Definition/General

Introduction:
-Ovarian adenocarcinoma NOS (Not Otherwise Specified) represents malignant epithelial tumors that cannot be classified into specific subtypes (serous, mucinous, endometrioid, clear cell) based on morphologic and immunohistochemical features
-Accounts for 5-10% of ovarian carcinomas and requires extensive workup to exclude specific subtypes.
Origin:
-Arises from ovarian surface epithelium or inclusion cysts derived from coelomic epithelium
-Some cases may represent poorly differentiated tumors where specific lineage markers are lost
-Others may be mixed carcinomas without predominant pattern or metastatic deposits from unknown primary.
Classification:
-According to WHO 2020 classification, diagnosis of adenocarcinoma NOS should be made only after comprehensive IHC workup excludes specific subtypes
-Classified under surface epithelial-stromal tumors
-Extensive sampling and ancillary studies mandatory before final classification.
Epidemiology:
-Affects women in 6th-7th decades (mean age 58-65 years)
-In Indian population, accounts for 8-12% of epithelial ovarian cancers
-Associated with similar risk factors as other epithelial ovarian cancers
-BRCA1/2 mutations found in 15-20% cases.

Clinical Features

Presentation:
-Most patients present with advanced disease (Stage III-IV in 75% cases)
-Common presentations include abdominal distension (80%), pelvic mass (70%), abdominal pain (65%), and constitutional symptoms
-May present as incidental finding during surgery for other conditions.
Symptoms:
-Abdominal distension and pain (85%), early satiety (60%), urinary frequency (45%), change in bowel habits (40%), fatigue (70%)
-Ascites present in 60% of advanced cases
-Weight loss (35%) and dyspnea due to pleural effusion (25%) in metastatic disease.
Risk Factors: Age >50 years, nulliparity, early menarche, late menopause, family history of ovarian/breast cancer, BRCA1/2 mutations (15-20%), Lynch syndrome, prolonged hormone replacement therapy, endometriosis, obesity.
Screening:
-Transvaginal ultrasound shows complex adnexal mass with solid components
-CA-125 elevated in 80% cases (>35 U/mL)
-CT/MRI for staging and surgical planning
-HE4 and ROMA index may aid in diagnosis
-PET-CT for metastatic workup.

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Gross Description

Appearance:
-Tumors typically measure 10-20 cm in greatest dimension
-Cut surface shows predominantly solid areas with variable cystic components
-Surface may be smooth or nodular with frequent capsular rupture
-Areas of hemorrhage, necrosis, and calcification commonly present.
Characteristics:
-Firm to hard consistency with heterogeneous cut surface
-Color ranges from gray-white to yellow-tan with hemorrhagic areas
-May show papillary excrescences in cystic areas
-Extensive necrosis in high-grade tumors
-Surface involvement with peritoneal implants common.
Size Location:
-Size ranges from 5-25 cm (median 15 cm)
-Bilateral involvement in 40-60% cases, suggesting advanced disease
-May involve entire ovary with surface nodularity
-Extension to fallopian tube, uterus, and pelvic organs in advanced cases.
Multifocality:
-Bilateral ovarian involvement common (60%)
-Peritoneal carcinomatosis pattern with multiple small nodules throughout peritoneal cavity
-Omental caking frequent
-Lymph node metastases in 70% of advanced cases
-Pleural involvement in 30%.

Microscopic Description

Histological Features:
-Tumors show adenocarcinomatous features without specific differentiation
-Architecture includes solid sheets, irregular glands, and cribriform patterns
-Lacks characteristic features of serous (psammoma bodies), mucinous (abundant mucin), endometrioid (squamous differentiation), or clear cell (clear cells) carcinomas.
Cellular Characteristics:
-Cells show moderate to marked nuclear pleomorphism with hyperchromatic nuclei and prominent nucleoli
-Cytoplasm is eosinophilic to amphophilic with variable amount
-High mitotic activity (>20 per 10 HPF in high-grade tumors)
-Tumor giant cells may be present.
Architectural Patterns:
-Solid growth pattern (60%) - sheets of malignant cells with minimal glandular differentiation
-Glandular pattern (30%) - irregular, angulated glands
-Papillary pattern (25%) - without psammoma bodies
-Cribriform pattern focally present
-Extensive necrosis common.
Grading Criteria:
-Graded using WHO/FIGO system: Grade 1 (5%) - well-formed glands, mild pleomorphism, <5 mitoses/10 HPF
-Grade 2 (15%) - moderate glandular differentiation, moderate pleomorphism, 5-15 mitoses/10 HPF
-Grade 3 (80%) - solid growth, marked pleomorphism, >15 mitoses/10 HPF.

