Continuing Education Activity

The diagnosis and management of clear cell carcinoma of the cervix is complex, and new approaches are constantly evolving. Clear cell adenocarcinoma of the uterine cervix accounts for only 4% of all adenocarcinoma cases, and about two-thirds are associated with intrauterine diethylstilbestrol (DES) exposure. Nevertheless, cases of clear cell adenocarcinoma have been reported in both adult women and children lacking a history of DES exposure. Compared to adults who suffer from adenocarcinoma, there is a high incidence of stage III and stage IV disease in children and adolescents. The incidence of disease outside of the usual screening age for cervical cancer emphasizes the importance of clinical recognition of the disease so that timely treatment can be delivered. Given the proportion of cases identified in the pediatric and young adult population, fertility-sparing treatment has been emphasized when possible.

To optimize patient survival, the clinical aspects of clear cell carcinoma of the cervix must be clearly defined, particularly regarding screening, diagnosis, and treatment. This activity describes the epidemiology, predisposing factors, clinical presentation, and management of clear cell carcinoma of the cervix and highlights the role of the interprofessional team in fostering the best possible outcomes for individuals with this condition.

Objectives:

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

• Assess the clinical presentation of a patient with clear cell adenocarcinoma of the cervix and implement the appropriate diagnostic techniques and imaging modalities necessary for diagnosis.

• Differentiate among patients with clear cell carcinoma who are candidates for various current treatment options, including fertility preservation options.

• Collaborate with members of an interprofessional team, including gynecologic oncologists, medical oncologists, gynecologists, pediatricians, and family medicine practitioners, to provide efficient, comprehensive, coordinated, and timely care.

Introduction

Clear cell carcinoma of the uterine cervix is a rare and highly invasive variant of adenocarcinoma and accounts for 4% of all cervical adenocarcinomas.[1] Although this condition has been historically associated with in-utero exposure to diethylstilbestrol (DES), cases of clear cell adenocarcinoma have been reported in both adult women and children without this exposure.[2] Of note, there is a higher incidence of late-stage (stage III and IV) disease in the pediatric population when compared to adult patients in whom this condition is diagnosed.[3] Patients often present to their physician with abnormal vaginal bleeding (premenarchal, intermenstrual, postcoital, postmenopausal), abnormal vaginal discharge, abdominal pain, or lower extremity edema.[4]

The diagnosis of clear cell carcinoma of the uterine cervix is mainly established based on histopathological examination of biopsy-obtained specimens. Histologically, clear cell carcinoma of the uterine cervix is predominantly composed of clear or hobnail cells whose architectural patterns are mixed with solid and tubulocystic patterned areas, mainly composed of nests of cells with clear eosinophilic cytoplasm and hyperchromatic nuclei.[5] Treatment is dependent upon the stage at diagnosis and patients’ desires to preserve fertility and can include a combination of surgical, radiation, and chemotherapeutic options.

Etiology

Historically, clear cell carcinoma of the cervix has been associated with prior intrauterine exposure to DES, a synthetic nonsteroidal estrogen hormone and teratogen with the ability to cross the placenta, although cases have been diagnosed in the absence of exposure.[6] Analysis of molecular mechanisms suggests that DES exposure in utero might lead to a persistent overexpression of protooncogenes that are associated with increased proliferation (c-jun, c-fos, c-myc) or decreased apoptosis (bcl-2, bcl-x), resulting in unregulated cell growth and subsequent carcinogenesis.[7] Moreover, growth factor genes (such as EGF and TGF-α) have demonstrated overexpression after in utero exposure to DES.[8] Other estrogen-responsive genes, such as the lactoferrin gene, have been shown to be induced by DES exposure.[9]

