Oxaliplatin-induced Liver Injury Mimicking Metastatic Tumor on Images: A Case Report

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1 Jpn J Clin Oncol 2013;43(10) doi: /jjco/hyt113 Advance Access Publication 19 August 2013 Oxaliplatin-induced Liver Injury Mimicking Metastatic Tumor on Images: A Case Report Kaori Uchino 1,2,*, Masayoshi Fujisawa 1, Takanori Watanabe 3, Yoshikatsu Endo 3, Tetsuji Nobuhisa 3, Yusuke Matsumoto 3, Kyohei Kai 3, Shiso Sato 3, Kenji Notohara 4 and Akihiro Matsukawa 2 1 Department of Pathology, Japanese Red Cross Society Himeji Hospital, Himeji, 2 Department of Pathology and Experimental Medicine, Graduated School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 3 Department of Gastroenterological Surgery, Japanese Red Cross Society Himeji Hospital, Himeji and 4 Department of Anatomic Pathology, Kurashiki Central Hospital, Kurashiki, Japan *For reprints and all correspondence: Kaori Uchino, Department of Pathology, Japanese Red Cross Society Himeji Hospital, Shimoteno, Himeji , Japan. kaoriuchino@yahoo.co.jp Received April 21, 2013; accepted July 18, 2013 Oxaliplatin-based chemotherapy is widely used for advanced colorectal cancer treatment, but it occasionally induces liver injury that is characterized histologically by sinusoidal dilatation, hepatic plate atrophy and/or venular obstruction. Most of the patients do not reveal apparent radiological abnormalities, however. Here, we report the case of a 47-year-old man with a radiologically detectable mass-forming oxaliplatin-induced sinusoidal injury that mimicked multiple liver tumors. These mass lesions were found on computed tomography images after the administration of six cycles of folinic acid, fluorouracil and oxaliplatin therapy as adjuvant chemotherapy for Stage III rectal cancer. The patient had to undergo liver resection because imaging studies could not exclude metastases. The histological examination revealed that a resected mass lesion was composed of severe sinusoidal dilatation. Milder dilatation was also seen in the surrounding parenchyma. We diagnosed the patient as having an oxaliplatininduced sinusoidal injury with severe deviation. As oxaliplatin is a standard agent in colorectal cancer therapy today, all clinicians and pathologists should be aware of such nonneoplastic lesions as one of the rare differential diagnoses of metastatic liver tumor, to prevent overtreatment. Key words: colorectal liver metastases oxaliplatin sinusoidal obstruction syndrome INTRODUCTION Oxaliplatin, a cisplatin derivative, is a major chemotherapeutic agent administered to patients with colorectal cancer. Compared with cisplatin, adverse drug reactions seen in the kidney are rarer after oxaliplatin treatment. However, there is accumulating evidence that oxaliplatin can cause damage to non-tumor-bearing liver (1 5). It preferentially injures hepatic sinusoids, and such lesions have been designated as veno-occlusive disease, sinusoidal obstruction syndrome or sinusoidal injury. These lesions are not detected on radiological images, and clinicians have little difficulty in distinguishing these lesions from metastatic tumors. Here, we report a case of a regionally severe form of oxaliplatin-induced sinusoidal injury which appeared as multiple mass-forming lesions on computed tomography (CT) and magnetic resonance (MR) images and could not be differentiated from metastatic tumors. CASE REPORT The patient was a 47-year-old man who had undergone a lowanterior resection for rectal cancer 4 months ago. The # The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Jpn J Clin Oncol 2013;43(10) 1035 histological diagnosis was mucinous adenocarcinoma, pt4n1m0 (Stage IIIA). Oxaliplatin-based adjuvant chemotherapy (modified FOLFOX 6: folinic acid, fluorouracil and oxaliplatin (6)) was administered 1 month after resection. After six cycles of chemotherapy, a CT scan revealed multiple low-density areas in the patient s liver. There were at least four lesions mm in diameter; they were located only in the right lobe (Fig. 1b). Ordinary ultrasonography (US) vaguely depicted these lesions (Fig. 2a), and with sonazoid contrast, they were clearly visualized as mass defects in the Kupffer phase (Fig. 2b). MR images showed these lesions as low-intensity masses on T 1 -weighted images (Fig. 3a) and high-intensity masses on T 2 -weighted images (Fig. 3b). Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid contrast-enhanced MR (EOB-MR) imaging showed the lesions as slightly enhanced masses in a vascular phase and as mass defects in a hepatocellular phase (Fig. 3c). Diffusion-weighted images did not highlight the lesions (Fig. 3d). The imaging studies findings except for negativity on diffusion-weighted MRI were consistent with neoplastic liver tumor. Because there had been no liver lesions on the CT images at the patient s first presentation (Fig. 1a), multiple cancer metastases were suspected and a right lobectomy was planned. The patient had no symptoms, and the results of Figure 1. Computed tomography (CT) images with contrast enhancement. No mass lesion was depicted in the liver before chemotherapy (a). After the administration of oxaliplatin, CT images revealed multiple low-density areas in the right lobe of the liver slightly enhanced with contrast (b, arrows). his serological examination for hepatic enzymes, tumor markers including CEA and CA19-9 and hepatitis virus were normal. During the operation, the liver surface seemed to be heterogeneously congestive. All of the tumors detected on images were not palpable. Under the guidance of sonazoid contrast-enhanced US, one of the tumors was resected. The intraoperative histological examination revealed that the lesion is characterized by severe sinusoidal dilatation. The right lobectomy was not done, and the other mass lesions remained untreated. On gross inspection, it was found that the resected lesion was an 18 mm dark red area with an ill-defined contour (Fig. 4a and b). Histologically, the lesion was characterized by extremely severe sinusoidal dilatation and congestion with atrophy of the hepatic plate, which was vaguely accentuated at the medio-centrilobular zone (Fig. 4c). A similar sinusoidal dilatation also affected the surrounding liver parenchyma, although the changes were milder (Fig. 4f). No obvious obstruction or narrowing of a hepatic vein or other large vessels was identified within the resected liver. An immunohistochemical study revealed a decrease of CD31-positive sinusoidal endothelial cells (Fig. 4d and g), and CD163-positive Kupffer cells were decreased in the severely dilated area (Fig. 4e and h). The patient s postoperative course was uneventful. With cessation of the FOLFOX therapy, the multiple low-density areas became undetectable on CT images by 3 months after the partial hepatectomy. DISCUSSION There are an increasing number of reports indicating that oxaliplatin-based chemotherapy can cause liver damage (1 5). Oxaliplatin-induced liver damage is characterized histologically by sinusoidal dilatation, hepatocyte atrophy and/or fibrosis and venular obstruction (1,2,4,5). The only radiological findings of this condition that have been reported to date are diffuse or reticular signal changes in contrastenhanced MR images (7 9). Although some authors have pointed out the heterogeneous distribution of these histological changes within the liver (5), we are not aware of previous reports of oxaliplatin-induced sinusoidal injury as a massforminglesiondetectableonimages.evenso,itisapparent that the lesions of the present patient were caused by oxaliplatin for several reasons, which are as follows. (i) The histological findings were consistent with the preceding descriptions. (ii) Such histological changes were observed not only at the mass-forming area, but also in the surrounding parenchyma with milder features. (iii) The mass lesions appeared after the administration of chemotherapy including oxaliplatin and (iv) the lesions disappeared after the cessation of oxaliplatin treatment. The unique point of the present case is the locally severe involvement of the injury. The course of such heterogeneity is unclear, but factors related to tolerance to drug toxicity, the concentrations of drugs administered and

3 1036 Mass-forming oxaliplatin liver injury Figure 2. Ordinary ultrasonography (US) images vaguely depicted the lesion (a, arrow). With sonazoid contrast, there was a mass defect in the Kupffer phase (b, arrow). Figure 3. MR images showed these lesions (arrows) as low-intensity masses on T 1 -weighted images (a), as high-intensity masses on T 2 -weighted images (b). Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid contrast-enhanced MR (EOB-MR) images depicted these lesions as mass defects on the hepatocellular phase (c). Diffusion-weighted images did not highlight these lesions (d).

