What is Clear Cell Carcinoma of the Cervix?
Clear cell carcinoma of the uterine cervix is a rare and extremely invasive form of adenocarcinoma, which makes up 4% of all adenocarcinomas in the cervix. Historically, this condition has been tied to exposure to a drug called diethylstilbestrol (DES) before birth. However, there have been instances of clear cell adenocarcinoma in adult women and children who have not been exposed to DES. Importantly, there’s a higher rate of this condition entering a severe, late stage (stage III and IV) in children compared to adults where it is diagnosed. Symptoms often include abnormal vaginal bleeding (before first period, between periods, after sex, after menopause), unusual vaginal discharge, abdominal pain, or swelling in the lower extremities.
The diagnosis of this condition is primarily determined through a detailed examination of tissue samples collected via biopsy. Under the microscope, the carcinoma is mostly made up of clear or ‘hobnail’ cells, with a mixed structure including solid areas and areas resembling tubes or small cysts. These areas are mostly formed of cell groups with clear, pinkish cellular material and highly pigmented cell centers. Treatment depends on the stage at diagnosis and the patient’s preference to maintain fertility; options can include a mix of surgery, radiation, and chemotherapy.
What Causes Clear Cell Carcinoma of the Cervix?
Clear cell carcinoma of the cervix has traditionally been linked with exposure in the womb to a synthetic hormone known as DES. Despite this, cases can still occur without any DES exposure. Studies suggest that this in-womb exposure could affect certain genes which spikes cell growth or reduces the natural cell death process, which may lead to unrestricted cell growth and potential for cancer. It can also overstimulate the expression of certain growth factor genes. Additionally, genes responsive to estrogen like the lactoferrin gene can be activated by DES exposure.
Latest studies show that HPV (Human Papillomavirus) likely doesn’t contribute to the development of clear cell carcinoma of the cervix, which makes it unique among most other types of cervical cancer. Cervical endometriosis may lead to clear cell carcinoma of the cervix in women who haven’t been exposed to DES, due to a known link between endometriosis and clear cell carcinoma at other sites. However, the exact cause and development process of these tumors is not fully understood. There’s no concrete precursor lesion identified though some reports suggest that such cancers may develop from cervical endometriosis or tubo-endometrioid metaplasia.
Risk Factors and Frequency for Clear Cell Carcinoma of the Cervix
Clear cell carcinoma, a type of cancer found in the cervix, is the second most common kind that is not caused by HPV and makes up about 3% of all cases. It’s most common in two age groups: young adults around 26 years old (ranges from 17 to 37) and older adults around 71 (ranges from 44 to 88). Interestingly, patients who have been exposed to a drug called DES tend to be younger, with the peak age being 19.
- Clear cell carcinoma is a cervical cancer and the second most common type not caused by HPV.
- It accounts for about 3% of all cervical cancer cases.
- The disease tends to appear most frequently in people around 26 years old (but can be from 17 to 37 years old) and 71 years old (but can be from 44 to 88 years old).
- Patients exposed to the drug DES often get this type of cancer when they are younger, typically around 19 years old.
Signs and Symptoms of Clear Cell Carcinoma of the Cervix
Clear cell carcinoma of the uterine cervix is a condition that often shows up as abnormal vaginal bleeding. This bleeding can be after sexual intercourse or between periods and tends not to respond well to hormonal treatments. A physical examination may reveal a cervical abnormality, often described as a ‘fullness’ of the cervix. However, the tumour is usually not felt during a rectal examination.
Testing for Clear Cell Carcinoma of the Cervix
Imaging methods like magnetic resonance imaging (MRI), positron emission tomography/computed tomography (PET/CT), and cytology are often used in the detection and assessment of pre-cancerous conditions like clear cell carcinoma of the cervix. These techniques help doctors plan treatments, forecast how the condition could progress, and make surgical decisions.
MRI scans are typically used for multiple tasks: determining the stage of the tumor, gauging the effectiveness of treatments, detecting whether the tumor has come back, and spotting any potential complications.
Another imaging method, using fluorodesoxyglucose and positron emission tomography with computed tomography (F-18 FDG PET/CT), can be useful in examining cases of clear cell carcinoma of the cervix that have spread to the lymph nodes in the pelvic cavity and the space behind the abdomen (also known as the retroperitoneum).
On the other hand, cytology, or the study of cells, may not be as effective for diagnosing cancers of the cervix such as adenocarcinomas. Researchers found that in a sample of 31 patients with cervical clear cell carcinoma, only 6 (or about 18%) showed abnormalities on their Pap test, suggesting that cytology wasn’t very helpful in detecting this type of cancer.
Treatment Options for Clear Cell Carcinoma of the Cervix
The treatment for clear cell carcinoma, a type of cancer, shares similarities with how cervical cancer is treated. Because of this, the patient’s outcome largely depends on the stage of the disease. However, it’s less clear how much risk comes with this specific type of cancer.
A common surgical treatment for early-stage cervical carcinoma, stages IB or IIA, is a radical hysterectomy and a pelvic lymphadenectomy. This treatment can result in the patient being unable to have children. For stages IIB and IIIB, the go-to treatment is external beam radiotherapy.
It’s important to mention that the findings from the clinic and the lab, as well as the prognosis of patients with clear cell carcinoma stages IB–IIB who weren’t exposed to a particular drug (DES) while in the womb, are alike to those of patients with other types of cancer, such as squamous cell carcinomas and non-clear cell adenocarcinomas.
