Clear Cell Carcinoma (CCC) of the Cervix Is a Human Papillomavirus (HPV)-independent Tumor Associated With Poor Outcome

Abstract

Cervical clear cell carcinoma (CCC) is a rare human papillomavirus-independent adenocarcinoma. While recent studies have focused on gastric-type endocervical adenocarcinoma (GTA), little is known about CCC. A total of 58 (CCCs) were collected from 14 international institutions and retrospectively analyzed using univariable and multivariable methods and compared with 36 gastric-type adenocarcinomas and 173 human papillomavirus-associated (HPVA) endocervical adenocarcinoma (ECA) regarding overall survival (OS) and recurrence-free survival (RFS). Most cases were FIGO stage I (72.4%), with Silva C pattern of invasion (77.6%), and the majority were treated with radical surgery (84.5%) and adjuvant therapy (55.2%). Lymphovascular invasion was present in 31%, while lymph node metastasis was seen in 24.1%; 10.3% were associated with abdominopelvic metastases at the time of diagnosis; 32.8% had recurrences, and 19% died of disease. We did not find statistically significant differences in OS and RFS between CCC and GTA at 5 and 10 years (P = 0.313 and 0.508, respectively), but there were significant differences in both OS and RFS between CCC and HPVA ECA (P = 0.003 and 0.032, respectively). Also, OS and RFS in stage I clear cell and GTA were similar (P = 0.632 and 0.692, respectively). Multivariate analysis showed that OS is influenced by the presence of recurrence (P = 0.009), while RFS is influenced by the FIGO stage (P = 0.025). Cervical CCC has poorer outcomes than HPVA ECA and similar outcomes to human papillomavirusindependent GTA. Oncologic treatment significantly influences RFS in univariate analysis but is not an independent prognostic factor in multivariate analysis suggesting that alternative therapies should be investigated.

Recurrent WWTR1S89W mutations and Hippo pathway deregulation in clear cell carcinomas of the cervix

“…cCCCs, while curable in the early stage, are associated with poor prognosis in the advanced setting [6]. Treatment options for metastatic or recurrent cCCC remain limited in part due to a lack of understanding of its genetic basis and pathogenesis.…”

“…Historically, CCCs of the lower genital tract were associated with in utero exposure to diethylstilbestrol (DES) [3,4]; however, today most CCCs are sporadic without a known etiology [2]. Although early-stage cCCCs have a good overall prognosis following radical surgical resection, cCCCs have a greater propensity to recur and metastasize, and advanced-stage disease is often incurable and associated with high mortality [5,6]. Current treatment options for recurrent or metastatic disease are limited, and novel therapeutic approaches for cCCCs are needed.…”

Herlyn-Werner-Wunderlich syndrome (HWWS)-associated gynecological malignancies: A case report and literature review

“…Interestingly, the histological trend in which CCC and endometrioid carcinoma are predominant is consistent with that observed in endometriosis-associated ovarian cancer ( Murakami et al, 2020 Jun 24 ). The precise reason for this trend is unknown, but human papillomavirus (HPV) cannot, as cervical or vaginal CCC is known to be an HPV-independent tumor ( Stolnicu et al, 2022 ). We believe this can be explained by a common feature between obstructed hemivagina/hemicervix in HWWS and ovarian endometriosis: accumulation of menstrual blood containing excess iron and iron-induced reactive oxygen species, which theoretically can accelerate malignant transformation of exposed cells by inducing gene mutations or DNA methylation ( Stolnicu et al, 2022 ).…”

“…The precise reason for this trend is unknown, but human papillomavirus (HPV) cannot, as cervical or vaginal CCC is known to be an HPV-independent tumor ( Stolnicu et al, 2022 ). We believe this can be explained by a common feature between obstructed hemivagina/hemicervix in HWWS and ovarian endometriosis: accumulation of menstrual blood containing excess iron and iron-induced reactive oxygen species, which theoretically can accelerate malignant transformation of exposed cells by inducing gene mutations or DNA methylation ( Stolnicu et al, 2022 ). However, as there is no evidence to support this hypothesis, future mechanistic investigations using clinical samples obtained from the affected patients are warranted.…”

Clear Cell Carcinoma (CCC) of the Cervix is a Human Papillomavirus (HPV)-independent Tumor Associated With Poor Outcome: A Comprehensive Analysis of 58 Cases: Erratum

“…In the article by Stolnicu et al, which published in the June 2022 issue of American Journal of Surgical Pathology , an author’s last name was misspelled 1. The name should have appeared as Daniela Fanni, MD.…”