Mixed (composite) glandular-endocrine cell carcinoma of the gallbladder

Abstract

Background

A mixed pattern of glandular and neuroendocrine elements is rare in tumours at any site within the gastrointestinal tract but particularly so in the gallbladder.

Case outline

A 72-year-old woman presented with abdominal pain and jaundice and was found to have a large mass in the fundus of the gallbladder.The mass was radically excised to include a wedge of liver and the hepatoduodenal lymph nodes. Histopathological examination of the resected gallbladder showed an invasive tumour composed of both adenocarcinoma and endocrine cell carcinoma, with apparent transitions between them. The patient received no further treatment and died two months later.

Discussion

There are 14 previous case reports of mixed adeno/endocrine carcinoma of the gallbladder. Histochemical similarities between the two neoplastic components of the present tumour would support their origin from a common precursor cell, but the alternative hypothesis of coincidental neoplastic change in two different cell types cannot be excluded.

Introduction

Gastrointestinal tumours displaying both glandular and neuroendocrine differentiation are uncommon. Most of them arise in the appendix, but they also occur in the colon, stomach, oesophagus and duodenum ¹,². In the gallbladder, tumours of this kind are rare, only 14 cases being reported in the literature ³,⁴,⁵,⁶,⁷,⁸,⁹,¹⁰,¹¹,¹²,¹³. We present a case of a gallbladder composite tumour displaying features of both adenocarcinoma and endocrine cell carcinoma, and we discuss the histogenesis of these unusual tumours and the prognostic implications of this diagnosis.

Case report

A 72-year-old Caucasian woman was admitted to the hospital complaining of abdominal pain, nausea and vomiting for the previous 12 hours. She had a 6-month history of epigastric discomfort, loss of weight (7 kg) and slowly progressive jaundice. Laboratory tests showed increased levels of alkaline phosphatase and total serum bilirubin. A CT scan revealed dilatation of the intra- and extrahepatic bile ducts, extensive thickening of the gallbladder wall and swelling of the head of the pancreas. A cholecystectomy was performed with wedge liver resection and extensive clearance of hepatoduodenal lymph nodes. No liver metastases were grossly detected, and the pancreas appeared normal.

The resected gallbladder measured 9.5×5.0 cm and was filled with bile and gallstones. There was a greyish-white tumour in the fundus, with a slightly elevated and partially eroded surface, measuring 7.0×6.2×1-6 cm. It invaded deeply into the wall of the gallbladder without reaching the serosa. Microscopically, this tumour consisted of both adenocarcinoma and endocrine cell carcinoma. The two elements were randomly distributed through the gallbladder wall, closely juxtaposed, but also with apparent transitions between them in many areas. The adenocarcinoma was a well-differentiated tubular tumour, and the endocrine cell carcinoma was composed of solid or cribriform nests of medium-sized cells with amphiphilic cytoplasm, hyperchromatic moderately pleomorphic nuclei and a high mitotic rate. Additionally, there was focal necrosis, fibrosis, extension to the adjacent liver tissue, vascular invasion and metastasis to the excised lymph nodes. The overlying mucosa was partially eroded and showed papillary hyper-plasia and dysplasia. The adenocarcinoma cells stained positively for mucicarmine and alcian blue at the luminal margins, and so did the intraluminal material of the carcinomatous tubules. There was intense staining for epithelial membrane antigen (EMA) and keratins of low molecular weight (Figure 1). The endocrine cell carcinoma showed diffuse and moderately intense staining for neuron specific enolase (NSE) (Figure 2). No argyrophilic or argentaffin granules and no staining for chromogranin or synaptophysin were observed. Focal alcian blue positivity was identified within the intraluminal material of the cribriform structures.

Figure 1. .

Mixed tumour of the gallbladder, exhibiting features of both tubular adenocarcinoma (arrow) and endocrine cell carcinoma (arrowheads). Cytokeratin immunopositivity is confined to the adenocarcinoma (arrow).

Figure 2. .

Histological transition between endocrine cell carcinoma and adenocarcinoma (arrowhead). NSE immunopositivity is confined to the endocrine cell carcinoma (arrow).

The patient's postoperative course was uneventful. No adjuvant treatment was given, and she died 2 months later. No autopsy was performed.

Discussion

Malignant tumours of the gallbladder are uncommon, accounting for 0.5% of all cancers in western countries. Most of them are adenocarcinomas, while neuroendocrine tumours are rare, representing only 0.5% of all gallbladder tumours ¹⁴. Mixed tumours are even more rare, with only 14 cases reported in the literature ³,⁴,⁵,⁶,⁷,⁸,⁹,¹⁰,¹¹,¹²,¹³. In these cases, the carcinomatous component has been defined as either an ordinary adenocarcinoma, an undifferentiated carcinoma or a signet-ring carcinoma, while the neuroendocrine component has been defined as carcinoid or endocrine cell carcinoma.

The histogenesis of composite gastrointestinal tumours is not clear. Two hypotheses have been proposed: (a) coincidental neoplastic change in two different cell types ³, and (b) neoplastic change of a single common precursor cell ¹. The first hypothesis is controversial. Cancer is supposed to be a monoclonal proliferation, and so the occurrence of a tumour simultaneously derived from two different precursor cells in the same area seems very unlikely. Nevertheless, there are cases in which the two elements appear rather separated or the glandular component seems to arise in an adenomacarcinoma sequence, so that the possibility of a collision between two independent synchronous or metachronous tumours cannot be excluded ¹⁵.

The second hypothesis of a common precursor cell is more compatible, given the presence of transition zones between the carcinomatous and neuorendocrine components, the intricate admixture of the different cell types and patterns within the tumours, and the presence of amphicrine cells, features that can be seen in most composite tumours of the gut ¹. The case we present displayed features of both adenocarcinoma and endocrine cell carcinoma. The frequent transitions between the two components and their similar histochemical properties further support the hypothesis of the neoplastic change of a single common precursor cell.

The morphological subtyping of mixed tumours of the gastrointestinal tract may be of clinical importance. Available data suggest that gastric and colonic adenoendocrine carcinomas seem to behave no differently from ordinary adenocarcinomas ¹⁶. The reported cases of mixed gallbladder tumours are too few for definite conclusions about their behaviour. According to Hsu ¹², it seems the presence of pure or predominant neuroendocrine differentiation in carcinomas of the extrahepatic biliary tract is associated with shorter survival time than carcinomas with pure or predominant exocrine differentiation, regardless of the extent of the disease, the treatment rendered or the location of the tumour. The documentation of more cases of composite gallbladder tumours would help provide more meaningful correlative clinicopathological studies.