Definition/General

Introduction:
-Fallopian tube serous carcinoma is the most common subtype of primary fallopian tube carcinoma, accounting for 60-70% of all tubal malignancies
-It is predominantly high-grade serous carcinoma (HGSC) with aggressive biological behavior
-Recent evidence suggests that many ovarian high-grade serous carcinomas actually originate from the fallopian tube fimbria
-The tumor has a strong association with BRCA1/2 mutations and hereditary breast-ovarian cancer syndrome.
Origin:
-Originates from the secretory epithelial cells of the fallopian tube, predominantly from the fimbrial end
-Serous tubal intraepithelial carcinoma (STIC) is the recognized precursor lesion
-The p53 signature represents the earliest change, progressing to STIC and then invasive carcinoma
-BRCA1/2 mutations predispose to malignant transformation through defective DNA repair
-The fimbrial epithelium is most susceptible due to cyclical shedding and regeneration.
Classification:
-WHO classification recognizes high-grade serous carcinoma as the predominant type (95% of serous carcinomas)
-Low-grade serous carcinoma is extremely rare in fallopian tubes
-FIGO staging follows the same system as ovarian carcinoma
-Molecular classification based on homologous recombination deficiency and BRCA status
-Grade is uniformly high in HGSC
-p53 mutation status is universal in high-grade serous carcinoma.
Epidemiology:
-Peak incidence in 6th-7th decades (median age 63-65 years)
-BRCA1/2 mutations present in 40-60% of cases
-BRCA1 carriers develop tumors at younger age (55-60 years)
-Hereditary cases account for majority of fallopian tube serous carcinomas
-Ashkenazi Jewish population has higher prevalence due to founder BRCA mutations
-Prophylactic salpingo-oophorectomy reveals occult carcinomas in 2-17% of BRCA carriers.

Clinical Features

Presentation:
-Pelvic pain (60-70% of cases) due to tubal distension
-Abnormal vaginal bleeding (postmenopausal or irregular cycles)
-Watery vaginal discharge (pathognomonic when present, 30% of cases)
-Palpable adnexal mass (40-50% of cases)
-Abdominal distension and bloating
-Ascites in advanced cases (50-60%)
-Constitutional symptoms (weight loss, fatigue) indicating advanced disease.
Symptoms:
-Hydrops tubae profluens (intermittent discharge of clear watery fluid)
-Pelvic pressure and cramping pain
-Postmenopausal bleeding or irregular menstrual cycles
-Early satiety and abdominal fullness
-Urinary frequency due to mass effect
-Bowel symptoms (constipation, bloating)
-Back pain from retroperitoneal involvement
-Dyspnea from pleural effusion in advanced cases.
Risk Factors:
-BRCA1/2 germline mutations (strongest risk factor, 40-60% of cases)
-Family history of breast/ovarian cancer
-Personal history of breast cancer
-Hereditary breast-ovarian cancer syndrome
-Ashkenazi Jewish ancestry
-Nulliparity and infertility
-Late menopause (>55 years)
-Never having used oral contraceptives (protective effect of OCP use).
Screening:
-Risk-reducing salpingo-oophorectomy (RRSO) for BRCA carriers after age 35-40 and completion of childbearing
-Transvaginal ultrasound and CA-125 monitoring for high-risk women (limited effectiveness)
-MRI screening may detect early lesions in BRCA carriers
-Genetic counseling and testing for women with strong family history
-SEE-FIM protocol (sectioning and extensively examining fimbriae) in all salpingo-oophorectomy specimens.

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Gross Description

Appearance:
-Enlarged, distended fallopian tube with loss of normal plicae
-Solid and papillary masses projecting into tubal lumen
-Gray-white to tan cut surface with areas of necrosis and hemorrhage
-Friable, easily bleeding surface
-Fimbrial involvement is characteristic (80-90% of cases)
-Extension to ovarian surface common
-Calcifications may be visible (psammoma bodies).
Characteristics:
-Papillary architecture visible on gross examination
-Solid areas alternating with cystic spaces
-Necrotic areas with yellow-brown discoloration
-Hemorrhage within tumor and tubal lumen
-Firm consistency in areas of desmoplasia
-Calcified areas (psammoma bodies) appear as gritty white deposits
-Serous fluid may exude from cut surface.
Size Location:
-Size ranges from microscopic STIC lesions to large masses (up to 20 cm)
-Fimbrial end most commonly involved (80-90% of cases)
-Ampullary portion frequently affected
-Entire tubal length may be involved in extensive cases
-Bilateral involvement in 20-30% of cases
-Ovarian surface implants present in 60-70% of cases.
Multifocality:
-Multifocal STIC lesions commonly present (50-70% of cases)
-p53 signatures (precursor lesions) may be scattered throughout fimbria
-Skip lesions with normal epithelium between affected areas
-Bilateral tubal involvement more common than other subtypes
-Concurrent ovarian involvement (primary vs metastatic determination challenging)
-Peritoneal implants present at diagnosis in advanced cases.

