Neoadjuvant chemotherapy in locally advanced clear cell carcinoma of the cervix leading to complete disease resolution; a case report

Highlights

• •Clear cell carcinoma of the cervix is a rare form of cervical cancer, typically treated akin to other subtypes of cervical cancer.
• •Unlike other subtypes of cervical cancer, clear cell carcinoma is radioresistant, presenting challenges in treatment of locally advance disease.
• •This article presents a case of locally advanced clear cell carcinoma of the cervix treated with neoadjuvant chemotherapy, followed by radical hysterectomy, with final pathology showing no residual disease.

Abstract

Objectives

Cervical clear cell carcinoma, a rare form of cervical adenocarcinoma, is traditionally treated with regimens based on those used in more prevalent forms of cervical cancer. However, those with locally advanced disease typically have worse outcomes, likely due to its poor radiosensitivity, raising the question whether alternative treatment regimens should be considered.

Methods

This paper presents the case of a 46-year-old female with newly diagnosed locally advanced clear cell cervical carcinoma who underwent treatment with neoadjuvant chemotherapy with cisplatin/paclitaxel/pembrolizumab/bevacizumab followed by radical hysterectomy.

Results

Post-treatment imaging and post-operative final pathology specimen showed complete resolution of disease.

Conclusions

This is the first report to our knowledge of this novel neoadjuvant treatment regimen for cervical clear cell carcinoma; based on this patient’s excellent response, further investigation is needed to clarify the optimal neoadjuvant treatment for patients with this rare and difficult to treat disease.

1. Introduction

Cervical clear cell carcinoma is a rare subtype of cervical adenocarcinoma, typically treated akin to the more prevalent squamous cell carcinoma (SCC) of the cervix (Jhavar et al., 2024, Stolnicu et al., 2022). While, locally advanced cervical cancer (FIGO stage IB3 through IVA) is primarily treated with chemoradiotherapy, clear cell carcinoma of the cervix is traditionally not radiosensitive which raises doubts regarding radiotherapy as primary treatment for the disease (Li et al., 2025). In this case report, a patient with newly diagnosed clear cell carcinoma of the cervix was treated with neoadjuvant chemotherapy followed by radical hysterectomy; final pathology specimen and imaging were notable for complete resolution of disease.

2. Case report

In January 2025, a 46-year-old female was referred to Gynecologic Oncology for evaluation of a cervical mass first visualized at her annual exam by her benign gynecologist. Pap smear was notable for atypical glandular cells, suspicious for endocervical adenocarcinoma, with negative HPV testing. Her past medical history was unremarkable, and she denied history of tobacco use. Surgical history was notable for a cesarean section with bilateral tubal ligation and abdominoplasty. She had no family history of breast, ovarian, endometrial, cervical, or colon cancer.

At her initial Gynecologic Oncology visit, physical exam was notable for a necrotic appearing mass present within the endocervical canal, approximately 6–7 cm in diameter. Biopsy was performed at the time of exam, with pathology ultimately showing clear cell cervical adenocarcinoma (Fig. 1). Immunohistochemical stains were also consistent with clear cell adenocarcinoma; PD-L1 staining was notably positive with a combined positive score of 50. MRI showed a 7.5-centimeter cervical mass extending into the parametrium (Fig. 2 A). A 2.8-centimeter heterogenous nodule adjacent to the left ovary, possibly representative of an ovarian lesion versus an enlarged lymph node and borderline enlarged external iliac nodes were also visualized. Follow up PET/CT imaging confirmed the findings of her earlier CT and further elucidated her disease, demonstrating a hypermetabolic 9.2-centimeter cervical mass extending throughout the entirety of the endometrium and into the uterine fundus, with an additional component extending through the left lateral wall of the endocervical region and into the left adnexa (corresponding with the previously described nodule adjacent to the left ovary) (Fig. 2 B). Mildly enlarged and hypermetabolic left inguinal and pelvic sidewall lymph nodes were seen, suspicious for malignant lymphadenopathy.

Fig. 1.

Pathology from initial biopsy. A-B) Hematoxylin and eosin (H&E) stain showed characteristic clear cell carcinoma cytologic features with nuclear atypia, clear cytoplasm, hob nailing, and hyalinizing stroma growing in a tubulocystic architectural pattern. C) HNF1β immunohistochemical (IHC) stain is diffusely positive in tumor cells. NapsinA (not shown) was also positive in tumor cells. D) p16 IHC is patchy and variably weakly positive, with HPV in situ hybridization (ISH) also negative (not shown), consistent with an HPV-independent process.

Fig. 2.

