Hepatoid carcinoma of the pancreas combined with serous cystadenoma: a case report and review of the literature

Introduction

Hepatoid carcinoma (HC) is a neoplasm exhibiting features of hepatocellular carcinoma (HCC) in terms of morphology and immunohistochemistry which grows outside the liver. Since its first description by Ishikura et al. in the stomach which is the most common location, it has been described in different organs such as lung, pancreas, esophagus, papilla of Vater, colon, urinary bladder, renal pelvis, ovaries, biliary tract and the gallbladder (1-9). The true incidence and exact behavior of pancreatic HC still remain unclear as only few case reports are available in the literature. This paper reports a case of incidentally detected HC combined with a serous cystadenoma arising from pancreas in a 47-year-old male patient.

Case report

A 47-year-old gentleman was referred to our institute because of an incidentally detected pancreatic mass while being evaluated for renal calculi. He had recurrent left sided loin to groin pain and associated backache for 6 months. Physical examinations on admission were unremarkable. Ultrasound of abdomen showed bilateral renal calculi and a fairly well defined hypoechoic lesion measuring 2.3 cm × 2 cm in relation to the tail of pancreas with mild internal vascularity. Contrast enhanced computed tomography (CECT) of abdomen showed two morphologically different lesions in the distal body and proximal tail of pancreas (Figure 1). Larger lesion was with well-defined margins and partially exophytic from the tail with mild heterogeneous enhancement. Smaller lesion was moderately enhancing and situated in the junction of body and tail of pancreas close to posterior margin. The margins of lesion demonstrated higher enhancement. MRI also revealed similar findings and a small calculus in the neck of gall bladder. The distal lesion was of size 3.13 cm × 2.98 cm × 2.67 cm and mildly hypointense in T1W1, nearly isointense in T2W1 image. It showed moderate uniform enhancement in arterial phase, partial washout in portal phase and further wash out in hepatic venous phase (Figure 2). The tumor was mildly hypointense in VIBE (volumetric interpolated breath-hold examination) sequence, isointense in TRUFI (true fast imaging with steady-state free precession) sequence and minimally hyperintense in diffusion weighted imaging (DWI)-B400 with high apparent diffusion coefficient (ADC) in the central part with peripheral areas showing mild restriction in ADC images (Figures 3,4). The proximal lesion was of size 1.55 cm × 2.11 cm × 1.57 cm with moderate enhancement at periphery and a central non enhancing area (Figure 2). Laboratory panel showed (our lab’s normal range in brackets); CA 19-9: 13.61 U/mL (0-35 U/mL), carcinoembryonic antigen (CEA): 1.68 ng/mL (0-3 ng/mL), chromogranin A: 41.35 ng/mL (<100 ng/mL), amylase: 113 U/L(28-100 U/L) and lipase: 153 U/L (13-60 U/L). With a possibility of non-functional neuroendocrine tumor, patient was taken up for surgery. Laparoscopic distal pancreatectomy with splenectomy and cholecystectomy were done. There was no evidence of any hepatic, peritoneal or lymph node metastasis.

Figure 1 CECT of patient showing an exophytic lesion with mild heterogeneous enhancement in the tail of pancreas (arrow) and another smaller moderately enhancing lesion proximally (arrow head). CECT, contrast enhanced computed tomography.

Figure 2 MR multiphase contrast imaging of pancreas showing enhancement patterns of tumors. (A) Arterial phase; (B) portal phase; (C) venous phase. Distal lesion (arrow) shows moderate uniform enhancement in arterial phase, washout in portal phase and further wash out in venous phase. The proximal (arrow head) lesion has moderate enhancement at periphery and a non enhancing area at the center.

Figure 3 MRI signal intensity characteristics. (A) Distal tumor (arrow) is mildly hypointense and proximal tumor (arrow head) is moderate hypointense in VIBE sequence; (B) distal (arrow) tumor isointense and proximal tumor (arrow head) is hyperintense in TRUFI sequence. VIBE, volumetric interpolated breath-hold examination.

Figure 4 MRI signal intensity characteristics. (A) Distal lesion (arrow) has minimal hyperintensity and proximal one (arrow head) is hyperintense in diffusion weighted imaging (DWI)-B400; (B) proximal lesion (arrow head) has high apparent diffusion coefficient (ADC) in ADC image, while the distal lesion (arrow) has high ADC in the central part with mild restriction in the periphery.

