Continuing Education Activity

The management of clear cell carcinoma of the cervix is complex, and new approaches have been recently introduced. To achieve optimal outcomes, the basic and clinical aspects of clear cell carcinoma of the cervix must be clearly defined. This activity reviews the etiology, predisposing factors, epidemiology, and pathophysiology of clear cell carcinoma of the cervix and focuses on the evaluation, management, and complications of clear cell carcinoma of the cervix, and highlights the role of the interprofessional team in fostering the best possible outcomes to women with clear cell carcinoma of the cervix.

Objectives:

• Identify the risk factors for clear cell carcinoma of the cervix.

• Describe the clinical picture and investigations used in diagnosing clear cell carcinoma of the cervix.

• Review the current treatment options available for the successful management of women diagnosed with clear cell carcinoma of the cervix, including fertility preservation options.

• Explain the role of the interprofessional team in planning care and highlight the importance of coordinated communication with other professionals in improving clinical outcomes and lowering complications.

Introduction

Clear cell carcinoma of the uterine cervix is a rare variant of adenocarcinoma accounting for only 4% of all cervical carcinomas. Its etiology and pathogenesis are unclear. The diagnosis of clear cell carcinoma of the uterine cervix is mainly established based on histopathological examination.  Histologically, clear cell carcinoma of the uterine cervix is predominantly composed of clear or hobnail cells whose architectural patterns are solid, tubulocystic, and/or papillary.[1][2]

Etiology

The etiology and pathogenesis of clear cell carcinoma of the cervix are unclear. However, many reports have associated this cancer subtype with prior intrauterine exposure to diethylstilbestrol (DES), a synthetic nonsteroidal estrogen hormone and teratogen with the ability to cross the placenta.[3] Although there are conflicting data from small series and isolated case reports, larger studies showed that HPV (human papillomavirus) likely does not play an etiologic role in clear cell carcinoma of the cervix.[4] Cervical endometriosis, the use of the oral contraceptive pill, and HIV infection are the suspected etiological factors for clear cell carcinoma of the cervix.

Epidemiology

Clear cell carcinoma of the cervix has a bimodal age distribution. The first peak occurs in women aged between 17 and 37 years (mean age is 26 years), and the second peak occurs in women aged between 44 and 88 years (mean age is 71 years).

Pathophysiology

Cervical clear cell carcinoma (cCCC) is an extremely rare subtype of cervical cancer. Consequently, its pathogenesis remains largely unknown, with no cell lines established from primary tumors.[5] Researchers investigated genetic instability in these tumors as manifested by somatic mutation of microsatellite repeats. Evidence of microsatellite instability was present in 50% of clear cell carcinomas of the uterine cervix not associated with DES exposure and in all DES-associated tumors examined.[6] No evidence of mutations in HRAS proto-oncogenes or the KRAS or, the Wilms tumor (WT1) tumor suppressor gene or the estrogen receptor gene was present in clear cell carcinoma of the uterine cervix.[6]

Histopathology

Cervical clear-cell carcinoma has a similar histologic appearance to clear-cell carcinomas found elsewhere in the gynecologic tract such as the vagina, the endometrium, and the ovary.

Macroscopic Findings 

The tumor is often located in the endocervical canal and can have either an exophytic or an endophytic appearance.

Microscopic Findings 

Histologically, there are three growth patterns:

• Tubulocystic
• Papillary
• Solid

The cells can range from flat to hobnail with mild to severe atypia. The cytoplasm can be optically clear or eosinophilic. Mitotic figures are infrequent. Cervical squamous cell carcinoma has a well-known precursor lesion, as do many types of adenocarcinoma. However, to date, no premalignant analog of cervical clear cell adenocarcinoma has been described.

Immunohistochemical Study 

The immunohistochemical study is usually noncontributory to the diagnosis of clear cell carcinoma of the uterine cervix.

Napsin A and HNF1-beta are positive; PR, ER, and p16 are negative, normal p53 expression in most cases.[7][8]

History and Physical

Clear cell carcinoma of the uterine cervix commonly presents with abnormal per-vaginal bleeding due to cervical ulceration (postcoital bleeding, intermenstrual bleeding).[9] This vaginal bleeding is usually refractory to hormonal therapy.

Physical examination usually depicts cervical abnormality often described as a “Fullness” of the cervix.

The tumor is not palpable during the rectal examination.

Clear cell carcinoma of the uterine cervix correlates with genitourinary malformations such as [10]:

• Double uteri and vagina with unilateral renal agenesis
• Atretic hemicervix and ipsilateral renal agenesis
• Bicornuate uterus

Evaluation

Diagnostic imaging of clear cell carcinoma of the uterine cervix contributes to therapeutic management, surgical planning, and the prediction of prognosis.

Magnetic Resonance Imaging 

MRI findings tend to be hypointensity on T1-weighted images, hyperintensity on T2-weighted images, and heterogeneous enhancement in the contrast-enhanced phase.

F-18 FDG PET/CT 

According to some authors, F-18 FDG PET/CT can be valuable for evaluating clear cell carcinoma of the uterine cervix with metastatic lymphadenopathy in the pelvic cavity and retroperitoneum.

Cytology 

Cytology has been found to be less efficient in diagnosing cervical adenocarcinomas.[11][12] Some authors reported that only 6 of 31 cervical clear cell carcinoma patients (18%) had an abnormal Pap test. Cytology was of no benefit in the diagnosis.[12]

Treatment / Management

The treatment of clear cell carcinoma is similar to that of cervical cancer. Radical hysterectomy and pelvic lymphadenectomy constitute a standard surgical treatment for patients with early-stage cervical carcinoma FIGO stage IB or IIA, which results in permanent infertility in the patient. External beam radiotherapy is the standard of care for stage IIB and IIIB.

