Continuing Education Activity

The diagnosis of primary vaginal cancer is rare, comprising 1-2% of all female reproductive tract cancers because most lesions are metastatic, typically arising from other reproductive organs such as the cervix, endometrium, or ovary; however, they can also metastasize from distant sites such as the colon, breast, and pancreas. Primary vaginal cancer is strictly defined as a disease without evidence of cervical or vulvar cancer or a history of either within the past five years. When primary vaginal cancer is suspected, a biopsy is done for histopathologic confirmation. This activity reviews the background, diagnosis, treatment, and management of vaginal cancer and highlights the importance of proper knowledge and familiarity with this topic by the interprofessional team.

Objectives:

• Describe the staging of vaginal cancer.
• Implement recommended evaluation and staging processes for patients after biopsy-confirmed diagnoses of vaginal cancer.
• Select optimal treatment options after vaginal cancer has been staged, including medical, surgical, and radiation oncology approaches.
• Collaborate with the interprofessional team to plan coordinated treatment strategies to improve patient care and outcomes.

Introduction

Primary vaginal cancer is rare, comprising 1-2% of all female reproductive tract cancers.[1] The vagina is a 7 to 10-centimeter-long fibromuscular tube extending from the cervix to the vulva, sitting posterior to the urethra and bladder and anterior to the rectum. It is divided into three parts, which are essential for classifying tumor location and lymphatic drainage. The lower third is below the level of the bladder base with the urethra anteriorly, the middle third is adjacent to the bladder base, and the upper third is at the level of the vaginal fornices, denoted as anterior, posterior, and lateral to the cervix.[2]

Primary vaginal cancer is strictly defined as a disease without evidence of cervical or vulvar cancer or a history of either within the past five years. Most vaginal lesions (80-90%) originate from cervical or vulvar lesions or other local sites such as the endometrium, bladder, rectosigmoid, or ovary. Distant sites of metastasis include the colon, breast, and pancreas. When primary vaginal cancer is suspected, a biopsy is done for histopathologic confirmation.[1][3]

While current estimates of vaginal cancer are higher than vulvar cancer, these estimates include primary and other genital lesions.[4] Currently, there are no randomized trials for the treatment of vaginal cancers due to the rarity of the disease, and guidelines are generally based on limited studies.[5]

Etiology

The pathways of carcinogenesis for vaginal cancer can be divided into human papillomavirus (HPV) induced and non-HPV induced.[6] As with cervical cancer, the HPV 16 virus strain accounts for most HPV-positive patients.[7] Within the HPV DNA, the activity of the viral reading frames E6 and E7 create proteins that interfere with critical cell cycle points. E6 interferes with suppressive tumor protein p53 and E7 with retinoblastoma protein (pRB). These are significant factors in HPV-related neoplasia, including primary vaginal cancer. The E5 protein may also play a role in immune evasion.[8]

Historically, diethylstilbestrol (DES), a synthetic estrogen used to prevent miscarriages and preterm labor, has been associated with vaginal clear cell adenocarcinoma in offspring.[9] The incidence of this cancer has decreased since the routine use of DES was discontinued in the 1970s.

Epidemiology

Squamous cell carcinoma (SCC) of the vagina accounts for 90% of all patients with primary vaginal cancer, followed by adenocarcinoma, clear cell adenocarcinoma, melanoma, sarcoma, and lymphoma of the vagina.[5]

Invasive vaginal cancer shares many risk factors with cervical cancer, such as tobacco use, younger age at first intercourse, HPV infection, and multiple sexual partners.[10]

The incidence of vaginal cancer arising primarily from the vagina increases with age, with approximately 50% of patients presenting over the age of 70 years and 20% over 80 years.[11]  Of these cancers, SCC is by far the most common.[12] The average age of diagnosis is 67 years. Approximately 15% of women are diagnosed under age 50; these are usually associated with cervical cancer.[5]

Vaginal melanomas most likely originate from mucosal melanocytes and most commonly present as vaginal bleeding in White women with a mean age of 60 years.[13]

Verrucous carcinoma is a low-grade malignant variant of SCC and presents as a large warty-appearing mass. This variant can be aggressive locally but is rarely metastatic.[14] 

