VAGINAL MALIGNANCY

Jay R. Patibandla, MD • Michael P. Hopkins, MD, MEd

 BASICS

DESCRIPTION

•  Carcinomas of the vagina are uncommon: 3% of gynecologic malignancies, 2,300 new cases annually.

•  Vaginal intraepithelial neoplasia (VAIN), defined by squamous cell atypia, is classified by the depth of epithelial involvement:

–  VAIN 1: 1/3 thickness

–  VAIN 2: 2/3 thickness

–  VAIN 3 and carcinoma in situ (CIS): >2/3 with CIS, designating full-thickness neoplastic changes without invasion through the basement membrane

•  Invasive malignancies: Vaginal malignancies include squamous cell carcinoma (85–90%), adenocarcinoma (5–10%), sarcoma (2–3%), and melanoma (2–3%). Clear cell carcinoma is a subtype of adenocarcinoma. Invasive squamous cell carcinoma has the potential for metastasis to the lungs and liver.

•  To be classified as a vaginal malignancy, only the vagina can be involved. If the cervix or vulva is involved, then the tumor is classified as a primary cancer arising from the cervix or the vulva.

•  Most vaginal malignancies are metastatic (e.g., cervix, vulva, endometrium, breast, ovary).

Pregnancy Considerations

This malignancy is not associated with pregnancy.

EPIDEMIOLOGY

Incidence

•  An estimated 4,070 new cases will be diagnosed in 2015 with 910 resulting deaths (1).

•  Predominant age

–  CIS: mid-40 to 60 years

–  Invasive squamous cell malignancy: mid-60 to 70 years

–  Adenocarcinoma: any age; 50 years is the mean age. Peak incidence is between 17 and 21 years of age.

–  Clear cell adenocarcinoma occurs most often in females <30 years with a history of exposure to diethylstilbestrol (DES) in utero.

–  Mixed müllerian sarcomas and leiomyosarcomas in the adult population: mean age 60 years

Pediatric Considerations

Vaginal tumors are extremely rare. Rhabdomyosarcoma (botryoid and embryonal subtype) is the most common malignant neoplasm of the vagina. Less common entities are germ cell tumor and clear cell adenocarcinoma.

Prevalence

In the United States, it is one of the rarest of all gynecologic malignancies (3%).

ETIOLOGY AND PATHOPHYSIOLOGY

•  Women with a history of cervical malignancy have a higher probability of developing squamous cell malignancy in the vagina even after hysterectomy.

•  Human papillomavirus (HPV) is found in 80–93% of patients with vaginal CIS and 50–65% of the patients with invasive vaginal carcinoma (2,3).

•  HPV-16 is the most common, found in 66% of CIS and 55% of invasive vaginal cancers.

•  Smokers have a higher incidence.

•  Clear cell adenocarcinoma of the vagina in young women has been associated with DES exposure. The incidence, however, is exceedingly rare, estimated at 1/1,000 to 1/10,000 exposed females.

•  Metastatic lesions can involve the vagina, spreading from the other gynecologic organs.

•  Although rare, renal cell carcinoma, lung adenocarcinoma, GI cancer, pancreatic adenocarcinoma, ovarian germ cell cancer, trophoblastic neoplasm, and breast cancer can all metastasize to the vagina.

Genetics

No known genetic pattern

RISK FACTORS

•  Similar risk factors as cervical cancer

•  Age

•  African American

•  Smoking

•  Multiple sex partners, early age of first sexual intercourse

•  History of squamous cell cancer of the cervix or vulva

•  HPV infection

•  Vaginal adenosis

•  Vaginal irritation

•  DES exposure in utero

COMMONLY ASSOCIATED CONDITIONS

Due to the field effect, patients with vaginal cancer are more likely to develop malignancy in the cervix or vulva and should be followed closely.

 DIAGNOSIS

HISTORY

•  Abnormal bleeding is the most common symptom.

•  Postcoital bleeding can result from direct trauma to the tumor.

•  Vaginal discharge

•  Dyspareunia

•  Urinary symptoms, including hematuria and increased frequency

•  Constipation

•  Pain along with symptoms and signs of hydroureter are late findings when the tumor has spread into the paravaginal tissues and extends to the pelvic sidewall.

Pediatric Considerations

In children, sarcomas can present either as a mass protruding from the vagina or as abnormal genital bleeding.

PHYSICAL EXAM

Pelvic examination

•  The vagina, uterus, adnexa (fallopian tubes and ovaries), bladder, and rectum should be evaluated for unusual changes.

•  Vaginal malignancies are found most commonly on the posterior wall in the upper 1/3 of the vagina.

DIFFERENTIAL DIAGNOSIS

•  Premalignant changes: VAIN 1, 2, 3, and CIS

•  Adequate biopsies ensure that invasive lesions are not overlooked. Invasive lesions penetrate the basement membrane and cannot be treated conservatively.