The most recent literature suggests that HPV (human papillomavirus) unlikely plays an etiologic role in clear cell carcinoma of the cervix, which sets it apart from most other variants of cervical cancer.[10] Cervical endometriosis might contribute to the occurrence of clear cell carcinoma of the cervix in women in the absence of DES exposure, given the known association of endometriosis and clear cell carcinoma of the ovary and other sites.[11][12][13] Overall, the etiology and pathogenesis of these tumors are not well established, and no clear-cut precursor lesion has been identified, though a few reports suggest that some clear cell carcinomas of the cervix may develop from cervical endometriosis or tubo-endometrioid metaplasia.[14]

Epidemiology

Clear cell carcinoma of the cervix is the second most common HPV-independent endocervical adenocarcinomas, representing about 3% of all cases.[15] A bimodal age distribution has been described in clear cell carcinoma of the cervix, with peaks at 26 years of age (17 to 37) and 71 years of age (44 to 88). DES-exposed patients tend to be younger, with a peak age of 19 years.[16][13]

Pathophysiology

Induction of genomic instability may be an important mechanism of DES-induced carcinogenesis. Somatic mutations of microsatellite repeats have been identified in all DES-associated tumors and 50% of DES-unrelated tumors.[17] Other studies suggest that mutations in the p53 gene, overexpression of the BCL-2 gene, and even cervical endometriosis contribute to the occurrence of clear cell adenocarcinoma.[18][19]

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 

Clear cell adenocarcinoma of the cervix can appear as a visible exophytic lesion, an endophytic lesion (grossly normal appearing cervix), or a barrel-shaped cervix. On physical examination, lesions can have variable presentations and have presented as everting nodular red lesions or small punctate ulcers.[20] The average size of a lesion at the time of diagnosis is 3.3 cm.[21]

Microscopic Findings 

Clear cell carcinoma of the cervix is characterized microscopically by solid, tubulocystic, and papillary morphology and can sometimes be admixed within the same tumor. The tumor cells are characterized by abundant clear, glycogen-rich cytoplasm with prominent cell membranes and hyperchromatic nuclei. Clear cell carcinoma can appear as hobnail-type tumor cells and signet ring-type tumor cells.[22] 

Immunohistochemical Studies

The immunohistochemical study is usually noncontributory to the diagnosis of clear cell carcinoma of the uterine cervix. However, it should be noted that CEA stains are negative, which distinguishes it from other types of cervical adenocarcinoma.[23] Periodic acid-Schiff stains strongly positive in the cytoplasm consistent with glycogen, strongly suggestive of clear cell adenocarcinoma given the glycogen-rich nature of tumor cells.[24] In a large study comparing clear cell carcinoma of the endometrium and cervix versus the ovary, it was determined that clear cell carcinomas of the gynecologic tract have a similar spectrum of histopathologic features, with the exception that endometrial clear cell carcinomas have focal solid components more often than clear cell adenocarcinoma of the cervix, and ovarian clear cell carcinomas, with endometrial clear cell carcinomas have a slightly higher average mitotic index. Endometrial and cervical clear cell carcinomas were positive for HNF1β and napsin A and rarely expressed estrogen and progesterone, and HNF1β was a sensitive marker for clear cell carcinoma at all 3 sites.[25] 

History and Physical

Clear cell carcinoma of the uterine cervix commonly presents with abnormal vaginal bleeding due to cervical ulceration (postcoital bleeding and/or intermenstrual bleeding). This vaginal bleeding is usually refractory to hormonal therapy.[4]

Physical examination usually depicts a cervical abnormality, often described as a “fullness” of the cervix. The tumor is usually not palpable during the rectal examination.[22]

Evaluation

Diagnostic imaging of clear cell carcinoma of the uterine cervix contributes to therapeutic management, surgical planning, and the prediction of prognosis. The main diagnostic modalities utilized in the diagnosis of clear cell carcinoma of the cervix include magnetic resonance (MRI), positron emission tomography/computed tomography (PET/CT), and cytology.