While other sarcomas can arise in the vagina, the most common is embryonal rhabdomyosarcoma (ERMS) or sarcoma botryoides, a rare subtype of ERMS. These occur in infants and young children, clinically appearing as soft nodular lesions.[15]

Pathophysiology

Like the premalignant cervical lesions and carcinoma of the cervix, continual HPV infection, especially the HPV 16 subtype, is associated with the long-term development of high-grade squamous intraepithelial lesions (HSIL) and carcinoma of the vagina. The squamous cells of the vaginal mucosa are similar to the cells of the ectocervix. Recently, the terminology for precancerous lesions has changed from vaginal intraepithelial lesion (VAIN) 1 to low-grade squamous intraepithelial lesion (LSIL) and VAIN 2-3 to high-grade squamous intraepithelial lesion (HGSIL). Because the vaginal epithelium does not transform via squamous metaplasia, vaginal tissue less commonly undergoes malignant transformation from HPV infection.

Primary melanomas arising from the female reproductive system are uncommon and aggressive cancers. The vulva is the most frequent site (70%), followed by the vagina and, more rarely, the cervix.[16] Tumors that involve the vagina or cervix are strongly associated with high-risk clinicopathologic features, including increased tumor thickness, ulceration, positive surgical margins, lymph node metastasis, and poor long-term clinical outcomes, including death.[17]

Histopathology

Approximately 90% of all primary vaginal cancers are SCC. Primary adenocarcinoma of the vagina is quite rare. DES-related clear cell carcinoma of the vagina occurred mainly in young women, but DES-related tumors are becoming rare as the DES-exposed cohort ages.[18] Histopathologic grades (G) are given to cancers to provide prognostic information about the tumor.

• GX: Grade cannot be assessed
• G1: Well differentiated
• G2: Moderately differentiated
• G3: Poorly or undifferentiated

Verrucous carcinoma histologically is composed of large papillary fronds covered by dense keratin. It has relatively indistinct borders in the deep margins as opposed to the well-demarcated borders of benign condyloma acuminate.[14]

A small percentage of patients with vaginal cancer are diagnosed with sarcoma and melanoma. Primary vaginal melanoma is a rare mucosal neoplasm and is more aggressive than cutaneous melanoma.[19]

History and Physical

In addition to a complete medical and surgical history, attention should be given to any history of pelvic neoplasia or other malignancy. The most common presenting symptom of vaginal cancer is abnormal vaginal bleeding.[20] However, up to 20% of women may be asymptomatic and discovered on pelvic examination or with cytology for cervical cancer screening. Other nondescript symptoms may be present, such as watery, malodorous, or blood-tinged vaginal discharge.[21] Patients may report a vaginal mass, and local extension of vaginal cancer can present as urinary or gastrointestinal symptoms. Pelvic pain is often indicative of advanced disease. One of the most important aspects of the patient's history is the preexistence of cervical cancer. In a retrospective study, vaginal cancer was the most common metachronous malignancy after a cervical cancer diagnosis.[22] 

Evaluation for suspected vaginal cancer requires a thorough physical exam, including a digital exam, a rectovaginal exam, a speculum exam, palpation of inguinal nodes, and colposcopy with biopsies. Visualizing the entire vagina by rotating the speculum to expose anterior and posterior surfaces is important. Applying Lugol solution (iodine) during colposcopy can help visualize vaginal neoplasia.[23]

It is also important to determine whether or not the patient has been appropriately vaccinated, as a reduction of vaginal neoplasia after HPV DNA vaccination has been described.[24]

Evaluation

There are no routine screening indications for vaginal cancer. If cervical cytology is abnormal and no cervical lesions are seen, evaluation for vaginal lesions should be undertaken. Vaginal cytology after hysterectomy for benign disease is not indicated due to low yield and high false positive rates. However, long-term surveillance is suggested after a hysterectomy for high-grade cervical intraepithelial neoplasia (CIN). This is especially true for immunologically compromised individuals.[25][26]

Low-grade VAIN does not require treatment and can be followed with cytology and colposcopy.[27]

Biopsy remains the gold standard for diagnosing vaginal cancer. This can be best accomplished by an examination under anesthesia and should include inspection of the vaginal fornices and biopsies of the cervix. Clinical evaluation without anesthesia can also be performed if the patient is comfortable. Staging is essential to developing a treatment plan if a primary invasive lesion is discovered. The current staging systems include the International Federation of Gynecology and Obstetrics (FIGO) staging, Tumor, Node, Metastasis (TNM) staging, and the American Joint Commission on Cancer (AJCC) staging.[28] Treatment planning may be modified based on imaging studies.

