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Multicenter Study
. 2018 Jun;42(6):750-760.
doi: 10.1097/PAS.0000000000001042.

Next-generation Sequencing Reveals Recurrent Somatic Mutations in Small Cell Neuroendocrine Carcinoma of the Uterine Cervix

Deyin Xing  1 , Gang Zheng  1 , John Kenneth Schoolmeester  2 , Zaibo Li  3 , Aparna Pallavajjala  1 , Lisa Haley  1 , Michael G Conner  4 , Russell Vang  1 , Chien-Fu Hung  1 , Tzyy-Choou Wu  1 , Brigitte M Ronnett  1
Affiliations
Multicenter Study

Next-generation Sequencing Reveals Recurrent Somatic Mutations in Small Cell Neuroendocrine Carcinoma of the Uterine Cervix

Deyin Xing et al. Am J Surg Pathol. 2018 Jun.

Abstract

Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix is a rare but extremely aggressive tumor. While high-risk human papillomavirus (HPV) is involved at an early stage of oncogenesis in many tumors, additional driving events have been postulated to facilitate the progression of SCNECs. Identification of oncogenic drivers could guide targeted therapy of this neoplasm. Clinicopathologic features of 10 cervical SCNECs are reported. Analyses included immunohistochemical evaluation of p16, p53, synaptophysin, and chromogranin expression; in situ hybridizations and polymerase chain reaction for high-risk HPV and/or HPV 18; and next-generation sequencing based on a 637-gene panel. The patients ranged in age from 28 to 68 years (mean, 45.6 y; median, 40.5 y). All tumors had diffuse p16 and synaptophysin expression. All but 1 tumor was positive for chromogranin (extent of staining ranged from focal to diffuse). HPV 18 was detected in 6 tumors and HPV 35 in 1 tumor. At least 1 driver mutation was detected in 8 tumors. Four cases harbored TP53 somatic mutations, 3 of which correlated with an aberrant p53 staining pattern. Four PIK3CA mutations (p.G106A, p.N345T, p.E545K, and p.E545D) were detected in 3 tumors, 2 of which also harbored TP53 mutations. Oncogenic driver mutations involving KRAS, Erbb2, c-Myc, NOTCH1, BCL6, or NCOA3 were detected in 4 tumors. Mutations in caretaker tumor suppressors PTEN, RB1, BRCA1, BRCA2, and ARID1B were also identified in 4 tumors that commonly coharbored activating oncogenic mutations. Targeted next-generation gene sequencing identified genetic alterations involving the MAPK, PI3K/AKT/mTOR, and TP53/BRCA pathways in SCNECs. The presence of genetic alterations that are amenable to targeted therapy in SCNECs offers the potential for individualized management strategies for treatment of this aggressive tumor.

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Conflict of interest statement

Conflict of interest: The authors have no competing interests to declare.

Figures

Figure 1
Figure 1
Representative histologic and immunohistochemical images of small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix. The tumor displays monotonous population of cells (A, case 1) that have ovoid to angulated nuclei with molding, scanty cytoplasm, abundant mitotic and apoptotic activity (B, case 1) and rosette-like structures (C, case 10). SCNEC (case 1) shows diffuse synaptophysin (D) and p16 expression (E) and contains high-risk HPV as detected by RNA in situ hybridization (F).
Figure 2
Figure 2
PCR-based detection and typing of HPV. Case 1 with ISH-detected HPV 18 was used as positive control (A, B). The samples (cases 2, 4, 8, 9, 10) with no detectable high-risk HPV by ISH were checked for DNA integrity by amplifying β-globin as a housekeeping gene (A). The DNA samples (cases 4, 9, 10) with positive test results for β-globin were subsequently studied by nested PCR using MY09/MY11 and GP05/GP06 primers. The PCR products (A) were subjected to direct DNA Sanger sequencing to analyze the HPV type. Case 4 with HPV 35 (C); case 10 with HPV 18 (D); case 9 with no PCR-detectable HPV (A).
Figure 3
Figure 3
Somatic mutations detected by next-generation sequencing. The mutated activating oncogenic and caretaker tumor suppressor genes in SCNECs are plotted (arranged in descending order of number of mutations (A). Representative mutations of PIK3CA (missense mutation, B) and BRCA2 (deletion/frameshift mutation, C) are shown in the middle and right.
Figure 4
Figure 4
SCNEC with aberrant loss of p53 expression associated with TP53 frameshift mutation (case 4). The tumor (A, H&E) demonstrates aberrant/mutation-type complete loss of p53 expression (“null” pattern, B) because truncated p53 protein cannot be recognized by the p53 antibody. Insertion of nucleotides AG in the codon 80 of TP53 gene lead to frameshift mutation, premature translation termination and p53 protein truncation (C).
Figure 5
Figure 5
SCNEC with aberrant p53 expression associated with TP53 missense mutation (case 2, p.C238W). The tumor (A, H&E) demonstrates aberrant/mutation-type p53 over-expression (B) consistent with a missense mutation staining pattern. The presence of more than 90% frequency of mutant TP53 allele is indicative of a bi-allelic pattern (C).
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