Hepatoid carcinoma of the pancreas

Abstract

BACKGROUND

The majority of primary extrahepatic neoplasms exhibiting features of hepatocellular carcinoma in terms of morphology, immunohistochemistry, and behavior have been described in the stomach. To the authors' knowledge only a few cases have involved other organ sites. They frequently are associated with other histologic type tumors such as adenocarcinoma, and portend an aggressive behavior.

METHODS

Two examples of hepatoid carcinoma arising from the pancreas are reported in the current study.

RESULTS

One case was a malignant islet cell tumor with a full-blown clinical syndrome of glucagon overproduction, histologic evidence of hepatocytic differentiation, bile production, and α-fetoprotein (AFP) positivity. The second tumor was a ductal carcinoma showing periodic acid–Schiff positive and diastase-resistant hyaline globules, AFP production, and ultrastructural resemblance to hepatocytic cells.

CONCLUSIONS

The rare observation of cellular phenotypic transformation that corresponds with the process of hepatocytic transdifferentiation of pancreatic cells demonstrated in animal models and the common embryologic foregut derivation of the pancreas and liver also may explain the phenomenon of pancreatic hepatoid carcinoma. Cancer 2000;88:1582–9. © 2000 American Cancer Society.

After Ishikura et al.1 reported a striking hepatocellular carcinoma (HCC)-like differentiation in a primary gastric tumor in 1985, subsequent documentation of this unique histopathologic feature has been made in other extrahepatic sites including the esophagus, papilla of Vater, colon, lung, gallbladder, adrenal gland, kidney, urinary bladder, ovary, uterus, vagina, and testicle.2 This broad new category of neoplasm has been referred to collectively as “hepatoids” and predominantly occurs with concomitant foci of a more common differentiation, with adenocarcinoma being the most common type, admixed together in varying proportions. Diagnosis principally is in terms of morphology (histologic and cellular) supported by other evidence linked to hepatic lineage, including α-fetoprotein (AFP) production (concanavalin A [Con A] affinitive and lens culinares agglutin [LCA] reactive), positive immunohistochemistry of several liver-synthesized proteins, presence of periodic acid–Schiff (PAS) positive, diastase-resistant intracytoplasmic globules, bile production, and, recently, the more specific and sensitive in situ hybridization detection of albumin's messenger RNA (mRNA).1–3 The tumors tend to behave aggressively and the majority manifest with metastasis at the time of diagnosis.

This report pertains to two cases of hepatoid carcinoma arising from the pancreas; one was associated with an islet cell glucagonoma and the second with a ductal cell carcinoma.

Case Reports

Case 1

A 57-year-old white male was diagnosed with ischemic optic neuritis due to diabetes mellitus. Diet and oral hypoglycemics resulted in some symptomatic improvement. There also were episodes of intermittent and nondescript skin rashes that were interpreted as allergies. One year later the patient presented with nausea, emesis, diarrhea (6–10 stools per day), and a 50-pound weight loss. Physical findings were pallor, epigastric mass, abnormally flexible nails, and diffuse skin rashes. The latter appeared erythematous, scaly, and bullous with evidence of resolving lesions involving the face, scalp, buttocks, scrotal and perianal skin, lower legs, and ankle area. Pertinent laboratory data were normocytic, normochromic anemia and glucagon levels of approximately 4000 pg/mL. Other investigative findings localized the tumor mass to the pancreas. In the ensuing exploratory laparotomy, a distal two-thirds pancreatectomy (Fig. 1) with splenectomy and biopsy of a liver nodule was performed. A lobulated, unencapsulated, and poorly demarcated tumor measuring 6 cm × 4 cm × 3.5 cm diffusely obliterated the underlying pancreas. The mass was firm and solid with grey-tan, bulging cut surfaces. The spleen was moderately enlarged and congested. The wedge liver biopsy appeared to show a metastatic lesion with a grey-tan surface. Microscopically, the tumor in the pancreas as well as in the metastatic location (liver) was comprised of nests, sheets, and cords of monotonous, small, endocrinoid cells with a round to oval cell body, eosinophilic to granular cytoplasm, and vesicular nuclei. Prominent nucleoli and few abnormal mitoses were observed. Evidence of perineural lymphatic space and blood vessel invasion by the tumor was present. Also striking were findings of hepatoid changes, demonstrating liver-like appearance, trabecular pattern, and sinusoidal vascularity as well as golden yellow bile production (Fig. 2). By electron microscopy, numerous peripherally located, cytoplasmic, neurosecretory granules characterized by a highly dense core with a medium halo and limiting membrane, consistent with glucagon, were noted. Immunocytology revealed immunoreactive glucagon and AFP in the cytoplasm of neoplastic cells. The clinical course of the patient was marked by disease remissions and exacerbations of symptoms and signs that closely paralleled the ups and downs of blood glucagon levels. Intravenous di-amino triazeno-imidazol carboxamide, 400 mg for 5 days every 6 weeks, was administered and usually resulted in clinical improvements and decreased circulating glucagon. From the time of diagnosis, the patient survived approximately 8.5 years. He died of a widespread hepatoid islet cell carcinoma. No postmortem examination was performed.