Comparison of patient’s initial MRI and PET/CT imaging with that following neoadjuvant therapy (four cycles for PET/CT and five cycles for MRI) and that following surgery for surveillance. A & B. Initial imaging. C & D. Post neoadjuvant therapy imaging. E. Post surgery imaging for surveillance.

Her case was reviewed at our institution's multidisciplinary tumor board conference, and, after discussion with Radiology, the left inguinal lymph node was consistent with reactive changes; thus, she was clinically staged as FIGO (2018) IIIC1. Treatment options considered included neoadjuvant chemotherapy/immunotherapy followed by surgery/radiation versus upfront chemoradiation. The patient was extensively counseled on management options and through shared decision making she elected to proceed with neoadjuvant cisplatin (50 mg/m²)/paclitaxel (175 mg/m²)/pembrolizumab (200 mg)/bevacizumab (15 mg/kg). After four 21-day cycles, repeat PET/CT imaging showed an interval decrease in size and metabolic resolution of the cervical mass and interval resolution of the previously visualized lymphadenopathy, indicative of excellent treatment response (Fig. 2 D).

In May 2025, her case was again reviewed at our institution’s multidisciplinary tumor board and recommendation was to proceed with an additional two cycles of neoadjuvant chemotherapy, followed by radical hysterectomy. During her fifth cycle, she experienced an infusion reaction to pembrolizumab, consisting of flushing, shortness of breath, and a globus sensation in her throat. After cycle five, she underwent additional imaging with pelvic MRI which again demonstrated resolution of the cervical mass with no residual parametrial extension (Fig. 2 C). With pre-medication of additional dexamethasone for cycle six, she tolerated pembrolizumab without further issue.

She underwent a modified radical abdominal hysterectomy with bilateral salpingo-oophorectomy, bilateral ureterolysis, upper vaginectomy, removal of right pelvic nodule, and closure of umbilical hernia in July 2025. Post-operative course was uncomplicated, and she was discharged home in stable condition on post-operative day two. Surgical pathology demonstrated no malignancy within bilateral ovaries, fallopian tubes, and the right pelvic nodule. The uterus, cervix, parametria and upper vagina showed features consistent with neoadjuvant chemotherapy effect without malignancy; no residual tumor was identified (Fig. 3).

Fig. 3.

Pathology from post-neoadjuvant surgical resection. A-C) H&E stain of cervix showed sheets of foamy histiocytes in the tumor bed (area in brackets). D) Immunohistochemical staining with pancytokeratin is negative in the tumor bed. E) IHC for CD168 confirms the cells are histiocytes.

Her case was once again reviewed by our institution’s tumor board and consensus was for maintenance treatment with pembrolizumab (200 mg)/bevacizumab (15 mg/kg). Additionally, she was started on estradiol for surgical menopause symptoms.

She continues to be followed with serial physical exams which have demonstrated no evidence of disease recurrence, as well as PET/CT imaging which have similarly shown no evidence of malignancy (Fig. 2E). As of the time of submission, she has remained disease-free for eight months.

3. Discussion

Clear cell carcinoma of the cervix is a rare variant of HPV-independent adenocarcinoma, estimated to account for less than 5% of cervical adenocarcinomas (Stolnicu et al., 2022). The disease has a bimodal age distribution (with diagnosis occurring in women aged 26 and 71 on average) and has been associated with in utero exposure to DES (Stolnicu et al., 2022, Thomas et al., 2008). The histology of cervical clear cell carcinoma is overall similar to that of the uterus and ovary; its tumor cells have varying architectural patterns with abundant clear, glycogen-rich cytoplasm (Stolnicu et al., 2022).

Due to its rarity, the treatment of clear cell carcinoma of the cervix is typically based on regimens used in SCC and non-clear cell adenocarcinomas, which are primarily treated based on stage (Jhavar et al., 2024). Surgery is the main treatment for patients for early stage disease (Wang et al., 2019, Baalbergen et al., 2013). Patients with locally advanced disease typically undergo primary chemoradiotherapy while systemic chemotherapy is used for those with metastatic disease (Li et al., 2025, Thomas et al., 2008). At earlier stages, patients with clear cell carcinoma of the cervix have a similarly positive prognosis as their counterparts with similarly staged SCC (Thomas et al., 2008, Peng et al., 2024, Huo et al., 2017). However, those with locally advanced disease have worse outcomes, likely reflecting poor sensitivity to radiotherapy and current treatment regimens when compared to squamous cell or endometrioid carcinomas (Li et al., 2025, Thomas et al., 2008, Peng et al., 2024, Huo et al., 2017). A retrospective study of patient outcomes with clear cell cervical cancer demonstrated those with locally advanced disease who underwent radical surgery compared to primary radiotherapy exhibited a significantly prolonged overall survival (Li et al., 2025). Unfortunately, clear cell carcinoma of the cervix also has a higher predilection for lymphatic and parametrial involvement meaning patients are less likely to be candidates for surgical management at time of diagnosis (Thomas et al., 2008, Huo et al., 2017). Negative prognostic factors include tumor size greater than 4 cm, positive lymph nodes, and advanced staging (Thomas et al., 2008, Huo et al., 2017).

