Sections

Vaginal Cancer

Archetype D 38 regimens (Main Regimens) vaginal

Squamous cell carcinoma, adenocarcinoma, and melanoma of the vagina

DefinitionClick to collapse

Vaginal cancer is a rare gynecologic malignancy representing 1% to 2% of all gynecologic neoplasms. Vaginal carcinomas account for <1% of cancers affecting individuals assigned female at birth (AFAB) worldwide [1], [2]. The majority of invasive vaginal carcinomas are squamous cell carcinoma (SCC), which most commonly arises in the upper portion of the posterior wall of the vagina [6]. Anatomically, the vagina is divided into thirds (upper, middle, lower), and tumor site is documented accordingly. Only a minority of vaginal cancers originate in the vagina; the remaining are generally metastatic from other sites, and if vaginal lesion(s) involve the cervix or vulva, they are not considered vaginal cancer [b]. Embryologically, the proximal and intermediate thirds of the vagina derive from the Müllerian ducts, while the distal third (introitus) derives from the urogenital sinus. HPV-independent SCCs are more common in the distal vagina and often exhibit keratinizing histology [11]. Primary vaginal cancer is defined only when a prior (<5 years) history of cervical or vulvar carcinoma is excluded [VAG-A 2 of 2]. For HPV-associated precursors, the terminology includes low-grade SIL (LSIL) and high-grade SIL (HSIL), with vaginal intraepithelial lesion (VAIN) also used and graded 1, 2, or 3 [14], [15]. The risk of progression from HSIL or VAIN to invasive SCC approximates 5% [VAG-A 1 of 2]. Definitive diagnosis requires biopsy, and workup includes history and physical, pelvic examination, imaging (pelvic MRI with vaginal gel, FDG-PET/CT), and assessment of HPV and HIV status in select patients [VAG-1].

EpidemiologyClick to collapse

Vaginal cancer is a rare disease, representing 1% to 2% of all gynecologic neoplasms [1]. In 2025, an estimated 8070 new cases of vaginal and other genital cancers will be diagnosed in the United States, and 1950 people are estimated to die from the disease [2]. The age-standardized incidence rate of vaginal preinvasive neoplasia ranges between 0.5 and 1.3 per 100,000 individuals AFAB (before HPV vaccination) [5]. The risk of invasive vaginal cancer increases with age, most commonly affecting individuals AFAB over 70 years [MS-2]. Those aged 60 to 69 years are at greater risk for preinvasive neoplasia [5]. Vaginal cancer is also the most common type of metachronous malignancy after cervical cancer diagnosis, followed by vulvar and anal cancers [3]. In individuals with cervical intraepithelial neoplasia at the time of hysterectomy, the risk of contracting vaginal cancer is more than double compared to non-hysterectomized individuals [4]. The majority of invasive vaginal carcinomas are squamous cell carcinoma (SCC), accounting for 80–90% of cases [6]. The second most common type is melanoma, but management of vulvovaginal melanoma is covered in the NCCN Guidelines for Vulvar Cancer [VAG-0]. HPV-dependent SCC is more common, while HPV-independent SCC is seen in older postmenopausal individuals (median age 73 years) [VAG-A 1 of 2]. Because of the rarity of the disease, most evidence comes from retrospective or comparative studies, and phase 3 trials specifically for vaginal cancer have not been carried out [MS-1]. Incidence rates for vaginal cancer are expected to decline with HPV vaccination [8], [189], [190].

SubtypesClick to collapse

80–90% of vaginal carcinomas
HPV-associated squamous cell carcinoma

The predominant histologic type, linked to high-risk HPV infection, most commonly HPV16. These tumors typically arise in the proximal or intermediate third (Müllerian portion) of the vagina and show non-keratinizing morphology. p16 IHC is positive.

Rare; exact frequency not specified but described as 'much less common'
HPV-independent squamous cell carcinoma

Much less common, often seen in postmenopausal individuals AFAB (median age 73 years). Predominantly keratinizing type histology, negative p16, and aberrant p53 IHC [VAG-A 1 of 2]. Typically arise in the distal vagina (introitus) from urogenital sinus epithelium [11].

Very rare
HPV-associated vaginal adenocarcinoma

A rare histologic type of vaginal carcinoma associated with high-risk HPV infection. Includes variants such as endometrioid carcinoma and clear cell carcinoma.

Individually very rare; collectively account for <10%
Other rare vaginal carcinomas

Includes clear cell carcinoma, mucinous carcinoma (gastric and intestinal types), mesonephric adenocarcinoma, carcinosarcoma, mixed tumor of the vagina, adenocarcinoma of Skene gland origin, adenosquamous carcinoma, adenoid basal carcinoma, neuroendocrine carcinomas, adenosarcoma, and germ cell tumors [VAG-A 1 of 2].

