Indian Journal of Pathology and Microbiology

: 2015  |  Volume : 58  |  Issue : 4  |  Page : 543--545

Mixed adenoneuroendocrine carcinoma of the gallbladder, histopathological features

Shweta Azad1, Deepti Shukla1, Ankur Garg2, Sanjay Singh Negi2, Veena Malhotra1,  
1 Department of Histopathology, BLK Hospital, Pusa Road, New Delhi, India
2 Department of Hepatobiliary Surgery, BLK Hospital, Pusa Road, New Delhi, India

Correspondence Address:
Dr. Veena Malhotra
Department of Histopathology, BLK Hospital, Pusa Road, New Delhi


An unusual case of mixed adenoneuroendocrine carcinoma is described which posed a diagnostic challenge in view of neuroendocrine component mimicking signet ring cells of adenocarcinoma. Diagnostic criteria for these mixed tumors, their histogenesis and treatment modalities are highlighted.

How to cite this article:
Azad S, Shukla D, Garg A, Negi SS, Malhotra V. Mixed adenoneuroendocrine carcinoma of the gallbladder, histopathological features.Indian J Pathol Microbiol 2015;58:543-545

How to cite this URL:
Azad S, Shukla D, Garg A, Negi SS, Malhotra V. Mixed adenoneuroendocrine carcinoma of the gallbladder, histopathological features. Indian J Pathol Microbiol [serial online] 2015 [cited 2020 Oct 31 ];58:543-545
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Full Text


Mixed adenoneuroendocrine carcinomas (MANECs) are rare neoplasms. Their presence in the gallbladder is even rarer. We describe an unusual case of MANEC of the gallbladder, where glandular adenocarcinoma was intermixed with cells with vacuolated cytoplasm. These cells were initially considered as signet ring cells of adenocarcinoma. However, careful morphological evaluation and immunohistochemical staining for neuroendocrine markers revealed that cells with vacuolated cytoplasm represented the neuroendocrine component akin to goblets cells carcinoid of the appendix.

 Case Report

A 62-year-old female had a blunt abdominal trauma for which contrast-enhanced computed tomography scan was done. Gallbladder wall thickening suspicious of malignancy was detected. The patient was referred to our hospital for definitive management. Serum bilirubin was 1.07 mg/dl, aspartate transaminase: 92.5 U/L, alanine transaminase: 81.9 U/L and Alkaline phosphates were 77 U/L. Radical cholecystectomy was performed. Gallbladder, segment IVb, and V of the liver, hepatoduodenal and retropancreatic lymph nodes were resected.

Gallbladder measured 6 cm × 3 cm × 2.5 cm with attached segment of the liver measuring 6 cm × 5 cm × 3.5 cm. A grey-white firm area was seen at the fundus measuring 2 cm × 2 cm. The rest of the gallbladder wall was normal in thickness. The posterior fundic wall was adherent to the liver. However, the liver was grossly normal. Microscopic examination of gallbladder sections showed a neoplasm with distinct areas of adenocarcinoma having complex glandular morphology mixed with sheets of cells with vacuolated cytoplasm [Figure 1]a. These cells showed mild nuclear pleomorphism and had signet ring morphology. In focal areas, these vacuolated cells were arranged in a microglandular pattern, similar to that seen in appendiceal adenocarcinoid. Tumor cells were infiltrating muscle coat and were extending into serosa. Cystic duct margin was free of tumor. Liver tissue, hepatoduodenal, and retropancreatic lymph nodes did not show tumor infiltration. Immunohistochemical stain for synaptophysin revealed positive staining in the cells with vacuolated cytoplasm thus confirming their neuroendocrine nature [Figure 1]b. However, the complex adenocarcinoma component was negative for synaptophysin.{Figure 1}

Cytokeratin positivity was seen in goblet cells, as well as complex glandular adenocarcinoma areas [Figure 1]c. Staining for carcinoembryonic antigen (CEA) and epithelial membrane antigen (EMA) was positive in both exocrine, as well as neuroendocrine goblet cell component [Figure 1]d,[Figure 1]e,[Figure 1]f. Proliferative index (Ki 67) of the neuroendocrine component was about 15/100 cells, whereas that in complex glandular component was 40/100 cells. Neuroendocrine component comprised of approximately 40–50% of the total tumor mass. The tumor was diagnosed as MANEC of intermediate grade malignancy.


Scattered neuroendocrine cells can be seen in gastrointestinal carcinomas. Their presence does not qualify these tumors as mixed tumors. In 2000, WHO classification of endocrine tumors, mixed exocrine endocrine tumors were defined as neoplasms in which each component formed at least 30% of the tumor.[1] In 2010, WHO classification these were designated as MANECs.[2] In these tumors, both components are malignant. In our case, both exocrine and endocrine component formed almost equal part of the tumor, and thus the tumor qualified as a true mixed tumor.