Figure 1. Macroscopic appearance of the resected tumor in Case 1. A rim of residual pancreatic tissue is identifiable (arrow).

Figure 2. (A and B) The hepatoid component of the malignant islet cell carcinoma with golden yellow bile production (arrows). (H & E, ×100 [A] and ×400 [B]).

Case 2

A 28-year-old white male was admitted for lumbosacral backache. Workups were noninformative. Two months later, the patient presented with severe abdominal and back pain. Computed tomography scan and magnetic resonance imaging revealed an 8 cm × 8 cm × 6 cm retroperitoneal mass (Fig. 3), anterior to the right kidney and adjacent to the stomach. It was nonpalpable because of severe abdominal tenderness. Exploratory laparotomy demonstrated a left upper quadrant retroperitoneal mass that was surgically unresectable. The pathologic interpretation of wedge tissue biopsy material was diffuse hepatoid ductal carcinoma of the pancreas (Fig. 4). The neoplastic cells were arranged in solid and loose medullary sheets of poorly differentiated, large sized, cuboidal to polygonal, liver-like carcinoma cells. Their cytoplasm was strikingly eosinophilic, granular, and abundant. The nuclei usually were vesicular with prominent nucleolus or nucleoli. Glandular pattern essentially was absent. Variable extracellular and intracellular eosinophilic inclusions mimicking Councilman bodies also were noted (Fig. 5). Another exploratory laparotomy was followed by debulking of a tumor in the pancreatic area with macroscopic invasion of the gastric, ileal, and colonic serosa. Microscopic, histochemical, and ultrastructural evaluation reaffirmed the diagnosis of hepatoid ductal carcinoma. A postoperative complication of intraabdominal infection was treated appropriately with specific antibiotics, as well as with morphine for pain. Chemotherapic regimens provided no discernable effect. He developed signs and symptoms of gastric outlet obstruction associated with spiking fever and other effects of malignancy. The patient subsequently deteriorated progressively and died 14 months after the initial hospitalization. No autopsy was permitted.

Figure 3. Magnetic resonance imaging in Case 2 distinctly delineates a large mass lesion in the area of the pancreas (*).

Figure 4. (A and B) Light microscopy shows a diffuse sheet of poorly differentiated large cell carcinoma, exhibiting abundant, eosinophilic cytoplasm and variably sized cytoplasmic and extracellular Councilman-like bodies (arrows). (H & E, ×100 [A] and ×400 [B]).

Figure 5. Electron microscopy of a tumor cell reveals cytoplasmic organelles and dense, granular, Councilman-like inclusion (*), with a resemblance to hepatocytes (×9000).

DISCUSSION

A review of the literature found that there have been only three cases of HCC-like differentiation primarily arising from the pancreas reported to date. In 1987, Hruban et al.4 documented a case of a pancreatic acinar cell neoplasm with foci of hepatocellular differentiation and in 1988 Obara et al.5 and, most recently, Yano et al.6 described a case of an AFP-producing hepatoid adenocarcinoma of the pancreas. To our knowledge, Case 1 in the current study is the first reported association between a hepatoid carcinoma and a pancreatic islet cell tumor, and Case 2 marks the third reported instance of hepatoid differentiation in pancreatic ductal carcinoma. Table 1 summarizes the clinicopathologic characteristics of hepatoid carcinoma of the pancreas.