Molecular PathogenesisClick to collapse

The predominant pathway for vaginal squamous cell carcinoma (SCC) and its precursors (vaginal SIL) is persistent infection with high-risk human papillomavirus (HPV) types, most commonly HPV16 [VAG-A 1 of 2], [5]. HPV16 is detected in 46% to 77% of vaginal cancers, while HPV18 is found in 3% to 27% [5]. p16 INK4A overexpression (by IHC) is a surrogate marker for HPV-associated tumors and is associated with improved survival: patients with p16-positive vaginal cancer have significantly better survival (~49.5 months) compared to p16-negative disease (~25.3 months) [39]. In HPV-independent SCC, which is less common, the key molecular event is mutation of TP53, detectable by aberrant p53 IHC or next-generation sequencing; these tumors demonstrate negative p16 and aberrant p53 IHC [VAG-A 1 of 2]. TP53 mutations are implicated in carcinogenesis of keratinizing carcinomas and are associated with increased recurrence and disease-specific mortality [43], [44]. The 2020 WHO Classification of Female Genital Tumors emphasizes distinguishing HPV-associated from HPV-independent types based on pathogenesis [11]. Comprehensive molecular profiling is recommended for recurrent, progressive, or metastatic disease, including testing for PD-L1 (CPS), microsatellite instability (MSI), tumor mutational burden (TMB), NTRK gene fusions, RET gene fusions, HER2 (IHC with or without FISH), and mismatch repair (MMR) by IHC [VAG-A 2 of 2]. TMB-high (≥10 mut/Mb) tumors and MSI-H/dMMR tumors are responsive to pembrolizumab [22], [21]. NTRK gene fusions (found in ~1% of solid tumors) can be targeted with larotrectinib, entrectinib, or repotrectinib [25], [23], [29]. RET gene fusions are rare and targetable with selpercatinib [36]. HER2 expression (IHC 3+ or 2+) is seen in a small subset and can be treated with fam-trastuzumab deruxtecan-nxki [35]. These data are primarily extrapolated from cervical cancer due to the rarity of vaginal cancer [MS-1].

Risk FactorsClick to collapse

Persistent high-risk HPV infection

HPV16 is the most common type (46–77% of vaginal cancers; 49–81% of VaIN 2/3). HPV18 is detected in 3–27% of vaginal cancers. HPV infection is the predominant pathway for vaginal SIL and SCC.

Cigarette smoking

History of smoking is a shared risk factor with cervical cancer. Smoking cessation is recommended.

Prior hysterectomy

Particularly if hysterectomy was performed for cervical intraepithelial neoplasia, risk is more than doubled.

Immunosuppression

Includes chronic immunosuppression from autoimmune diseases or HIV. HIV testing is recommended in select patients (especially younger).

Prior cervical cancer or vulvar cancer

Vaginal cancer is the most common metachronous malignancy after cervical cancer. Must be excluded as a secondary primary (prior <5 years).

Sexual behavior

Early age of onset of coitus, larger number of sexual partners, history of sexually transmitted disease.

Parity and oral contraceptive use

Higher parity and oral contraceptive use are associated with increased risk.

Other suggested factors

Vaginal damage from ring pessaries, chronic vaginitis, birthing trauma, obesity, exposure to chemicals in the vagina.

Clinical FeaturesClick to collapse

Typical Presentation

Vaginal cancer is a rare gynecologic malignancy, representing 1%–2% of all gynecologic neoplasms and <1% of cancers in individuals assigned female at birth (AFAB) worldwide [VAG-A 1 of 2], [MS-1]. The most common histology is squamous cell carcinoma (80%–90%), typically arising in the upper posterior vagina and predominantly associated with high-risk HPV (most frequently HPV16) [MS-2]. HPV-independent squamous cell carcinomas are less common, occurring in older postmenopausal women (median age 73 years) with keratinizing histology and aberrant p53 [VAG-A 1 of 2]. The classic presentation includes abnormal vaginal bleeding (postmenopausal, postcoital, or intermenstrual), vaginal discharge (often watery or blood-tinged), urinary symptoms (retention, frequency, dysuria), and rectal symptoms (constipation, tenesmus, hematochezia) [MS-3]. However, up to 20% of patients may be asymptomatic, with disease discovered incidentally during pelvic examination, cervical cytology, or colposcopy [MS-3]. A thorough history often reveals cofactors such as prior hysterectomy, immunosuppression, smoking, or a history of cervical cancer; vaginal cancer is frequently a metachronous or synchronous tumor with cervical, vulvar, or anorectal primaries [VAG-1]. Importantly, only a minority of vaginal cancers originate in the vagina; the remainder are metastatic from other sites, and if the lesion involves the cervix or vulva, it is not considered primary vaginal cancer [VAG-1].

Symptoms

Most common (estimated >50% of symptomatic patients)
Abnormal vaginal bleeding

Postmenopausal bleeding, postcoital spotting, or intermenstrual bleeding; the most common presenting symptom.

Common (up to 30–40%)
Vaginal discharge

Watery, serosanguinous, or foul-smelling discharge.

Less common (15–25%)
Urinary symptoms

Frequency, urgency, dysuria, or urinary retention due to tumor compression or invasion.

Less common (10–20%)
Rectal symptoms

Constipation, tenesmus, or blood per rectum from posterior wall involvement.

Variable (may indicate advanced disease)
Pelvic pain or pressure

Dull ache or pressure in the pelvis, sometimes radiating to the back.

Up to 20% of patients
Asymptomatic

No symptoms; discovered on routine pelvic exam, Pap smear, or colposcopy.

Signs

Most common
Visible vaginal lesion

Exophytic mass, ulceration, or induration on speculum examination; may be friable.

Common in stage II or higher
Palpable mass on bimanual exam

Firm or irregular mass felt through the vaginal wall; may extend to paravaginal tissues.

Less common (advanced disease)
Rectovaginal findings

Thickening or fixation of rectovaginal septum on rectovaginal exam; may indicate posterior invasion.