Cut section of the distal lesion was well circumscribed, encapsulated and let out bile. Cut section of the proximal tumor showed tiny cystic spaces. Microscopic examination of the distal tumor revealed an encapsulated neoplasm with features of hepatocellular tissue. It was composed of cells in trabecular pattern separated by sinusoids (Figure 5A). Tumor cells had moderate eosinophilic granular cytoplasm and vescicular nucleus with prominent nucleolus and intranuclear eosinophilic inclusions. Canalicular and intercellular bile plugs were seen (Figure 5B). There was no bile ductule or portal triad. Kupffer cells were, however, present. Smaller proximal neoplasm had multiple cystically dilated spaces lined by cuboidal cells (Figure 5C). Peripancreatic lymph nodes showed reactive hyperplasia only. Resection margins were negative for neoplasm. Immunohistochemically the distal tumor was strongly positive for hepatocyte specific antigen (Figure 6A), glypican 3 (focal) and cytokeratins (AE1/AE3, CK8 and CK18), with weak positivity for alphafetoprotein (Figure 6B). Tumor cells were immunonegative for chromogranin (Figure 6C), EMA and CK-7. The liver like tissue showed CD 34 expressing capillarized sinusoids. Gallbladder revealed no specific pathology. Based on these findings the distal tumor was diagnosed as hepatoid tumor of pancreas and the proximal one as serous microcystic cystadenoma. Alpha fetoprotein (AFP) detected 2 weeks post resection was 1.75 IU/mL (<6.0 IU/mL). At eighth month of follow up AFP is 3.14 IU/mL and CECT of abdomen shows no evidence of recurrence.

Figure 5 (A) Microscopy of distal tumor showing normal pancreas with a well encapsulated neoplasm composed of cells arranged in trabecular pattern and separated by sinusoids (H&E, ×40); (B) tumor cells are polygonal with abundant granular cytoplasm, centrally placed nucleus with prominent nucleoli. Canalicular and intracellular bile plugs are evident (H&E, ×200); (C) smaller proximal lesion showing serous cystadenoma-cystic spaces lined by cuboidal epithelium (H&E, ×100).

Figure 6 (A) Immunohistochemical (IHC) staining of the distal tumor for hepatocyte specific antigen-neoplastic cells are strongly positive (×100); (B) immunohistochemical (IHC) staining of the distal tumor for AFP-weakly positive (×200); (C) immunohistochemical (IHC) staining of the distal tumor for chromogranin-negative (×200).

Discussion

HC of the pancreas is an extremely rare neoplasm and only 23 cases have been reported in the literature so far (Table 1). The first pancreatic form of HC was reported by Hruban et al. in 1987 (10). The etiology and pathogenesis of pancreatic HC is still not clear and proposed theories of its origin mainly revolve around the transdifferentiation of pancreatic cells into hepatocytes and the common embryologic foregut derivation of the pancreas and liver (13,23). Though reported ages at presentation range from 21 to 80, most patients (16/23, 69%) were above 50 years of age. There is a clear male predominance (14/23, 60%). The most common presenting symptom was pain (6/23, 26%), either back or epigastric, followed by jaundice and weight loss. Many cases reported in the literature were asymptomatic or incidentally discovered (6/23, 26%) like our patient. More than 50% of Pancreatic HCs were located in the body or tail of the pancreas (13/23). Liver and lymph nodes are the most frequent sites of metastasis (23,31).

Table 1 Review of main features of hepatoid carcinomas of the pancreas reported in the literature and our case
Full table

Preoperative diagnosis is often challenging, even with appropriate imaging and cytological examination. In a contrast enhanced CT scan of abdomen HC often reveals as a heterogeneous mass with irregular enhancement (32) as it is observed in this reported case. MR imaging features of pancreatic HC in our case are similar to neuroendocrine tumors, except for mild diffusion signals in the lesion (Table 2). When diagnosing primary pancreatic HC, it is important to exclude metastatic HCC by clinical and pathological examination. Serum AFP levels is found to be elevated in most cases and can be used postoperatively to assess completeness of resection and extent of response to chemotherapy, and to detect recurrence of the tumor during follow up (24,31,33,34). However, AFP secretion can also be noticed in other pancreatic tumors like acinar and ductal neoplasms, neuroendocrine tumors and pancreatoblastomas (13,35,36). Diagnosis mainly depends on specific pathological findings. The characteristic pathological features are medium to large polygonal cells with eosinophilic to clear cytoplasm, vesicular nuclei and prominent nucleoli growing in a perisinusoidal pattern, along with the demonstration of the presence of bile and an immunohistochemical profile characteristic of HCC (37). Bile production in the tumor as in our case though a rare finding is more conclusive for hepatoid neoplasm (13). IHC markers used for diagnosis include immunoreactivity with polyclonal antibodies against AFP, CEA, and more specific markers like hepatocyte-specific Hep-Par1 antibody and albumin mRNA detected by in situ hybridization (13,20).