Staging includes data from the physical examination, cystoscopy, proctoscopy, and chest and skeletal radiography. Biopsy of lymph nodes may be included in the TNM staging, as well as data from a final resected specimen. No specific lab abnormalities exist for diagnosing vaginal cancer; elevated liver function tests can suggest metastatic disease but are nonspecific.

Magnetic resonance imaging (MRI) of the pelvis is useful in staging vulval and vaginal neoplasms to assess tumor size, local tumor extent, and the presence of lymph node metastases. Further indications for MRI are the diagnosis of post-therapeutic changes and tumor recurrence.[29] 

Although imaging studies have limited utility in diagnosing vaginal cancer, FIGO encourages using computed tomography (CT), MRI, and positron emission tomography (PET), to guide therapy. However, the imaging findings may not be used to change or reassign the stage.[30] In one study, FIGO evaluated the use of PET/CT to assess suspected or known disease (primary or recurrent). They reported a change in prognostic impression and intended patient management in 51% and 36% of studies performed, respectively.[31]

It is essential to understand that the vaginal lymphatic system is extensive. The middle to upper vagina drains with the cervical lymphatics into the pelvic obturator node, the internal and external iliac chains, and the para-aortic nodes. Of note, the inguinal nodes are the first drainage from the distal third of the vagina, then to the pelvic nodes. The posterior wall lymphatics drain with the rectal lymphatics.[32]

Treatment / Management

Early vaginal cancers are generally treated with surgery or radiation therapy. Advanced cancers are treated with radiation therapy and the simultaneous administration of combined chemotherapy; surgery has a limited role due to the proximity of the bladder, urethra, and rectum.[20] It may be helpful in small stage I and II tumors or more extensive surgery in patients with a fistula from late-stage disease or recurrence after radiation.[33]

Local excision may be possible for small (<2 cm) lesions confined to the mucosa. For upper vaginal disease, radical hysterectomy (if the uterus is present) plus radical vaginectomy and pelvic lymphadenectomy is an option. For lower vaginal disease, radical excision with groin node dissection is a treatment option. The goal for lower and upper disease is 1 cm disease-free margins.[34]  Radical surgery for stage I and II cancers has reported good outcomes; however, the series is small and retrospective.[35] A literature review reported that early-stage disease had a mean five-year survival rate of 77%.[12] Pelvic exenteration may be offered in central recurrences after radiation, but the significant risks and morbidity need to be addressed with the patient before taking this approach. Palliative surgery for fistulas may be necessary.[34][36]

A study from the National Cancer Database showed the use of combined chemoradiation therapy (CCRT) for patients with vaginal cancer has increased and is associated with a significant improvement. CCRT should be incorporated into treatment guidelines for vaginal cancer.[37] Enough success in treating cervical cancer with CCRT has moved the modality to vaginal cancer. Due to the rarity of vaginal cancer, data is limited for CCRT compared to radiation therapy alone. However, a 2013 retrospective review of 71 patients demonstrated a disease-free and overall survival benefit from combined therapy.[38] Standard therapy for locally advanced vaginal cancer generally consists of combined external beam radiation therapy (EBRT) and brachytherapy, plus weekly cisplatin-based therapy.[39][40]

Vaginal melanoma is rare, and there is no standard treatment. Surgery for excision, including exenterative surgery, has been reported, and there is limited evidence to support adjuvant therapy. The use of targeted therapy such as PD-L1 blockade has increased and improved prognosis in cutaneous melanoma; however, vaginal melanoma has a different genetic profile with fewer BRAF mutations and more c-KIT mutations.[41]

Individualized treatment of high-grade VAIN can prevent malignant conversion. Reported treatment modalities include laser ablation, surgical excision, and topical treatments such as imiquimod and topical chemotherapy with 5-fluorouracil.[27]