Variable (10–30% at diagnosis)
Inguinal or pelvic lymphadenopathy

Palpable enlarged nodes in groin (distal vaginal tumors) or pelvic sidewall (proximal tumors).

Red FlagsClick to collapse

InvestigationsClick to collapse

Diagnostic

History and physical (H&P) including sexual history, smoking, prior hysterectomy, gynecologic and anorectal symptoms

Identify risk factors, potential synchronous primaries, and metastatic sources.

Pelvic exam (bimanual and rectovaginal), cervical evaluation and Pap smear, colposcopy, vulvar evaluation

Assess local extent, visualize lesion, and rule out cervical or vulvar primary.

Examination under anesthesia (EUA) with biopsies (consider cystoscopy/proctoscopy as clinically indicated)

Gold standard for diagnosis; allows thorough palpation and directed biopsies; assess bladder/rectal invasion.

Complete blood count (CBC) and comprehensive metabolic panel (CMP)

Baseline assessment; identify anemia, renal/hepatic dysfunction, or hydronephrosis.

HPV and HIV testing in select patients

HPV testing aids classification (HPV-associated vs. independent); HIV testing recommended especially in younger patients.

Smoking cessation counseling and assessment for distress

Smoking is a risk factor; distress screening (including social determinants of health) is recommended per NCCN Guidelines.

Staging

Pelvis MRI with and without IV contrast and vaginal gel (preferred for local disease extent)

Superior soft tissue resolution to assess tumor size, invasion into paravaginal tissues, pelvic sidewall, bladder, and rectum.

Neck/chest/abdomen/pelvis/groin FDG-PET/CT (preferred) or chest/abdomen/pelvis CT with contrast

Evaluate for metastatic disease in lymph nodes (pelvic, inguinal, para-aortic) and distant organs.

Other imaging as indicated by symptomatology (e.g., bone scan, brain MRI)

Directed evaluation for specific symptoms suggesting metastases.

Biomarkers

p16 immunohistochemistry (IHC) or RNA in situ hybridization (ISH) or DNA sequencing to determine HPV status

Classify tumor as HPV-associated (p16 positive) vs. HPV-independent; p16 positivity is a strong prognostic factor for improved survival.

p53 IHC (or next-generation sequencing as alternative) to determine TP53 status

Aberrant p53 is characteristic of HPV-independent vaginal carcinomas (often keratinizing) and associated with worse prognosis.

PD-L1 IHC (combined positive score [CPS])

Predicts response to pembrolizumab and other checkpoint inhibitors; required for first-line and second-line immunotherapy eligibility.

HER2 IHC (with reflex to FISH if equivocal)

HER2 overexpression (IHC 3+ or 2+) may guide treatment with fam-trastuzumab deruxtecan-nxki.

Comprehensive molecular profiling (FDA-approved or CLIA-validated) including at least MSI, TMB, NTRK, RET

Identify rare pan-tumor targetable alterations (MSI-H/dMMR, TMB-H ≥10 mut/Mb, NTRK fusions, RET fusions) that qualify for specific therapies.

Mismatch repair (MMR) IHC (consider)

MMR deficiency (dMMR) leads to MSI-H, another predictor of pembrolizumab response.

StagingClick to collapse

AJCC Cancer Staging Manual, 8th Edition (2017) with corresponding FIGO 2009 stages; clinical staging is used primarily [ST-1], [MS-4].

T Categories

StageDescription
TXPrimary tumor cannot be assessed.
T0No evidence of primary tumor.
T1 (FIGO I)Tumor confined to the vagina.
T1a (FIGO I)Tumor confined to the vagina, measuring ≤2.0 cm.
T1b (FIGO I)Tumor confined to the vagina, measuring >2.0 cm.
T2 (FIGO II)Tumor invading paravaginal tissues but not to pelvic sidewall.
T2a (FIGO II)Tumor invading paravaginal tissues but not to pelvic wall, measuring ≤2.0 cm.
T2b (FIGO II)Tumor invading paravaginal tissues but not to pelvic wall, measuring >2.0 cm.
T3 (FIGO III)Tumor extending to the pelvic sidewall* and/or causing hydronephrosis or nonfunctioning kidney. *Pelvic sidewall defined as muscle, fascia, neurovascular structures, or skeletal portions of bony pelvis; on rectal examination, no cancer-free space between tumor and pelvic sidewall.
T4 (FIGO IVA)Tumor invading the mucosa of the bladder or rectum and/or extending beyond the true pelvis (bullous edema is not sufficient evidence to classify as T4).

N Categories

StageDescription
NXRegional lymph nodes cannot be assessed.
N0No regional lymph node metastasis.
N0(i+)Isolated tumor cells in regional lymph node(s) no greater than 0.2 mm.
N1 (FIGO III)Pelvic or inguinal lymph node metastasis.

M Categories

StageDescription
M0No distant metastasis.
M1 (FIGO IVB)Distant metastasis.