Our case was initially considered as adenocarcinoma with glandular and signet ring morphology. However, the careful evaluation revealed that vacuolated cells were dominantly cohesive and showed a microglandular pattern in focal areas. Neuroendocrine goblet cells are cohesive in comparison to signet ring cells of adenocarcinoma which are usually dis-cohesive. Nuclear atypia is absent in goblet cells and is seen in signet ring cells of adenocarcinoma. Morphological evaluation for differentiation of goblet cells from signet ring cells may be the key point.[3] Immunohistochemistry helps in the final confirmation of the neuroendocrine nature of cells.

The prognosis of these tumors will depend on the degree of differentiation of each component. La Rosa et al. have provisionally classified gastrointestinal MANECs as (1) high grade malignant which contain adenoma/adenocarcinoma and poorly differentiated neuroendocrine carcinoma (small, intermediate and large cell type), (2) intermediate grade malignant which contain mixed adenocarcinoma and G1/G2 neuroendocrine tumor (NET). Besides these two well-defined types, a provisional category which is not included in WHO 2010 classification has been described. This is indolent low-grade malignant mixed tumor which has adenomatous component and NET. It is designated as the mixed adenoneuroendocrine tumor and not as carcinoma in view of indolent behavior.[4] In general, clinical behavior of gastrointestinal tract (GIT) MANECs will depend on grade of the adenocarcinomatous component if the neuroendocrine component is well-differentiated and upon the grade of neuroendocrine component if it is poorly differentiated. The prognosis will depend on the stage of the tumor as well.

For assessing the differentiation of neuroendocrine component in a mixed tumor, the proliferative index is now almost mandatory. Grade 1 NET (carcinoid) has a proliferative index of up 2, Grade 2 NET (intermediate grade) has a proliferative index between 3 and 20 and high grade tumor has a proliferative index of more than 20.

Our case showed a moderately differentiated adenocarcinoma and a neuroendocrine component showing proliferative index around 15. Thus, this tumor was considered as intermediate grade malignant mixed neoplasm.

In 1987, Lewin classified these tumors as (1) composite or collision tumor when exocrine and endocrine components occur in separate areas of the same lesion, (2) combined tumors when both components are intimately mixed and (3) amphicrine tumors when exocrine and neuroendocrine features are present in the same neoplastic cell.[5] Histogenetically, these tumors can arise from a coincidental neoplastic change in two different cell types or from stem cell capable of divergent differentiation. Origin from precursor epithelial cell capable of divergent differentiation is a likely pathogenetic mechanism as a simultaneous neoplastic change in two different cells in the same location is unlikely. In our case, both exocrine and neuroendocrine component of the tumor was intimately intermixed, and the tumor showed areas of apparent transition. The neuroendocrine component in our case was akin to goblet cell carcinoid of the appendix. Goblet cell carcinoids show mucin, as well as neuroendocrine granules in tumor cells and are themselves considered as mixed tumors arising from amphocrine cells. EMA and CEA positivity usually seen in exocrine component were present in both exocrine and neuroendocrine component in our case. This can be explained in view of goblet cell carcinoid morphology of neuroendocrine component. Cytokeratin positivity can be seen in both exocrine and endocrine components. The histopathological and immunohistochemistry in our case supports an origin from stem cell with divergent differentiation in these tumors.

Mixed tumors have been described at various sites in GIT. In the stomach it has been suggested that they can be seen in association with autoimmune chronic atrophic gastritis, intestinal tumors in association with long-standing inflammatory bowel disease and an esophageal MANEC with Barrett's esophagus.[4]

Recently a number of MANEC have been reported in the gallbladder.[6],[7],[8],[9],[10] The neuroendocrine component in these tumors has shown varying degree of differentiation. Tumor with the poorly differentiated neuroendocrine component is an aggressive tumor.

The usual treatment consists of radical cholecystectomy and regional lymphadenectomy. As these tumors are rare, there is no agreement on whether these patients should receive chemotherapy. Various drugs such as doxorubicin, 5-fluorouracil, cisplatin, and streptozocin have been used either alone or in combination, with poor overall response rates.[10] Biotherapy using somatostatin analogs has been assessed in the treatment of metastatic disease; it has demonstrated tumor static effects with symptomatic improvement.[10] In our case, the tumor was confined to the gallbladder and was completely resected. The patient was not willing for further treatment and is asymptomatic for last 2 years.

MANECs pose a diagnostic challenge as a neuroendocrine component can have varied morphology, and morphological evaluation and immunohistochemistry is essential for precise diagnosis. The treatment options will depend on the grade of the mixed tumor, and differentiation of each component. Multimodal treatment should be the aim with a focus on the more aggressive component.

This case was especially more challenging as the neuroendocrine component with vacuolated cells could be easily mistaken as signet ring cells in a background of adenocarcinoma.

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Conflicts of interest

There are no conflicts of interest.


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