Definition/General

Introduction:
-Vaginal adenocarcinoma is a rare malignant tumor accounting for 10-15% of all primary vaginal cancers
-It arises from the glandular epithelium or from müllerian remnants within the vaginal wall
-Primary vaginal adenocarcinoma must be distinguished from metastatic disease, which is more common
-The most well-known subtype is clear cell adenocarcinoma associated with in utero DES exposure.
Origin:
-Originates from müllerian remnants (mesonephric or paramesonephric ducts) within the vaginal wall
-Endometrioid type arises from müllerian-type epithelium
-Clear cell type develops from mesonephric remnants or müllerian epithelium
-Mucinous type can arise from endocervical-type epithelium
-Intestinal type may develop from heterotopic intestinal epithelium
-Most commonly located in the upper third of the vagina.
Classification:
-WHO classification includes several subtypes: Endometrioid adenocarcinoma (most common)
-Clear cell adenocarcinoma (DES-associated)
-Mucinous adenocarcinoma (endocervical or intestinal type)
-Serous adenocarcinoma (rare)
-Mesonephric adenocarcinoma (very rare)
-Grading follows three-tier system based on architectural pattern and nuclear features
-FIGO staging similar to vaginal squamous cell carcinoma.
Epidemiology:
-Accounts for 10-15% of primary vaginal cancers
-Peak incidence in 5th-6th decades
-Clear cell adenocarcinoma occurs in younger women (20-40 years) with DES exposure history
-Endometrioid type occurs in postmenopausal women
-Strong association with DES (diethylstilbestrol) exposure in utero for clear cell type
-Overall incidence is 0.5-1 per 100,000 women per year.

Clinical Features

Presentation:
-Abnormal vaginal bleeding (80-90% of cases), particularly postmenopausal bleeding
-Vaginal discharge (watery, mucoid, or bloody)
-Pelvic pain and pressure symptoms
-Dyspareunia and post-coital bleeding
-Urinary symptoms (frequency, urgency) in advanced cases
-Bowel symptoms with posterior wall involvement
-Palpable vaginal mass in advanced cases.
Symptoms:
-Vaginal bleeding (most common, especially intermenstrual or postmenopausal)
-Mucoid or bloody discharge with characteristic watery consistency
-Pelvic discomfort and pressure sensation
-Dyspareunia due to tumor mass effect
-Urinary incontinence or retention in advanced disease
-Constipation and tenesmus with rectal involvement
-Leg edema from lymphatic obstruction
-Constitutional symptoms in advanced stages.
Risk Factors:
-DES (diethylstilbestrol) exposure in utero (strong association with clear cell type)
-Prior history of gynecological malignancy (cervical, endometrial)
-Immunosuppression (HIV, organ transplantation)
-Radiation therapy to pelvis (secondary malignancy)
-Chronic inflammation and irritation
-Age (most cases in postmenopausal women except DES-related)
-Genetic predisposition (rare familial cases).
Screening:
-Annual pelvic examination for high-risk women
-Pap smear may detect glandular cells of vaginal origin
-Colposcopy with directed biopsy for suspicious lesions
-DES daughters require lifelong surveillance with annual examination
-Transvaginal ultrasound may detect masses
-MRI for evaluation of extent in diagnosed cases.

Master Vaginal Adenocarcinoma Pathology with RxDx

Access 100+ pathology videos and expert guidance with the RxDx app

Gross Description

Appearance:
-Polypoid or nodular growth with smooth or lobulated surface
-Clear to tan-white coloration depending on subtype
-Mucoid or gelatinous consistency in mucinous types
-Cystic areas may be present, especially in clear cell type
-Hemorrhage and necrosis in larger tumors
-Firm consistency in endometrioid types.
Characteristics:
-Smooth, glistening surface in early lesions
-Ulceration may develop in advanced cases
-Mucoid secretions on cut surface in mucinous types
-Clear, watery fluid in cystic areas of clear cell adenocarcinoma
-Invasion into vaginal wall creates firm, indurated areas
-Extension to paravaginal tissues in advanced cases.
Size Location:
-Size ranges from small nodules to large masses (up to 8-10 cm)
-Upper third of vagina most commonly affected (70-80%)
-Posterior and lateral walls more frequently involved
-Anterior wall involvement may extend to bladder
-Multifocal disease is uncommon
-Involvement of vaginal fornices common in upper third tumors.
Multifocality:
-Multifocal presentation is rare (<5% of cases)
-Skip lesions may occur in DES-related cases
-Concurrent cervical involvement must be excluded for primary vaginal diagnosis
-Bilateral ovarian involvement suggests metastatic disease
-Endometrial involvement indicates possible primary endometrial origin with vaginal metastasis.