Differential Diagnosis

The differential diagnosis for vaginal cancer is diverse and can include lesions not typical of the reproductive system. Sexually transmitted infections, such as herpes simplex and syphilis, can cause lesions that can mimic cancer. Vaginal trauma and atrophy can also present with bleeding similar to vaginal cancer. Benign vaginal masses include but are not limited to polyps, Gartner duct cysts, Bartholin gland cysts, and vaginal adenosis. From an oncologic perspective, cervical and vulvar cancer must be ruled out when determining if a lesion is a primary vaginal carcinoma. Metastatic lesions from the bladder and colorectal cancer have been reported.[42]

Surgical Oncology

Surgical management can be considered in stage I lesions that are amenable to hysterectomy with upper vaginectomy and lymph node dissection. Ideally, the lesions will be present in the apex of the posterior fornix of the vagina. Lower lesions can be approached with vulva-vaginectomy, but this procedure is uncommon due to its complex nature and associated complications. For young women with vaginal cancer requiring radiation as primary treatment, ovarian transposition can be offered before definitive radiation treatment to prevent the adverse effects of radiation-induced menopause. In selected patients, laparoscopic or extraperitoneal removal of bulky lymph nodes can be done as part of staging and treatment planning.[1] 

Radiation Oncology

Radiation is the cornerstone of treatment for vaginal cancer, particularly in advanced stages. It combines EBRT and intracavitary radiotherapy (ICRT) or brachytherapy. The principal advantage of radiation is organ preservation. The standard of care EBRT to the pelvis includes the external iliac and obturator nodes. Additionally, the inguinal nodes may be included if the tumor is in the distal vagina.[1] Careful treatment planning to cover the area of the tumor, the involved region(s), and the lymph nodes is essential for the best outcomes. Integration of CT and MRI has been shown to aid proper radiation treatment.[38] A dose of at least 70 Gy improves outcomes.[43] 

CCRT for patients with vaginal cancer has increased and has demonstrated significant improvement in survival in several studies. In a National Cancer Database study of 13,689 patients, the median overall survival was 56.2 months with CCRT and 41.2 months with radiation alone (p<0.0005).[37]

Radiation treatment is contraindicated in patients with verrucous carcinoma because it can provoke anaplastic transformation and worsen the prognosis.[14]

Pertinent Studies and Ongoing Trials

 Due to its rarity, there are currently no randomized trials regarding vaginal cancer treatment.

Toxicity and Adverse Effect Management

In a review of 138 patients treated for vaginal cancer from the Korean Radiation Oncology Group, 12% had grade 3 or 4 acute toxicity, including skin, gastrointestinal, and genitourinary. Twelve patients (8%) showed late toxicity. The volume of the tumor and FIGO stage were foreboders of severe late toxicity. Ultimately, the data showed that a later stage of disease was associated with a worse survival outcome and more toxicity from treatment.[44]

In extrapolation from radiotherapy for cervical cancer, vaginal toxicity from radiation for vaginal cancer includes the following: dryness (18-21%), shortening (15-22%), tightening (16-22%), dyspareunia (9-21%), and compromised enjoyment (37-47%). Hormone replacement therapy in this study showed significant improvement in alleviating symptoms.[45]

Vaginal dilator therapy is recommended for women undergoing pelvic radiation to prevent vaginal stenosis; however, no standard protocols exist. A recent expert opinion suggests starting dilation around four weeks after treatment, using it 2 or 3 times per week for 1 to 3 minutes, and continuing it for up to a year. Using plastic dilators of varying sizes had the best outcomes.[46] Literature suggests that a multidisciplinary clinic for sexual health may be beneficial after pelvic radiotherapy.[47]

Medical Oncology

The use of chemotherapy in vaginal cancer is relatively new, and most research has been extrapolated from data on cervical cancer treatment. Treatment with cisplatin or 5-fluorouracil has demonstrated some efficacy.[48] Chemoradiation can be considered in the management plan of vaginal cancer following a recent retrospective review suggesting an encouraging improvement in overall and disease-free survival rates.[38] Although it was a small review of 71 patients, a significant difference was shown in overall survival and disease-free survival rates between women who received radiation alone versus those who received chemoradiation as initial treatment (three-year overall survival of 56% versus 79% and three-year disease-free survival of 43% versus 73%).[38]

