Molecular pathology and clinical treatment of independent HPV primary serous carcinoma of the uterine cervix (USCC): A case report.

On October 23, 2020, a 69‐year‐old Chinese female patient was admitted to Yuncheng Hospital with a 5‐month history of postmenopausal bleeding and lower abdominal pain. In May 2020, she experienced occasional vaginal bleeding, which subsided naturally within 4–5 days. She noticed occasional blood in her stool but not in her urine. Her last menstrual period occurred over 14 years ago. During the gynecological examination, the patient exhibited vulvar hypopigmentation, atrophy, and a smooth vagina. An examination of the uterine cervix revealed a small cauliflower‐like mass, approximately 5 cm in diameter, on the anterior lip. The cervix was mobile with a crispy texture, and there was atrophy in the shallow vaginal fornix. No palpable abnormalities were detected in the bilateral adnexal areas. A color Doppler ultrasound of the pelvis revealed an enlarged cervix with unevenly reduced echo, measuring 5.7 × 4.0 cm, indicating a possible diagnosis of cervical cancer. On October 19, 2020, a cervical cone biopsy was performed, revealing high‐grade endometrioid glands lined by columnar cells with eosinophilic cytoplasm and pseudostratified nuclei. The biopsy also showed typical papillary and micropapillary architectures with highly atypical nuclei (Figure  1A,B ). Immunohistochemistry testing revealed focal positivity for PR and ER, along with positive staining for p16, p53, EMA, CK7, WT‐1, and Ki67 (Figure  2 ). However, the immunohistochemistry of MUC 6, CK20, Vimentin, Napsin A, HNF1β, and CEA all yielded negative results (Figure  2 ), and the HPV test was also negative. In October 2020, a pelvic MRI displayed an anteverted uterus with left deviation, abnormalities in the anterior and posterior lips, and an irregular mass measuring 3.0 × 5.0 × 4.1 cm (Figure  3A ). The diffusion‐weighted MRI indicated mild heterogeneity. The fundus of the uterus exhibited uneven thickening and heterogeneous internal signaling. Bilateral appendages appeared normal, with scattered small lymph nodes adjacent to the right iliac vessels. Pathology results suggested a cervical tumor at Figo II A stage. Therefore, the diagnosis favored USCC (as per the 2014 WHO classification of Female Genital Tumors) or other HPV‐independent adenocarcinomas of the uterine cervix, confirmed after ruling out other possible differentials (as per the 2020 WHO classification of Female Genital Tumors). Histology of serous carcinoma of the uterine cervix shows endometrioid gland lined by columnar cells with eosinophilic cytoplasm and pseudostratified nuclei, hematoxylin and eosin staining, ×100 (A), ×400 (B). Immunohistochemistry testing revealed focal positivity for PR and ER, along with positive staining for p16, p53, EMA, CK7, WT‐1, PAX8, and Ki67. However, the immunohistochemistry of MUC 6, CK20, Vimentin, Napsin A, HNF1β, and CEA all yielded negative results (magnification: ×100). Responses to neoadjuvant chemotherapy treatment assessed by MRI before (A) and after (B) 3 cycles of chemotherapy show regression of the paracervical mass. To further explore the molecular pathology and develop an effective treatment strategy, the biopsy was transferred to Zhejiang Shaoxing Topgen Biomedical Technology Co., Ltd. for somatic tumor gene mutation detection. A positive result according to NGS revealed two variants uncertain significance of PAX8 c.1230C>G (p.Tyr 410 Ter) and TP53 c.740A>T (p.Asn247Ile). The tumor exhibited microsatellite stable (MSS) status, a Tumor Mutation Burden (TMB) score of 7.33 Muts/Mb, and a high tumor neoantigen load.

Lina Niu: Conceptualization; data curation; supervision; writing – original draft; writing – review and editing. Fangying Ruan: Writing – original draft; writing – review and editing. Qisheng Yang: Writing – original draft; writing – review and editing. Chaoran Xia: Conceptualization; formal analysis; project administration; supervision. Tao Xu: Data curation; software; visualization. Fei Dong: Data curation; visualization. Lizhen Zhang: Data curation; project administration. Sheng Guo: Formal analysis; visualization. Weiqin Lv: Conceptualization; data curation; supervision; visualization. Junxia Wang: Data curation; software; visualization. Yun Shang: Conceptualization; supervision; writing – review and editing.

The study involving a human participant was reviewed and approved by The Yuncheng Central Hospital, Shanxi, China.

No funding was received.

The patient provided consent for publication.

The patient underwent 3 cycles of neoadjuvant chemotherapy with docetaxel (100 mg/3 h/intravenous), carboplatin (450 mg/1 h/intravenous), and thiopefilgrastim (6 mg/injection). On December 25, 2020, a pelvic MRI scan revealed a significant reduction in tumor size to approximately 2.5 × 1.9 × 3.0 cm (Figure  3B ). On January 20, 2021, a radical hysterectomy was performed, including bilateral adenoxetomy, pelvic paraaortic lymph node dissection, and omentectomy. Pathological examination confirmed the presence of serous carcinoma of the uterine cervix (Figure  S1D ). The tumor had invaded the muscle layer of the vaginal fornix and the lower uterine segment. The endometrium and bilateral fallopian tubes were initially extensively sectioned using the SEEFIM protocol and then submitted in toto. The results indicated that the serous intraepithelial carcinoma was not identified (see Figure  S1A–D ). No evidence of adenomyosis or endometriosis was found, and lymph nodes were negative for malignancy. Postoperative immunohistochemical results indicated CDX‐2(−), p53 (+), PAX‐8(+), and SATB‐2(−). Following the surgery, the patient underwent an additional 3 cycles of chemoradiation therapy (docetaxel [100 mg/3 h, intravenous], carboplatin [500 mg/1 h, intravenous]), along with 25 cycles of intensity‐modulated radiotherapy DT46Gy/2Gy/23f with concurrent cisplatin (450 mg/1 h). The patient experienced Grade IV myelosuppression (Table  S1 ) as a result of the treatment. Subsequent follow‐ups were conducted every 3 months, and a CT scan on August 3, 2022, showed no evidence of recurrence (Figure  S2 ).

