CLINICAL OBSERVATIONS IN HEPATOLOGY Hepatocellular Carcinoma and Nodular Regenerative Hyperplasia After Chemotherapy for Metastatic Colorectal Carcinoma Julien Calderaro,1,2 Daniel Azoulay,2,3 and Elie-Serge Zafrani1,2


olorectal carcinoma (CRC) is the third-most common cancer worldwide.1 Liver is the dominant metastatic site and synchronous hepatic metastases are identified in approximately 40%-50% of patients2 during diagnostic evaluation or in the course of treatment. Neoadjuvant oxaliplatin-based chemotherapy is widely used to reduce the risk of cancer relapse after surgery and, in many cases, to reduce tumor burden in order to allow complete resection.2 However, oxaliplatin-based chemotherapy may induce vascular liver injury, namely, sinusoidal obstruction syndrome (SOS), with or without nodular regenerative hyperplasia (NRH).3 We report on the case of a patient with oxaliplatin-induced vascular liver injury with NRH, in which several foci of hepatocellular carcinoma (HCC) developed. A 50-year-old man underwent partial hepatectomy for CRC metastasis. Preoperative chemotherapy included folic acid, 5-fluorouracil, and oxaliplatin (12 courses). No nodule suggestive of HCC was identified on preoperative magnetic resonance imaging. Gross examination of the surgical specimen revealed a firm nodule measuring 5 mm in diameter and located at the site of the metastatic tumor, as well as widespread hemorrhagic foci and marked nodularity. Histologically, the small nodule consisted of fibrous tissue with no remaining neoplastic cells. Also noted

were moderate intimal thickening and partial occlusion of occasional terminal hepatic veins (SOS), marked centrilobular sinusoidal dilatation (Fig. 1A), and diffuse NRH, with small regenerative nodules distributed evenly throughout the liver (Fig. 1B). Within regenerative nodules, three areas of malignant transformation into well-differentiated HCC, measuring 4, 2, and 2 mm in diameter, respectively, were fortuitously identified: Cytological abnormalities included thickened trabeculae and canalicular pseudoglands (Fig. 1C,D). Immunohistochemistry revealed diffuse glutamine synthetase expression in areas of malignant transformation, in contrast to the staining of few layers of perivenular hepatocytes in the adjacent liver (Fig. 1E,F), a feature that further supports the diagnosis of HCC.4 There was no nuclear translocation of bcatenin, and glypican 3 was not detected. Nodular regenerative hyperplasia is part of the spectrum of hepatic vascular lesions that may develop in patients with CRC treated by chemotherapy, especially with oxaliplatin-based regimens.3 HCC has very rarely been reported as a complication of NRH.5 The present case is, to the best of our knowledge, the first HCC reported in a patient with metastatic CRC with oxaliplatin-induced NRH. It suggests that such patients might be at higher risk of HCC development.

Abbreviations: CRC, colorectal carcinoma; HCC, hepatocellular carcinoma; NRH, nodular regenerative hyperplasia; SOS, sinusoidal obstruction syndrome. From the 1Department of Pathology, Henri Mondor Hospital, Cr e teil, e Paris-Est Cr e teil, Cr e teil, France; 3Department of Digestive France; 2Universit and Hepatobiliary Surgery, Henri Mondor Hospital, Cr e teil, France. Received October 11, 2013; accepted February 6, 2014. Address reprint requests to: Julien Calderaro, M.D., D e partement de Pathologie, H^ opital Henri Mondor, 51 avenue du Mar e chal de Lattre de Tassigny, 94010 Cr e teil, France. E-mail: [email protected]; Fax: 133149812733. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at DOI 10.1002/hep.27115 Potential conflict of interest: Nothing to report.

JULIEN CALDERARO, M.D.1,2 DANIEL AZOULAY, M.D., PH.D.2,3 ELIE-SERGE ZAFRANI, M.D.1,2 1 Department of Pathology Henri Mondor Hospital Cre teil, France 2 Universite Paris-Est Cr e teil Cre teil, France 3 Department of Digestive and Hepatobiliary Surgery Henri Mondor Hospital Cre teil, France


HEPATOLOGY, Vol. 60, No. 4, 2014



Fig. 1. Microscopic examination demonstrated marked centrilobular sinsusoidal dilatation (Sirius red and hematoxylin: 3400, panel A), along with diffuse parenchymal nodularity (Gordon and Sweet’s stain: 320, panel B). Foci of malignant transformation were characterized by thick trabeculae (Gordon and Sweet’s stain: 3200, panel C), cytological abnormalities, and pseudoglandular formation (3Sirius red and hematoxylin: 3400, panel D). The majority of neoplastic cells expressed glutamine synthetase (320, panel E and 3400, panel F).

References 1. International Agency for Research on Cancer. GLOBOCAN 2008 v2.0: cancer incidence and mortality worldwide. CancerBase no. 10. 2010. Lyon, France: International Agency for Research on Cancer. Available at: Accessed October 4, 2013. 2. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008;371:1007-1016.

3. Rubbia-Brandt L, Audard V, Sartoretti P, Roth AD, Brezault C, Le Charpentier M, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 2004;15:460-466. 4. Kojiro M, Wanless IR, Alves V, Badve S, Balabaud C, Bedossa P, et al. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. HEPATOLOGY 2009;49:658-664. 5. Stromeyer FW, Ishak KG. Nodular transformation (nodular “regenerative” hyperplasia) of the liver. A clinicopathologic study of 30 cases. Hum Pathol 1981;12:60-71.

Hepatocellular carcinoma and nodular regenerative hyperplasia after chemotherapy for metastatic colorectal carcinoma.

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