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Final Diagnosis: Small cell carcinoma of the gallbladder

Discussion (Slide show at bottom of this page):

Small cell carcinoma of the gallbladder is a rare entity first described by Albores-Saavedra et al. in 1981.1 Today, around 100 cases have been reported in the English literature, and neuroendocrine carcinomas are reported to represent around 2% of all gallbladder carcinomas.2 The average age at diagnosis is 62 years (range 25-89) with a slight female predilection.3 Much like gallbladder adenocarcinoma, gallbladder neuroendocrine carcinoma is associated with cholelithiasis. Due to the lack of intrinsic neuroendocrine cells within the gallbladder, these tumors are thought to evolve either from a multipotent stem cell precursor or neuroendocrine cells that are present in gastric or intestinal metaplasia which occurs following cholelithiasis or other causes of chronic inflammation.4

The clinical presentation of gallbladder neuroendocrine carcinoma is the same as other gallbladder carcinomas in that there is a large amount of overlap with the symptoms of gallstones and biliary colic. However, upon imaging, a mass or wall thickening is usually seen. In comparison to gallbladder adenocarcinoma, gallbladder neuroendocrine carcinomas typically have a more well-defined margin, with intact overlying mucosa, and larger hepatic and lymph node metastases on CT imaging.5 The majority of patients present with lymph node metastases at the time of diagnosis (reported rate of 66%).6 Overall prognosis is poor, with median survival of 13 months. However, this is greatly affected by the presence of metastatic disease at the time of diagnosis (average survival of 9 months versus 31 months for local disease only).3

The gross appearance is often a large white-tan tumor with extensive hemorrhage and/or necrosis.3 As seen on studies of CT imaging, there is usually a well-defined border to the tumor when compared to adenocarcinomas of the gallbladder. Additionally, an intact overlying mucosa can sometimes be appreciated.5

Histologically, these tumors resemble small cell neuroendocrine tumors that appear elsewhere in the gastrointestinal tract, with sheets of small pleomorphic cells with hyperchromatic nuclei, high nucleus to cytoplasmic ratios, nuclear molding, and high mitotic rate.7-8 These tumors stain positively for neuroendocrine markers such as synaptophysin, chromogranin, and CD56, and have a high proliferation rate as shown by a Ki67 >20% (although usually much higher, as seen in the current case).9

The main differential diagnosis clinically is gallbladder adenocarcinoma versus metastases. Histologically, the possibility of metastases from a more common source, such as the pancreas or gastrointestinal tract, should be considered. A helpful clue to the possibility of a primary gallbladder neuroendocrine carcinoma histologically is the direct invasion of the gallbladder mucosa by tumor cells. However, a thorough clinical workup for other sources of the tumor should still be performed due to the rarity of this entity. Additionally, mixed adenoneuroendocrine tumor should also be considered when making this rare diagnosis.

References:

1. Albores-Saavedra J, Cruz-Ortiz H, Alcantara Vazques A, and DE Henson, “Unusual types of gallbladder carcinoma. A report of 16 cases,” Arch Pathol Lab Med 1981; 105(6): 287-293.

2. Chen C, Wang L, Liu X, Zhang G, Zhao Y, and Z Geng, “Gallbladder neuroendocrine carcinoma: Report of 10 cases and comparison of clinicopathologic features with gallbladder adenocarcinoma,” Int J Clin Exp Pathol 2015;8(7): 8218-8226.

3. Carrera C, Kunk P, and O Rahma, “Small Cell Carcinoma of the Gallbladder: Case Report and Comprehensive Analysis of Published Cases,” J Oncol 2015; Article ID 304909, 8 pages.

4. Edge SB, Byrd DR, Compton CC, et al., editors. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. Gallbladder; 211–17.

5. Kim TH, Kim SH, Lee KB, and JK Han, “Outcome and CT differentiation of gallbladder neuroendocrine tumours from adenocarcinomas,” Eur Radiol 2017; 27: 507-517.

6. Mahipal A and S Gupta, “Small-cell carcinoma of the gallbladder: report of a case and literature review,” Gastrointest Cancer Res 2011; 4(4): 135-136.

7. Mithal U, Herror A, Khan K, Dudhat S, Jagganath P, Soman CS, and LJ Desouza, “Small cell carcinoma of the gall bladder,” Indian J Gastroenterol 2000; 19(1): 33.

8. Debois, JM, De Vriendt P, and K Charels, “Small cell carcinoma of the gallbladder,” Acta Chirurgica Belgica 1998; 98(3): 110-112.

9. Williams GT. Endocrine tumours of the gastrointestinal tract: selected topics. Histopathology. 2007;50(1):30- 41.


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