Definition/General

Introduction:
-Ovarian signet ring cell carcinoma is an extremely rare variant characterized by cells with signet ring morphology (eccentric nucleus displaced by intracytoplasmic mucin)
-Primary ovarian cases are exceptionally rare (<1% of ovarian carcinomas)
-Metastatic disease from gastrointestinal tract much more common (>95% cases)
-Shows aggressive behavior with poor prognosis.
Origin:
-Primary ovarian: Arises from ovarian surface epithelium with mucinous differentiation
-Metastatic: Most commonly from gastric adenocarcinoma (70-80%), colorectal (10-15%), breast (5-10%)
-Krukenberg tumor pattern when metastatic from stomach
-Shows intracytoplasmic mucin accumulation displacing nucleus peripherally.
Classification:
-WHO 2020 distinguishes primary vs
-metastatic signet ring cell carcinoma
-Primary cases classified under mucinous adenocarcinoma variants
-Krukenberg tumor when metastatic from GI tract
-FIGO staging applies for primary cases
-Grading typically high-grade (Grade 3) due to poor differentiation.
Epidemiology:
-Primary ovarian: Fewer than 200 cases reported worldwide
-Peak incidence 4th-5th decades (mean age 45-55)
-Metastatic cases: More common in Asian populations
-Gastric primary association higher in Japan, Korea
-Indian population shows increasing gastric cancer rates
-Bilateral involvement suggests metastatic origin.

Clinical Features

Presentation:
-Bilateral ovarian masses (80-90% if metastatic)
-Rapid onset symptoms (weeks to months)
-Abdominal distension and ascites (70-80%)
-Pelvic pain and discomfort (60-70%)
-Constitutional symptoms (weight loss, fatigue) prominent
-GI symptoms if primary gastric cancer.
Symptoms:
-Abdominal bloating and fullness (80-90%)
-Early satiety and nausea (70-80%)
-Pelvic pressure and pain (60-70%)
-Dyspepsia and gastric symptoms (if gastric primary)
-Bowel obstruction (advanced cases)
-Dyspnea if pleural involvement
-Back pain (retroperitoneal spread).
Risk Factors:
-Primary gastric adenocarcinoma (major risk factor for metastatic)
-Helicobacter pylori infection (gastric cancer risk)
-CDH1 mutations (hereditary diffuse gastric cancer)
-Lynch syndrome (colorectal primary)
-BRCA mutations (breast primary)
-Family history of GI cancers.
Screening:
-CA-125 elevated in 70-80% cases (often >200 U/mL)
-CEA significantly elevated (>50 ng/mL) suggests GI primary
-CA 19-9 elevated in GI primaries
-AFP usually normal
-Upper GI endoscopy essential if bilateral masses
-Colonoscopy to exclude colorectal primary.

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Gross Description

Appearance:
-Bilateral solid masses (80-90% if metastatic) with smooth, bosselated surface
-Gray-white to pink cut surface with gelatinous areas
-Firm to soft consistency depending on mucin content
-Minimal necrosis compared to other high-grade carcinomas
-Mucoid appearance characteristic.
Characteristics:
-Solid, fleshy masses with smooth external surface
-Homogeneous cut surface with gelatinous quality
-Minimal cystic change
-Mucin-rich areas appear translucent
-Preserved ovarian shape often maintained (Krukenberg tumor)
-Capsular surface involvement common.
Size Location:
-Bilateral involvement in 80-90% metastatic cases
-Mean size 8-12 cm each ovary (range 5-20 cm)
-Asymmetric sizes common
-Surface nodularity may be present
-Unilateral if primary ovarian (rare)
-Preserved ovarian contour characteristic of Krukenberg tumor.
Multifocality:
-Bilateral synchronous involvement typical of metastatic disease
-Peritoneal implants and ascites common
-Omental involvement (omental cake) frequent
-Retroperitoneal nodes enlarged
-Liver metastases in advanced cases
-Primary GI tumor may be small and missed.

Microscopic Description

Histological Features:
-Signet ring cells (>50% of tumor) with eccentric, crescentic nuclei
-Abundant intracytoplasmic mucin displacing nucleus
-Pools of extracellular mucin
-Desmoplastic stromal reaction
-Single-file infiltration pattern
-Lymphovascular invasion common.
Cellular Characteristics:
-Large cells (15-25 μm) with abundant cytoplasmic mucin
-Eccentric, crescent-shaped nuclei compressed to cell periphery
-Hyperchromatic nuclei with irregular contours
-Prominent nucleoli in some cells
-Intracytoplasmic mucin vacuoles (PAS-positive, diastase-resistant)
-Rare mitotic figures.
Architectural Patterns:
-Diffuse infiltrative growth pattern predominant
-Single-file arrangement between ovarian stroma
-Small clusters and individual cells
-Mucin pools with floating signet ring cells
-Minimal glandular formation
-Indian-file pattern in fibrous stroma
-Preserved ovarian architecture initially.
Grading Criteria:
-High-grade (Grade 3) by definition due to poor differentiation
-Absence of glandular formation (score 3)
-Marked nuclear pleomorphism (score 2-3)
-Variable mitotic rate (score 1-3)
-Signet ring morphology indicates poor differentiation
-Ki-67 proliferation index variable (20-70%).

