What are the other Names for this Condition? (Also known as/Synonyms)

• Invasive Squamous Cell Carcinoma of Vagina, Verrucous Type
• Vaginal Verrucous Squamous Cell Carcinoma
• Verrucous Type Squamous Cell Carcinoma of Vagina

What is Verrucous Carcinoma of Vagina? (Definition/Background Information)

• Squamous Cell Carcinoma (SCC) of Vagina is a rare, malignant condition affecting the skin and mucosal membranes of the vagina, generally in middle-aged and older women. A vast majority of cancers arising from the vagina are squamous cell carcinomas
• Verrucous Carcinoma of Vagina is a rare histological variant of Vaginal Squamous Cell Carcinoma. This differentiation is based on the appearance of cells when observed under a microscope by a pathologist. Verrucous carcinomas are more commonly observed to develop on the vulva (area around the external opening of the vagina)
• This sub-classification of the tumor is important, as it may dictate the type of treatment to be provided and the prognosis of the cancer. Almost all types of variants are related to human papilloma virus (HPV) infection
• Almost all vaginal cancers are believed to originate from a premalignant lesion, known as high-grade vaginal intraepithelial neoplasia (VaIN). Its association with high-risk human papilloma virus (HPV) is responsible for a transformation to squamous cell carcinomas
• This malignant carcinoma, which may be present as a lesion on the vagina, has the potential to metastasize (spread), usually to the regional lymph nodes. Most tumors are known to form in the upper one-third portion of the vagina, nearer to the uterine cervix
• If the biopsy shows Verrucous Carcinoma of Vagina; then, the tumor is staged (growth and spread of cancer is examined) and treatment options chosen, based on the staging and other factors. The treatment may involve a combination of surgery, chemotherapy, and radiation therapy
• The prognosis of Verrucous Carcinoma of Vagina depends upon a set of several factors including the stage of the tumor, age of the individual, the size of the tumor, and many other factors. In general, early detection and adequate treatment can help achieve a better outcome. The prognosis of Vaginal Verrucous Squamous Cell Carcinoma is among the best, when compared to the other SCC subtypes affecting the vagina

Who gets Verrucous Carcinoma of Vagina? (Age and Sex Distribution)

• Verrucous Carcinoma of Vagina is very rare. It usually affects women who are above the age of 50 years. Some cases have been also noted in women below 40 years
• No geographical, racial, or ethnic preference is generally noted. Nevertheless, Vaginal Squamous Cell Carcinomas affect dark-skinned women more than white-skinned women

What are the Risk Factors for Verrucous Carcinoma of Vagina? (Predisposing Factors)

Risk factors that contribute to Verrucous Carcinoma of Vagina formation include:

• Infection with human papilloma virus (HPV) types:
  • HPV infection is the most important risk factor predisposing one to cervical cancer
  • The virus is transmitted sexually
  • Different subtypes of the virus exist: Types 16, 18, 31, 33, and 45, are the high-risk types associated with cancer; of which HPV-16 is the most common type and HPV-18  the second common type
• Lack of periodic/regular Pap smear tests
• Sexual promiscuity (multiple sexual partners) and high-risk sexual behavior
• Poor immune system: HIV infection or AIDS, organ transplantation, immunosuppressant medications, greatly increase risk for chronic infection
• Smoking
• Use of oral contraceptives for long time duration
• Having the first child at a young age (before 17 years) and having had multiple pregnancies
• Presence of other sexually-transmitted infections (such as chlamydia)
• Chronic inflammation, in some cases
• A diet lacking fruits and vegetables
• Poverty or poor socio-economic status
• Cervical cancer, including precancers, can increase the risk for cancer of the vagina
• Vaginal adenosis (in rare cases): The presence of benign cervical glandular tissue or benign endometrial glandular tissue in the vaginal wall that may occurs due to various factors (such as exposure to hormones, DES, etc.). It may be idiopathic too, where the cause remains unknown
• In very rare cases, vaginal irritation caused by uterine prolapse or during treatment of the prolapse using a pessary (a medical device to support and keep the uterus in place), is known to increase the risk for vaginal cancer
• Longstanding ulcerative lichen planus of vagina

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Verrucous Carcinoma of Vagina? (Etiology)

The human papilloma virus (HPV) infection is a major cause behind the development of Verrucous Carcinoma of Vagina.

