Case Report

A 61 year old lady presented in the department of surgery at our institute with complaints of pain right upper abdomen for past 6 months. Pain was associated with nausea and vomiting. She had no complaints of high colored urine and yellow colored sclera. Abdominal examination revealed mild tenderness on right hypochondrium but no mass was palpable. There were no enlarged neck, axillary or inguinal lymph nodes.

Laboratory test revealed hypochromic anemia. Liver function test and renal functional test were within normal limits. Hepatitis B and C serology were negative. CA19.9 and CEA levels were not raised but serum alpha protein levels were not done preoperatively. Abdominal ultrasonography showed gall bladder with presence of few calculus with upper para-aortic and parapancreatic lymph nodes. Abdominal CECT showed focal heterogeneously enhancing thickening of gall bladder with presence of gall stones. Multiple pericholedochal, peri-pancreatic, para-aortic and retroperitoneal lymph nodes were seen. Patient underwent open cholecystectomy. At surgery adhesion were found between gall bladder and liver. On cut section of gall bladder 2 calculus were found, anterior gall bladder wall has an irregular growth of size 1×1cm.

On gross examination of there was a growth in the fundus of gall bladder and cut section of growth was homogenously grey white with areas of haemorrhage. Microscopically, tumor cells were arranged in sheets, nests, trabeculae and chords. Tumor cells were showing irregular enlarged vesicular nuclei and granular eosinophilic cytoplasm. Invasion into serosa, perineural invasion were seen but resection margins were free of tumor. Immunohistochemistry showed that tumor cells were positive for Hep- Par-1, CK10 and focal alpha fetoprotein expression was also present. On the basis of these findings diagnosis of HAC gall bladder with nodal metastasis was made. Post-operative CECT showed enlarged lymph nodes as the only presence of disease. Patient was started on mitomycin C and 5-FU based chemotherapy. Till now she has received 3 cycles of chemotherapy but further chemotherapy was stopped as patient developed severe hematological toxicities.

HAC is a very rare tumor which was originally identified as gastric carcinoma [1]. HAC has been reported in other sites such as gall bladder by Watanabae et al. [2]. Vardaman and Albores Saavedra in 1995 described clear cell carcinoma of gall bladder which was positive for α-FP and CEA containing areas of hepatoid differentiation [3].

The WHO classification of tumors in gastrointestinal tract defines gastric HAC as an adenocarcinoma composed of large polygonal eosinophilic hepatocyte like neoplastic cells expressing AFP in situ and in serum4. Raised AFP levels is the consistent feature of tumors with hepatoid differentiation, still AFP production is not necessary in the diagnosis of many reported cases of HAC. It can be diagnosed on the base of morphological feature of hepatocellular differentiation and some on the hepatocellular markers like HepPar-1, glypican -3, arginase, albumin and SALL-4. CK19 is positive in100% gastric and gall bladder HAC5. CK7 is also a significant marker of HAC [5]. Tumor with hepatocellular differentiation, differential diagnosis includes HAC, hepatocellular carcinoma and hepatoid yolk sac tumor. Tumor location of ovaries or testes, young age of patient and PLAP or CD117 positivity favors the diagnosis of hepatoid yolk sac tumor. Hepatocellular carcinoma and HAC resemble closely due to similar clinical and pathological features. Clinical correlation, lab investigations, imaging studies and pathological details are important in the diagnosis. History of cirrhosis, hepatitis

C or B and dynamic imaging showing arterial uptake followed by venous washout of contrast are suggestive of the diagnosis of hepatocellular carcinoma. HAC are common in old age, clinically aggressive and metastasize to lymph nodes.

Surgery is the cornerstone for treatment with curative intent. Currently, there is no specific chemotherapy protocol for advanced stage of disease. Various agents like flurouracil, cisplatin, irinotecan, docetaxel, paclitaxel, methrexate and mitomycinC and varios treatment schedules have been used in treatment of metastatic HAC. The scarce information provides scattered information. A recent systemic review of case report’s authors concluded that cisplatin based chemotherapy is most efficient first line chemotherapy [6]. In our patient chemotherapy based on mitomycin C (6mg/m2) and 5- flurouracil (400mg/m2) was given and repeated after every 3 weeks. Patient received three cycles but further chemotherapy was stopped due to intolerance and haematological toxicities.

1. Ishikura H. et al. “An AFP-producing gastric carcinoma with features of hepatic differentiation: A case report.” Cancer, vol. 56, no. 4, 1985, pp. 840-848.

2. Watanabe M. et al. “Alpha-fetoprotein-producing carcinoma of the gallbladder.” Digestive Diseases and Sciences, vol. 38, no. 3, 1993, pp. 561-564.

3. Vardaman C. et al. “Clear cell carcinomas of the gallbladder and extrahepatic bile ducts.” The American Journal of Surgical Pathology, vol. 19, no. 1, 1995, pp. 91-99.

4. World Health Organization. WHO classification of tumours of the digestive system. International Agency for Research on Cancer, 2010, Lyon.

5. Sun B. et al. “Diagnosis of hepatoid carcinoma of extrahepatic origins: Cell markers and pathologic standards.” Department of Pathology and Department of Medicine, Arizona.

6. Simmet V. et al. “Chemotherapy of metastatic hepatoid adenocarcinoma: Literature review and two case reports with cisplatin etoposide.” Oncology Letters, vol. 15, no. 1, 2018, pp. 48-54, doi:10.3892/ol.2017.7263.