Magnetic Resonance Imaging 

MRI is the method of choice for local-regional tumor staging, evaluation of the treatment response, tumor recurrence detection, and possible complications.[26]

F-18 FDG PET/CT 

According to some authors, 18 F-fluorodesoxyglucose–positron emission tomography with computed tomography (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.[27]

Cytology 

Cytology has been found to be less efficient in diagnosing cervical adenocarcinomas.[20] 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.[28]

Treatment / Management

The treatment of clear cell carcinoma is similar to that of cervical cancer, and thus, the prognosis is stage-dependent, although the inherent risk associated with this histology is not well established.[29] 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.[30] External beam radiotherapy is the standard of care for stages IIB and IIIB.

The clinicopathologic findings and prognosis of surgically treated patients with stage IB–IIB clear cell carcinomas without exposure to DES in utero are similar to those of patients with squamous cell carcinomas and non-clear cell adenocarcinomas.[31] 

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.[32]

Differential Diagnosis

When evaluating patients with symptoms suggestive of clear cell carcinoma of the cervix, it is essential to consider differential diagnoses that may present similarly, such as cervical squamous cell carcinoma, other cervical adenocarcinoma, benign cervical lesions, or infections like cervicitis. Discriminating between these conditions is crucial for accurate diagnosis and appropriate management. Differential diagnoses include the following:

• 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
• Benign cervical lesions
• Cervicitis

Pertinent Studies and Ongoing Trials

Fertility Preserving Surgery

Upon diagnosis with clear cell adenocarcinoma of the cervix, women of reproductive age usually desire to preserve their fertility. However, only the histological characteristics of squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma are incorporated into the widely accepted criteria for radical trachelectomy.[4] Clear cell adenocarcinoma is generally considered an aggressive subtype, and fertility-sparing surgery is only recently being considered and explored in this subtype.[33] In most recent studies, fertility preservation surgery has been offered to those with stage IA–IB disease. In a retrospective study by Liu et al, no recurrence or death was detected, and the obstetric outcomes were quite favorable, with a pregnancy rate of 100%, a live birth rate of 100%, and a preterm birth rate of 50%.[4] This suggests that fertility-sparing treatment in reproductive-aged patients with early-stage clear cell carcinoma of the cervix could be safe and feasible and eventually become more widely practiced. Nevertheless, it is currently recommended by the lead investigators in these studies that fertility preservation be offered prudently because of the currently limited but growing knowledge on this issue.

Medical Oncology

Weekly cisplatin plus radiotherapy is the standard regimen for advanced cervical cancer.[4] Previous studies have evaluated whether platinum-based doublet therapy improves survival compared to weekly cisplatin plus radiotherapy. Lee et al reported that in cervical cancer with pelvic lymph node metastasis, platinum-based polychemotherapy as combination chemotherapy conferred favorable survival compared to weekly cisplatin, reducing the risk of recurrence by 77%.[34] A systematic review supported that in patients with locally advanced cervical cancer who underwent chemoradiotherapy, cisplatin-based doublets had improved overall survival, progression-free survival, and local control in comparison with concomitant cisplatin chemotherapy.[35] The goal is for this combined therapy to lead to increased cytotoxicity and radiosensitization compared to cisplatin as a single agent. Since adenocarcinoma of the cervix is not as radiosensitive as squamous cell carcinoma, clear cell adenocarcinoma of the cervix, as a subtype of adenocarcinoma, may best be treated with platinum-based doublet therapy plus radiotherapy.[36]

Staging

Staging according to the new International Federation of Gynecology and Obstetrics (FIGO) classification is as follows: [26]

Stage 1

The tumor is limited to the cervix. 

Stage 1A

Microinvasive carcinoma limited to the cervix that is only microscopically visible. The maximum invasion depth is <5 mm.

1A1 stromal invasion <3 mm

1A2 stromal invasion ≥3 mm and ≤5 mm

Stage 1B

Invasive carcinoma limited to the cervix with stromal invasion of ≥5 mm or a clinically visible tumor

1B1 clinically visible tumor <2 cm or microscopically visible lesion with an invasion depth of ≥5 mm

1B2 invasive carcinoma with a diameter of ≥2 cm and ≤4 cm

1B3 invasive carcinoma with a diameter of ≥4 cm

Stage 2

The tumor is not limited to the cervix and infiltrates the upper 2/3 of the vagina or the parametria. 

