Diagnosis of Hepatoid Carcinoma of Extrahepatic Origins: Cell Markers and Pathologic Standards

Hepatoid adenocarcinoma (HAC) or hepatoid carcinoma is a rare (adeno)carcinoma with hepatocellular differentiation but arises from extrahepatic tissues. HAC was initially reported as an alpha fetal protein (AFP) producing tumor of gastric origin in 1970 [1]. Later, Ishikura et al. [2] proposed the term “hepatoid carcinoma” for AFP-producing ovarine adenocarcinoma in 1987. Up to date, there have been approximately 408 HAC cases from different origins reported in the English literature. Most of HACs have arisen in stomach, much less in ovary, lung, pancreas, gallbladder, and rare in uterus, esophagus, jejunum, colon, rectum, or extrahepatic bile duct. The diagnostic standards in defining “hepatoid” has been variable in practice. Some HACs have been diagnosed based on elevated serum AFP as a defining feature of hepatocellular differentiation, some based on morphological features of hepatocytes, and some required immunohistochemical expression of hepatocellular markers including AFP, HepPar1, glypican-3, arginase, albumin or Sall-4 [3,4]. The diagnosis of HAC can be challenging, especially in differentiating extrahepatic HAC with liver metastasis versus Received: February 04, 2019


Introduction
Hepatoid adenocarcinoma (HAC) or hepatoid carcinoma is a rare (adeno)carcinoma with hepatocellular differentiation but arises from extrahepatic tissues. HAC was initially reported as an alpha fetal protein (AFP) producing tumor of gastric origin in 1970 [1].
Later, Ishikura et al. [2] proposed the term "hepatoid carcinoma" for AFP-producing ovarine adenocarcinoma in 1987. Up to date, there have been approximately 408 HAC cases from different origins reported in the English literature. Most of HACs have arisen in stomach, much less in ovary, lung, pancreas, gallbladder, and rare in uterus, esophagus, jejunum, colon, rectum, or extrahepatic bile duct.
The diagnostic standards in defining "hepatoid" has been variable in practice. Some HACs have been diagnosed based on elevated serum AFP as a defining feature of hepatocellular differentiation, some based on morphological features of hepatocytes, and some required immunohistochemical expression of hepatocellular markers including AFP, HepPar1, glypican-3, arginase, albumin or Sall-4 [3,4]. The diagnosis of HAC can be challenging, especially in differentiating extrahepatic HAC with liver metastasis versus hepatocellular carcinoma with extrahepatic metastasis. We herein have reported four challenging HAC cases encountered in our institute and reviewed HACs reported in English literature to summarize the characteristic features and useful markers up to date for the pathologic diagnosis of HACs.

Case Two
A 53 years old male with a medical history of coronary artery disease, hypothyroidism and pemphigus vulgaris, presented with orthopnea and generalized weakness and stridor two weeks later.
He was diagnosed with neuromuscular disorder with high suspicion for myasthenia gravis or paraneoplastic syndrome. The patient continued to have respiratory failure on ventilator and passed away in one week. An autopsy was performed. A 17x14x10cm large multi-nodular cystic mass was found at the head of the pancreas.
The tumor was infiltrative and invading peri-pancreatic soft tissue.

Case Three
A 58 years old female with a medical history of thyroid carcinoma post thyroidectomy, presented with persistent right hip pain.
Abdominal MRI showed multiple metastasis throughout liver with the largest lesion measuring 2.7cm. Osseous metastasis involved lower thoracic vertebra and right iliac bone. A 4.7cm enhancing tumor in the left lung base, was most suggestive of a primary lung carcinoma. In addition, there were a 5.8cm cystic renal cell carcinoma and a 4.2cm degenerative right adrenal adenoma. A biopsy on the bone lesion at an outside hospital reported "suggestive of adenocarcinoma, unknown primary". The liver biopsy in our institution showed poorly differentiated carcinoma with nested, pleomorphic polygonal cells with eosoinophilic cytoplasma and hyperchromatic nuclei ( Figure 2D). Immunohistochemical stains showed that the tumor cells were strongly positive for HepPar-1 ( Figure 2E), CK19 ( Figure 2F), CK7, weakly nuclear positive for CDX2 and Pax 8, and negative for TTF1, CK20, CD10, RCC, estrogen receptor, progesterone receptor and vimentin. A diagnosis of hepatoid carcinoma was made but the tumor origin remained uncertain. The patient was treated with chemotherapy but passed away three months later.

