Definition/General

Introduction:
-Ovarian medullary carcinoma is an extremely rare subtype of ovarian carcinoma characterized by syncytial growth pattern with extensive lymphocytic infiltrate
-It represents less than 0.1% of all ovarian carcinomas
-This entity shows sheets of tumor cells with pushing borders and prominent tumor-infiltrating lymphocytes
-It is often associated with BRCA1 mutations and microsatellite instability.
Origin:
-Arises from ovarian surface epithelium through malignant transformation
-Most commonly develops as a variant of high-grade serous carcinoma
-May also occur in association with endometrioid adenocarcinoma
-Molecular pathogenesis involves DNA mismatch repair deficiency and BRCA1 pathway alterations
-Strong association with Lynch syndrome and hereditary breast-ovarian cancer syndrome.
Classification:
-WHO 2020 classification recognizes medullary pattern as a morphological variant of ovarian carcinoma
-Can occur in serous, endometrioid, or undifferentiated types
-FIGO staging system applies with stages I-IV
-Binary grading system: typically high-grade due to nuclear features
-Microsatellite instability testing recommended for all cases.
Epidemiology:
-Extremely rare with peak incidence in 5th-6th decades (45-60 years)
-Very rare in Indian population with estimated incidence less than 0.05 per 100,000 women
-Strong association with BRCA1 mutations (60-70% cases)
-Associated with Lynch syndrome in 20-30% cases
-Ashkenazi Jewish population shows higher frequency
-Family history of breast/ovarian cancer common.

Clinical Features

Presentation:
-Often presents at earlier stage compared to conventional serous carcinoma
-Pelvic mass with abdominal symptoms
-Better prognosis than conventional high-grade serous carcinoma
-May present with synchronous breast cancer in BRCA1 carriers
-Family history of Lynch syndrome cancers may be present
-Young age at presentation relative to other ovarian cancers.
Symptoms:
-Pelvic pain (70% cases)
-Abdominal distension (60%)
-Abnormal vaginal bleeding (40%)
-Constitutional symptoms: fatigue, weight loss (30%)
-Urinary symptoms (25%)
-Bowel symptoms if large mass (20%)
-Family history of cancer often present
-Early satiety and bloating.
Risk Factors:
-BRCA1 mutations (strongest risk factor, 60-70% cases)
-Lynch syndrome (20-30% cases)
-Family history of breast/ovarian cancer
-Ashkenazi Jewish ancestry
-Personal history of breast cancer
-Nulliparity (moderate risk)
-Age >40 years
-HNPCC-associated cancers in family.
Screening:
-Genetic counseling and testing essential for BRCA1/Lynch syndrome
-CA-125 may be elevated but non-specific
-Transvaginal ultrasound for high-risk patients
-MRI for complex masses
-Family history assessment crucial
-Prophylactic surgery considered in high-risk carriers
-MSI testing recommended for all cases.

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Gross Description

Appearance:
-Well-circumscribed mass with pushing borders
-Cut surface shows solid, fleshy appearance with gray-white to tan color
-Soft consistency compared to conventional carcinomas
-Minimal necrosis and hemorrhage
-Smooth external surface
-May show focal cystic areas
-Well-demarcated from surrounding ovarian tissue.
Characteristics:
-Soft, fleshy consistency with brain-like appearance
-Homogeneous cut surface with minimal heterogeneity
-Gray-white color throughout
-Well-circumscribed borders
-Minimal surface involvement
-Rare calcifications
-Absence of papillary excrescences
-Firm but not hard consistency.
Size Location:
-Size ranges from 3-15 cm (average 6-10 cm)
-Unilateral in 80-90% cases
-Bilateral involvement rare (10-20%)
-No site predilection within ovary
-Replacement of normal ovarian architecture
-Minimal surface involvement at diagnosis
-Early-stage presentation common.
Multifocality:
-Limited peritoneal spread compared to conventional serous carcinoma
-Rare omental involvement at presentation
-Lymph node metastases less common
-Pushing rather than infiltrative growth pattern
-Synchronous breast cancer in BRCA1 carriers
-Other Lynch syndrome cancers may be present
-Better stage distribution at diagnosis.

Microscopic Description

Histological Features:
-Characteristic syncytial growth pattern with sheets of tumor cells
-Pushing borders rather than infiltrative growth
-Extensive lymphocytic infiltrate throughout tumor
-Minimal stromal desmoplasia
-Vesicular nuclei with prominent nucleoli
-Moderate to abundant cytoplasm
-Lymphocytes intimately admixed with tumor cells.
Cellular Characteristics:
-Large tumor cells with vesicular nuclei
-Prominent nucleoli in most cells
-Moderate nuclear pleomorphism
-Abundant eosinophilic cytoplasm
-Distinct cell borders
-High mitotic activity (>20 per 10 HPF)
-Syncytial appearance due to indistinct cell borders
-Occasional multinucleated cells.
Architectural Patterns:
-Solid sheets and nests of tumor cells
-Syncytial growth with minimal gland formation
-Pushing borders with surrounding tissue
-Lymphocytic infiltrate throughout tumor
-Minimal stromal component
-Absence of papillary architecture
-No cribriform pattern
-Geographic necrosis may be present.
Grading Criteria:
-Typically high-grade by nuclear features and mitotic activity
-Nuclear grade 2-3 features
-High mitotic index (>12 per 10 HPF)
-Solid growth pattern supports high-grade
-Prominent nucleoli and pleomorphism
-Ki-67 proliferation index typically >50%
-p53 expression pattern variable
-MSI-high phenotype common.