Stage 2A

Infiltration of the upper 2/3 of the vagina

Stage 2B

Infiltration of the parametria but the pelvic wall is not affected

Stage 3

Infiltration of the lower 1/3 of the vagina or the pelvic wall

Stage 3A

Tumor extends to the lower 1/3 of the vagina but does not reach the pelvic wall

Stage 3B

Infiltration of the pelvic wall or the ureters resulting in hydronephrosis. Per definition, pelvic wall infiltration is present when the iliac vessels, the obturator internus muscle, the piriformis muscle, or the levator ani muscle is infiltrated.

Stage 3C

Pelvic and/or retroperitoneal lymph node metastases, regardless of tumor size or extent

3C1 pelvic lymph node metastases

3C2 retroperitoneal lymph node metastases in the TNM classification; the involvement of retroperitoneal lymph nodes is categorized as distant metastasis (M1).

Stage 4

Detection of infiltration of the bladder and/or rectum or extension of the tumor beyond the borders of the small pelvis

Stage 4A

Infiltration of the bladder and/or rectum to the mucosa 

Stage 4B

Presence of distant metastases 

Prognosis

Studies regarding prognosis are conflicting; some report equivalent outcomes with conventional cervical adenocarcinoma, whereas others report a much more aggressive disease course.[33]

Important parameters for the determination of prognosis of cervical clear cell carcinoma include the following:

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

The most significant prognostic factors for progression-free survival and overall survival among those above are the FIGO stage and pelvic node status.[37]

There are no published data on the differences in prognosis between clear cell carcinoma and gastric type endocervical adenocarcinoma subtype and between clear cell carcinoma and HPV-associated cervical adenocarcinoma. Other than case reports demonstrating that clear cell carcinomas have a worse prognosis than HPV-associated cervical adenocarcinoma, the 2 largest studies did not correlate clear cell carcinoma survival with those of HPV-associated cervical adenocarcinoma and/or with gastric-type cervical adenocarcinoma since these studies were performed before the introduction of the etiology-based classification system.[38][21]

Another larger study comparing treatment prognosis for clear cell carcinoma versus gastric-type endocervical adenocarcinoma subtype noted that clear cell carcinomas have poorer outcomes than HPV-associated endocervical adenocarcinomas and similar outcomes to HPV-independent gastric-type adenocarcinoma, but are stage dependent.[14][38]

Complications

Most studies concur that clear cell carcinoma is a tumor associated with lymphovascular space invasion and lymph node metastases, with pelvic lymph node involvement noted in as high as 25% of cases.[38] Similarly, Stolnicu et al, found lymphovascular invasion in 31% and lymph node metastases in 24.1%.[14] In addition, 10.3% were associated with abdomino-pelvic metastases, 32.8% had recurrences and 19% died of disease.[14] 

The sites of recurrence included the following: lung, liver, bone, brain, peritoneum, retroperitoneum, mediastinal lymph nodes, vagina and sigmoid colon.[39] Most recurrences of clear cell carcinoma of the uterine cervix are diagnosed within 3 years after primary tumor treatment.[32] However, late recurrences have been reported with a few cases, 8 years after initial diagnosis.[40] 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.[37]

Consultations

Consultations are pivotal in the comprehensive care of patients diagnosed with clear cell carcinoma of the cervix, ensuring multidisciplinary collaboration and tailored management. Appropriate consultations may include the following:

• Gynecologist
• Surgical/ Gynecologic oncologist
• Medical oncologist
• Radiation oncologist
• Pathologist
• Reproductive endocrinologist
• Pharmacy oncology specialist
• Oncology nurse
• Palliative care specialist

Deterrence and Patient Education

Deterrence and prevention of clear cell carcinoma of the cervix primarily hinge on addressing modifiable risk factors and promoting regular screening practices. Education on avoiding exposure to known carcinogens, such as DES, during pregnancy is crucial.

