Malignant mesothelioma of the peritoneum invading the liver and mimicking metastatic carcinoma: A case report

Pathology – Research and Practice 207 (2011) 395–398

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Malignant mesothelioma of the peritoneum invading the liver and mimicking metastatic carcinoma: A case report Shigenori Nagata a , Miki Tomoeda a , Chiaki Kubo a , Hidenori Yoshizawa a , Michiko Yuki a , Masanori Kitamura a , Akemi Takenaka a , Katsuyuki Nakanishi b , Toshiya Yagi c , Fumio Imamura c , Yasuhiko Tomita a,∗ a

Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan Department of Diagnostic Radiology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan c Department of Clinical Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan b

a r t i c l e

i n f o

Article history: Received 3 August 2010 Received in revised form 8 April 2011 Accepted 11 April 2011 Keywords: Cancer of unknown primary site Liver invasion Malignant peritoneal mesothelioma

a b s t r a c t We present a case of malignant mesothelioma of the peritoneum with massive direct invasion to the liver in a 58-year-old Japanese woman. She had no history of asbestos exposure or other malignancies. Abdominal computed tomography revealed one 8-cm intrahepatic mass adjacent to the abdominal wall with peritoneal thickening, multiple smaller nodules in the peritoneal cavity, and intra-abdominal lymphadenopathy. Liver biopsy showed a small cluster of atypical cells similar to epithelial neoplasm, which formed a tubulopapillary structure. The tumor cells were positive for calretinin with strong nuclear and cytoplasmic expression together with podoplanin (D2-40) and some cytokeratins, but were negative for hepatocyte paraffin 1 and other adenocarcinoma markers. We confirmed a diffuse peritoneal mesothelioma with direct invasion to the liver. Liver masses with other peritoneal nodules are mostly encountered as metastatic diseases. However, the possibility of mesothelioma should be considered, even in women without an apparent history of asbestos exposure. © 2011 Elsevier GmbH. All rights reserved.

Introduction Peritoneal malignant mesothelioma (PMM) is a highly aggressive neoplasm, but it often takes a long time to reach an accurate diagnosis, because the symptoms and radiological manifestations of PMM are nonspecific in most cases [2,12]. Although PMM is usually confined to the peritoneal cavity for most of its natural history, several intra- and extra-abdominal organs, such as the lymph nodes, lung, bone, liver, and umbilicus, might be involved by metastatic PMM [6,8]. Liver involvement by PMM mainly presents as hematogenous metastases at far-advanced stages, and the apparent direct invasion of PMM is a minor form of tumor involvement because the typical growth pattern of PMM is locally expansive rather than infiltrative. A variety of primary or secondary peritoneal neoplasms should be considered in the differential diagnosis if there is no evidence of a visceral primary malignancy. The sex of the patient greatly affects the differential diagnosis of primary and secondary peritoneal neoplasms because a few histological types of peritoneal tumors occur exclusively in women [9,10]. Here, we report a female

∗ Corresponding author. Tel.: +81 6 6972 1181; fax: +81 6 6981 8336. E-mail address: [email protected] (Y. Tomita). 0344-0338/$ – see front matter © 2011 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2011.04.004

patient with PMM who was suspected to have peritoneal carcinomatosis of unknown origin as the initial presentation. However, the pathological examination of a biopsy specimen from the liver clearly demonstrated primary PMM with extensive hepatic invasion. Case report A 58-year-old Japanese woman who had complained of abdominal discomfort for 2 months was admitted to our hospital. She had no past medical history of malignancy or asbestos exposure. Physical examination showed no significant signs. Although the patient had neither clinical evidence of hepatorenal failure nor hematopoietic disease, hematological and blood chemistry tests revealed marked hypoalbuminemia (serum albumin level, 2.8 g/dL) and anemia (hemoglobin, 10.6 g/dL; hematocrit, 33.0%). Elevated serum levels of C-reactive protein (4.8 mg/dL) and soluble interleukin-2 receptor (961 U/mL) were observed. Among selected tumor markers, cancer antigen 125 level was markedly elevated (706 U/mL). Abdominal ultrasonography revealed a huge mass of 8 cm in the largest diameter in the liver, accompanied by a small amount of ascites and pleural effusion. Abdominal computed tomography (CT) demonstrated an intrahepatic nodule with heterogeneous density in the posterior segment, which was adjacent to the dorsal abdom-

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Fig. 1. Abdominal CT. (a) Cross-section showing a huge intrahepatic mass with a heterogeneous density pattern within the tumor. (b) Coronal reconstruction revealed that the mass was partially attached to the dorsolateral abdominal wall and the thickened peritoneum, and extensively covered the surface of the right hepatic lobe (arrows).