Microscopic Description

Histological Features:
-Glandular architecture with various patterns depending on subtype
-Endometrioid type: tubular glands resembling endometrial adenocarcinoma
-Clear cell type: clear cells with hobnail pattern and tubulocystic architecture
-Mucinous type: mucin-containing cells with endocervical or intestinal features
-Invasive growth into vaginal stroma with desmoplastic response.
Cellular Characteristics:
-Columnar to cuboidal cells with enlarged nuclei and prominent nucleoli
-Clear cell type: cells with clear, glycogen-rich cytoplasm and hobnail morphology
-Endometrioid type: eosinophilic cytoplasm with oval nuclei
-Mucinous type: mucin-containing cells with basally located nuclei
-Mitotic activity varies with grade
-Nuclear pleomorphism and atypia in high-grade tumors.
Architectural Patterns:
-Tubular and glandular patterns in endometrioid type
-Tubulocystic and solid patterns in clear cell type
-Papillary architecture may be present in serous type
-Cribriform pattern in some cases
-Single cell infiltration in poorly differentiated areas
-Squamous differentiation (adenosquamous carcinoma) may occur.
Grading Criteria:
-Grade 1 (well-differentiated): >95% glandular architecture with mild nuclear atypia
-Grade 2 (moderately differentiated): 50-95% glandular architecture with moderate nuclear atypia
-Grade 3 (poorly differentiated): <50% glandular architecture with severe nuclear atypia
-Nuclear grade and mitotic count also contribute to overall grade
-Clear cell adenocarcinoma is typically considered high-grade regardless of architecture.

Immunohistochemistry

Positive Markers:
-CK7 (positive in most adenocarcinomas)
-PAX8 (positive in müllerian-derived adenocarcinomas)
-ER/PR (positive in endometrioid type, variable in clear cell type)
-CEA (positive in mucinous intestinal type)
-CDX2 (positive in intestinal-type mucinous adenocarcinoma)
-CA125 (positive in serous and clear cell types)
-Napsin A (positive in clear cell adenocarcinoma).
Negative Markers:
-p40/p63 (negative, helps exclude squamous cell carcinoma)
-CK5/6 (negative in most adenocarcinomas)
-CK20 (negative except in intestinal-type mucinous adenocarcinoma)
-TTF-1 (negative, helps exclude lung metastasis)
-RCC marker (negative, helps exclude renal cell carcinoma)
-Hepatocyte antigen (negative, helps exclude hepatoid adenocarcinoma).
Diagnostic Utility:
-CK7+/CK20- pattern suggests müllerian origin
-PAX8 positivity supports gynecological origin
-ER/PR positivity suggests endometrioid type and guides therapy
-CDX2 positivity in mucinous tumors suggests intestinal differentiation
-Napsin A helps identify clear cell adenocarcinoma
-p16 may be positive in HPV-associated cases (rare)
-Panel approach essential for subtyping.
Molecular Subtypes:
-Endometrioid type (ER/PR positive, PAX8 positive, microsatellite instability possible)
-Clear cell type (Napsin A positive, ER variable, ARID1A loss common)
-Serous type (p53 aberrant, WT1 positive)
-Mucinous endocervical type (ER/PR positive, may be HPV-associated)
-Mucinous intestinal type (CDX2 positive, CK20 positive)
-Mesonephric type (TTF-1 positive, ER negative).