• Under normal circumstances, certain genes called tumor suppressor genes, keep a check on the growth and division of cervical cells
• HPV infection has been found to disrupt some tumor suppressor genes, thus allowing vaginal cells to grow and multiply uncontrollably

Almost all histological subtypes are rare and linked to high-risk HPV. Even more rarely, vaginal cancer can occur without a preceding HPV infection. In such cases, the cause of the condition is unknown.

Untreated (or delayed treatment of) squamous cell carcinoma in situ can result in invasive squamous cell carcinoma. Other factors that may contribute to the condition include compromised immune system, sexual promiscuity, smoking, and even poor hygiene.

What are the Signs and Symptoms of Verrucous Carcinoma of Vagina?

The signs and symptoms of Verrucous Carcinoma of Vagina may include:

• A majority are associated with abnormal vaginal bleeding, but in the absence of pain
• Abnormal vaginal discharge
• There may be pain and discomfort during sex
• The presence of a poorly-defined lesion on the vagina; the vaginal mass may be felt (palpable)
• The presence of skin ulceration is often noted, which can lead to the bleeding
• Most squamous cell carcinomas are seen in the upper vagina (top 1/3 portion)
• An outward tumor growth (exophytic) is seen in most cases; sometimes, an inward tumor growth (endophytic) that can constrict the vagina is known to occur
• Anemia (due to bleeding)
• Loss of weight, loss of appetite
• Usually, there are no symptoms, during the pre-cancer and early cancer stages (with small-sized tumors)

During the advanced stages of Verrucous Carcinoma of Vagina, the following signs and symptoms may be observed:

• Chronic pelvic pain; lower back pain
• Frequent urination
• Urinary bladder pain and blood in urine (hematuria)
• Involvement of the pelvic muscles by tumor cells can cause pain radiating along the leg
• If the urinary bladder is involved, then it may obstruct the bladder and lead to retention of urine
• Urinary retention can cause the abnormal formation of a fistula in the urogenital area (vesicovaginal fistula or even a rectovaginal fistula)
• Rectal tenesmus or the urge to keep emptying the bowel, even after it is emptied

How is Verrucous Carcinoma of Vagina Diagnosed?

Some of the tests that may help in diagnosing Verrucous Carcinoma of Vagina include:

• Evaluation of the individual’s medical history and a thorough physical examination
• Pelvic examination:
  • During a pelvic examination, the healthcare provider will exam the uterus, cervix, vagina, ovaries, fallopian tubes, bladder, and rectum to check for any abnormal changes in these organs
  • Also, during the exam, the tumor may appear as a polyp (exhibiting exophytic growth pattern), or it may appear as a firm, non-polyp area (exhibiting endophytic growth pattern)
• HPV DNA testing can be used as a tool to help screen for infections and administer vaccines

Blood tests to aid in the diagnostic process may include:

• Complete blood count (CBC) with differential of white blood cells
• Liver function test and kidney function test
• Blood tests called serum tumor markers that include:
  • CA-125 test
  • Human chorionic gonadotropin (hCG)
  • Alpha-fetoprotein (AFP)
  • Lactate dehydrogenase (LDH)
  • Inhibin (hormone)
  • Estrogen and testosterone levels

Some of the definitive tests that help in diagnosing the cancer include:

• Colposcopy:
  • The cervix (including the vagina) is examined with an instrument, called a colposcope. This helps the physician get a magnified view of the cervix
  • In order for this procedure to be performed, the individual has to lie on a table, as for a pelvic exam. An instrument, called the speculum, is placed in the vagina to keep the opening apart, in order to help the physician visualize the cervix. The colposcope is then used to get a magnified view of the inside

Although the above modalities can be used to make an initial diagnosis, a tissue biopsy of the tumor is necessary to make a definitive diagnosis to begin treatment. The tissue for diagnosis can be procured in multiple different ways which include: 