Table 2 MRI signal intensity and contrast characteristics of pancreatic hepatoid carcinoma in our case
Full table

Immunohistochemical profiling with cytokeratins (CK) can be helpful in differentiating hepatoid tumours from HCC. Hepatoid tumors are most often positive for pancytokeratin marker AE1/AE3 (92%), CK 19 (94-100%) and CK18, and negative for CK7 (38,39). CK20 positivity is seen in about 25-47% of hepatoid neoplasms (38,39). CK19 and 20 expression is very rarely seen in HCC (38-40). Monoclonal antibody HepPar1 is expressed by normal and neoplastic hepatocytes, and is considered more sensitive than AFP to diagnose HCC. It is also found to be positive in some cases of HCs, but diffuse positivity for HepPar1 is more consistent with HCC than hepatoid neoplasm (20,38,39). HCs can be differentiated from other AFP producing tumors like pancreatoblastoma and acinar cell carcinoma of pancreas by their histopathological features and by expression of liver specific proteins on immunohistochemistry. The presence of small acinar structures, mesenchymal components, or the characteristic squamous corpuscles would favor a diagnosis of pancreatoblastoma and in case of acinar cell carcinoma immunoreactivity with trypsin, chymotrypsin, or lipase can be detected.

Pancreatic HC can present in pure forms or in association with histologically different components such as adenocarcinoma or neuroendocrine tumors (20,24). Those with pure hepatoid or hepatocellular differentiation seem to have better survival and recurrence rates than patients with mixed-type tumors (27). In our case it was associated with a serous microcystic cystadenoma in an adjacent location. Only one out of 23 cases reported in the literature had microcystic cystadenoma as an associated component (15) (Table 1).

Surgical resection is considered as the mainstay of treatment whenever possible. Some authors have advocated adjuvant chemotherapy because of the metastatic potential of the tumor while others have found no added benefit (20). A certain degree of response to chemotherapy and multi-target tyrosine kinase inhibitor sorafenib was reported in locally unresectable, metastatic or recurrent disease (25). Petrelli et al. reported a case of metastatic HC (mainly to the liver, lymph nodes, and lungs) in a 37-year-old male treated with the multi-target tyrosine kinase inhibitor sorafenib (400 mg BD). It provided disease control for 8 months, which was confirmed by imaging and biochemical data. But they were forced to discontinue the therapy because of worsening liver failure (25). In 2012, Karayiannakis et al. reported an overall survival of 20 months in a 60-year-old female patient with hepatoid adenocarcinoma of the gallbladder treated with surgery followed by sorafenib for 15 months until her disease progressed (33). Lucas et al. reported a case of hepatoid adenocarcinoma of peritoneal cavity (which was closely related to colon) treated with FOLFOX (5-fluorouracil, leucovorin and oxaliplatin) after complete resection of the tumor. They report more than 3 years of follow up without any evidence of recurrence (38). Successful disease control with a regimen of 5-FU plus paclitaxel has been reported in a 64-year-old male patient with metastatic gastric hepatoid adenocarcinoma by Takeyama et al. in 2007 (34).

HCs of the gastrointestinal tract are generally considered as very aggressive neoplasms and have an unfavorable prognosis (39). Survival appears to be mainly depends upon the extent of the disease and completeness of resection. Longest survival reported with metastatic HC after resection is 8.5 years (13) (Table 1). Steen et al. reported more than 5-year survival without any recurrence after complete resection of a HC localized to the tail of pancreas, without any adjuvant therapy (30). Owing to its rarity further studies and long term follow up are needed to standardize the treatment and to correctly assess prognostic features.

Conclusions

In conclusion, though HC of pancreas is extremely rare it should be considered in preoperative differential diagnosis of pancreatic tumors especially when the lesion is associated with atypical clinical presentation and image findings. The diagnosis is mainly based on histopathological and immunohistochemical features and an early detection is vital as complete resection of the tumor appears to be the best option of the treatment.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Informed Consent: Informed consent was obtained from the patient for publication of this case report and any accompanying images.

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