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 Table of Contents  
Year : 2021  |  Volume : 10  |  Issue : 6  |  Page : 333-335

Hepatoid adenocarcinoma of gallbladder: A mimicker of hepatocellular carcinoma

Department of Pathology, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India

Date of Submission26-Jan-2021
Date of Decision18-May-2021
Date of Acceptance05-Jun-2021
Date of Web Publication11-Dec-2021

Correspondence Address:
Kavita Mardi
Set No 14, Type VI Quarters, IAS Colony, Meheli, Shimla, Himachal Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ccij.ccij_13_21

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How to cite this article:
Mardi K, Sarohi M. Hepatoid adenocarcinoma of gallbladder: A mimicker of hepatocellular carcinoma. Clin Cancer Investig J 2021;10:333-5

How to cite this URL:
Mardi K, Sarohi M. Hepatoid adenocarcinoma of gallbladder: A mimicker of hepatocellular carcinoma. Clin Cancer Investig J [serial online] 2021 [cited 2022 Jan 28];10:333-5. Available from:


Hepatoid adenocarcinoma (HAC) is a rare carcinoma showing hepatocellular differentiation, arising in extrahepatic organs. This tumor was initially reported as an alpha-fetal protein (AFP)-producing tumor of gastric origin in 1970.[1] Later, Ishikura and Scully[2] proposed the term “hepatoid carcinoma” for AFP-producing ovarian adenocarcinoma in 1987. Nearly 408 HAC cases of HAC arising from different origins have been reported till date.[3] They are more common in the stomach compared to other parts of GIT.[3] Their occurrence in the gallbladder is rare.[3],[4],[5],[6],[7] We report one such rare occurrence in the gallbladder of a 60-year-old female who presented with a complaint of pain in the right hypochondrium for 3 months. Ultrasonography revealed cholelithiasis and an enlarged peripancreatic lymph node. CECT abdomen revealed a focal heterogeneously enhancing thickening of the gallbladder wall with abdominal lymphadenopathy. The liver was within normal limits. Radiological findings were suspicious for malignancy.

Cholecystectomy was done, and we received the specimen of the gallbladder which grossly revealed a polypoidal exophytic growth measuring 1.5 cm × 1 cm × 0.5 cm [Figure 1]. Cut section of the growth was gray white and extending into the serosa. Microscopic examination revealed sheets, nests, and trabecular cords of tumor cells [Figure 2] with focal glandular pattern in superficial lamina propria. These tumor cells revealed round to irregular enlarged vesicular nuclei, prominent one to multiple nucleoli, and abundant finely granular eosinophilic cytoplasm with distinct cytoplasmic border. Occasional hyaline globules and intranuclear inclusions, atypical mitosis, and focal necrosis were seen. Mucosa adjacent to the growth revealed adenocarcinoma in situ [Figure 3]. A diagnosis of HAC of the gallbladder was made, and immunohistochemistry was positive for AFP but negative for HepPar1.
Figure 1: Gross specimen showing polypoidal exophytic growth in the gallbladder

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Figure 2: Hepatoid tumor cells arranged in trabecular pattern (H and E, ×20)

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Figure 3: Foci of adenocarcinoma in superficial lamina propria (H and E, ×40)

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HACs most commonly arise from the stomach. Less commonly, they arise from the ovary, lung, pancreas, and rarely, in the uterus, esophagus, jejunum, colon, rectum, gallbladder, or extrahepatic bile duct.[3] Vardaman and Albores-Saavedra[8] described the first well-documented case of HAC of the gallbladder, and subsequently, to the best of our knowledge, approximately 15 cases have been reported in the English literature.[3],[4],[5],[6],[7]

The diagnostic criteria for defining “hepatoid carcinoma” have been variable in practice. Some consider elevated serum AFP as a defining feature of hepatocellular differentiation, and others rely on morphological features of hepatocyte. Hepatoid differentiation manifests as large polygonal cells with abundant clear and eosinophilic cytoplasm that are arranged in trabeculae, nests, and rosettes. The hepatoid nature of the tumor cells is demonstrated by bile production.[9] Some others have reported the immunohistochemical expression of hepatocellular markers including AFP, HepPar1, glypican-3, arginase, albumin, or Sall-4 in tumor cells.[9],[10]