Table 1. Clinicopathologic Characteristic of Hepatoid Carcinoma of the Pancreas

Cases	Age (yrs)	Gender	Clinical presentation	Location	Size (cm)	Serum enzyme elevation	Metastasis	Survivala
F: female; NA: not available; M: male; AFP: α-fetoprotein. a From time of diagnosis. b Detected at autopsy.
Hruban et al.4	53	F	Increasing abdominal girth, polyarthritis, tender subcutaneous nodules	Tail	1	Lipase	Liver, lymph nodeb	Died, 2.75 mos
Obara et al.5	NA	NA	NA	NA	NA	NA	NA	NA
Yano et al.6	57	M	Epigastric pain, fever, emesis	Head	9 × 7 × 5	AFP	Liver, peritoneum	Died, 3 mos
Case 1 (current study)	57	M	Epigastric mass, nausea, emesis, diarrhea, severe dermatosis, anemia, diabetes mellitus	Distal	6 × 4 × 3.5	Glucagon	Liver	Died, 8.5 yrs
Case 2 (current study)	28	M	Severe abdominal and back pain	Diffuse	8 × 8 × 6	—	Gastric, ileal, colonic serosa	Died, 14 mos

Hepatoid neoplastic cells can appear in several histologic patterns (trabecular, medullary, and glandular) and in varying degrees of differentiation from well differentiated “liver-like” large polyhedral cells with abundant eosinophilic cytoplasm having a round, vesicular, centrally placed nucleus and prominent nucleoli to less differentiated, haphazardly arranged pleomorphic cells.1–4 To our knowledge to date the more conspicuous histologic and cytologic descriptions have been the main basis for identification. Periodic acid–Schiff positive, diastase-resistant intracytoplasmic hyaline globules (Case 2) are a common finding, identified in 34 of 59 reported cases of gastric hepatoids,2 but these globules also were described in various tumors.1, 2 A more conclusive but rare finding is the presence of bile production (Case 1), which to our knowledge has been described in only 3 of 59 reported cases of gastric hepatoids.2 A peculiar hepatic-associated cytologic feature noted in the current study is the cytoplasmic and extracellular eosinophilic inclusions that mimic Councilman bodies (Case 2). Table 2 highlights the histology, serum markers, and immunohistochemical staining of hepatoid carcinoma of the pancreas.

Table 2. Histology, Serum Markers, and Immunohistochemical Staining of Hepatoid Carcinoma of the Pancreas

Cases	Histology				Serum markers		Tissue staining
	Hepatoid	Primary organ differentiation	PAS + Glob	Bile production	AFP (ng/mL)	CEA (ng/mL)	AFP	CEA
PAS: periodic acid-Schiff stain; Glob: globule; AFP: α-fetoprotein; CEA: carcinoembryonic antigen; +: positive; −: negative; NA: not available.
Hruban et al.4	+	Acinar cell carcinoma	−	−	< 10	1.4	−	−
Obara et al.5	+	Ductal cell carcinoma	NA	NA	NA	NA	NA	NA
Yano et al.6	+	Ductal cell carcinoma	NA	NA, bile canaliculi	177.6	76.5	+	+
Case 1 (current study)	+	Malignant glucagonoma	−	+	NA	NA	+	+
Case 2 (current study)	+	Ductal cell carcinoma	+	+, Councilman-like bodies	NA	NA	+	+

AFP, a known tumor marker for HCC and extragonadal germ cell tumor (EGCT),1, 7, 8 has been found to be elevated in the serum levels of 34 of 38 reported cases and positive for tissue stains in 45 of 59 reported cases of gastric hepatoids. However, AFP production also can be present in nonhepatoid tumors including pancreatic ductal carcinoma, acinar cell carcinoma, islet cell tumor, and poorly differentiated malignancies.7 In the case published by Hruban et al.,4 AFP was only < 10 ng/mL and neoplastic cells were negative for AFP stains. Both patients reported in the current study demonstrated positive cellular AFP staining. In AFP-producing pancreatic tumors, serum AFP levels are useful for the diagnosis and as a marker for evaluating recurrent disease and therapeutic response.7