Stage Groupings

GroupCriteriaClinical MeaningFive Yr SurvivalTreatment Intent
I (FIGO I)T1 N0 M0Tumor confined to the vagina without nodal or distant spread.5-year disease-specific survival (DSS) approximately 85% for patients treated with definitive radiation [1]. P16-positive tumors have significantly improved survival (~49.5 months vs. 25.3 months for p16-negative) [39].Curative
II (FIGO II)T2 N0 M0Tumor invades paravaginal tissues but not pelvic sidewall; nodes negative.5-year DSS approximately 78% [1].Curative
III (FIGO III)T3 N0 M0 OR T1–3 N1 M0Tumor extends to pelvic sidewall and/or causes hydronephrosis, OR any tumor with pelvic/inguinal nodal metastasis.5-year DSS approximately 58% for stage III–IVA combined [1]. Concurrent chemoradiation improves median OS (56.2 months vs. 41.2 months with RT alone) [3]. Brachytherapy reduces risk of death (HR 0.77) [5].Curative
IVA (FIGO IVA)T4 Any N M0Tumor invades bladder or rectal mucosa or extends beyond true pelvis; nodes may be involved.Included in stage III–IVA survival data above; outcomes poorer than earlier stages.Curative (definitive chemoradiation with brachytherapy preferred; surgery reserved for select cases)
IVB (FIGO IVB)Any T Any N M1Distant metastasis (including para-aortic nodes beyond pelvis, lung, liver, bone).Rarely curable; 5-year survival low (estimated <15% based on extrapolation from cervical cancer); median OS with modern systemic therapy approximately 12–16 months.Palliative (systemic therapy ± local treatment for limited disease; best supportive care)

Staging Pearls

  • Staging is primarily clinical (FIGO 2009) based on physical exam, biopsy, and imaging; surgical staging is not standard but lymph node assessment may be performed in select surgical cases [MS-4].
  • Pelvic sidewall involvement must be confirmed by rectovaginal exam with no cancer-free space between tumor and sidewall [ST-1].
  • Hydronephrosis or nonfunctioning kidney alone qualifies as T3, even without palpable sidewall fixation.
  • Bulious edema of bladder or rectum is NOT sufficient for T4; frank mucosal invasion is required [ST-1].
  • N1 includes both pelvic and inguinal nodes; isolated tumor cells ≤0.2 mm are classified as N0(i+).
  • MRI with vaginal gel is preferred for assessing local tumor extent; FDG-PET/CT is preferred for nodal and distant staging [VAG-B].
  • HPV-associated (p16+) tumors have better prognosis than HPV-independent (p53 aberrant) tumors regardless of stage [39], [VAG-A].
  • Overall treatment time for radiation should not exceed 8 weeks; brachytherapy improves survival across all stages and should be used when feasible [VAG-C 1 of 7], [5].
  • For early-stage (I–II) small lesions (<2 cm, thickness ≤5 mm), intracavitary brachytherapy alone may be sufficient; otherwise combine EBRT and brachytherapy [VAG-2].
  • Concurrent platinum-based chemotherapy (cisplatin preferred) improves outcomes in stage II–IVA disease but must be used with caution in frail/elderly patients [VAG-2].

Management PrinciplesClick to collapse

Vaginal cancer is a rare gynecologic malignancy representing 1%–2% of all gynecologic neoplasms, with an estimated 8070 new cases and 1950 deaths in the US in 2025 [MS-1]. The majority of invasive vaginal carcinomas are squamous cell carcinoma (SCC), accounting for 80%–90% of cases, most commonly arising in the upper portion of the posterior wall [MS-1]. Persistent infection with high-risk HPV, particularly HPV16 (46%–77% of cases), is a major etiologic factor [MS-2]. Treatment philosophy emphasizes a multimodal approach, with radiation therapy (RT) preferred over surgery as primary treatment due to improved organ preservation [VAG-2; VAG-C 1]. For the majority of vaginal cancers, definitive management includes either concurrent pelvic chemoradiation (platinum-based) plus brachytherapy or external beam RT (EBRT) plus brachytherapy [VAG-C 1]. The addition of brachytherapy to EBRT is preferred as the combination has been shown to improve control [VAG-C 1]. Surgical resection is considered only for select cases where complete resection with clear margins is feasible without excessive morbidity and with likelihood that no adjuvant RT would be required [VAG-E]. Overall treatment time should not extend beyond 8 weeks, and treatment delays/interruptions must be minimized [VAG-C 1].

curative

Stage I–IVA (invasive disease)

Radiation therapy (RT) is the primary modality, with options including intracavitary brachytherapy alone for select favorable cases (small lesions <2 cm, thickness ≤5 mm), EBRT + brachytherapy ± concurrent platinum-containing chemotherapy, or surgical resection ± lymph node assessment only for select cases. For stage II–IVA, chemoradiation (platinum-based) with brachytherapy is preferred [VAG-2].

curative/palliative

Locoregional recurrence (no prior RT, recurrence outside prior RT field, prior intracavitary brachytherapy only, or prior EBRT ± brachytherapy)

Options include EBRT ± brachytherapy, chemoradiation ± brachytherapy, individualized EBRT ± systemic therapy, pelvic exenteration ± IORT, reirradiation, limited excision, systemic therapy, or best supportive care, depending on prior treatment and disease location [VAG-5].

palliative

Stage IVB or recurrent distant metastases

Systemic therapy ± palliative RT and best supportive care. For limited disease, consider local treatment of primary (chemoradiation ± brachytherapy, surgery, EBRT, or ablative therapies) and/or metastases. For disseminated disease, systemic therapy ± palliative RT and best supportive care [VAG-6].

Multidisciplinary expertise is recommended. Consider referral to a center of expertise that specializes in the treatment of vaginal cancers [VAG-1].

Mdt Requirements

Chemoradiation may not be suitable for all patients. It should be used with caution in patients who are older, frail, and/or have multiple comorbidities [VAG-2].