• Fine needle aspiration (FNA) biopsy of the tumor: A FNA biopsy may not be helpful, because one may not be able to visualize the different morphological areas of the tumor. Hence, a FNA biopsy as a diagnostic tool has certain limitations, and an open surgical biopsy is preferred
• Core biopsy of the tumor
• Open biopsy of the tumor

Tissue biopsy:

• A tissue biopsy of the tumor is performed and sent to a laboratory for a pathological examination. A pathologist examines the biopsy under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis. Examination of the biopsy under a microscope by a pathologist is considered to be gold standard in arriving at a conclusive diagnosis
• Biopsy specimens are studied initially using Hematoxylin and Eosin staining. The pathologist then decides on additional studies depending on the clinical situation
• Sometimes, the pathologist may perform special studies, which may include immunohistochemical stains, molecular testing, and very rarely, electron microscopic studies to assist in the diagnosis

If a diagnosis of cancer is made on biopsy, further imaging (or other) studies may be conducted. These include:

• Ultrasound scan of the abdomen
• Transvaginal ultrasound: Transvaginal ultrasound inserts an ultrasound probe into the vagina designed to take pictures of the insides of the uterus
• CT or CAT scan with contrast of the abdomen and pelvis may show a well-defined mass. This radiological procedure creates detailed 3-dimensional images of structures inside the body
• MRI scans of the abdomen and pelvis: Magnetic resonance imaging (MRI) uses a magnetic field to create high-quality pictures of certain parts of the body, such as tissues, muscles, nerves, and bones. These high-quality pictures may reveal the presence of the tumor
• X-ray of the abdomen and pelvic region
• Chest X-ray: Chest X-rays are used to detect if the cancer has spread to the lung
• Barium enema X-ray
• Vascular radiological studies of abdomen and pelvic region
• Positron emission tomography (PET scan): A PET scan is a nuclear medicine imaging technique that uses three-dimensional images to show how tissue and organs are functioning. A small amount of radioactive material is required with this test. The radioactive material may be injected into a vein, inhaled, or swallowed. It may be performed to see if the cancer has metastasized/spread to other regions
• Cystoscopy (to look at the inside of the bladder)
• Proctoscopy (to look at the inside of the rectum)
• Sometimes, an intravenous pyelogram (to find any abnormality/blockage in the urinary tract) may be conducted
• Whole body bone scan

Note: Pap smears are not helpful as screening tools for vaginal cancers, because a Pap smear examines cells from the cervix and not from the vagina. Nevertheless, regular Pap smears are still important because a healthcare provider typically performs a pelvic exam at the time of collecting a Pap smear specimen. Incidentally, during such an examination, if there is a mass in the vaginal area, it may be revealed.

Note: This subtype of vaginal SCC is known to pose diagnostic challenges.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Verrucous Carcinoma of Vagina?

The complications of Verrucous Carcinoma of Vagina could include:

• Ulceration of large tumor masses may get secondarily infected with bacteria or fungus
• The malignant lesion can invade into the adjacent tissues and structures or metastasize (commonly to the lymph nodes):
  • Tumors nearer to the cervix (in the upper portion of the vagina) may cause lymph node of the pelvis to be affected (metastatic cancer) more often, and also spread to the cervix, causing cervical cancer
  • Lower vaginal tract SCCs can cause vulvar cancers and also affect the inguino-femoral lymph nodes (located in the inside of the upper thigh)
• The cancer can also spread to distant organs, such as to the lungs, peritoneum (abdominal cavity), liver, and GI tract
• Topical therapy for initial stage cancers can result in side effects such as severe vaginal and vulvar irritations
• Side effects of chemotherapy (such as toxicity) and radiation
• Sexual dysfunction can take place as a side effect of surgery, chemotherapy, or radiation therapy
• Recurrence of the cancer following incomplete surgical removal is less commonly observed

How is Verrucous Carcinoma of Vagina Treated?

Once a diagnosis of vaginal cancer has been made, the extent to which the tumor has spread is assessed, known as staging. The staging for vaginal cancer is based upon the FIGO (International Federation of Gynecology and Obstetrics) and the AJCC (American Joint Committee on Cancer) TNM staging systems.