Immunohistochemistry

Positive Markers:
-CK7 (95-100% cases)
-PAX8 (90-95% ovarian origin)
-p53 (variable pattern: wild-type or aberrant)
-Ki-67 (high proliferation index 50-80%)
-MSH6 (may be lost in Lynch syndrome)
-PMS2 (may be lost in Lynch syndrome)
-MLH1 (rarely lost)
-MSH2 (may be lost).
Negative Markers:
-CK20 (negative, excludes GI origin)
-CDX2 (negative, excludes colorectal)
-TTF1 (negative, excludes lung)
-ER/PR (usually negative or focal)
-WT1 (usually negative, unlike serous)
-Inhibin (negative, excludes sex cord-stromal)
-Calretinin (negative).
Diagnostic Utility:
-MMR protein testing essential: MLH1, MSH2, MSH6, PMS2
-MSI testing recommended for all cases
-p53 pattern assessment: often wild-type unlike conventional serous
-BRCA1 IHC may show loss
-Tumor-infiltrating lymphocytes: CD3, CD8 positive
-PD-L1 expression often positive
-Lynch syndrome screening crucial.
Molecular Subtypes:
-MSI-high subtype (30-40% cases)
-BRCA1-deficient subtype (60-70% cases)
-Homologous recombination deficient (HRD-positive)
-Immunogenic subtype with TILs
-p53 wild-type pattern common
-Lynch syndrome-associated subtype
-TMB-high (tumor mutational burden).

Molecular/Genetic

Genetic Mutations:
-BRCA1 mutations (60-70% cases)
-MMR gene mutations (MLH1, MSH2, MSH6, PMS2) in 20-30%
-TP53 mutations (40-50%, lower than conventional serous)
-PTEN mutations (15-20% cases)
-PIK3CA mutations (10-15%)
-KRAS mutations (rare, <5%)
-POLE mutations (5-10% cases).
Molecular Markers:
-Microsatellite instability (MSI-high) in 30-40%
-Homologous recombination deficiency (HRD-positive)
-High tumor mutational burden (TMB-high)
-Chromosomal instability less than conventional serous
-Hypermutation in POLE-mutated cases
-CpG island methylator phenotype (CIMP) in some cases.
Prognostic Significance:
-Better prognosis than conventional high-grade serous carcinoma
-BRCA1 mutations associated with platinum sensitivity
-MSI-high tumors respond to immunotherapy
-Stage remains most important prognostic factor
-Lymphocytic infiltrate associated with better survival
-Young age often associated with better outcome
-Hereditary cancer syndrome implications.
Therapeutic Targets:
-Immunotherapy: pembrolizumab for MSI-high tumors
-PARP inhibitors for BRCA1-mutated/HRD-positive
-Platinum-based chemotherapy shows good response
-Anti-PD-1/PD-L1 agents effective
-Immune checkpoint inhibitors promising
-Tumor vaccine strategies under investigation
-Adoptive cell therapy potential.

Differential Diagnosis

Similar Entities:
-High-grade serous carcinoma with lymphocytic infiltrate
-Undifferentiated carcinoma
-Large cell neuroendocrine carcinoma
-Metastatic breast carcinoma (medullary type)
-Malignant lymphoma
-Endometrioid carcinoma with solid areas
-Clear cell carcinoma (solid variant).
Distinguishing Features:
-Conventional serous: p53 aberrant, WT1+, papillary areas
-Undifferentiated: no specific lineage markers
-Neuroendocrine: chromogranin+, synaptophysin+
-Metastatic breast: GCDFP-15+, mammaglobin+, PAX8-
-Lymphoma: CD20+, CD3+, PAX8-
-Endometrioid: ER/PR+, squamous differentiation
-Clear cell: clear cytoplasm, HNF1β+.
Diagnostic Challenges:
-Distinguishing from lymphoma: requires epithelial markers
-Metastatic breast medullary: comprehensive IHC panel needed
-MSI testing may require specialized techniques
-BRCA1 status determination important
-Hereditary cancer syndrome identification
-Syncytial pattern may obscure glandular differentiation
-Family history assessment crucial.
Rare Variants:
-Medullary with glandular areas
-Mixed medullary-serous pattern
-Medullary with clear cell features
-Medullary with neuroendocrine differentiation
-POLE-mutated hypermutated variant
-Medullary with squamous differentiation
-Lymphoepithelioma-like variant.

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

Ovarian mass, [side], measuring [X x Y x Z] cm, with [associated structures]

Gross Description

Well-circumscribed mass with pushing borders. Cut surface: solid, fleshy, [color]. Consistency: soft. Necrosis: [present/absent].

Microscopic Findings

Medullary carcinoma with syncytial growth pattern. Extensive lymphocytic infiltrate. Pushing borders. Nuclear grade: [2/3]. Mitotic activity: [count] per 10 HPF.

Immunohistochemistry

CK7: positive. PAX8: positive. p53: [wild-type/aberrant]. MLH1: [retained/lost]. MSH2: [retained/lost]. MSH6: [retained/lost]. PMS2: [retained/lost].

Molecular Studies

MSI status: [MSI-high/MSS]. BRCA1 status: [wild-type/mutated/pending]. MMR gene testing: [recommended/pending].

Diagnosis

Ovarian Medullary Carcinoma [with MSI-high/BRCA1-associated if applicable]

Staging

FIGO Stage: [I/II/III]. TNM: T[X]N[X]M[X]. Lymph nodes: [X] examined, [X] positive.

Genetic Counseling

Recommend genetic counseling for [BRCA1/Lynch syndrome] testing. Family history assessment advised.

Prognostic Factors

Medullary type (favorable prognostic factor). Stage: [early/advanced]. MSI status: [MSI-high/MSS]. BRCA1 status: [mutated/wild-type].

Final Diagnosis

Ovarian Medullary Carcinoma, [unilateral/bilateral], FIGO Stage [X], [MSI-high/BRCA1-associated if applicable]