Performance Status Guide

Management PathwaysClick to collapse

Invasive Vaginal Cancer – Stage I (confined to vagina)

Branching: Tumor size and thickness, Surgical candidacy

Stage I, small lesions <2 cm and limited thickness (≤5 mm)
Intracavitary brachytherapy alone (select favorable cases) (preferred); EBRT + brachytherapy ± concurrent platinum-containing chemotherapy (alternative); Surgical resection ± lymph node assessment (select cases only) (alternative)
Postoperative risk factors determine adjuvant therapy: if negative margins and negative lymph nodes (if removed), observe; if close or positive margins for invasive disease or positive lymph nodes, adjuvant RT or chemoradiation and/or brachytherapy [VAG-3].
Stage I, lesions >2 cm or not meeting favorable criteria
EBRT + brachytherapy (interstitial if >0.5 cm residual at brachytherapy) ± concurrent platinum-containing chemotherapy (preferred); Surgical resection ± lymph node assessment (select cases only) (alternative)
Same as above: observe if negative margins/negative nodes; adjuvant RT/chemoradiation if close/positive margins or positive nodes [VAG-3].
Invasive Vaginal Cancer – Stage II–IVA (locally advanced)

Branching: Tumor invasion, Performance status, Surgical candidacy

Stage II–IVA
Concurrent platinum-containing chemoradiation + brachytherapy (preferred); EBRT + brachytherapy (without chemotherapy) (alternative)
Adjuvant Therapy Based on Postoperative Risk Factors

Branching: Margin status, Lymph node status

Negative margins and negative lymph nodes (if removed)
Observe (preferred)
Close or positive margin(s) for invasive disease or positive lymph nodes
Adjuvant RT or chemoradiation and/or brachytherapy (preferred)
Locoregional Recurrence – No Prior RT or Recurrence Outside Prior Radiated Field

Branching: Prior RT history, Location relative to prior field

No prior RT or recurrence outside previously radiated field
EBRT ± brachytherapy (option); Chemoradiation ± brachytherapy (option)
Locoregional Recurrence – Prior Intracavitary Brachytherapy Only

Branching: Prior treatment modality

Prior intracavitary brachytherapy only
Individualized EBRT ± systemic therapy ± interstitial brachytherapy (option); Systemic therapy (option); Best supportive care (option)
Locoregional Recurrence – Prior EBRT ± Brachytherapy

Branching: Central vs noncentral disease, Patient selection

Central disease (within previously irradiated central pelvis)
Pelvic exenteration ± intraoperative RT (IORT) (option); Consider reirradiation ± interstitial brachytherapy ± surgery (option); Limited (less than exenteration) excision (carefully selected patients) (option)
Noncentral disease (outside central pelvis, lateral pelvic sidewall, etc.)
Systemic therapy (option); Resection ± IORT (option); Reirradiation (option); Best supportive care (option)
Stage IVB or Recurrent Distant Metastases

Branching: Disease extent (limited vs disseminated), Biomarkers

Limited disease (oligometastatic, potentially amenable to local therapy)
Systemic therapy (preferred); Consider local treatment of primary (chemoradiation ± brachytherapy, surgery, individualized EBRT) or local ablative therapies (radiofrequency ablation, cryoablation, SBRT) (consider); Best supportive care (option)
Disseminated disease (widespread metastases)
Systemic therapy ± palliative RT (preferred); Best supportive care (option)

Pretreatment EvaluationClick to collapse

History & Physical
History and physical including sexual history, immunosuppression, prior hysterectomy, smoking history, gynecologic and anorectal symptoms [VAG-1]
Recommended
Pelvic exam (bimanual and rectovaginal), cervical evaluation and pap smear, colposcopy, vulvar evaluation [VAG-1]
Recommended
Consider examination under anesthesia (EUA) with biopsies (consider cystoscopy/proctoscopy) as clinically indicated [VAG-1]
Consider
Imaging
Pelvis MRI with vaginal gel to assess local disease extent (preferred) [VAG-B]
Preferred
Neck/chest/abdomen/pelvis/groin FDG-PET/CT (preferred) or chest/abdomen/pelvis CT to evaluate for metastatic disease [VAG-B]
Preferred
Other initial imaging based on symptomatology and clinical concern for metastatic disease [VAG-B]
As indicated
Laboratory & Pathology
Complete blood count (CBC), comprehensive metabolic panel (CMP) [VAG-1]
Recommended
HPV and HIV testing in select patients (consider HIV testing especially in younger patients) [VAG-1]
Consider
Smoking cessation and counseling intervention if indicated [VAG-1]
Recommended
Assess for distress; refer to NCCN Distress Thermometer and Problem List including social determinants of health [VAG-1]
Recommended
Rule out synchronous anorectal, cervical, endometrial, or vulvar primary with vaginal metastasis or extension, or recurrent disease from prior malignancy [VAG-1]
Essential
Pathologic Assessment
Procedure type (biopsy, local excision, partial vaginectomy, radical vaginectomy, trachelectomy) [VAG-A 2]
Document
Tumor site (upper, middle, or lower third) and size (greatest dimension plus two additional) [VAG-A 2]
Document
Histologic types: HPV-associated SCC, HPV-independent SCC, adenocarcinomas, etc. [VAG-A 2]
Report
Histologic grade (well, moderately, poorly differentiated), LVSI, precursor lesions (VAIN/SIL), surgical margin status, determination of primary site (exclude prior cervical/vulvar carcinoma <5 years) [VAG-A 2]
Document
Ancillary testing: HPV status (p16 IHC or RNA ISH or DNA sequencing), p53 IHC for HPV-negative tumors (NGS alternative), consider PD-L1 IHC for recurrent/progressive/metastatic disease, HER2 IHC (±FISH for equivocal) for advanced/recurrent/metastatic disease, consider comprehensive molecular profiling (MSI, TMB, NTRK, RET, MMR by IHC) [VAG-A 2]
Recommended