Immunohistochemistry

Positive Markers:
-CK7 (variable - primary ovarian often positive)
-CK20 (positive in GI primaries, 70-80%)
-CDX2 (positive in colorectal primaries, 80-90%)
-CEA (70-80% positive)
-MUC1 (60-70% positive)
-MUC2 (GI primaries, 50-60%)
-Mucin stains (PAS, mucicarmine positive).
Negative Markers:
-PAX8 (negative in GI primaries, positive in primary ovarian)
-WT1 (negative in most cases)
-ER/PR (negative unless breast primary)
-GCDFP-15 (negative unless breast primary)
-TTF-1 (negative)
-Inhibin (negative)
-Calretinin (negative).
Diagnostic Utility:
-CK7/CK20 pattern helps determine primary site
-CDX2 positivity strongly suggests GI primary
-PAX8 negativity favors metastatic origin
-GCDFP-15/ER positive suggests breast primary
-CEA elevation supports carcinoma diagnosis
-Mucin stains confirm signet ring cell nature.
Molecular Subtypes:
-Gastric-type (CK7+/CK20+, CDX2+)
-Colorectal-type (CK7-/CK20+, CDX2+)
-Breast-type (CK7+/ER+, GCDFP-15+)
-Primary ovarian (CK7+/PAX8+, CDX2-)
-Microsatellite status variable
-HER2 amplification in gastric subset.

Molecular/Genetic

Genetic Mutations:
-CDH1 mutations (E-cadherin) - hereditary diffuse gastric cancer
-TP53 mutations (60-70% cases)
-PIK3CA mutations (20-30% gastric type)
-KRAS mutations (colorectal primaries, 40-50%)
-ERBB2 amplification (HER2) in gastric subset (15-20%)
-Microsatellite instability (5-10% cases).
Molecular Markers:
-CEA levels markedly elevated (often >100 ng/mL)
-CA-125 elevated (70-80% cases)
-CA 19-9 elevated in GI primaries
-E-cadherin protein loss in CDH1-mutated cases
-p53 protein overexpression (60-70%)
-HER2 protein overexpression in subset.
Prognostic Significance:
-Universally poor prognosis (5-year survival <20%)
-Metastatic disease has worse outcome than primary
-Bilateral involvement indicates advanced stage
-CDH1 mutations associated with early onset and family clustering
-HER2 amplification may predict trastuzumab response
-MSI-high tumors may respond to immunotherapy.
Therapeutic Targets:
-Systemic chemotherapy based on primary site (gastric, colorectal protocols)
-Trastuzumab for HER2-positive gastric primaries
-Immunotherapy for MSI-high tumors (pembrolizumab)
-Anti-angiogenic agents (ramucirumab for gastric)
-CDK4/6 inhibitors under investigation
-Surgery limited role due to advanced stage.

Differential Diagnosis

Similar Entities:
-Metastatic gastric adenocarcinoma (most common)
-Metastatic colorectal adenocarcinoma
-Metastatic breast lobular carcinoma
-Primary ovarian mucinous carcinoma (with signet ring cells)
-Clear cell carcinoma (hobnail cells)
-Adult granulosa cell tumor (Call-Exner bodies).
Distinguishing Features:
-Gastric primary: CK7+/CK20+, CDX2+
-Colorectal primary: CK7-/CK20+, CDX2+
-Breast primary: ER+, GCDFP-15+
-Primary ovarian: PAX8+, unilateral
-Clear cell: clear cytoplasm, hobnail morphology
-Granulosa cell: inhibin+, Call-Exner bodies.
Diagnostic Challenges:
-Distinguishing primary vs
-metastatic requires extensive IHC panel
-Small gastric primaries may be endoscopically occult
-Bilateral involvement strongly suggests metastatic origin
-Clinical correlation essential for accurate diagnosis
-Upper GI workup mandatory
-Family history important for hereditary syndromes.
Rare Variants:
-Mixed signet ring and conventional adenocarcinoma
-Signet ring cell carcinoma with clear cell features
-Poorly cohesive carcinoma with signet ring cells
-Mucinous carcinoma with focal signet ring differentiation
-Signet ring cell carcinoma with neuroendocrine features.

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

Bilateral salpingo-oophorectomy specimen, right ovary measuring [X x Y x Z] cm, left ovary measuring [X x Y x Z] cm

Gross Description

Bilateral solid ovarian masses with smooth, bosselated surfaces, gray-white cut surface with gelatinous areas, [preserved/distorted] ovarian contour

Diagnosis

Bilateral ovarian signet ring cell carcinoma, [primary/metastatic - specify primary site if known]

Histological Features

Signet ring cells (>50% of tumor) with eccentric nuclei, abundant intracytoplasmic mucin, single-file infiltration pattern, desmoplastic stroma

Mucin Studies

PAS: Positive (intracytoplasmic mucin), Mucicarmine: Positive, Alcian Blue: [Positive/Negative]

Immunohistochemistry

CK7: [Positive/Negative], CK20: [Positive/Negative], CDX2: [Positive/Negative], CEA: [Positive/Negative], PAX8: [Positive/Negative], ER: [Positive/Negative]

Primary Site Assessment

Immunohistochemical profile [favors/consistent with]: [gastric/colorectal/breast/primary ovarian] primary

Staging

[Primary ovarian: FIGO Stage IV] / [Metastatic: Ovarian metastases from [primary site]]

Clinical Correlation

Clinical correlation with upper GI endoscopy, colonoscopy, and imaging studies recommended to identify primary site

Molecular Testing Recommendations

Consider: HER2 testing if gastric primary, MSI testing, CDH1 mutation testing if family history of diffuse gastric cancer

Prognostic Factors

High-grade morphology, bilateral involvement, [primary site], [stage], signet ring cell differentiation (poor prognostic factor)

Comments

Bilateral ovarian signet ring cell carcinoma is most commonly metastatic from GI tract. Clinical correlation and multidisciplinary team discussion essential.

Final Diagnosis

Bilateral ovarian signet ring cell carcinoma, [consistent with metastatic [primary site]/primary ovarian], Grade 3