•  Other malignancies, such as endometrial, cervix, bladder, or colon cancer, can invade directly into the vagina or metastasize to the vagina.

•  In the childbearing years, trophoblastic disease should be considered.

–  The vagina is a common site of metastases; however, biopsy should typically be avoided because the implants are very vascular and may hemorrhage if sampled.

–  The clinical presentation is typically obvious so histopathologic confirmation before treatment is not required.

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

•  Pap smear may incidentally detect asymptomatic lesions.

•  Biopsy suspicious lesions

•  Chest x-ray (CXR): to evaluate for metastatic disease

•  CT scan and MRI: to evaluate the liver and retroperitoneum, especially the lymph nodes in the pelvic and periaortic area

•  PET scan detects primary and secondary metastatic lesions more often than CT scan.

ALERT

PET scan correlation with CT scan lesions strongly suggests malignancy.

Follow-Up Tests & Special Considerations

•  Lymphoscintigraphy (sentinel lymph node mapping) as part of the pretreatment evaluation can result in a change in the radiation fields and improve comprehensive treatment planning in women with vaginal cancer.

•  HPV vaccination: Implementation of prophylactic HPV vaccination could prevent ~2/3 of the intraepithelial lesions in the lower genital tract but is yet unproven.

Diagnostic Procedures/Other

•  Colposcopy with directed biopsies for small lesions

•  Wide excision under anesthesia of superficial disease may be necessary to ensure that invasive cancer is not present.

•  Cystoscopy to rule out bladder invasion

•  Proctosigmoidoscopy to rule out rectal invasion

Test Interpretation

Tumors are staged clinically:

•  Stage 0: VAIN and CIS

•  Stage I: carcinoma limited to the vaginal wall (26%)

•  Stage II: involves the subvaginal tissues but has not extended to the pelvic wall (37%)

•  Stage III: extends to the pelvic wall (24%)

•  Stage IV: extends beyond the true pelvis (13%)

–  IVa: Tumor invades bladder and/or rectal mucosa and/or direct extension beyond the true pelvis.

–  IVb: spread to distant organs

 TREATMENT

GENERAL MEASURES

Treatment methods for VAIN and CIS include the following:

•  Wide local excision

•  Partial or total vaginectomy

•  Intravaginal chemotherapy with 5% fluorouracil cream

•  Laser therapy

•  Intracavitary radiation therapy

MEDICATION

•  Imiquimod

–  In a review of the effectiveness of 5% imiquimod cream in the treatment of VAIN, the following results were reported (4)[C]:

  26–100% of patients had complete regression.

  0–60% of patients had partial regression.

  0–37% experienced recurrence.

•  Contraindications

–  The diagnosis must be established with certainty prior to treatment.

–  If there is any doubt that a process beyond in situ disease exists, vaginectomy must be performed. These patients are often elderly, and aggressive therapy is limited by the patient’s performance status and ability to tolerate radical surgery, chemotherapy, or radiation.

ISSUES FOR REFERRAL

Patients should be treated by a gynecologic oncologist and/or a radiation oncologist.

ADDITIONAL THERAPIES

•  Treatment with radiotherapy depends on the stage of disease. This treatment option should be discussed with physicians experienced with this malignancy.

•  It is common to use radiotherapy and chemotherapy (chemoradiation) for better cancer control.

•  Early-stage primary squamous cell carcinoma treated with radiation alone has shown good results (5)[A].

•  Stage III vaginal cancer may benefit from combined radiation and hyperthermia (6)[C].

•  Patients with advanced squamous cell carcinoma or adenocarcinoma receive concurrent irradiation and cisplatin-based chemotherapy (7)[B].

•  Neoadjuvant chemotherapy followed by radical surgery may benefit select patients (8)[C].

•  In most tumor types, metastatic disease from the vagina to other sites is only minimally responsive to chemotherapy.

•  With one exception, no chemotherapeutic agents have shown a survival advantage. The exception is childhood sarcomas, which have been treated with combinations of the following:

–  Vincristine

–  Dactinomycin (actinomycin-D)

–  Cyclophosphamide (Cytoxan)

–  Cisplatin

–  Etoposide (VP-16)

SURGERY/OTHER PROCEDURES

•  Whenever there is a doubt as to the presence or absence of invasive disease, vaginectomy must be performed.

•  Invasive lesions usually are treated by radiation therapy, but stage I lesions can be treated with radical hysterectomy or radical vaginectomy with pelvic lymph node dissection (9)[A].

•  If the lesion involves the lower vagina, inguinal node dissection also must be done because cancer involving the lower vagina can metastasize to the groin region.

•  Premenopausal women who desire to retain ovarian function are better candidates for radical surgery for early-stage disease, with vaginal reconstruction possible afterward.