SurgeryClick to collapse

Surgery is not often utilized as primary treatment for vaginal cancer; radiation is preferred due to improved organ preservation. Surgery is only recommended if a complete resection with clear margins is feasible without excessive morbidity and with likelihood that no adjuvant RT would be required. Definitive surgical management is limited to select cases, and the alternative of radiation should always be considered [VAG-E].

Surgical Role

Patients should be evaluated by a gynecologic oncologist prior to any surgical treatment for vaginal cancer [VAG-E].

Examination under anesthesia (EUA) may be helpful to confirm diagnosis, obtain adequate tissue sampling for histologic evaluation and comprehensive molecular profiling (e.g., PD-L1), and assess extent of disease. Consider cystoscopy and proctoscopy concurrently to exclude bladder/rectal invasion. Perform evaluation of cervix and vulva to exclude other primary sites [VAG-E].

In premenopausal patients, ovarian preservation or transposition should be considered when feasible [VAG-E].

Fiducial markers may be placed to define the extent of vaginal lesion [VAG-E].

For microscopic lesions at the top of the vagina, upper vaginectomy ± hysterectomy may be reasonable. A radical hysterectomy may be appropriate for macroscopic lesions (<2 cm) [VAG-E].

For proximal lesions involving the upper two thirds of the vagina, pelvic lymph nodes should be assessed. For distal lesions involving the lower one third, inguinal lymph nodes should be assessed [VAG-E].

Vaginal reconstruction should be considered for appropriate candidates desiring such procedures [VAG-E].

Every effort should be made to obtain negative margins [VAG-E].

Pelvic exenteration may be considered for recurrent or persistent disease localized to the pelvis or when primary RT is not feasible [VAG-E].

Procedures

Upper vaginectomy ± hysterectomy

Microscopic lesions at the top of the vagina

Radical hysterectomy

Macroscopic lesions <2 cm

Partial vaginectomy

Small lesions with expected negative margins

Radical vaginectomy

Selected primary or recurrent disease without bladder/rectal invasion

Pelvic exenteration (anterior, posterior, or total)

Recurrent/persistent disease localized to pelvis or when primary RT not feasible

Radiation TherapyClick to collapse

Radiation is the primary treatment modality for most vaginal cancers due to improved organ preservation. Definitive management consists of either concurrent pelvic chemoradiation (platinum-based) plus brachytherapy or EBRT plus brachytherapy. The addition of brachytherapy to EBRT is preferred as the combination improves disease control. Overall treatment time should not exceed 8 weeks [VAG-C 1].

Principles

  • Brachytherapy is an essential component of definitive therapy; it improves survival when added to EBRT [VAG-C 1; VAG-C 3].
  • Image-guided adaptive brachytherapy (IGABT) is strongly encouraged, with adaptation of volumes as tumor responds [VAG-C 3].
  • Treatment delays/interruptions must be minimized [VAG-C 1].
  • For very-early-stage (<5 mm) not requiring EBRT, intracavitary brachytherapy alone may be used [VAG-C 3].
  • For postoperative cases with close/positive margins, EBRT boost (54–60 Gy) or brachytherapy boost can be given [VAG-C 1].
  • External beam boost (IMRT) may be used if brachytherapy is not feasible, aiming for total dose 65–70 Gy with careful OAR constraints [VAG-C 4].

Dose Frameworks

NameTotal DoseDose Per FractionFractionsScheduleIndication
EBRT (IMRT) – Whole pelvis45–50 Gy1.8–2.0 Gy25–28Daily, 5 days/weekPrimary pelvic irradiation for stage I–IVA disease [VAG-C 1]
EBRT boost to involved nodes55–70 Gy EQD2Variable (SIB or sequential)VariableIntegrated or sequentialGross nodal disease [VAG-C 1]
Postoperative EBRT boost (close/positive margins)54–60 Gy to postoperative bed1.8–2.0 Gy27–30DailyAfter surgical resection with close/positive margins [VAG-C 1]
Brachytherapy – Intracavitary alone (early stage, <5 mm)50–60 Gy EQD2 (HDR) or 60–70 Gy EQD2 (LDR) to vaginal surface5 Gy x 8 fx or 8 Gy x 5 fx (HDR)8 or 5Twice per weekVery early stage I, tumor <5 mm, no EBRT [VAG-C 3]
Brachytherapy – After 45 Gy EBRT (invasive disease)70–80 Gy EQD2 to HR-CTV (α/β=10)4.5–5.5 Gy x 5 fx (common HDR)5 (or alternative: 7 Gy x 3 fx, 3 Gy x 9–10 fx)Variable, typically weeklyStage I–IVA after EBRT; lower doses (70–75 Gy) for lower vagina, higher (75–80 Gy) for upper vagina; up to 85 Gy for bulky/poorly responsive [VAG-C 3]
Reirradiation (IORT)Single focused dose (varies per technique)Single fraction1Delivered during surgeryRecurrent disease in previously irradiated volume; highly selected [VAG-C 4]
Reirradiation (other techniques – SBRT, IMRT, proton, interstitial brachytherapy)IndividualizedVariableVariableIndividualizedHighly selected cases; depends on previous RT dose, overlap, time interval [VAG-C 4]