The TNM classification for vaginal cancer is given below:

Tumor extent (T):

• Tis: Cancer cells are only in the most superficial layer of cells of the vagina without growth into the underlying tissues. This stage is also called carcinoma in situ (CIS) or vaginal intraepithelial neoplasia 3 (VaIN 3). It is not included in the FIGO system
• T1: The cancer is only in the vagina
• T2: The cancer has grown through the vaginal wall, but not as far as the pelvic wall
• T3: The cancer is growing into the pelvic wall
• T4: The cancer is growing into the bladder or rectum or is growing out of the pelvis

Lymph node spread of cancer (N):

• N0: The cancer has not spread to lymph nodes
• N1: The cancer has spread to lymph nodes in the pelvis or groin (inguinal region)

Distant spread of cancer (M)

• M0: The cancer has not spread to distant sites
• M1: The cancer has spread to distant sites

Stage grouping: Once the T, N, and M categories have been assigned, this information is combined to assign an overall stage in a process called stage grouping. The stages identify tumors that have a similar outlook and are treated in a similar way.

Stage 0 (Tis, N0, M0):

• In this stage, cancer cells are only in the top layer of cells lining the vagina (the epithelium) and have not grown into the deeper layers of the vagina
• Cancers of this stage cannot spread to other parts of the body
• Stage 0 vaginal cancer is also called carcinoma in situ (CIS) or vaginal intraepithelial neoplasia 3 (VaIN 3)
• This stage is not included in the FIGO system

Stage I (T1, N0, M0):

• The cancer has grown through the top layer of cells but it has not grown out of the vagina and into nearby structures (T1)
• It has not spread to nearby lymph nodes (N0) or to distant sites (M0)

Stage II (T2, N0, M0):

• The cancer has spread to the connective tissues next to the vagina but has not spread to the wall of the pelvis or to other organs nearby (T2)
• The pelvis is the internal cavity that contains the internal female reproductive organs, rectum, bladder, and parts of the large intestine
• It has not spread to nearby lymph nodes (N0) or to distant sites (M0)

Stage III - either of the following:

• T3, any N, M0:
  • The cancer has spread to the wall of the pelvis (T3)
  • It may (or may not) have spread to nearby lymph nodes (any N), but it has not spread to distant sites (M0)

OR

• T1 or T2, N1, M0:
  • The cancer is in the vagina (T1) and it may have grown into the connective tissue nearby (T2)
  • It has spread to lymph nodes nearby (N1), but has not spread to distant sites (M0)

Stage IVA (T4, Any N, M0):

• The cancer has grown out of the vagina to organs nearby (such as the bladder or rectum) (T4)
• It may or may not have spread to lymph nodes (any N)
• It has not spread to distant sites (M0)

Stage IVB (Any T, Any N, M1):

• Cancer has spread to distant organs such as the lungs (M1)

(Source: “The FIGO/AJCC system for staging vaginal cancer”; information provided by the American Cancer Society, February 2016)

Vaginal cancers are treated using several methods depending on the stage of the cancer. The treatment options may include the following:

Initial stages: Stage 0 and Stage I

• Short-term topical therapy with medications (topical chemotherapy) or topical immunotherapy for small lesions on the vagina
• Partial vaginectomy (removal of the affected part of the vagina), if the tumors are not completely eliminated through topical therapy
• Intracavitary radiation therapy (known as brachytherapy), or in some cases, interstitial radiation therapy for stage I cancers that are small and confined to the vagina
• Radiation therapy may be administered following a vaginectomy (external radiation therapy)
• Total or radical vaginectomy, where the entire or a substantial portion of the vagina is removed (and followed by surgical reconstruction of the vagina), if a large portion of the vagina is affected/involved
• Cancers, nearer to the cervix (in the upper vaginal tract), may be treated through radical trachelectomy or radical hysterectomy, when required. If pelvic lymph node metastasis is noted, then the affected lymph nodes may be removed
• Surgical interventions are normally followed through by radiation therapies to destroy any remaining cancer cells in the region (post-operative radiation treatment)

Recurrent cancers are treated through radical vaginectomy or radical surgery, depending on their site of recurrence. Often, a combination of treatment measures may be used by the healthcare providers (including recommendation for clinical trials, when recurrence is associated with higher stage cancers).