The care providers should ensure that patients are instructed to immediately consult their providers if they develop any symptoms of abnormal uterine bleeding. Particular attention should be paid to instances of premenarchal, postmenopausal, and intermenstrual bleeding. These symptoms warrant immediate attention from a healthcare provider who should have a low threshold to biopsy any suspicious lesions identified on physical examination. 

The interprofessional team should ensure that patients are provided with written information or referred to educational websites to help patients better understand the nature of their condition, including its etiology, symptoms, diagnostic procedures, treatment options, potential adverse effects, and prognosis. Additionally, resources on coping mechanisms, support groups, and avenues for further information should be offered to empower patients in managing their disease and making informed decisions regarding their care.

Pearls and Other Issues

Screening

Women whose mothers took DES during pregnancy must undergo regular gynecologic exams throughout their lifetimes. These women should receive a cytological screening twice yearly until the age of 60 years.[41] DES-exposed women should receive a pelvic exam, pap smears of the cervix and vagina, and colposcopy.[42] The cervical Papanicolaou test may not be adequate for DES-exposed daughters. Therefore, the cervical Papanicolaou test must be supplemented with a Papanicolaou test of the vagina, known as the “four-quadrant” Papanicolaou test, which samples all sides of the upper vagina. Cervical and vaginal palpation of an irregular mass may initiate the workup that ultimately leads to a diagnosis of clear cell carcinoma of the cervix.[43]

Possible correlation with genitourinary malformations such as Mullerian anomalies

It has been reported that the prevalence of congenital malformations in cervical or vaginal clear cell carcinoma was 6%.[44] Additional studies have reported that 69% of the patients with genitourinary malformations had adenocarcinoma of the lower genital tract.[45] This raises the possibility that congenital anomalies are linked to an elevated risk of primary malignancies. The Müllerian epithelium, according to a theory by Sporri et al, may become vulnerable to carcinogenic substances due to teratogenic effects.[46] Direct causation at a genetic level has not been proven; however, it is recommended that in individuals with genitourinary abnormalities, it is necessary to determine their genetic profile and probability of developing cancer.[4] 

Enhancing Healthcare Team Outcomes

Successful management of clear cell carcinoma of the cervix requires an interprofessional approach involving a team that consists of a gynecologic oncologist, a medical oncologist, a radiation oncologist, a pathologist, and a radiologist with expertise in pelvic anatomy. Following successful treatment of clear cell carcinoma of the cervix, long-term follow-up over years is necessary to detect local and distant recurrences. The primary care provider and nurse practitioner must refer patients with any abnormal uterine bleeding to a gynecologist for further workup. Similarly, a gynecologist must refer patients to a gynecologic oncologist once a tissue sample is obtained, conferring the diagnosis of malignancy.

All healthcare professionals who care for female patients at various stages of their lives must be familiar with the presenting symptoms, diagnostic methods, and treatment of clear cell carcinoma of the cervix to reduce delays in care and subsequent advancement of disease and worsening of prognosis. Healthcare providers should also be aware of the incidence of clear cell carcinoma of the uterine cervix in children and adolescents and be able to refer to a tertiary gynecological oncology center promptly.

An interprofessional clinical team should collaborate and communicate amongst themselves and with the patient 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 while providing guidance regarding drug interactions and patient tolerance of adverse effects, as well as performing overall medication reconciliation and reporting to the healthcare team any concerns they encounter. A palliative care specialist should be available to help patients cope emotionally and clarify goals of care throughout the course of treatment and as the prognosis evolves. Ideal outcomes for those who have received a diagnosis of clear cell carcinoma of the cervix are only obtainable amidst collaboration among interprofessional team members and with guided shared decision-making in conjunction with the patient and her family.