Discussion
PHC is a very rare disease, and its diagnosis is mainly achieved through morphological analysis and immunohistochemical staining of the tissue specimens, since the clinical manifestation and the laboratory test results are often unspecific.
PHC exhibits morphological features similar to those of HCC, including large polygonal cells with an abundant eosinophilic cytoplasm and round nuclei, as well as prominent nucleoli in a trabecular or perisinusoidal pattern, occasionally featuring bile production and/or bile canaliculi formation. PHC has been previously reported in the literature in English, including 41 cases (4,17-52), which can be divided into four histological subtypes: HC with pure HCC-like morphology, HC with neuroendocrine differentiation, and HC with acinar or glandular differentiation [(4,18,33,53-54). As regards the pure HCC-like features, it has been differentially defined, including HC, hepatoid adenocarcinoma, ectopic HCC, a hepatoid variant of pancreatic cancer, primary HCC of the pancreas or a pancreatic tumor with hepatoid differentiation (19).
The pathogenesis of PHC is not yet completely understood, although some hypotheses have been proposed. Some researchers have reported that the pancreas and liver all originate from the same area of primitive embryonic foregut in direct continuation with the yolk sac (55). It is possible that pancreatic cells retain the potential to differentiate into hepatic cells. As previously demonstrated, following the treatment of the rat pancreatic exocrine cell line, AR42J, with the synthetic glucocorticoid, dexamethasone, cells resembling hepatocytes are then induced (56). Furthermore, mature hepatocytes have the ability to differentiate into pancreatic cells (57). It has also been reported that the pancreas contains hepatocyte multipotent cells that have the ability for use in liver reconstruction therapy in adult mice (58). Therefore, it can be hypothesized that genes associated with hepatocyte differentiation are suppressed by pancreatic stem cells, which can be activated in a particular environment. Less than 5% of HCC cases arise in an ectopic area of liver tissue. Cardona et al (21) claimed that HC arose from ectopic liver tissue. Steen et al (22) considered that their patient's HCC arose in ectopic liver tissue located in the pancreas, and eventually replaced all original ectopic liver tissue. Tong et al (59) reported a case of hepatoid adenocarcinoma originating from a heterotopic pancreas in the ileum.
Serum AFP levels have been found to be elevated in the majority of cases of PHC (4,18,20,24-28,31,32,38,41,44-45,47,52) similar to the case presented herein. Thus, AFP can be used to evaluate the integrity of surgical resection and response to therapies. However, it is not always specific to PHC. It is noteworthy that AFP levels may also be elevated in acinar cell carcinoma, as well as in ductal carcinoma of the pancreas, and in neuroendocrine, germ-cell tumors and undifferentiated pancreatic adenocarcinoma (60,61). PHC also shares immunohistochemical characteristics with HCC, such as AFP, Hep Par1, glypican-3, arginase-1, anti-albumin, anti-α-1-antitrypisine, anti-low molecular weight cytokeratin, anti-epithelial membrane antigen antibodies and CD10. Polyclonal CEA stains exhibiting focal canalicular patterns in PHC have been reported in the English literature (4,18,33). Due to the limited quantity of PHC cases reports in the literature, and PHC without specific performance in CT and MRI images, from the images, it cannot be distinguished whether this is a primary pancreatic tumor or metastatic HCC. In the case presented herein, the CT images revealed an ill-demarcated heterogeneous mass located in the tail of the pancreas that invaded the stomach, spleen and retroperitoneal lymph node; from the scans of the pancreas or stomach, a mixed and low attenuation right-liver mass was observed, suggestive of primary HCC, not excluding the metastatic lesions (Fig. 1A). Contrast-enhanced abdominal CT images revealed a mild-moderate enhancement (Fig. 1B). The MRI findings were suggestive of pancreatic cancer with synchronous liver, spleen, stomach and retroperitoneal lymph node metastasis (Fig. 2). There are no established diagnostic criteria available for PHC; however, without a doubt, these tumor marker stains play a vital role. Among these markers, Hep Par1 seems to be the most sensitive marker for PHC (62). In the case in the present study, the tumor cells in the tail of the pancreas were positive for glypican-3 (Fig. 4B), and the right liver was positive for CK-18 (Fig. 4A) and weakly positive for glypican-3. There are some novel and more specific tumor markers for the diagnosis PHC reported, such as PIVKA-II, which was described by Matsueda et al (25) to be increased in a case of PHC in 2006. In addition, other immunohistochemical markers, such as bile salt export pump (BSEP) and multidrug-resistance protein 3 (MDR3) may be helpful for the diagnosis (61) Some researchers have revealed spalt-like transcription factor 4 (SALL4) staining in one third of HC cases (38).