Other proteins in the hepatoid foci can be detected using immunohistochemical stains. The more frequently positive proteins include keratin/cytokeratin CAM 5.2/AE, albumin, α-1-antichymotrypsin, prealbumin, α-1-antitrypsin protease inhibitor, and transferrin.2 Unlike AFP and keratin, albumin can serve to establish hepatic lineage because it is made exclusively by the liver.9 However, due to diffusion artifacts, immunohistochemical demonstration of albumin is unreliable.9 In situ hybridization detection of albumin mRNA is highly specific (100%) and sensitive (95.5%) for hepatocellular lineage,9 and to our knowledge recently was used for the first time in a hepatoid tumor by Roberts et al.2

No morphologic findings of germ cell tissues (e.g., trophoblasts and Schiller-Duval bodies) were detected in our studies. Foci of hepatic tissues were observed in 9.3% cases of EGCT; some were reported in the retroperitoneal area, which is the anatomic region of the pancreas.8 However, retroperitoneal EGCT generally were observed in younger patients (ages 4 days–17 years).8 Histologically, diagnosis would be facilitated by seeking the more differentiated area comprised of cells with abundant eosinophilic cytoplasm more typical of hepatoid carcinoma.1 Using AFP isoforms also has been proposed to aid with their differentiation. Hepatoid carcinomas are associated with AFP that has a Con A binding property and is LCA reactive.1, 2

Differential diagnosis also must be made between a metastasis and a primary HCC or even an extrapancreatic hepatoid carcinoma.1, 2 The rate of incidence of HCC spreading to the pancreas is only between 2.7–5.6% and usually is a late finding.10

Hepatocyte induction in the pancreas has been demonstrated repeatedly in animal models, but the specific cell-type origin is being debated. Administration of a known pancreatic carcinogen, bis-(oxopryl) nitrosamine, to a hamster's pancreas and copper repletion after depletion in rats (nutritional mediated) both resulted in the induction of hepatocytes (morphologically and functionally very similar to liver hepatocytes) during pancreatic regeneration of predominantly acinar cells, concluding acinar cell transdifferentiation into hepatocytes.11 Makino et al.12 have suggested that it is the ductal cells from which the transdifferentiating hepatocytes in the hamster originate. In addition, intermediate cells with features of both acinar/islet cells and hepatocytes also have been identified.11 Nevertheless, these observations support the theory that the striking discordance between cellular phenotype (hepatic) and the organ of origin (pancreas) is in fact conceivable. The potentiality of hepatic differentiation to arise from any of the three main pancreatic cells (acinar, ductal, and islet cells) therefore is proven by the cases described in the current study. Pancreatic cells might possess liver specific genes normally in the repressed state that may be activated during the process of carcinogenesis, expressing cells with a hepatic phenotype. This is supported by the fact that the liver and the pancreas, both exocrine and endocrine,13 evolve from a common foregut endoderm of close embryonic proximity, compatible with the prevailing concept of hepatoid pathogenesis (considered because the stomach is the most common site for its occurrence).1–3 However, because hepatoid tumors subsequently have been described in organs of different germ layer origin such as the kidney, ovary, and testicle, the etiologic reference of this rare cellular transformation must be considerably more primordial to encompass tissues from other histologic ontogeny.

Rao et al.11 have quoted the principle of nuclear equivalence, stating that cell differentiation is accomplished through differential recruitment of genes and the expression of their products because the nuclei of all cells in a multicellular organism possess a complement of genes identical to those of the zygote. The process of transdifferentiation is possible through activation of dormant genes accompanied by the synthesis of new and different gene products.11 This provides us with a reason to consider that the emergence of these hepatoid differentiations represents an inherent but tenuous ability of cells in general to exhibit, under appropriate conditions (e.g., the influence of carcinogens), multiphenotypic differentiation with preponderance to closer progenies.

There are not enough cases of hepatoid carcinoma of the pancreas to establish a prognosis, although hepatoid carcinomas of the gastrointestinal tract in general have an unfavorable prognosis.1, 3, 14 The majority already have metastasized by the time of diagnosis, mostly to the liver and lymph nodes.1, 3, 14 They attain their biologic aggressiveness through massive lymphatic and venous invasion and florid proliferation within local veins, mimicking the behavior of HCC.14 Primary ductal carcinoma of the pancreas is known to have a dismal survival rate. With both these unfavorable characteristics concurring in a single clinicopathologic entity, we could expect an equally grave prognosis.