Molecular/Genetic

Genetic Mutations:
-PIK3CA mutations (common in endometrioid and clear cell types, 30-40%)
-KRAS mutations (common in mucinous types, 25-35%)
-PTEN mutations (endometrioid type, 20-30%)
-ARID1A mutations (clear cell type, 40-60%)
-TP53 mutations (serous type, 80-90%)
-CTNNB1 mutations (endometrioid type, 15-25%)
-Microsatellite instability (subset of endometrioid cases).
Molecular Markers:
-HER2 amplification (subset of serous and clear cell types)
-p53 overexpression (serous type and high-grade tumors)
-β-catenin nuclear accumulation (CTNNB1-mutated endometrioid cases)
-ARID1A loss (clear cell adenocarcinoma)
-Mismatch repair protein loss (MSI-high endometrioid cases)
-PD-L1 expression (variable, potential immunotherapy target).
Prognostic Significance:
-Histological subtype is major prognostic factor (clear cell and serous types have worse prognosis)
-Stage at diagnosis is most important prognostic factor
-Grade correlates with survival (high-grade tumors have worse prognosis)
-Age at diagnosis influences outcome (younger patients do better)
-DES exposure in clear cell cases may be associated with better prognosis
-MSI status may predict immunotherapy response.
Therapeutic Targets:
-ER/PR (hormonal therapy for positive cases)
-HER2 (trastuzumab for amplified cases)
-PI3K/AKT pathway (PI3K inhibitors for PIK3CA-mutated cases)
-PARP inhibitors (for homologous recombination deficient tumors)
-PD-1/PD-L1 (immunotherapy for PD-L1 positive or MSI-high cases)
-ARID1A loss (synthetic lethality approaches under investigation).

Differential Diagnosis

Similar Entities:
-Metastatic adenocarcinoma (cervical, endometrial, ovarian, gastrointestinal)
-Vaginal squamous cell carcinoma with glandular differentiation
-Adenosquamous carcinoma of vagina
-Vaginal clear cell adenocarcinoma vs renal cell carcinoma metastasis
-Primary vaginal vs extension from adjacent organs
-Benign vaginal glands (müllerian remnants, endometriosis).
Distinguishing Features:
-Primary vs metastatic: Clinical history, imaging, and absence of primary tumor elsewhere
-Adenocarcinoma vs SCC: CK7/PAX8 positive vs p40/p63 positive
-Clear cell vs RCC metastasis: PAX8 positive vs RCC marker positive
-Endometrioid vs endometrial primary: Location and lack of endometrial involvement
-Mucinous vs gastrointestinal metastasis: CK7+/CK20- vs CK7-/CK20+ pattern
-Malignant vs benign: Architectural complexity, nuclear atypia, mitotic activity.
Diagnostic Challenges:
-Determining primary vs metastatic disease requires comprehensive clinical workup
-Small biopsy interpretation may be limited by sampling
-Subtyping requires adequate tissue for immunohistochemistry
-Grade assessment may be difficult in small specimens
-Distinguishing invasion from artifact in fragmented specimens
-DES history may not be available in clear cell cases.
Rare Variants:
-Adenosquamous carcinoma (mixed glandular and squamous differentiation)
-Glassy cell carcinoma (large cells with ground-glass cytoplasm)
-Adenoid basal carcinoma (small basaloid cells with glandular differentiation)
-Adenoid cystic carcinoma (cribriform pattern, myoepithelial component)
-Small cell adenocarcinoma (neuroendocrine differentiation)
-Signet ring cell adenocarcinoma (mucin-containing signet ring cells).

Sample Pathology Report

Template Format

Sample Pathology Report

Complete Report: This is an example of how the final pathology report should be structured for this condition.

Specimen Information

Vaginal biopsy/excision from [location] measuring [size] cm

Diagnosis

Adenocarcinoma of vagina, [subtype]

Classification and Grade

[Endometrioid/Clear cell/Mucinous/Serous] adenocarcinoma, Grade [1/2/3]

Histological Features

Shows [architectural pattern] with [cellular characteristics] and [degree] nuclear atypia

Invasion and Extent

Depth of invasion: [X] mm, extent: [superficial/deep stromal/paravaginal]

Margins

Margins are [involved/uninvolved], closest margin [X] mm from tumor

Lymphovascular Invasion

Lymphovascular invasion: [present/absent]

Special Studies

CK7: [positive/negative], PAX8: [positive/negative], ER: [positive/negative], PR: [positive/negative]

[Subtype-specific markers]: [results]

Ki-67 index: [percentage]%

FIGO Staging

FIGO Stage: [I/II/III/IV] - [staging description]

Prognostic Factors

Subtype: [type], Grade: [1/2/3], Stage: [I/II/III/IV], LVI: [present/absent]

Final Diagnosis

Primary vaginal [subtype] adenocarcinoma, Grade [1/2/3], FIGO Stage [I/II/III/IV]