AFP positivity in tumor cells is particularly important for diagnosis. AFP levels are also elevated in the serum. However, HAC does not always produce AFP.[11],[12],[13] Although AFP positivity is important, it is not essential for a diagnosis of HAC. The diagnosis of HAC should be made on the basis of histopathological features of the tumor including immunohistochemical analysis, because the behavior of HAC is similar whether it produces AFP or not.[11] HepPar1 has been used as a marker of hepatic differentiation, but subsequent studies have refuted its specificity and sensitivity. In this case, AFP was positive [Figure 4], but HepPar1 was negative. The main differential diagnosis for HAC of the gallbladder is hepatocellular carcinoma (HCC) or combined HCC/cholangiocarcinoma invading the gallbladder. The clinical presentation of patients is important because HCC arising in nonfibrotic liver and without risk factors, such as hepatitis virus infection, is generally rare, as is lymph node metastasis at surgery. If the intramucosal foci of adenocarcinoma are detected histologically in a surgical specimen, the gallbladder origin is confirmed.[12] In our case, the gallbladder origin of the HAC was confirmed as there was a focus of adenocarcinoma and high-grade dysplasia/carcinoma in situ in the adjacent epithelium and the absence of cirrhosis.
Figure 4: Tumor cells showing positivity for alpha-fetal protein (Immunohistochemistry, ×40)

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HAC occurs predominantly in older patients and is characterized by a very aggressive course and a poor prognosis. Extensive hematogenous metastasis to the liver and the early and frequent involvement of lymph nodes is an important feature.[13]

  Conclusion Top

Although HAC of the gallbladder is a very rare malignancy, awareness of its existence is critical to avoid misdiagnosis and these tumors should be considered in the differential diagnosis of gallbladder masses.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Bourreille J, Metayer P, Sauger F, Matray F, Fondimare A. Existence of alpha feto protein during gastric-origin secondary cancer of the liver. Presse Med 1970;78:1277-8.  Back to cited text no. 1
Ishikura H, Scully RE. Hepatoid carcinoma of the ovary. A newly described tumor. Cancer 1987;60:2775-84.  Back to cited text no. 2
Sun B, Jain R, Cunningham J, Bhattacharyya A. Diagnosis of hepatoid carcinoma of extrahepatic origins: cell markers and pathologic standards. Biomed J Sci Tech Res 2019;15:11182-7.  Back to cited text no. 3
Devi NR, Sathyalakshmi R, Devi J, Lilly SM. Hepatoid adenocarcinoma of the gall bladder-A rare variant. J Clin Diagn Res 2015;9:D09-10.  Back to cited text no. 4
Shi X, Tao W, Chen Y, Wang G. Alpha-fetoprotein-producing hepatoid adenocarcinoma of the gallbladder: A case report and review of literature. Int J Clin Exp Pathol 2016;9:5740-5.  Back to cited text no. 5
Ji X, Dong H, Dong A. FDG PET/CT of Hepatoid adenocarcinoma of the gallbladder. Clin Nucl Med 2020;45:927-8.  Back to cited text no. 6
Lee JH, Lee KG, Paik SS, Park HK, Lee KS. Hepatoid adenocarcinoma of the gallbladder with production of alpha-fetoprotein. J Korean Surg Soc 2011;80:440-4.  Back to cited text no. 7
Vardaman C, Albores-Saavedra J. Clear cell carcinomas of the gallbladder and extrahepatic bile ducts. Am J Surg Pathol 1995;19:91-9.  Back to cited text no. 8
Osada M, Aishima S, Hirahashi M, Takizawa N, Takahashi S, Nakamura K, et al. Combination of hepatocellular markers is useful for prognostication in gastric hepatoid adenocarcinoma. Hum Pathol 2014;45:1243-50.  Back to cited text no. 9
Ushiku T, Shinozaki A, Shibahara J, Iwasaki Y, Tateishi Y, Funata N, et al. SALL4 represents fetal gut differentiation of gastric cancer, and is diagnostically useful in distinguishing hepatoid gastric carcinoma from hepatocellular carcinoma. Am J Surg Pathol 2010;34:533-40.  Back to cited text no. 10
Nakashima H, Nagafuchi K, Satoh H, Takeda K, Yamasaki T, Yonemasu H, et al. Hepatoid adenocarcinoma of the gallbladder. J Hepatobiliary Pancreat Surg 2000;7:226-30.  Back to cited text no. 11
Sakamoto K, Monobe Y, Kouno M, Moriya T, Sasano H. Hepatoid adenocarcinoma of the gallbladder: Case report and review of the literature. Pathol Int 2004;54:52-6.  Back to cited text no. 12
Ishikura H, Kishimoto T, Andachi H, Kakuta Y, Yoshiki T. Gastrointestinal hepatoid adenocarcinoma: Venous permeation and mimicry of hepatocellular carcinoma, a report of four cases. Histopathology 1997;31:47-54.  Back to cited text no. 13


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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