Immunohistochemistry

Positive Markers:
-Cytokeratin 7 (95%), EMA (90%), BerEP4 (85%)
-Variable expression of WT1 (30%), ER (25%), PR (20%)
-p53 shows wild-type or mutant pattern in 60%
-Ki-67 typically high (>40%) in grade 3 tumors.
Negative Markers:
-CK20 negative (excludes GI primary), TTF-1 negative (excludes lung primary), CDX2 negative, Calretinin negative (excludes mesothelioma), Inhibin negative (excludes sex cord-stromal tumors)
-Napsin-A negative, Hepatocyte negative.
Diagnostic Utility:
-Essential IHC panel for NOS diagnosis: CK7, CK20, WT1, p53, ER/PR to exclude specific ovarian subtypes
-TTF-1, Napsin-A to exclude lung primary
-CDX2, CK20 for GI primary
-Mammoglobin, GCDFP-15 for breast primary
-PAX8 supports Mullerian origin.
Molecular Subtypes:
-Molecular classification challenging due to lack of specific markers
-p53 mutation pattern may suggest high-grade serous-like behavior
-ARID1A loss in 20% cases
-MMR protein expression intact in most cases
-HER2 amplification rare (5%).

Molecular/Genetic

Genetic Mutations:
-TP53 mutations (60%) - most common alteration, associated with high-grade behavior
-BRCA1/2 mutations (15-20%) - germline or somatic
-PIK3CA mutations (15%), ARID1A mutations (20%), PTEN loss (10%)
-KRAS mutations (8%) less common than in mucinous type.
Molecular Markers:
-Homologous recombination deficiency (HRD) score elevated in 40% cases
-Microsatellite stability in >95% cases
-Tumor mutational burden generally low to intermediate
-PD-L1 expression (CPS ≥1) in 30% cases
-VEGF overexpression common.
Prognostic Significance:
-TP53 mutations associated with worse prognosis (median OS 36 vs 60 months)
-BRCA1/2 mutations predict better response to platinum-based chemotherapy and PARP inhibitors
-High HRD score correlates with improved survival
-PIK3CA mutations may predict resistance to standard therapy.
Therapeutic Targets:
-PARP inhibitors (olaparib, niraparib) for BRCA-mutated or HRD-positive tumors
-Anti-angiogenic agents (bevacizumab) for maintenance therapy
-Immunotherapy limited to MSI-high cases (<5%)
-PI3K inhibitors under investigation for PIK3CA-mutated tumors.

Differential Diagnosis

Similar Entities: High-grade serous carcinoma (lacks psammoma bodies, WT1 negative), poorly differentiated endometrioid carcinoma (ER/PR negative, lacks squamous differentiation), metastatic adenocarcinoma (breast, GI, lung), undifferentiated carcinoma, carcinosarcoma (lacks sarcomatous component).
Distinguishing Features:
-High-grade serous: WT1+, p53 aberrant, psammoma bodies
-Endometrioid: ER/PR+, squamous differentiation, ARID1A loss
-Breast metastasis: ER/PR+, mammoglobin+, GCDFP-15+
-GI metastasis: CDX2+, CK20+
-Lung metastasis: TTF-1+, Napsin-A+.
Diagnostic Challenges:
-Extensive sampling required to exclude specific differentiation
-IHC interpretation may be challenging with overlapping profiles
-Mixed tumors without predominant pattern
-Poorly preserved tissue limiting morphologic assessment
-Metastatic deposits from occult primary.
Rare Variants:
-Adenocarcinoma with neuroendocrine features - focal synaptophysin/chromogranin positivity
-Adenocarcinoma with sarcomatoid features - spindle cell areas without definite sarcoma
-Adenocarcinoma with giant cells - multinucleated tumor giant cells
-Cystic variant - predominantly cystic with malignant lining.

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

Right/Left ovary and fallopian tube, total weight: __ grams. Ovary measures __ x __ x __ cm. External surface shows smooth/nodular appearance with intact/ruptured capsule. Cut surface reveals predominantly solid tumor with areas of necrosis and hemorrhage, measuring __ cm in greatest dimension.

Diagnosis

Adenocarcinoma, NOS, Grade __ (WHO), with the following features: Solid/glandular growth pattern, moderate to marked nuclear pleomorphism, high mitotic activity, lymphovascular invasion present/absent, surface involvement present/absent.

Final Diagnosis

OVARIAN ADENOCARCINOMA, NOS, Grade __ (WHO 2020)\n\nStaging (FIGO 2014): Stage __\n\nIHC Profile: CK7 (+), CK20 (-), WT1 (-), p53 (wild-type/mutant pattern), ER/PR (-/+)\n\nNote: Extensive morphologic and immunohistochemical evaluation performed. Cannot classify into specific subtype (serous, mucinous, endometrioid, clear cell). Consider molecular testing for targeted therapy options.