Higher stages: Stage II to Stage IV

• Radiation therapy is the most frequently used treatment tool for higher stages of vaginal cancers. It may include the use of brachytherapy or external beam therapy
• Chemotherapy may be used in combination with radiation therapy, sometimes to shrink the tumor (decrease its size)
• Following this therapy, radical vaginectomy and pelvic exenteration may be employed, when necessary. However, if the cancer is greater than Stage III, then generally surgery is not undertaken
• Advanced stage tumors with metastasis may be treated on a case-by-case basis; often symptomatic treatment with radiation and/or chemotherapy is attempted

The treatment methods used to treat Verrucous Carcinoma of Vagina are explained below:

Surgery:

• Vaginectomy: It is the surgical removal of a part of the vagina (called partial vaginectomy), or the entire vagina (called total vaginectomy), or the vagina and its surrounding affected structures/tissues may also be removed (called radical vaginectomy)
• Radical trachelectomy: The surgeon removes the cervix, upper part of the vagina, and nearby lymph nodes, while preserving the ability to have children
• Hysterectomy: In this procedure, the uterus and cervix are removed. This is done by making an incision on the abdomen (termed abdominal hysterectomy), or through the vagina (termed vaginal hysterectomy), or by using a laparoscope (termed laparoscopic hysterectomy). Surgery is performed under general or epidural anesthesia, though the ability to have children is lost. Complications, such as bleeding, infection, or damage to the urinary tract, or the intestinal system may occur in rare cases
• Radical hysterectomy: The uterus, cervix, the upper part of the vagina and tissues, next to the uterus are removed. Additionally, some pelvic lymph nodes may also be surgically taken out. The surgery is performed under anesthesia and may be carried out, via an incision made on the abdomen or by using laparoscopy. With this invasive procedure, the ability to have children is lost. Rarely, complications such as bleeding, infection, or damage to the urinary tract or the intestinal system, may occur. Removal of lymph nodes may lead to swelling of legs (lymphedema)
• Hysterectomy (abdominal) with salpingo-oophorectomy: It is a surgical procedure involving the removal of the uterus, and of the fallopian tube and ovary (salpingo-oophorectomy)
• Pelvic exenteration: The entire vagina, the surrounding tissues, and the pelvic lymph nodes are removed. In addition, depending on the extent of tumor spread, parts affected around the region (such as the cervix, uterus, rectum, colon, etc.) may be removed. Recovery from this surgery usually takes a long period

Chemotherapy:

• Medications are used to kill the tumor cells, which may be given as oral pills or injected into veins
• A combination of chemotherapy medications may be used
• Chemotherapy may be used in addition to radiation and/or surgery, to treat cancers that have spread or recurred. When chemotherapy and radiation therapy are used together, it is called concurrent chemoradiation
• Side effects of chemotherapy may include nausea, vomiting, hair loss, loss of appetite, diarrhea, fatigue, increased risk of infection, mouth sores, and easy bruising, depending on the drugs used

Radiation therapy:

• This procedure uses high-energy beams to kill the cancer cells
• These beams may be delivered from outside the body (external beam radiation therapy) or the radioactive material maybe placed inside the vagina (internal radiation therapy or brachytherapy)
• Possible side effects may include:
  • Fatigue, nausea, vomiting, and diarrhea
  • Bladder irritation, leading to inflammation (cystitis)
  • Ovaries may be affected resulting in menstrual changes, or premature menopause
  • The vulva and vagina may be affected, causing soreness, or even scar tissue formation

Post-operative care is important and a minimum activity level is to be ensured, until the surgical wound heals. Also, long-term follow-up care with regular screening and check-ups are important and highly recommended.

How can Verrucous Carcinoma of Vagina be Prevented?

