Molecular Analysis of HPV-independent Primary Endometrial Squamous Cell Carcinoma Reveals TP53 and CDKN2A Comutations

Abstract

Human papillomavirus (HPV)-independent primary endometrial squamous cell carcinoma (PESCC) is a rare but aggressive subtype of endometrial carcinoma for which little is known about the genomic characteristics. Traditional criteria have restricted the diagnosis of PESCC to cases without any cervical involvement. However, given that modern ancillary techniques can detect HPV and characteristic genetic alterations that should identify the more common mimics in the differential diagnosis, including endometrial endometrioid carcinoma with extensive squamous differentiation and HPV-associated primary cervical squamous cell carcinoma, those criteria may benefit from revision. To further characterize PESCC, we identified 5 cases of pure squamous cell carcinoma dominantly involving the endometrium that had the potential to be PESCC: 1 case involving only the endometrium and 4 cases with some involvement of the cervix. Clinicopathologic features were assessed and immunohistochemical analysis (p16, estrogen receptor, progesterone receptor, and p53), HPV RNA in situ hybridization (highrisk and low-risk cocktails and targeted probes for 16 and 18), and molecular studies were performed. All tumors showed aberrant/mutation-type p53 expression, were negative for estrogen receptor, progesterone receptor, and p16, and had no detectable HPV. Per whole-exome sequencing, 4 of the 5 tumors demonstrated comutations in TP53 and CDKN2A (p16). Four patients died of disease within 20 months (range, 1 to 20 mo; mean, 9 mo), and 1 patient had no evidence of disease at 38 months. PESCC represents a unique, clinically aggressive subtype of endometrial cancer with TP53 and CDKN2A comutations. This characteristic profile, which is similar to HPVindependent squamous cell carcinoma of the vulva, is distinct from endometrioid carcinoma with extensive squamous differentiation and HPV-associated primary cervical squamous cell carcinoma and can be used to distinguish PESCC from those mimics even when cervical involvement is present. Diagnostic criteria for PESCC should be relaxed to allow for cervical involvement when other pathologic features are consistent with, and ancillary techniques are supportive of classification as such.

Treatment of primary squamous cell carcinoma of the endometrium and review of previous literature: A case report

“…Among the reported cases of PSCCE, some were P16-negative, and most were ER and PR-negative. [4,9,10,16,18] According to Hopkins et al, ER and PR expression may be limited. [10] Most studies have demonstrated a mutation in the p53 tumor suppressor gene, and Ki-67 was reported with a high labeling index, indicating the aggressive and malignant nature of the lesion.…”

“…[4,9,10,16,18] According to Hopkins et al, ER and PR expression may be limited. [10] Most studies have demonstrated a mutation in the p53 tumor suppressor gene, and Ki-67 was reported with a high labeling index, indicating the aggressive and malignant nature of the lesion. [2,4,10,16,19,20,21] In our patient, P16 was positive, and Ki-67 had a high labeling index (70%).…”

“…[10] Most studies have demonstrated a mutation in the p53 tumor suppressor gene, and Ki-67 was reported with a high labeling index, indicating the aggressive and malignant nature of the lesion. [2,4,10,16,19,20,21] In our patient, P16 was positive, and Ki-67 had a high labeling index (70%). Unfortunately, we did not detect ER, PR, and P53 expression.…”

“…[22] Therefore, women with early-stage cancer have a favorable prognosis; however, the survival rate is usually poor in cases of locally advanced cancer. [10] According to statistics, within the survival period of 14 to 36 months, the 1-year survival rates of stage I, stage III, and stage IV of endometrial carcinoma are 80%, 20%, and 0%, respectively, [4,5,7,22,24] while the prognosis of PSCCE is worse than that of endometrioid carcinoma. [4,5,7,22,24]…”

“…Ref in cases of locally advanced cancer. [10] According to statistics, within the survival period of 14 to 36 months, the 1-year survival rates of stage I, stage III, and stage IV of endometrial carcinoma are 80%, 20%, and 0%, respectively, [4,5,7,22,24] while the prognosis of PSCCE is worse than that of endometrioid carcinoma. [4,5,7,22,24] Goodman et al retrospectively analyzed 8 cases of PSCCE in 1995 and reviewed previous literature.…”