Cervical Carcinomas With Neuroendocrine Differentiation: A Report of 28 Cases With Immunohistochemical Analysis and Molecular Genetic Evidence of Common Clonal Origin With Coexisting Squamous and Adenocarcinomas

Abstract

Cervical neuroendocrine carcinomas are rare, aggressive tumors and their immunohistochemical features and clonal relationship to coexisting tumors are incompletely described. Twenty-eight cases were identified (17 small cell, 9 large cell, and 2 mixed), 10 of which had an invasive squamous or adenocarcinoma component. Staining for synaptophysin, chromogranin A, TTF1, c-kit, CD44, and p16 was performed. Analyses for loss of heterozygosity (LOH) at 5 polymorphic microsatellite markers (D3S1300, D9S171, D11S914, D13S319, and TP53) and X-chromosome inactivation were performed. Of 17 cases with available blocks, 13 (76%) were synaptophysin+, 8 (47%) were chromogranin A+, 8 (47%) were TTF1+, 7 (41%) were c-kit+, and 6 (35%) were CD44+. Strong patchy or strong diffuse p16 staining was seen in all cases. LOH and X-chromosome inactivation analysis were performed for 17 cases, 8 of which had a coexisting squamous or adenocarcinoma component. Five of the 8 (63%) cases with 2 components showed allelic loss in both components. All 5 of these cases demonstrated identical LOH between the neuroendocrine and squamous or adenocarcinoma components. Nonrandom X-chromosome inactivation was seen in the neuroendocrine and other components in 4 of the 8 cases. In all 4 cases the pattern of inactivation was identical between the 2 components. Cervical neuroendocrine carcinomas have features similar to other extrapulmonary neuroendocrine carcinomas, including expression of TTF1, c-kit, and CD44. Consistent staining for p16 is also seen. Concordant genetic alterations support common clonal origin for neuroendocrine carcinomas with a coexisting squamous or adenocarcinoma component.

Cervical small cell carcinoma frequently presented in multiple high risk HPV infection and often associated with other type of epithelial tumors

“…Ishida et al reported 10 cases of cervical small cell carcinoma, 7 of which were mixed with adenocarcinoma and/or squamous cell carcinoma, or cervical intraepithelial neoplasia [ 10 ]. Emerson et al reported that in 19 cases of cervical small cell carcinoma, 6 cases were associated with adenocarcinoma, and three patients also had adenosquamous carcinoma, squamous cell carcinoma in situ, and adenocarcinoma [ 5 ]. In this study, 15 patients also displayed squamous or glandular epithelial neoplasms, including squamous cell carcinoma ( n = 7), adenocarcinoma ( n = 3), squamous cell carcinoma in situ ( n = 4), and adenocarcinoma in situ (n = 1).…”

“…The clinicopathological features of cervical small cell carcinoma and its relationship with HPV infection has been widely studied, including case series and larger retrospective population-based reports [ 2 , 4 ]. Although some studies report that cervical small cell carcinoma is often associated with other cervical cancer or intraepithelial neoplasia [ 5 ], the clinicopathological features of cervical composite tumors, including small cell carcinoma, were rarely characterized. In these studies, HPV infection was detected using a variety of methods [ 3 , 6 ] such as immunohistochemistry, polymerase chain reaction (PCR), in situ hybridization (ISH), reverse dot blot hybridization (RDDH), and Southern blot hybridization.…”

Diagnostic value of four neuroendocrine markers in small cell neuroendocrine carcinomas of the cervix: a meta-analysis

“…26 studies provided information about positive expression rates for two markers. There were 15 studies about Syn and CD56 1 , 6 , 7 , 9 , 12 , 13 , 15 , 17 – 19 , 32 – 34 , 36 , 42 , 15 studies about Syn and NSE 1 , 3 , 6 , 7 , 12 , 13 , 17 , 18 , 22 , 25 , 32 – 34 , 38 , 42 , 23 studies about Syn and CgA 1 , 3 , 4 , 6 , 7 , 9 , 12 , 13 , 15 , 17 – 20 , 22 , 23 , 25 , 31 – 34 , 36 , 39 , 42 , 9 studies about CD56 and NSE 1 , 6 , 7 , 12 , 17 , 18 , 33 , 38 , 42 , 12 studies about CD56 and CgA 1 , 6 , 7 , 9 , 12 , 13 , 15 , 17 – 19 , 33 , 42 and 15 studies about NSE and CgA…”

“…26 studies provided information about positive expression rates for two markers. There were 15 studies about Syn and CD56 1,6,7,9,12,13,15,[17][18][19][32][33][34]36,42 , 15 studies about Syn and NSE 1,3,6,7,12,13,17,18,22,25,[32][33][34]38,42 , 23 studies about Syn and CgA 1,3,4,6,7,9,12,13,15,[17][18][19][20]22,23,25,[31][32][33][34]36,39,…”

Neuroendocrine Carcinoma of the Cervix: Clinicopathologic Study and Review of the Literature

“…plus two kinds of neuroendocrine markers (CgA,Syn,CD56, neuronspeci c enolase NSE) positive, diagnosis can be made, which of CD56 sensitivity is the most high, the positive rate can reach 80% (17). But its speci city is very poor, CD56 staining can be present in non-neuroendocrine carcinomas (18).…”