A recent study revealed oncologic outcomes of fertility-sparing radical trachelectomy versus radical hysterectomy for stage IB1 cervical carcinoma in young adult women and found no statistically significant survival differences, indicating that for early-stage cancer, fertility-sparing surgery is a safe option.[13]

Differential Diagnosis

• Metastatic clear cell carcinoma from other sites
• Arias-Stella reaction
• Adenosis
• Endometrioid adenocarcinoma with clear cell or secretory change
• Gastric-type of endocervical adenocarcinoma 
• Cervical yolk sac tumors
• Primary cervical alveolar soft part sarcomas

Pertinent Studies and Ongoing Trials

Clear cell adenocarcinoma of the cervix (CCAC) is a highly invasive malignant tumor, whose pathogenesis may not be associated with HPV infection. Radical hysterectomy combined with chemotherapy (paclitaxel + platinum) has the ideal short-term curative effect. In the future, larger samples of clinical data are required to confirm these insights.[2]

Staging

The FIGO (International Federation of Gynecology and Obstetrics) staging system is used most often for cancers of the female reproductive organs, including cervical cancer.

Another widely used clinical staging system for cervical cancer is the one adopted by both the International Union for Cancer Control (UICC) and the American Joint Commission on Cancer (AJCC). Its basis is in the TNM system (T, tumor; N, nodes; M, metastases).

Prognosis

Studies regarding prognosis are conflicting; some report equivalent outcomes with conventional cervical adenocarcinoma, whereas others report a much more aggressive disease course.

Important parameters for the determination of prognosis of cervical clear cell carcinoma are

• FIGO stage
• Tumor size
• Growth pattern
• Nuclear atypia
• Mitotic activity
• Depth of stromal invasion

Several studies showed a better prognosis in diethylstilbestrol-induced carcinoma than those with spontaneous clear cell carcinoma.[2]

Unfavorable prognosis is related to a larger size, higher stage, high mitotic rate, positive surgical margin, parametrial involvement, and lymphovascular spread.

According to some studies, the overall survival rate of patients with stages (I/II) is (81.5 to 91%).[11] The 10-year survival rate is 57%.

Complications

Clear cell carcinomas of the lower genital tract have a greater tendency to recur late and develop metastases in distant sites more frequently than squamous cell carcinomas.[14][15][15]

Metastasis is uncommon in clear cell carcinoma of the cervix, but local recurrence may occur.[16][9] Metastasis occurs in about 18% of patients with stage I disease but in nearly 50% of stage II tumors.

The most common extra-pelvic sites of recurrence are the lungs, liver, and skeletal system.[17]

Most recurrences of clear cell carcinoma of the uterine cervix get diagnosed within three years after primary tumor treatment.[18] However, late recurrences have been reported with few cases, eight years after initial diagnosis.[15]

High-risk factors for recurrence include positive parametrial extension, positive pelvic lymph nodes, and positive vaginal margins. In patients with these high-risk factors, chemoradiation is the postoperative adjuvant treatment of choice.

Consultations

• Gynecologist
• Surgical oncologist
• Oncologist
• Pharmacy oncology specialist
• Gynecologists with a specific interest in fertility preservation
• Oncology nurse
• Radiation oncologist
• Medical oncologist
• Pathologist

Deterrence and Patient Education

Patient education is key to the successful management of patients with clear cell carcinoma of the cervix. The care providers should ensure that patients are instructed to immediately consult their providers if they develop any symptoms of abnormal uterine bleeding. Patients must also be informed about the risk of taking DES during pregnancy as it may induce clear cell adenocarcinoma of the uterine cervix and vagina of the female offspring.

The interprofessional team should ensure that patients are provided with the required information about their disease and provide them with written information leaflets or refer them to educational websites, to help patients better understand their disease and the available treatment options.

Enhancing Healthcare Team Outcomes

Management of clear cell carcinoma of the cervix needs an interprofessional approach involving a team that consists of a surgical oncologist, a medical oncologist, a radiation oncologist, a pathologist, a radiologist, and an oncology nurse. After treatment of clear cell carcinoma of the cervix, long-term follow-up is necessary to detect local and distant relapse. The primary care provider and nurse practitioner must refer patients with any abnormal uterine bleeding to a gynecologist for further workup.

Practitioners must be familiar with the new clinical developments needed in the diagnosis and treatment of clear cell carcinoma of the cervix to maximize clinical outcomes and reduce the risk of complications.

Healthcare providers should have an awareness of clear cell carcinoma of the uterine cervix in adolescents, and the need for prompt referral to a tertiary gynecological oncology center is necessary among general practitioners, gynecologists, and surgeons.

Clear cell carcinoma of the uterine cervix should be considered as a possible differential diagnosis of bloodstained vaginal discharge without a history of DES exposure or sexual abuse.

The interprofessional clinical team should work together and communicate to obtain the best results. The oncology specialty nurse should assist with patient and family education and arrange coordination between the specialists. A pharmacist plays a crucial role throughout the management of oncology patients and should assist with pain management and provide guidance in regards to drug interactions before surgical intervention, as well as performing overall medication reconciliation and reporting to the healthcare team any concerns they encounter. The best possible outcomes for patients with clear cell carcinoma of the cervix are only obtainable without collaboration among the interprofessional team members. [Level 5]