Primary cervical HPV‐independent invasive adenocarcinomas with serous‐like features are characterized by the morphological features of complex papillary and/or micropapillary structures with high‐grade nuclear atypia. 6 This report provides a case of primary HPV‐independent invasive adenocarcinoma of the uterine cervix, along with molecular analysis, demonstrating effective treatment and 20 months of disease‐free status as of now. Immunohistochemistry (IHC) plays a vital role in the diagnosis and classification of uterine cervical carcinomas. 7 Serous carcinoma shows positive expression of p53 and p16 through IHC. 1 , 8 Serous carcinoma of the ovary exhibits positive expression of WT‐1 and ER, 9 while USCC typically displays weak or negative expression. 10 Napsin A and HNF‐1β are frequently positive in clear carcinoma of the uterine cervix, ovary, and endometrium. 11 Gastric type is the most common subtype of cervical HPV‐independent adenocarcinoma, and the markers of gastric type are frequently positive for MUC6, PAX8, CEA, CK7, and CK20, and negative for p16, ER, and PR. However, in our case, the immunohistochemistry (IHC) results were different from the gastric type, as they were positive for p16, p53, EMA, Ki67, PR, and CK7 and weakly positive for WT‐1 and ER. The IHC results were negative for MUC6, CK20, Vimentin, Napsin A, HNF1, and CEA biomarkers. Microsatellite status and TMB status are rarely considered in uterine serous carcinoma. 12 In fact, the patient in this report had MSS and a TMB of 7.33Muts/Mb, and high tumor neoantigen load. To our knowledge, only a limited study has reported the genetic features of the primary HPV‐negative serous carcinoma of the cervix. Jenkins et al. recently reported that cervical serous carcinoma ( n  = 6, HPV‐negative) harbors mutations in TP53 (50%), KRAS (33%), PIK3CA (17%), and PTEN (17%). 13 However, in this case, two variants of PAX8 c.1230C>G (p.Tyr 410 Ter) and TP53 c.740A>T (p.Asn247Ile) were identified in the patient. Our case expands the understanding of the molecular features of cervical serous carcinoma and contributes to the knowledge of underlying molecular mechanisms. Neoadjuvant chemotherapy followed by radical surgery is a standard treatment in cervical cancer, with response rates ranging from 69.4% to 90.2% in clinical practice. 14 In our study, the patient exhibited a favorable response to neoadjuvant chemotherapy, remaining free of disease for a remarkable 20 months thus far. While conventional guidelines typically suggest 2–3 cycles of neoadjuvant chemotherapy for stage IB3 or IIA2 uterine cervical cancer, our study took a different approach. The clinician administered 3 cycles of neoadjuvant chemotherapy, followed by an additional 3 cycles of adjuvant chemoradiation therapy to address this rare carcinoma subtype. Our innovative treatment strategy has resulted in an extended disease‐free period, with no recurrence detected in the patient thus far. However, due to the rarity of this pathological type of cervical cancer, this single case report involves a unique molecular pathology, making it challenging to draw broader conclusions or apply the findings to other patients with similar conditions. Cervical serous carcinoma is an exceptionally rare tumor with limited reported pathological and molecular data. This report provides valuable insights into the molecular characteristics of a typical serous carcinoma and offers potential guidance for future management and diagnostic strategies.

Written informed consent was obtained from the patient, and all procedures were conducted in accordance with the Declaration of Helsinki.

Serous carcinoma of the uterine cervix (USCC) is a rare subtype of cervical adenocarcinoma that shares morphological characteristics with serous carcinoma found in other locations such as the ovaries, fallopian tubes, endometrium, and peritoneum. 1 Diagnosing primary USCC poses a challenge due to the limited number of published reports. The World Health Organization (WHO) classified USCC in 2014 under the Classification of Tumors‐Female Genital Tumors, describing its morphological features as complex papillary and/or micropapillary structures. 2 However, the 2020 WHO classification reorganized this category. 3 The most recent WHO classification (2020) focused on the association between HPV infection and cervical carcinoma. 4 Accordingly, USCC was subdivided into HPV‐associated and HPV‐independent tumors. The treatment guidelines for HPV‐independent cervical adenocarcinoma have yet to be established, possibly due to a lack of knowledge regarding its pathology. 5 Thus, providing the molecular characteristics of a typical HPV‐independent USCC is essential for future management and diagnostic strategies. In this report, we present the pathological diagnosis and detailed treatment of independent HPV in primary USCC (or HPV‐independent invasive adenocarcinomas of the uterine cervix) in a Chinese female patient who has remained free of disease progression for 20 months.

We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

Table S1. Click here for additional data file. Figure S1. Click here for additional data file. Figure S2. Click here for additional data file.