Given that clear cell carcinoma of the cervix is traditionally not radiosensitive, our initial treatment framework was based on the results of the INTERLACE trial where induction chemotherapy was given prior to radiation therapy, and demonstrated improved progression-free and overall survival in patients with locally advanced cervical cancer (Barcellini et al., 2025, McCormack et al., 2024). Pembrolizumab, a monoclonal antibody which binds to the PD-1 receptor to block its interaction with PD-L1 and PD-L2, was initially shown to improve progression-free and overall survival when added to standard of care chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer (KEYNOTE 826) (Colombo et al., 2021). KEYNOTE A18 further demonstrated pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer (Lorusso et al., 2024). The question in patients with locally advanced cervical cancer that is often discussed is whether to follow the INTERLACE or KEYNOTE A18 protocol. In this patient, based on her tumor’s positive PD-L1 expression and concern for poor radiosensitivity, a combination of each approach was taken, and pembrolizumab was added to her induction chemotherapy regimen.

Data supporting the use of immunotherapy in clear cell cervical cancer is limited and often derived from larger trials containing all histologies. There was a phase II clinical trial (PEACOCC) of pembrolizumab use in patients with advanced clear cell gynecologic cancers (Kristeleit et al., 2025); unfortunately, it only included one patient with cervical cancer and her specific outcome was not reported. However, it did find clinical benefit in the use of immunotherapy with clear cell histology overall. Beyond this, there is a case report of a patient with recurrent clear cell cervical cancer who had complete response to a PD-1 inhibitor (Levinson et al., 2020).

To optimize her induction chemotherapy regimen further, our group weighed the benefits of the addition of bevacizumab. In GOG 240, bevacizumab, an anti-VEGF monoclonal antibody, was determined to be a beneficial complement to combination chemotherapy in improving overall survival of patients with recurrent, persistent, or metastatic cervical cancer (Tewari et al., 2014). Additionally, due to its positive effect on adjuvant and maintenance treatment of ovarian clear cell carcinoma, bevacizumab has been proposed as an advantageous addition to treatment of cervical clear cell carcinoma (Sachdeva et al., 2025, Inomata et al., 2025); though few studies have reported administration, this rationale, in combination with GOG 240, prompted its addition to this patient’s induction regimen.

Following six cycles of induction chemotherapy with cisplatin/paclitaxel/pembrolizumab/bevacizumab, the patient did not have any residual disease on imaging or clinical exam. Initially, adjuvant radiation was discussed; however, it was not administered due to concern for side effects, predicted poor radiosensitivity of the tumor, and lack of targetable disease on repeat scan (Barcellini et al., 2025). Instead, radical resection of the primary tumor was performed which provided information regarding residual disease and treatment response. The decision was made to perform a radical hysterectomy given the tumor’s initial parametrial involvement, which was also visualized on imaging; despite its resolution on the post-neoadjuvant imaging, it was felt a radical hysterectomy would be best to ensure resection of the entire tumor with adequate margins and assess for chemotherapy response. Nodal evaluation was deferred given lack of clear benefit and potential long term side effects such as lymphedema, pain, and lymphocele formation. Because this is a rare subtype of cervical cancer, there is no clear treatment regimen that is most beneficial for these patients. Following surgery, she continued on maintenance of pembrolizumab/bevacizumab based on the previously aforementioned studies.

4. Conclusion

This case report describes the novel use of cisplatin/paclitaxel/pembrolizumab/bevacizumab as neoadjuvant treatment for cervical clear cell carcinoma. The literature review undertaken to contextualize this case demonstrates that this is the first time this specific regimen has been used. Though limited by its use in a single patient, the exceptional response of this patient’s tumor should prompt quality research to clarify the optimal neoadjuvant treatment for patients with this rare disease. Extrapolation from the current data should be used by clinicians to provide treatment options for a cancer that historically has had limited treatment modalities and is notoriously radioresistant.

Statement OF Consent.

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review on request.

CRediT authorship contribution statement

Emily Fronk: . Michelle Whittum: Writing – review & editing, Writing – original draft, Conceptualization. Dijana Poljak: Writing – review & editing, Writing – original draft, Conceptualization. Ashlee Smith: Writing – review & editing, Supervision, Project administration, Conceptualization.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

Data will be made available on request.