inal wall with peritoneal thickening (Fig. 1). It revealed too little ascites to obtain in the right lateral parahepatic gutter, whose CT Hounsfield number (23.9) did not strongly indicate viscous fluid. Multiple nodular lesions in the pelvic cavity and para-aortic and intra-abdominal lymphadenopathy were also observed. There was no clinical evidence of a visceral primary malignancy, except in the liver. The patient underwent a liver needle biopsy with aspiration cytology. Histological sections stained with hematoxylin and eosin (H&E) showed a small cluster of atypical cells 0.5 mm × 0.2 mm in size (Fig. 2a). The atypical cells formed a tubulopapillary structure and were embedded in the normal liver parenchyma, with an unclear margin and modest stromal collagen with moderate inflammatory infiltrates. The proliferating cells had relatively abundant, eosinophilic or clear cytoplasm and large nuclei, many of which had prominent nucleoli. Our differential diagnosis included primary and secondary liver neoplasms, such as hepatocellular carcinoma, cholangiocellular carcinoma, and adenocarcinoma that had metastasized from an unknown primary site. Other diagnostic candidates were mesenchymal or mesothelial neoplasms that can present with epithelioid features. Aspiration cytology revealed relatively large cell clumps with an increased nuclear to cytoplasmic ratio and unclear cell borders (Fig. 2b). Concentric round nuclei were uniform in shape and size, having prominent nucleoli. Intercellular windows were not apparent on the cytology specimen. The cytological appearance indicated epithelial or epithelioid malignant neoplasm, although it was inconclusive. Immunohistochemical analysis was performed, considering in the differential diagnosis several histological types of tumor, such as adenocarcinoma, hepatocellular carcinoma, and epithelioid mesothelioma. Obvious nuclear and cytoplasmic expression of calretinin (Nichirei, Tokyo, Japan) and membranous podoplanin (D2-40) (Nichirei) staining in most tumor cells suggested a strong possibility of mesothelioma. Most tumor cells were also positive for cytokeratin (CK) 19, faintly positive for h-caldesmon (Lab Vision, Fremont, CA, USA) and CK 7, but negative for thrombomodulin (Lab Vision), hepatocyte paraffin 1 (Hep Par-1), monoclonal carcinoembryonic antigen (CEA), EA Ber-EP4, MOC-31, TAG-72 (B72.3) (Lab Vision), CA 19-9, CK 5/6, Wilms’ tumor 1 (WT-1), and estrogen receptor (all the antibodies except for calretinin, podoplanin, hcaldesmon, thrombomodulin, and TAG-72 from Dako A/S, Glostrup, Denmark). Based on these findings, we confirmed a diagnosis of dif-

fuse epithelioid PMM with extensive liver involvement. Essential immunohistochemical figures are shown in Fig. 2c–k. Discussion Primary PMM is an uncommon malignant neoplasm that accounts for 6–10% of all malignant mesotheliomas [1]. Diffuse mesothelioma in the peritoneal cavity is highly aggressive and incurable, with only a few exceptions, such as well-differentiated papillary mesothelioma in women. The majority of all malignant mesotheliomas occur in men, with a median age of 60 years at presentation. In women, PMM occurs in a slightly younger age group (mean age, 50 years) [4]. Asbestos exposure has been shown to be the etiology in 60% of PMMs in men and 23% in women [4]. At the early presentation of PMM, a suspected diagnosis of peritoneal carcinomatosis of unknown origin is occasionally given to patients because their symptoms and clinical course are usually elusive in PMM. The exact percentage of PMMs among tumors initially interpreted as a neoplasm of unknown origin is unclear. One report has described that diagnostic laparoscopy and peritoneal biopsy have confirmed peritoneal mesothelioma in one (0.8%) of 129 male and female patients with ascites of unknown origin [3]. Primary peritoneal tumors, such as diffuse mesothelioma, multicystic mesothelioma, papillary serous carcinoma (PSC), leiomyomatosis peritonealis and desmoplastic small round cell tumor, are a rare group of malignant or potentially malignant neoplasms that share clinical manifestations because of a common site of origin, and affect diverse patient populations [9,10]. Primary peritoneal PSC occurs almost exclusively in women. It is histologically identical to ovarian PSC and can be indistinguishable from metastatic ovarian carcinoma. Secondary peritoneal tumors often manifest as peritoneal carcinomatosis, and can be of ovarian, gastric, pancreatic, colonic, and, more rarely, breast origin [2,11]. Knowledge of the spectrum of differential diagnoses in primary and secondary peritoneal tumors is essential for a precise diagnosis, along with their clinical and radiological characteristics. CT findings of PMM are not sufficient to establish a definitive diagnosis of mesothelioma, although they are useful for detection, staging, and guiding biopsy of peritoneal masses. Distinct patterns on cross-sectional images that reflect gross appearance of diffuse PMM have been described as follows: diffuse involvement of the peritoneal cavity, focal intraperitoneal masses, or both

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Fig. 2. Cytohistological features of peritoneal malignant mesothelioma on H&E-stained (a, 200×) and Papanicolaou-stained (b, 400×) specimens. Immunohistochemically, the tumor cells are positive for calretinin (c, 200×), podoplanin (d, 200×), and CK 19 (e, 200×), faintly positive for h-caldesmon (f, 200×) and CK 7 (g, 200×), but negative for thrombomodulin (h, 200×), Hep Par-1 (i, 200×), MOC-31 (j, 200×), and estrogen receptor (k, 200×).