Results and Discussion
These four HAC cases emphasize the challenge in diagnosing HAC based on morphology and immunoprofile of the tumor.
We have reviewed the reported HACs in the English literature to summarize the diagnostic standards of HACs and the markers which may help to define the primary origin. Table 1 lists the summary of 408 HACs from variable organs reported in the English literature. 72% of reported HACs were originated from stomachs, about 9% from ovaries, 7% from lung, 6% from pancreas, 2% from gallbladder or urinary bladder and rare case from uterus, esophagus, jejunum, colon, rectum, and extrahepatic bile duct.
Up to date, our case #1 is the third case of HAC arising from extrahepatic bile duct [12,13]. Hepatoid adenocarcinoma was initially proposed by Ishikura et al. [2] to describe seven excessive AFP producing adenocarcinoma. Later in 1993, Motoyama et al. [5] subdivided gastric adenocarcinoma with high AFP-production into three subtypes: hepatoid type, fetal gastrointerstinal type and yolk sac tumor-like. The hepatoid type represents the best recognizable morphologic features of hepatocellular differentiation. The fetal gastrointestinal type morphologically appears as tubular adenocarcinomas, producing high level of AFP and possibly derived from fetal gastrointestinal epithelium. The yolk sac tumor-like type morphologically represents yolk sac tumor with production of AFP and possibly derived from yolk sac metaplasia.
Recently, Arora et al [6] applied three categories to tumors with hepatocellular differentiation as type I (hepatoid), type II (fetal type gastrointestinal adenocarcinoma), and type III (positive for at lest two hepatocyte specific markers but lacking morphological evidence of hepatocellular differentiation). The WHO classification of tumors in digestive system defines gastric HAC as an adenocarcinoma composed of large polygonal eosinophilic hepatocyte-like neoplastic cells expressing AFP detected in situ or in serum [7].
Although HAC is defined mostly based on elevated serum AFP as a feature of hepatocellular differentiation, AFP production is not necessary in the diagnosis of many reported HACs. As shown in ( A variety of markers with variable specificity to hepatocellular differentiation have been utilized for the diagnosis of HACs. As shown in Table 1, HepPar 1 has been considered a specific marker  appears to be frequently positive in HACs. As shown in Table 2, CK19 is positive in 100% of gastric and gallbladder HACs tested but is reported positive in only 15% of hepatocellular carcinoma.
Three of our 4 HACs were tested for CK19 and two were positive.
Thus, if a morphologically hepatoid tumor is positive for CK19, HAC is strongly suggested. Another significant marker is CK7 which is positive in 67% of ovarian HACs and 50% of lung HACs tested, but CK7 is positive in only about 5% of hepatocellular carcinoma. Polyclonal CEA may be useful in diagnosis of lung HAC as showing diffuse staining pattern in 5 of 6 lung HAC tested, but less useful in urinary bladder and pancreatic HAC as most showing canalicular pattern similar to hepatocytes. Our case #1, the extrahepatic bile duct HAC, also shows canalicular pattern of polyclonal CEA staining. The organ-specific markers have not been shown useful in identifying the primary origin of HAC; such as TTF1, a marker for lung, has been found negative in all three lung HACs tested in literature and negative in our two likely lung HAC cases. There is no identified marker which can be used for pancreatic or gallbladder HACs. Other markers, such as PLUNG [9] MUC1, CD10, A1-antitrypsin, alpha-1-chymotrypsin, SALL4 [4], bile salt export pump (BSEP) and multidrug-F.