Approaches

NameDose FractionationConcurrent ChemotherapyIndicationKey TrialToxicities
Concurrent chemoradiation + brachytherapyEBRT 45–50 Gy + brachytherapy boost to 70–80 Gy EQD2Cisplatin 40 mg/m2 weekly (or carboplatin if cisplatin intolerant) [VAG-2; VAG-D]Preferred for stage II–IVA; also for select stage I and locoregional recurrence without prior RTData from cervical cancer extrapolation; NCCN recommends based on series showing improved outcomes [MS-10; MS-13]Acute: GI, GU, hematologic; late: fibrosis, vaginal atrophy, fistula, secondary cancer risk
EBRT alone + brachytherapy (without chemotherapy)EBRT 45–50 Gy + brachytherapy to 70–80 Gy EQD2NoneAlternative for patients not suitable for chemoradiation (older, frail, comorbidities) [VAG-2]Retrospective series: Frank et al. 5-year DSS 85% stage I, 78% stage II, 58% stage III–IVA [VAG-C ref 1]Similar to chemoradiation but less acute toxicity; late effects possible
Intracavitary brachytherapy alone50–60 Gy EQD2 (HDR) or 60–70 Gy EQD2 (LDR) to vaginal surface; e.g., 5 Gy x 8 fx or 8 Gy x 5 fx [VAG-C 3]NoneEarly stage I, tumor <2 cm, thickness ≤5 mm, favorable [VAG-2]LDR data: improved outcomes with 60–70 Gy EQD2 [VAG-C 3]; HDR data variedVaginal mucositis, stenosis, sexual dysfunction
Reirradiation (IORT, SBRT, interstitial)Individualized (IORT: single dose; SBRT: 3–5 fractions; interstitial: variable)May or may not be givenLocoregional recurrence after prior RT; central or noncentral disease; carefully selected patients [VAG-5; VAG-C 4]Retrospective series show feasibility [VAG-C ref 5; MS-22]High risk of late toxicity (fibrosis, necrosis, fistula); must balance with tumor control
External beam boost (IMRT) as brachytherapy alternativeTotal dose 65–70 Gy to tumor; EQD2 similar to brachytherapy [VAG-C 4]May be given with platinum agentPatients who are poor candidates for brachytherapy or tumors very close to rectum/anus [VAG-C 4]No direct trial; based on dosimetric comparisonPotential increased rectal/bladder toxicity if not carefully planned

Systemic TherapyClick to collapse

Systemic therapy recommendations for primary vaginal cancer are extrapolated from cervical cancer due to similar disease etiologies and rarity of vaginal cancer. There are no category 1 recommendations for vaginal cancer. All recommendations are category 2A unless otherwise indicated [VAG-D 1]. The majority of cases in the vagina might be arising from another site, in which case refer to corresponding NCCN Treatment Guidelines [VAG-D 1]. An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy [VAG-D 1A]. For immunotherapy regimens, also refer to NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities [VAG-D 1A]. For DPYD testing, see NCCN Guidelines for Colon Cancer [VAG-D 1A].

Chemoradiation (primary treatment for stage I–IVA and select recurrence)
Concurrent platinum-based chemoradiation improves outcomes compared to RT alone; extrapolated from cervical cancer trials showing 30%–50% risk reduction [MS-13]. Cisplatin is the preferred radiosensitizing agent [VAG-2].
Preferred: Cisplatin (single agent) weekly during EBRT, or carboplatin if cisplatin intolerant [VAG-D 1]
First-line therapy for recurrent or metastatic disease
Based on KEYNOTE-826 trial in cervical cancer showing improved PFS and OS with pembrolizumab added to chemotherapy ± bevacizumab in PD-L1–positive patients [MS-14]. ORR 68.1% vs 50.2%; median OS 28.6 vs 16.5 months in PD-L1–positive [MS-14].
Preferred: For PD-L1–positive tumors (CPS ≥1): Cisplatin/Paclitaxel + Pembrolizumab ± Bevacizumab OR Carboplatin/Paclitaxel + Pembrolizumab ± Bevacizumab [VAG-D 1]
Second-line or subsequent therapy for recurrent or metastatic disease
KEYNOTE-158 and other studies showed durable responses in biomarker-selected populations; tumor-agnostic approvals [MS-16].
Preferred: Pembrolizumab (for TMB-H ≥10 mut/Mb, MSI-H/dMMR, or PD-L1–positive tumors) [VAG-D 1]