Limited studies on chemotherapy for recurrent vaginal cancer are available. Benefits and toxicity should be carefully considered when using systemic chemotherapy for these patients. Data on the use of chemotherapy is mainly from case reports. Cisplatin is the most common agent reported, and immunotherapy with pembrolizumab and nivolumab has been reported in a small number of patients. The poor prognosis for recurrent or stage IV disease may encourage further investigation of these agents.[5]

Staging

Staging (modified from American Cancer Society)

• Stage I- limited to the vaginal mucosa
• Stage II- involvement of the subvaginal tissue without extension to the pelvic sidewall
• Stage III- extension to the pelvic sidewall
• Stage IVA- spread to adjacent organs
• Stage IVB- spread to distant organs

In a recent study of 124 patients, data revealed the following distribution: Stage I - 31%, Stage II - 36%, Stage III - 16%, and Stage IV - 17%.[49]

Prognosis

Many prognostic factors can influence the management plan. Lymph node metastasis is an important prognostic factor. Other factors include histology, size, and the patient's age. In a Surveillance, Epidemiology, and End Results (SEER) analysis of more than 2000 patients, the five-year disease-specific survival was 84% for stage I, 75% for stage II, and 57% for advanced tumors.[20]

Complications

Complications from the treatment of vaginal cancer depend on many factors and can be divided into treatment-based and patient-based. Treatment-based factors include radiation intensity, type of surgery, and type of chemotherapy. Patient-based factors include age, hormonal status, and personal hygiene. The complications from radiation include edema, erythema, and mucositis with or without ulceration. Usually, these effects resolve within a few months after treatment. See the Toxicity and Side Effect Management section.

Deterrence and Patient Education

A cross-sectional survey of outpatient visits showed female patients with cancer have unmet sexual and vaginal health needs. Preferences for receiving sexual health information vary by age. Improved physician-patient communication, awareness, and educational resources using proven sexual health promotion strategies can help women cope with treatment side effects.[50]

Enhancing Healthcare Team Outcomes

Gynecologic cancers require an interprofessional team-based approach, especially in patients with a rare disease such as vaginal cancer. Once the diagnosis is made, coordinated care should include the involvement of social workers, nurse navigators, radiation oncologists, and gynecologic oncologists.[20]

Ideally, vaginal cancer should be reviewed at case-based conferences. Interprofessional team members can include gynecologic oncology, plastic surgery, urology, radiation oncology, and operations staff. It is essential to coordinate with outpatient nurses, clinical nurse specialists, physician assistants, administrative assistants, physical medicine and rehabilitation specialists, social workers, sexual counselors, and the cancer survivorship practice.[51]

Clinical nurse specialists assist the team by providing psychological support to the patients living with cancer and their caregivers.[52] Their role in interprofessional care has contributed successfully where medical factors (complex comorbidities) or non-medical factors (patient preference) impact treatment.[53] Nurses will assist in the evaluation and can assist during surgical procedures. They can also coordinate activities between different specialists and counsel patients. When chemotherapy is part of the treatment regimen, specialized oncology pharmacists will be a valuable asset to the team, helping to direct agent selection and dosing, performing medication reconciliation, and counseling patients on what to expect from their medication regimen.

The issue of sexuality and sexual dysfunction is important, especially with treatment for vaginal cancer. Both physical and psychological issues need to be addressed; common patient complaints include lack of sexual desire, dyspareunia, decreased sensation in the genital area, and the inability to achieve orgasm.[54] An interprofessional approach focusing on the physical and psychosexual aspects of sexuality is needed to treat sexual difficulties effectively.[55]

Pain management during and after therapy is essential, especially in light of the current opioid crisis. Communication about pain in patients with vaginal cancer should be tailored to the individual patient experience.[56] Here again, pharmacists and nurses can make significant contributions to patient care.

All care team members must maintain meticulous records so that everyone on the interprofessional team has the latest and most accurate information for patient decisions as a part of team communication. The interprofessional approach to care will yield optimal patient outcomes. [Level 5]