Further evidence of non-asbestos-related mesothelioma: A review of the literature. ScandJ Work Environ Health 14:141-144, 1988 6. Peterson JT, Greenberg SD, Buffler PA: Non-asbestus-related malignant mesothelioma: A review. Cancer 54:951-960, 1983 7. Sheard JD, Taylor W, Soorae A, et ah Pneumothorax and malignant mesothelioma in patients over the age of 40. Thorax 46:584-585, 1991 8. Situnayake RD, Middleton WG: Recurrent pneumothorax and malignant pleural mesothelioma. Respir Med 85:255-256, 1991 9. Mannes GP, Gouw AS, Berendsen HH, et ah Mesothelioma presenting with pneumothorax and interlobar mmour. Eur Respir J 4:120-121,1991 10. Hammar SP: Common neoplasms. In Dail DH, Hammar SP (ed): Pulmonary Diseases, ed 2. New York, Springer-Verlag, 1994 11. KossM, Travis W, Moran C, et al: Psendomesotheliomatous adenocarcinoma: a reappraisal. [Review]. Semin Diag Pathol 9:117-123, 1992 12. Cagle PT, Wessels R, Greenberg SD: Concurrent mesothelioma and adenocarcinoma of the lung in a patient with asbestosis. Mod Pathol 6:438441, 1993 13. Cagle PT: Concurrent mesothelioma and adenocarcinoma of the lung in a patient with asbestosis. Mod Pathol 6:438, 1993 [letter; comment]. Mod Pathol 7:148-149, 1994 (letter) 14. Nakajima M, Manabe T, Yagi S: Appearance of mesothelioma cells in sputum. A case report. Acta Cytol 36:731-736, 1992 15. Scully RE, Mark EJ, McNeely WF, et al: Case records of the Massachusetts Generel Hospital: Weekly clinicopathological excises: Case 23-1987. N Engl J Med 4:1462-1470, 1987

SMALL CELL UNDIFFERENTIATED CARCINOMA OF THE COLON ASSOCIATED WITH HEPATOCELLULAR CARCINOMA IN AN IMMUNODEFICIENT PATIENT HOWARDJ. ZIRIaN, MD, JACOVLEVY,MD, AND LEONIDKATCHKO,MD Small cell undifferentiated carcinoma (oat cell carcinoma) is a malignant epithelial neoplasm with neuroendocrine features. It can appear as a primary tumor in many organs besides the lung, including the colon. We report a case of primary small cell undifferentiated carcinoma of the left colon with omental metastases in a 23-year-old man with a history of X-linked hyper-IgM syndrome. The patient had a simultaneous primary hepatocellular carcinoma. A literature review of this rare colonic malignancy is presented together with a discussion of the possible relationship of this tumor with hepatic malignancy andimmunodeficiency. HuM PATHOL27:992-996. Copyright© 1996 by W.B. Saunders Company

Key words: small cell undifferentiated carcinoma of colon, oat cell carcinoma, neuroendocrine tumor, hepatocellular carcinoma, Xlinked hyper-IgM syndrome. Abbreviations: SCUC-C, small cell undifferentiated carcinoma of the colon; Ig, immunoglobulin; ANF, antinuclear factor; ANC, absolute neutrophil count; M G , intravenous immunoglobulin; NSAID, non-steroidal anti-inflammatory drug; PCR, polymerase chain reaction; IMIG, intramuscular immunoglobulin; AIDS, acquired immune deficiency syndrome; HIV, human immunodeficiency virus.

From the Institute of Pathology, Department of Pediatrics, and Soroka Medical Center, the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Address correspondence and reprint requests to Howard J. Zirkin, MD, Akrav 38, PO Box 423, M e t a l Israel 85025. Copyright © 1996 by W.B. Saunders Company 0046-8177/96/2709-002655.00/0

S m a l l cell u n d i f f e r e n t i a t e d c a r c i n o m a o f t h e c o l o n (SCUC-C) w i t h o a t cell-like h i s t o l o g y a n d n e u r o e n d o c r i n e f e a t u r e s by u l t r a s t r u c t u r a l analysis ( m e m b r a n e - b o u n d d e n s e c o r e g r a n u l e s ) h a s b e e n k n o w n since 1978.1 Clinically, t h e s e t u m o r s a r e c h a r a c t e r i z e d by aggressive b e h a v i o r w i t h early l y m p h n o d e a n d liver m e t a s t a s e s Y A n a s s o c i a t i o n w i t h c o l o n i c a d e n o m a s h a s also b e e n r e p o r t e d . ~

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