During the diagnosis of primary PHC, metastatic HCC from the liver to the pancreas needs to be taken into consideration. Furthermore, other primary pancreatic tumors with an eosinophilic cytoplasm, such as neuroendocrine tumors, acinar cell carcinoma and solid pseudopapillary neoplasm should be distinguished (20,27). These can be distinguished by their own histological characteristics and immunohistochemistry. Acinar cell carcinoma is negative for arginase-1(62), whereas the reported poorly differentiated HCCs are positive for the marker (63-65). Hence, it is considered that arginase-1 seems to be a promising marker which can be used to discriminate poorly differentiated HCCs from acinar cell carcinoma. In addition, pancreatic neuroendocrine tumors are negative for glypican-3. Solid pseudopapillary neoplasms are often positive for glypican-3(66).
Due to no unified standards available for treatment and according to recommendations from previous reports, that according to patients' tolerance, surgical resection is the preferred alternative for a disease-free survival. An early detection is also crucial (29,60). A pervious study reported a case in which the oral multitarget tyrosine kinase inhibitor, sorafenib, with the function of promoting apoptosis and anti-angiogenesis, was used in the treatment of metastatic PHC (30). Ma et al (31) reported a case of PHC with liver metastasis treated with neoadjuvant modified-FOLFIRINOX (mFOLFIRINOX) chemotherapy followed by surgical resection; the patient's progression-free survival was 13 months. Other authors have described a case in which pancreatic neuroendocrine carcinoma was successfully treated with surgery followed by six cycles of post-operative chemotherapy (gemcitabine intravenously); the patient survival was 46 months (32). Pellini Ferreira et al (33) reported a case which was diagnosed as PHC with an increase in glucagon levels; treatment with octreotide intramuscular (IM) injections followed by chemotherapy was recommended with oral capecitabine and temozolomide; the patient ran a 10-mile marathon following 15 months of treatment. There are differential opinions regarding chemotherapy. Some authors recommend adjuvant chemotherapy, whereas others consider that a short-term regression can be achieved; however, no additional benefits have been found in the long-term (31,39). Further studies and novel treatment methods are required in order to reveal the histobiological characteristics of PHC and its effectiveness and sensitivity to chemotherapy. Chang et al (34) first reported a case of HC with Caris Molecu-lar Intelligence® 600 gene sequencing; the mutational analysis revealed BAP1 and NOTCH1 with known alterations. The utilization of next-generation nucleic acid sequencing may help to determine the nature of genetic mutations and may help to reveal the detailed characteristics of this rare tumor and may also guide therapy. Next-generation profiling is a promising approach for rare tumors.
Due to its rarity and the lack of evidence-based data, the prognosis cannot be predicted precisely. PHC tends to have an aggressive outcome. It is considered that those with a pure HCC-like morphology have a better prognosis than those with neuroendocrine differentiation and glandular or acinar differentiation. In the majority of cases, metastases to the liver and lymph nodes have also been observed (30,60). Early tumor cells formed between the lymphatic sinuses benefit cancer cell invasion and AFP inhibition immunoreaction (1). In the case presented herein, the patient presented with metastasis to the liver, stomach and spleen. According to limited reports, after 3 years, 50% of adult patients who are initially diagnosed usually succumb to the disease (60). In conclusion, although PHC is extremely rare, its characterization is essential.
In conclusion, PHC is very rare, and it is more easily diagnosed via morphological and immunohistochemical staining of the tissue specimens, as the clinical manifestation and the laboratory test results are often unspecific. Among these markers, Hep Par1 seems to be the most sensitive marker for PHC. Some novel tumor markers for the diagnosis PHC have been reported, such as PIVKA-II, BSEP and MDR3, which may prove to be helpful for the diagnosis. As there are currently no unified standards available for treatment, and in accordance with reports on the disease, the recommendation is as per patients' tolerance, surgical resection is the preferred alternative for disease-free survival. However, due to its rarity and the lack of evidence-based data, the prognosis of PHC cannot be predicted precisely. PHCs also tend to have an aggressive outcome and early detection is crucial.