Definition/General

Introduction:
-Endometrial signet ring cell carcinoma is an extremely rare variant of endometrial adenocarcinoma
-It is characterized by signet ring cells containing intracytoplasmic mucin
-It represents less than 1% of all endometrial carcinomas
-It has an aggressive clinical behavior.
Origin:
-Arises from endometrial glandular epithelium
-May develop from conventional adenocarcinoma
-Can occur as pure signet ring cell carcinoma
-May be mixed with other histotypes
-Mucin production characteristic feature.
Classification:
-Classified as special variant of endometrial adenocarcinoma by WHO
-Type II endometrial carcinoma
-High-grade malignant neoplasm
-May be pure or mixed with other patterns
-Poorly differentiated by definition.
Epidemiology:
-Extremely rare variant
-Peak incidence in 6th-7th decades
-Postmenopausal women predominantly affected
-No clear ethnic predilection
-Associated with advanced stage at presentation
-Poor prognosis compared to conventional types.

Clinical Features

Presentation:
-Abnormal uterine bleeding (most common)
-Postmenopausal bleeding
-Rapidly enlarging uterus
-Pelvic pain
-Advanced disease at presentation
-Ascites may be present.
Symptoms:
-Heavy uterine bleeding
-Pelvic pain and pressure
-Abdominal distension
-Weight loss
-Constitutional symptoms
-Bowel symptoms (if peritoneal involvement).
Risk Factors:
-Age >60 years
-No association with typical endometrial cancer risk factors
-Not associated with estrogen exposure
-Lynch syndrome association unclear
-TP53 mutations common.
Screening:
-No specific screening recommendations
-Endometrial sampling for abnormal bleeding
-Imaging studies for staging
-CA-125 may be elevated
-Peritoneal cytology important.

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Gross Description

Appearance:
-Polypoid or ulcerative mass in endometrial cavity
-Gray-white cut surface
-Soft, friable consistency
-Areas of necrosis and hemorrhage
-Myometrial invasion common.
Characteristics:
-Size ranges from 2-8 cm
-Infiltrative margins
-Cut surface shows solid areas
-Necrotic foci common
-Mucoid areas may be present.
Size Location:
-Variable size at presentation
-Involves endometrial cavity
-Deep myometrial invasion common
-Cervical extension frequent
-Extrauterine spread at diagnosis.
Multifocality:
-Usually unifocal but aggressive
-Extensive local invasion
-Lymphovascular invasion common
-Peritoneal seeding frequent
-Lymph node metastases common.

Microscopic Description

Histological Features:
-Signet ring cells with eccentric nuclei
-Intracytoplasmic mucin displacing nucleus
-Infiltrative growth pattern
-High nuclear grade
-Abundant mucin production
-Areas of conventional adenocarcinoma may be present.
Cellular Characteristics:
-Large cells with abundant mucin-filled cytoplasm
-Eccentric, crescent-shaped nuclei
-Prominent nucleoli
-High nuclear-to-cytoplasmic ratio
-Mucin vacuoles compressing nucleus
-Mitotic activity variable.
Architectural Patterns:
-Single cell infiltration
-Small clusters of signet ring cells
-Mucin pools
-Desmoplastic stroma
-Lymphovascular invasion
-May show conventional glandular areas.
Grading Criteria:
-Considered high-grade by definition
-FIGO Grade 3 equivalent
-Poorly differentiated morphology
-High mitotic rate
-Extensive necrosis
-Solid growth pattern.

Immunohistochemistry

Positive Markers:
-Cytokeratins (CK7, CK20 variable)
-EMA
-CEA (often positive)
-Mucin stains (PAS, mucicarmine)
-ER (usually negative)
-p53 (often overexpressed)
-MLH1 (may be lost).
Negative Markers:
-WT1 (negative)
-p16 (usually negative)
-GATA3 (negative)
-TTF-1 (negative)
-CDX2 (usually negative)
-Vimentin (negative).
Diagnostic Utility:
-Cytokeratin positivity confirms epithelial origin
-Mucin stains highlight intracytoplasmic mucin
-p53 overexpression common
-ER negativity typical
-Mismatch repair proteins may be lost.
Molecular Subtypes:
-TP53-mutant molecular subtype
-Microsatellite stable (usually)
-POLE mutations rare
-Copy number high subtype
-p53 abnormal pattern.

Molecular/Genetic

Genetic Mutations:
-TP53 mutations (>80% cases)
-PIK3CA mutations
-PTEN loss
-FBXW7 mutations
-PPP2R1A mutations
-ARID1A mutations.
Molecular Markers:
-p53 overexpression or complete loss
-High tumor mutational burden
-Chromosomal instability
-Copy number alterations
-Aneuploidy.
Prognostic Significance:
-TP53 mutations indicate poor prognosis
-High-grade histology correlates with aggressive behavior
-Advanced stage at presentation common
-Chemoresistance frequent
-Overall survival poor.
Therapeutic Targets:
-Platinum-based chemotherapy
-Immunotherapy (pembrolizumab)
-PARP inhibitors (if HRD positive)
-PI3K/mTOR inhibitors
-Anti-angiogenic agents
-Combination therapy approaches.

Differential Diagnosis

Similar Entities:
-Metastatic signet ring cell carcinoma (gastric, breast, lung)
-Primary peritoneal carcinoma
-Ovarian signet ring cell carcinoma
-Mucinous adenocarcinoma
-Clear cell carcinoma.
Distinguishing Features:
-Gastric: CDX2 positive
-Breast: GATA3, ER positive
-Endometrial: CK7 positive, CK20 negative
-Endometrial: Site of origin
-Ovarian: WT1 positive
-Clear cell: Clear cytoplasm, different architecture.
Diagnostic Challenges:
-Distinguishing from metastatic disease
-Identifying primary site
-Recognizing signet ring morphology
-Differentiating from other mucin-producing tumors
-Immunohistochemistry and clinical correlation essential.
Rare Variants:
-Pure signet ring cell carcinoma
-Mixed with conventional adenocarcinoma
-Signet ring cell component in carcinosarcoma
-Mucinous variant with signet ring 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

[specimen type], measuring [size] cm in greatest dimension

Diagnosis

Endometrial adenocarcinoma, signet ring cell variant

WHO Classification

Endometrial adenocarcinoma, special variant (signet ring cell type)

Histological Features

Signet ring cells with intracytoplasmic mucin, [percentage]% of tumor

Grade

FIGO Grade: 3 (high-grade by definition)

Myometrial Invasion

Myometrial invasion: [depth] mm, [percentage]% of wall thickness

Lymphovascular Invasion

Lymphovascular invasion: [present/absent]

Special Stains and Immunohistochemistry

Mucin stains: Mucicarmine [+/-], PAS [+/-]

Epithelial markers: CK7 [+/-], EMA [+/-]

p53: [overexpressed/wild-type/null], ER: [+/-]

Final Diagnosis

Endometrial adenocarcinoma, signet ring cell variant, FIGO Grade 3