Microscopic Description

Histological Features:
-Complex papillary architecture with hierarchical branching pattern
-High-grade nuclear atypia with enlarged, pleomorphic nuclei
-Prominent nucleoli and irregular nuclear membranes
-High mitotic activity (>12 mitoses per 10 HPF)
-Slit-like glandular spaces and pseudoendometrioid pattern
-Psammoma bodies (concentrically laminated calcifications) in 30-50% of cases
-Necrosis commonly present.
Cellular Characteristics:
-Large epithelial cells with moderate to abundant eosinophilic cytoplasm
-Enlarged nuclei with prominent nucleoli and irregular contours
-Marked nuclear pleomorphism with variation in size and shape
-Bizarre multinucleated cells may be present
-Loss of cellular polarity and cohesion
-Mitotic figures including atypical forms
-Apoptotic bodies frequently seen.
Architectural Patterns:
-Complex papillary pattern with fine fibrovascular cores
-Solid sheets and nests in poorly differentiated areas
-Cribriform pattern with slit-like spaces
-Micropapillary pattern without fibrovascular cores
-Glandular pattern resembling endometrioid architecture (pseudoendometrioid)
-Single cell infiltration into stroma
-Lymphovascular invasion commonly present.
Grading Criteria:
-High-grade serous carcinoma is by definition Grade 3 (poorly differentiated)
-Nuclear grade 3: marked pleomorphism, prominent nucleoli
-High mitotic rate (>12 per 10 HPF)
-Architectural complexity with loss of glandular organization
-Extensive necrosis indicates aggressive behavior
-No grading system for high-grade serous as all are considered high-grade
-Low-grade serous (extremely rare) would show uniform nuclei and low mitotic rate.

Immunohistochemistry

Positive Markers:
-PAX8 (nuclear, positive in >95% of cases)
-WT1 (nuclear, positive in 80-90% of serous carcinomas)
-p53 (nuclear, aberrant pattern in 95% - overexpression or null)
-CK7 (cytoplasmic, diffusely positive)
-CA125 (cytoplasmic/luminal, positive in 90%)
-p16 (nuclear/cytoplasmic, block-positive pattern)
-Cyclin E (nuclear, overexpressed in many cases).
Negative Markers:
-CK20 (negative, helps exclude gastrointestinal origin)
-CDX2 (negative, excludes intestinal differentiation)
-TTF-1 (negative, excludes lung metastasis)
-Napsin A (negative in serous, positive in clear cell)
-ER/PR (usually negative or weakly positive)
-p40/p63 (negative, excludes squamous differentiation)
-Inhibin (negative, excludes sex cord-stromal tumors).
Diagnostic Utility:
-PAX8 positivity confirms müllerian origin
-WT1 positivity supports serous differentiation over endometrioid
-p53 aberrant pattern (overexpression >80% or complete loss) is characteristic of HGSC
-p16 block positivity supports high-grade diagnosis
-CK7+/CK20- pattern consistent with gynecological primary
-Negative ER/PR helps distinguish from endometrioid type.
Molecular Subtypes:
-BRCA1-deficient subtype (basal-like gene expression, better prognosis)
-BRCA2-deficient subtype (luminal gene expression)
-Homologous recombination proficient (worse prognosis, platinum-resistant)
-p53 aberrant pattern (universal in HGSC)
-High proliferation subtype (high Ki-67, aggressive behavior)
-Immune-active subtype (high PD-L1, better immunotherapy response).