•  Patients who have not completed their family can occasionally be treated with limited resection and localized radiation to the area.

•  Sarcomas are treated by radiation therapy followed by pelvic exenteration if persistent disease is present.

Pediatric Considerations

The treatment of vaginal tumors today mainly consists of neoadjuvant chemotherapy followed by local control with surgery or radiotherapy.

Geriatric Considerations

Older patients, many with a long history of smoking, are at a higher risk for malignancies requiring surgical treatments.

 ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

•  Patients are usually ambulatory and able to resume full activity by 6 weeks after surgery.

•  Most patients are fully active while receiving chemotherapy and radiation therapy.

Patient Monitoring

•  Pelvic examination and Pap smear every 3 months for 2 years, then every 6 months for the next 3 years and then yearly thereafter

•  Annual CXR

PATIENT EDUCATION

•  Printed patient information available from American College of Obstetricians and Gynecologists, 409 12th St., SW, Washington, DC 20024-2188; 800-762-ACOG: http://www.acog.org

•  American Cancer Society: http://www.cancer.gov

•  Medline Plus: http://www.nlm.nih.gov/medlineplus/vaginalcancer.html

PROGNOSIS

Stage and 5-year survival (10)

•  I: 77.6%

•  II: 52.2%

•  III: 42.5%

•  IVA: 20.5%

•  IVB: 12.9%

COMPLICATIONS

•  Those typically associated with major abdominal surgery or radiation therapy

•  Common complications of treatment include rectovaginal or vesicovaginal fistulas, rectal/vaginal strictures, radiation cystitis, and/or proctitis.

REFERENCES

  1.  Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.

  2.  Daling JR, Madeleine MM, Schwartz SM, et al. A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Oncol. 2002;84(2):263–270.

  3.  Smith JS, Backes DM, Hoots BE, et al. Human papillomavirus type-distribution in vulvar and vaginal cancers and their associated precursors. Obstet Gynecol. 2009;113(4):917–924.

  4.  Iavazzo C, Pitsouni E, Athanasiou S, et al. Imiquimod for treatment of vulvar and vaginal intraepithelial neoplasia. Int J Gynaecol Obstet. 2008;101(1):3–10.

  5.  Tran PT, Su Z, Lee P, et al. Prognostic factors for outcomes and complications for primary squamous cell carcinoma of the vagina treated with radiation. Gynecol Oncol. 2007;105(3):641–649.

  6.  Franckena M, van der Zee J. Use of combined radiation and hyperthermia for gynecological cancer. Curr Opin Obstet Gynecol. 2010;22(1):9–14.

  7.  Dalrymple JL, Russell AH, Lee SW, et al. Chemoradiation for primary invasive squamous carcinoma of the vagina. Int J Gynecol Cancer. 2004;14(1):110–117.

  8.  Benedetti Panici P, Bellati F, Plotti F, et al. Neoadjuvant chemotherapy followed by radical surgery in patients affected by vaginal carcinoma. Gynecol Oncol. 2008;111(2):307–311.

  9.  Tjalma WA, Monaghan JM, de Barros Lopes A, et al. The role of surgery in invasive squamous carcinoma of the vagina. Gynecol Oncol. 2001;81(3):360–365.

10.  Beller U, Benedet JL, Creasman WT, et al. Carcinoma of the vagina. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006;95(Suppl 1):S29–S42.

ADDITIONAL READING

•  Creasman WT. Vaginal cancers. Curr Opin Obstet Gynecol. 2005;17(1):71–76.

•  Fernandez-Pineda I, Spunt SL, Parida L, et al. Vaginal tumors in childhood: the experience of St. Jude Children’s Research Hospital. J Pediatr Surg. 2011;46(11):2071–2075.

•  Frumovitz M, Gayed IW, Jhingran A, et al. Lymphatic mapping and sentinel lymph node detection in women with vaginal cancer. Gynecol Oncol. 2008;108(3):478–481.

•  Gray HJ. Advances in vulvar and vaginal cancer treatment. Gynecol Oncol. 2010;118(1):3–5.

•  Hampl M, Sarajuuri H, Wentzensen N, et al. Effect of human papillomavirus vaccines on vulvar, vaginal, and anal intraepithelial lesions and vulvar cancer. Obstet Gynecol. 2006;108(6):1361–1368.

 CODES

ICD10

•  C52 Malignant neoplasm of vagina

•  D07.2 Carcinoma in situ of vagina

•  N89.3 Dysplasia of vagina, unspecified

CLINICAL PEARLS

•  Vaginal cancer is rare; 85–90% of vaginal cancers are squamous cell.

•  Vaginal malignancies are found most commonly on the posterior wall in the upper 1/3 of the vagina.

•  Most vaginal malignancies are metastatic (from cervix, vulva, endometrium, breast, or ovary).