Squamous Cell Carcinoma of Vagina may be prevented through the timely and adequate treatment of in situ Vaginal SCC. Some steps for the prevention of Verrucous Carcinoma of Vagina may include:

• Use of measures to prevent sexually-transmitted infections, such as usage of condoms, avoiding multiple sexual partners, and circumcision in men
• Avoidance of smoking
• Regular screening to detect pre-cancers:
  • The American Cancer Society recommends screening of women from age 21 years
  • A Pap smear is recommended every 3 years, from ages 21-29 years
  • From age 30-65 years, a Pap smear and HPV testing is recommended, once every 5 years
  • More frequent screenings are advised for women having a high-risk for cervical cancer

Note: Per se, Pap smears can only help in detecting cervical cancers. They are not helpful in screening for vaginal cancers. However, since cervical cancers are much more frequently noted, early screening to detect precancers is important.

• Vaccination against human papilloma virus (HPV):
  • Two vaccines have been studied and approved for use in the United States - Gardasil (against HPV types 6, 11, 16, and 18) and Cervarix (against HPV types 16 and 18)
  • Cervarix has been approved for use in females aged 10-25 years, while Gardasil may be used in the 9-26 years age group
  • The American Cancer Society recommends routine vaccination of girls at 11-12 years of age
  • HPV vaccines are not successful against women who are already infected though

What is the Prognosis of Verrucous Carcinoma of Vagina? (Outcomes/Resolutions)

• In general, Verrucous Carcinoma of Vagina has the best prognosis (on a stage-to-stage comparison) with respect to all other histological subtypes of Vaginal Squamous Cell Carcinomas
• The survival rates are observed to be the highest among women with verrucous carcinomas. Also, following a complete excision of the tumor, recurrence or metastasis of the tumor to the lymph nodes is not typically noted
• In general, the 5-year overall survival rate was 45% (according to a study) and stage 1 tumors after 5 years showed 75% survival rate for squamous cell carcinomas affecting the vagina
• Many studies indicate that the overall survival and disease-free periods were higher for HPV-associated SCCs, than squamous cell carcinomas that were not associated with HPV, when age and stage of tumor were not considered
• The poor predictors of SCC of Vagina, considered independently, were old age, size of tumor over 4 cm, and advanced disease stage when metastasis to the regional lymph nodes (such as to the inguinal or rectovaginal lymph nodes) had occurred
• The prognosis for Verrucous Carcinoma of Vagina depends upon a set of several factors that include:
  • The size of the tumor and the extent of its invasion: Individuals with small-sized tumors fare better than those with large-sized tumors
  • Stage of cancer per FIGO (or TNM): With lower-stage tumors, when the tumor is confined to site of origin, the prognosis is usually excellent with appropriate therapy. In higher-stage tumors, such as tumors with metastasis, the prognosis is poor
  • Histological subtype of the tumor
  • Cell growth rate of the cancer
  • Overall health of the individual: Individuals with overall excellent health have better prognosis compared with those with poor health
  • Age of the individual: Older individuals generally have poorer prognosis than younger individuals
  • Individuals with bulky disease have a poorer prognosis
  • Involvement of the regional lymph nodes, which can adversely affect the prognosis
  • Involvement of vital organs may complicate the condition
  • The surgical respectability of the tumor (meaning, if the tumor can be removed completely)
  • Whether the tumor is occurring for the first time, or is a recurrent tumor. Recurring tumors have worse prognosis compared to tumors that do not recur
  • Response to treatment: Tumors that respond to treatment have better prognosis compared to tumors that do not respond to treatment
  • Progression of the condition makes the outcome worse
• An early diagnosis and prompt treatment of the tumor generally yields better outcomes than a late diagnosis and delayed treatment
• The combination chemotherapy drugs used, may have some severe side effects (like cardio-toxicity). This chiefly impacts the elderly adults, or those who are already affected by other medical conditions. Individuals, who tolerate chemotherapy sessions better, generally have better outcomes

Additional and Relevant Useful Information for Verrucous Carcinoma of Vagina:

In order to be diagnosed with Vaginal Squamous Cell Carcinoma, the World Health Organization (WHO) informs that there should be no preceding history of cancer (invasive SCC) of the cervix and/or vulva in the last 10 years (as a minimum), and there should be no present/current SCC, either affecting the cervix or vulva.