[10,13]. Occasionally, one large mass and multiple serosal implants in the peritoneal or pelvic cavities are seen, as in our case. The amount of ascites associated with the tumor is variable, and ranges from massive ascites to focal, loculated fluid collections [10]. In the present case, the abdominal CT scan revealed the huge intrahepatic mass continuous to the same-density peritoneal thickening of the abdominal wall, suggesting a tumor arising from the peritoneal wall. Histological examination of the liver-biopsy specimen with expanded immunohistochemical panels provided clear evidence of mesothelioma [5,9,14]. Immunohistochemical panels are essential for the pathological diagnosis of PMM. In the guideline, markers useful for differentiation between PMM and PSC are summarized as follows [9]: calretinin as a positive marker for PMM; and MOC-31, BG8, BerEP4, and estrogen receptor as positive markers for PSC. All of these have both a high sensitivity and a relatively high specificity. D2-40 is frequently positive in PMM, but also has a wide spectrum of positivity in PSC (13–65%). B72.3 is almost always negative in PMM and positive in the majority of PSC (65–100%), but focal staining occasionally seen in PSC causes its limited util-

ity [9]. Other investigators have described h-caldesmon as a useful marker for PMM with 100%-sensitivity and 95%-specificity [5]. Thrombomodulin is not useful for differentiation between PMM and PSC because of conflicting positive rates in PMM (33–74%) and PSC (1–35%) [5,14]. Markers useful to distinguish PMM from non-gynecological adenocarcinoma are as follows: calretinin and WT-1 as positive markers for PMM; MOC-31, BG8, Ber-EP4, CEA, and B72.3 as positive markers for non-gynecological adenocarcinomas mainly originating from the digestive system [5]. In the present case, the diagnostic significance of CK 19 was limited because most PMM and cholangiocellular carcinoma, as well as some hepatocellular carcinomas, are positive for it [7,15]. We considered the tumor as a diffuse PMM rather than a localized type although the other peritoneal nodules were not examined pathologically. In diagnosing a typical localized PMM, there needs to be clear evidence of pure localization beyond information obtainable from microscopic slides [4,10]. The tumor in our case did not show any appearances characteristic of localized PMM, such as a solitary lesion having a sharp circumference without any other peritoneal nodularity. Most diffuse PMM spread along the parietal

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and visceral peritoneal surfaces and form a continuous tumor rind that encases the peritoneal cavity and intraperitoneal organs [4,10]. In advanced disease, the tumor may spread into viscera, particularly into the wall of the bowel and the omentum in the peritoneal cavity. Although minor hepatic invasion or intrahepatic metastasis may occur in diffuse PMM, massive direct invasion of the liver has not been found in our search of the literature. When liver masses are detected together with some peritoneal nodules, the principal diagnostic concern is metastatic disease, which is most frequently encountered. However, pathologists should consider a variety of primary and secondary peritoneal tumors in the differential diagnosis, including PMM with direct invasion of the liver, even if the patients are women without evident history of asbestos exposure. References [1] R.L. Attanoos, A.R. Gibbs, Pathology of malignant mesothelioma, Histopathology 30 (1997) 403–418. [2] P.M. Baker, P.B. Clement, R.H. Young, Malignant peritoneal mesothelioma in women: a study of 75 cases with emphasis on their morphologic spectrum and differential diagnosis, Am. J. Clin. Pathol. 123 (2005) 724–737. [3] C.M. Chu, S.M. Lin, S.M. Peng, C.S. Wu, Y.F. Liaw, The role of laparoscopy in the evaluation of ascites of unknown origin, Gastrointest. Endosc. 40 (1994) 285–289. [4] A. Churg, P.T. Cagle, V.L. Roggli, Diffuse malignant tumors of the serosal membranes, in: A. Churg, P.T. Cagle, V.L. Roggli (Eds.), AFIP Atlas of Tumor Pathology, Series 4, Tumors of the Serosal Membranes, ARP Press, Silver Spring, MD, USA, 2006, pp. 33–82. [5] C.E. Comin, C. Saieva, L. Messerini, h-Caldesmon, calretinin, estrogen receptor, and Ber-EP4: a useful combination of immunohistochemical markers for differ-

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