Molecular/Genetic

Genetic Mutations:
-TP53 mutations (present in 95-100% of high-grade serous carcinomas)
-BRCA1 germline mutations (30-40% of cases)
-BRCA2 germline mutations (10-15% of cases)
-BRCA1/2 somatic mutations (additional 5-10%)
-Homologous recombination pathway genes (PALB2, RAD51C, RAD51D, CHEK2)
-RB1 pathway alterations (CCNE1 amplification, CDKN2A loss)
-PI3K pathway mutations (less common in serous).
Molecular Markers:
-Homologous recombination deficiency (HRD) score (elevated in BRCA-deficient tumors)
-Chromosomal instability (widespread copy number alterations)
-p53 protein accumulation (correlates with TP53 mutations)
-CCNE1 amplification (cyclin E overexpression)
-MYC amplification (aggressive behavior)
-PD-L1 expression (variable, immunotherapy biomarker)
-Microsatellite stability (MSS in majority of cases).
Prognostic Significance:
-BRCA mutation status (BRCA-associated tumors have better prognosis and platinum sensitivity)
-Homologous recombination deficiency predicts PARP inhibitor response
-Stage at diagnosis is most important prognostic factor
-Residual disease after cytoreductive surgery crucial for outcome
-Age at diagnosis influences survival
-Performance status affects treatment tolerance
-CA-125 normalization after treatment correlates with survival.
Therapeutic Targets:
-PARP inhibitors (olaparib, niraparib, rucaparib for BRCA-mutated and HRD tumors)
-Platinum-based chemotherapy (first-line treatment, better response in HRD tumors)
-Anti-angiogenic agents (bevacizumab for maintenance therapy)
-PD-1/PD-L1 inhibitors (pembrolizumab for high TMB or MSI-H tumors)
-ADP-ribosylation inhibitors (synthetic lethality in BRCA-deficient cells)
-WEE1 inhibitors (adavosertib in p53-mutated tumors)
-CDK inhibitors (targeting cell cycle checkpoints).

Differential Diagnosis

Similar Entities:
-Primary ovarian high-grade serous carcinoma (morphologically identical)
-Primary peritoneal serous carcinoma (similar morphology and behavior)
-Metastatic serous carcinoma from other sites (breast, lung, pancreas)
-Endometrial serous carcinoma with tubal involvement
-Serous tubal intraepithelial carcinoma (STIC) without invasion
-Serous borderline tumor (extremely rare in tubes)
-Reactive tubal epithelial changes.
Distinguishing Features:
-Primary tubal vs ovarian: Tubal mucosal origin, transition from normal tubal epithelium, normal ovaries
-Primary vs peritoneal: Tubal involvement, absence of surface ovarian involvement
-Primary vs metastatic: Clinical history, imaging, immunohistochemistry panel
-Invasive vs STIC: Stromal invasion vs confined to epithelium
-High-grade vs borderline: Nuclear atypia, mitotic activity, stromal invasion.
Diagnostic Challenges:
-Determining primary site when tube, ovary, and peritoneum involved
-Distinguishing from ovarian primary requires careful gross and microscopic examination
-STIC vs early invasive carcinoma requires assessment of basement membrane
-Bilateral tubal involvement may suggest synchronous primaries vs metastatic spread
-Small tumor volume may be missed without thorough sampling
-Frozen section interpretation can be difficult.
Rare Variants:
-Micropapillary variant (small papillae without fibrovascular cores)
-Solid variant (predominantly solid growth pattern)
-Transitional-like variant (resembling urothelial carcinoma)
-Mixed müllerian tumor (carcinosarcoma) (serous carcinoma with mesenchymal elements)
-SET variant (solid, endometrioid-like, transitional-like areas)
-Low-grade serous carcinoma (extremely rare in fallopian tubes)
-Serous carcinoma with rhabdoid features (very rare, aggressive).

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

[Unilateral/Bilateral] salpingo-oophorectomy with SEE-FIM protocol, fallopian tube measuring [size] cm

Diagnosis

High-grade serous carcinoma of fallopian tube

Classification

High-grade serous adenocarcinoma (Grade 3)

Histological Features

Shows complex papillary architecture with high-grade nuclear atypia, prominent nucleoli, and high mitotic activity

Site of Origin

Primary site: [fimbrial/ampullary], with transition from normal tubal epithelium

STIC (Serous Tubal Intraepithelial Carcinoma)

STIC: [present/absent], Distribution: [focal/multifocal], Location: [fimbrial/ampullary]

Extent of Disease

Size: [X] cm, Invasion: [through tubal wall], Serosal involvement: [present/absent]

Ovarian Involvement

Ovarian surface: [involved/uninvolved], Pattern: [surface implants/stromal invasion]

Lymphovascular Invasion

Lymphovascular invasion: [present/absent]

Special Studies

PAX8: positive, WT1: [positive/negative], CK7: positive

p53: [aberrant overexpression/null pattern] - consistent with TP53 mutation

Ki-67 index: [high, >50%]

Molecular Testing Recommendations

BRCA1/2 germline testing: recommended for all patients. HRD testing: consider for treatment planning

FIGO Staging

FIGO Stage: [IA/IB/IC/II/III/IV] - [staging details]

Prognostic Factors

High-grade serous carcinoma, Stage: [I/II/III/IV], LVI: [present/absent], BRCA status: [pending testing]

Final Diagnosis

Primary fallopian tube high-grade serous carcinoma, FIGO Stage [IA/IB/IC/II/III/IV]