4 Jpn J Clin Oncol 2013;43(10) 1037 Figure 4. On gross inspection of the resected liver, an 18 mm relatively circumscribed dark red severely congestive lesion was identified. The surrounding liver parenchyma was also congestive (a). The congestive tumor-like area was composed of severe sinusoidal dilatation and congestion (b) (H&E staining, arrow heads). Sinusoidal dilatation was mainly accentuated at the medio-centrilobular zone with liver plate atrophy (c). Immunohistochemically, CD31-positive sinusoidal endothelial cells and CD163-positive Kupffer cells were decreased in the severely affected tumor-like area (d and e). Microscopic findings of the surrounding liver showed milder sinusoidal dilatation (f). Immunohistochemically, sinusoidal cells (g) and Kuppfer cells (h) were preserved in this area. the pre-existing abnormal blood flow to the affected area are suspected to be contributors (10). To our knowledge, this is the first case report of massforming oxaliplatin-induced sinusoidal injury. However, it is possible that similar cases had been reported under other diagnoses, because the entity of oxaliplatin-induced liver injury was established only recently. Indeed, our search of the relevant literature revealed a case of liver mass diagnosed as focal peliosis hepatis that appeared after the administration of oxaliplatin-based chemotherapy for gastric cancer. Although the authors of that report did not provide the detailed clinical information or discuss the association between peliosis hepatis and chemotherapy, the study s liver biopsy specimen figure showed only moderate sinusoidal dilatation, which seems more likely to be related to sinusoidal injury (11). The presence of such a condition could make it difficult or confusing to arrive at a diagnosis based on the images. For colorectal cancer patients under adjuvant chemotherapy, a newly formed mass lesion of the liver would naturally be suspected to be metastases. Although recent imaging methods using specific contrast agents have achieved high sensitivity in detecting colorectal cancer liver metastases (12 16), it seems very difficult to differentiate such lesions. In fact, in the present case, we could not consider nonneoplastic lesions until hepatectomy. The lesions were visualized as mass defects on EOB-MR images and sonazoidcontrast US. This pattern is thought to be characteristic of neoplastic lesions. This phenomenon observed in our patient is easily explained histologically; the atrophy of hepatocytes and sparsity of Kupffer cells correspond to decreases in EOB

5 1038 Mass-forming oxaliplatin liver injury and sonazoid uptake, respectively. On the other hand, diffusion-weighted MR imaging would be helpful for differentiating such lesions; metastatic tumors are expected to have high signals, and our patient showed no elevated signals, atypically for metastatic tumors (14). Positron emission tomography CT would be useful (16), but the patient unfortunately did not have the opportunity to undergo this imaging modality. When there are any aspects that are not typical of metastatic tumors on images, a preoperative needle biopsy or intraoperative frozen section could be obtained, to avoid excessive therapy. The cessation of drug treatment could also aid the clinical diagnosis, but further experience is needed to determine whether these lesions are reversible or not. In summary, our experience with this patient indicated that oxaliplatin-induced liver injury can appear as one or more mass-forming lesions and mimic metastatic carcinoma on images. A careful observation of the clinical course, intense radiological analysis with several modalities, and even biopsy will be needed to make a precise diagnosis and avoid overtreatment. Conflict of interest statement None declared. References 1. Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 2004;15: Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 2006;24: Zorzi D, Laurent A, Pawlik TM, Lauwers GY, Vauthey JN, Abdalla EK. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg 2007;94: Rubbia-Brandt L, Lauwers GY, Wang H, et al. Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis. Histopathology 2010;56: Ryan P, Nanji S, Pollett A, et al. Chemotherapy-induced liver injury in metastatic colorectal cancer: semiquantitative histologic analysis of 334 resected liver specimens shows that vascular injury but not steatohepatitis is associated with preoperative chemotherapy. Am J Surg Pathol 2010;34: Cheeseman SL, Joel SP, Chester JD, et al. A modified de Gramont regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer 2002;87: Ward J, Guthrie JA, Sheridan MB, et al. Sinusoidal obstructive syndrome diagnosed with superparamagnetic iron oxide-enhanced magnetic resonance imaging in patients with chemotherapy-treated colorectal liver metastases. J Clin Oncol 2008;26: O Rourke TR, Welsh FK, Tekkis PP, et al. Accuracy of liver-specific magnetic resonance imaging as a predictor of chemotherapy-associated hepatic cellular injury prior to liver resection. Eur J Surg Oncol 2009;35: Shin NY, Kim MJ, Lim JS, et al. Accuracy of gadoxetic acid-enhanced magnetic resonance imaging for the diagnosis of sinusoidal obstruction syndrome in patients with chemotherapy-treated colorectal liver metastases. Eur Radiol 2012;22: Crawford JM. Vascular disorders of the liver. Clin Liver Dis 2010;14: Kim SH, Lee JM, Kim WH, Han JK, Lee JY, Choi BI. Focal peliosis hepatis as a mimicker of hepatic tumors: radiological pathological correlation. J Comput Assist Tomogr 2007;31: Kanematsu M, Kondo H, Goshima S, et al. Imaging liver metastases: review and update. Eur J Radiol 2006;58: Floriani I, Torri V, Rulli E, et al. Performance of imaging modalities in diagnosis of liver metastases from colorectal cancer: a systematic review and meta-analysis. J Magn Reson Imaging 2009;31: Lowenthal D, Zeile M, Lim WY, et al. Detection and characterisation of focal liver lesions in colorectal carcinoma patients: comparison of diffusion-weighted and Gd-EOB-DTPA enhanced MR imaging. Eur Radiol 2011;21: Larsen LP, Rosenkilde M, Christensen H, et al. The value of contrast enhanced ultrasonography in detection of liver metastases from colorectal cancer: a prospective double-blinded study. Eur J Radiol 2007; 62: Sacks A, Peller PJ, Surasi DS, Chatburn L, Mercier G, Subramaniam RM. Value of PET/CT in the management of liver metastases, part 1. AJR Am J Roentgenol 2011;197:W256 9.