Interestingly, a recent study compared two treatment options for stage IB1 cervical carcinoma in young women who wish to maintain their fertility. The study found no significant differences in survival rates between fertility-preserving radical trachelectomy and radical hysterectomy, indicating that the fertility-preserving surgery is a safe choice for early-stage cancer.
What else can Clear Cell Carcinoma of the Cervix be?
When a doctor is examining a patient for symptoms that could indicate a cervical cancer type known as clear cell carcinoma, it’s important to check for other potential conditions that can show similar symptoms. These might be other types of cervical cancer such as squamous cell carcinoma and other cervical adenocarcinomas. They could also be less severe conditions like benign (not cancerous) cervical lesions or infections like cervicitis (inflammation of the cervix). Correctly identifying the condition is crucial to provide the right treatment. The list of conditions the doctor may consider includes:
- Metastatic clear cell carcinoma (Cancer that has originated from other body parts)
- Arias-Stella reaction (A condition often related to pregnancy)
- Adenosis (A benign condition marked by an excess of glandular tissue)
- Endometrioid adenocarcinomas (a type of uterine cancer) showing certain specific changes
- Gastric-type of endocervical adenocarcinoma (a rare type of cervical cancer)
- Cervical yolk sac tumors (a rare type of ovarian germ cell tumor)
- Primary cervical alveolar soft part sarcomas (a rare type of soft tissue tumor)
- Benign cervical lesions (non-cancerous cervical conditions)
- Cervicitis (inflammation of the cervix)
What to expect with Clear Cell Carcinoma of the Cervix
Research regarding the outcome of cervical clear cell carcinoma is inconsistent. Some studies show outcomes equivalent to typical cervical adenocarcinoma, whereas others suggest a much more aggressive course of disease.
A prognosis for this condition depends on several factors:
* The FIGO stage of the cancer
* The size of the tumor
* The growth pattern of the cancer cells
* Irregularities in the nucleus of the cells (nuclear atypia)
* Mitotic activity, which reflects how rapidly the cancer cells are dividing
* How deep into the stroma (connective tissue that supports organs) the cancer has invaded
The most important factors affecting the likelihood of disease progression and overall survival are the FIGO stage and the status of the pelvic nodes.
There’s no existing data comparing the prognosis between clear cell carcinoma and other subtypes such as gastric type endocervical adenocarcinoma and HPV-associated cervical adenocarcinoma. While there are case reports suggesting clear cell carcinomas have a worse prognosis than HPV-associated cervical adenocarcinoma, two large-scale studies did not find a connection, possibly due to these studies being carried out before a system to classify the causes of these cancers was introduced.
In another bigger study, when comparing treatment outcomes, clear cell carcinomas fared worse than HPV-associated endocervical adenocarcinomas but had similar outcomes to HPV-independent gastric-type adenocarcinoma. However, these results were dependent on the stage of the cancer.
Possible Complications When Diagnosed with Clear Cell Carcinoma of the Cervix
Research shows that clear cell carcinoma, a type of tumor, is often linked with the invasion of lymphovascular spaces and the spread of cancer to lymph nodes. In fact, up to 25% of cases noted involvement of lymph nodes in the pelvis. Some researchers found that, in 31% of cases, the lymphovascular system was invaded and, in 24.1% of cases, lymph nodes were affected. Furthermore, 10.3% of cases were linked with spread (metastases) in the abdomen and pelvis, 32.8% experienced a return (recurrence) of disease, and 19% of patients passed away due to the disease.
The sites where the disease commonly comes back include:
- Lung
- Liver
- Bone
- Brain
- Peritoneum (lining of the abdomen)
- Retroperitoneum (area at the back of the abdomen)
- Mediastinal lymph nodes (in the chest)
- Vagina
- Sigmoid colon (part of the bowel)
Mostly, the reappearance of clear cell carcinoma of the uterine cervix is observed within 3 years of the initial treatment. However, in a few cases, the recurrence has been noted as late as 8 years after the initial diagnosis. Factors that increase the risk of recurrence include the spread of disease to the tissues surrounding the uterus (parametrial extension), pelvic lymph nodes, and the edge of the vagina. For patients with these high-risk factors, a combination of chemotherapy and radiation (chemoradiation) is the preferred choice of treatment after surgery.
Preventing Clear Cell Carcinoma of the Cervix
Preventing and fighting against clear cell carcinoma of the cervix, a type of cervical cancer, mainly involves addressing changeable risk factors and encouraging regular health checks. It’s key that people are taught to steer clear of known cancer-causing substances, such as DES, when they are pregnant.
Healthcare professionals should make sure their patients know to seek advice at once if they start to experience any unusual uterine bleeding. Special attention should be given to bleeding that occurs before the first menstrual cycle, after menopause, or between menstrual periods. Such symptoms need quick medical attention. Doctors should be prepared to take a tissue sample from any abnormal areas found during a physical examination.
The healthcare team should provide patients with written information or refer them to useful websites, so they understand more about their condition. This includes knowledge about what causes it, its symptoms, how it is diagnosed and treated, possible side effects, and what can be expected in the future. It’s also helpful to provide resources on ways to cope, support groups, and other sources of information to keep patients informed, in control, and capable of making decisions about their treatment.