Key Regimens

Cisplatin (for chemoradiation)
Cisplatin 40 mg/m2 IV Weekly during RT
Carboplatin (for chemoradiation, cisplatin intolerant)
Carboplatin AUC 2 IV Weekly during RT
Cisplatin/Paclitaxel + Pembrolizumab ± Bevacizumab
Pembrolizumab 200 mg (or 400 mg q6w) IV (or SC as pembrolizumab/berahyaluronidase) Day 1 + Cisplatin 50 mg/m2 IV Day 1 (or 2) + Paclitaxel 175 mg/m2 IV Day 1 + Bevacizumab 15 mg/kg IV Day 1
Carboplatin/Paclitaxel + Pembrolizumab ± Bevacizumab
Pembrolizumab 200 mg (or 400 mg q6w) IV or SC Day 1 + Carboplatin AUC 5 IV Day 1 + Paclitaxel 175 mg/m2 IV Day 1 + Bevacizumab 15 mg/kg IV Day 1
Cisplatin/Paclitaxel + Bevacizumab (without immunotherapy)
Cisplatin 50 mg/m2 IV Day 1 + Paclitaxel 175 mg/m2 IV Day 1 + Bevacizumab 15 mg/kg IV Day 1
Pembrolizumab monotherapy (for TMB-H, MSI-H/dMMR, or PD-L1+ second-line)
Pembrolizumab 200 mg q3w or 400 mg q6w IV or SC Day 1
Tisotumab vedotin-tftv
Tisotumab vedotin-tftv 2 mg/kg IV Day 1
Cemiplimab
Cemiplimab 350 mg q3w IV Day 1
Ipilimumab + Nivolumab
Nivolumab 3 mg/kg q2w + Ipilimumab 1 mg/kg q6w OR Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg q3w x4 then Nivolumab 240 mg q2w IV Variable
Fam-trastuzumab deruxtecan-nxki (for HER2+ IHC 3+ or 2+)
Fam-trastuzumab deruxtecan-nxki 5.4 mg/kg IV Day 1
Selpercatinib (for RET gene fusion)
Selpercatinib 160 mg PO Twice daily
Larotrectinib (for NTRK gene fusion)
Larotrectinib 100 mg PO Twice daily
Entrectinib (for NTRK gene fusion)
Entrectinib 600 mg PO Once daily
Repotrectinib (for NTRK gene fusion)
Repotrectinib 160 mg PO Once daily

Treatment Response AssessmentClick to collapse

Title

Post-Treatment Response Assessment and Surveillance

Timing

Post-treatment imaging at 3–4 months after completion of treatment to assess response [VAG-4]. If prior RT, FDG-PET/CT (preferred) at 3–4 months after RT [VAG-B]. Further imaging as indicated based on symptoms or examination findings suspicious for recurrence [VAG-4].

Response Logic

  • Early post-treatment imaging is generally performed approximately 3–4 months after completion of chemoradiation to assess response; principles are largely analogous to cervical cancer [MS-11].

  • Recurrences should be proven by biopsy before proceeding to treatment planning [VAG-4].

  • Clinical evaluation and management of potential long-term and late effects of treatment and patient education is important [VAG-4]. Patient education should include symptoms of potential recurrence, lifestyle, obesity, exercise, sexual health (including vaginal dilator use, lubricants/moisturizers, and local estrogen and hormone therapy for menopause), smoking cessation, and nutrition counseling [VAG-4].

  • For patients with persistent or recurrent disease, additional imaging studies as clinically indicated, biopsy with or without EUA, and surgical exploration in selected cases followed by therapy for relapse [MS-11].

Imaging Recommendations

  • FDG-PET/CT (preferred) at 3–4 months after RT [VAG-B].

  • MRI abdomen/pelvis and chest CT or chest/abdomen/pelvis CT if unable to obtain FDG-PET/CT or needed for clarification of FDG-PET/CT or exam findings [VAG-B].

  • Repeat imaging if clinically indicated [VAG-B].

  • For initial workup: pelvic MRI with vaginal gel (preferred) and neck/chest/abdomen/pelvis/groin FDG-PET/CT (preferred) or chest/abdomen/pelvis CT to evaluate for metastatic disease [VAG-B].

Biopsy Or Salvage Logic

  • Any clinically suspected recurrence must be biopsied to confirm local and/or distant recurrence before proceeding to treatment planning [VAG-4].

  • For locoregional recurrence: if no prior RT or recurrence outside prior field, offer EBRT ± brachytherapy or chemoradiation ± brachytherapy. If prior brachytherapy only, individualized EBRT ± systemic therapy ± interstitial brachytherapy. If prior EBRT ± brachytherapy, central disease: pelvic exenteration ± IORT, consider reirradiation ± interstitial brachytherapy ± surgery, or limited excision; noncentral disease: systemic therapy, resection ± IORT, reirradiation, or best supportive care [VAG-5].

  • For stage IVB or recurrent distant metastases: limited disease – systemic therapy, consider local treatment of primary and/or metastases (chemoradiation ± brachytherapy, surgery, EBRT, ablative therapies), best supportive care; disseminated disease – systemic therapy ± palliative RT and best supportive care [VAG-6].

  • If not used previously, agents from first-line can be used as second-line or subsequent therapy as clinically appropriate [VAG-D 1A].

  • Consider additional testing (comprehensive molecular profiling, PD-L1, MSI, TMB, NTRK, RET, HER2, p53) to identify subsequent therapy options [VAG-A 2; VAG-5; VAG-6].

  • Patients who experience recurrence after second-line definitive therapy have poor prognosis and can be treated with systemic therapy, best supportive care, or enrollment in clinical trial [MS-12].

Protective FactorsClick to collapse

  • HPV vaccination: Immunization against HPV is expected to prevent persistent infection and prevent HPV-associated vaginal cancer [8], [189], [190]. The guideline states 'The hope is that immunization against HPV will prevent persistent infection and therefore prevent specific HPV-associated cancers, including vaginal cancer.'
  • Regular gynecologic examinations and Pap cytology/cervicography aid in early detection and prevention of progression from preinvasive disease [7].