Definition/General
Introduction:
Fallopian tube signet ring cell carcinoma is an extremely rare variant of tubal adenocarcinoma characterized by signet ring cells containing intracytoplasmic mucin
It represents less than 0.5% of all fallopian tube carcinomas
The tumor is defined by the presence of signet ring morphology in >50% of tumor cells
It demonstrates aggressive biological behavior with poor prognosis
The intracytoplasmic mucin displaces the nucleus to the periphery, creating the characteristic signet ring appearance.
Origin:
Originates from the epithelial cells of the fallopian tube that undergo mucinous differentiation
The signet ring morphology results from accumulation of intracytoplasmic mucin
Mucin production may be related to aberrant secretory function
The tumor may arise de novo or from transformation of conventional adenocarcinoma
Molecular alterations affecting mucin metabolism contribute to morphology.
Classification:
WHO classification recognizes it as a rare morphological variant of tubal adenocarcinoma
Signet ring features must be present in >50% of tumor cells
High-grade adenocarcinoma with specific cytological features
May show mixed patterns with conventional adenocarcinoma
Distinguished from metastatic signet ring cell carcinoma from GI tract
Grading typically high-grade (Grade 3).
Epidemiology:
Extremely rare with fewer than 15 cases reported in literature
Peak incidence in 5th-6th decades (similar to other tubal carcinomas)
No specific racial predilection
No established association with BRCA mutations
May be more aggressive than conventional adenocarcinomas
Likely underdiagnosed due to rarity and potential confusion with metastatic disease
Poor overall prognosis.
Clinical Features
Presentation:
Rapidly progressive pelvic mass with aggressive course
Severe pelvic pain and cramping
Heavy vaginal bleeding or postmenopausal bleeding
Abdominal distension and bloating
Constitutional symptoms (weight loss, fatigue, anorexia)
Ascites may develop rapidly
Advanced stage at presentation common.
Symptoms:
Persistent, severe pelvic pain
Irregular or heavy menstrual bleeding
Postmenopausal bleeding
Early satiety and abdominal fullness
Nausea and vomiting
Urinary frequency or urgency
Bowel symptoms (bloating, constipation)
Rapid clinical deterioration.
Risk Factors:
Advanced age (>50 years)
Nulliparity and infertility
Family history of gynecological cancers
Personal history of breast cancer
No established BRCA association for this variant
Environmental factors (unclear role)
Hormonal factors (possible association).
Screening:
No specific screening protocols due to extreme rarity
Standard gynecological surveillance for high-risk women
Pelvic examination and imaging for masses
CA-125 monitoring (may be markedly elevated)
Consider GI evaluation to exclude primary GI source
Imaging studies to assess extent of disease.
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Gross Description
Appearance:
Solid, firm to hard tumor with irregular surface
Gray-white to tan cut surface
Mucoid or gelatinous areas may be present
Extensive necrosis and hemorrhage common
Infiltrative margins
May show cystic degeneration
Calcifications may be visible.
Characteristics:
Heterogeneous appearance with solid and mucoid areas
Firm consistency with areas of softening
Gray-white coloration with mucoid translucency
Extensive hemorrhage and necrosis
Irregular, infiltrative borders
May exude mucoid material on sectioning.
Size Location:
Size ranges from 4-15 cm (often large at presentation)
May involve entire fallopian tube length
Extension beyond tube common at diagnosis
Bilateral involvement in some cases
Peritoneal implants frequently present
Ovarian surface involvement common.
Multifocality:
Often extensive within the fallopian tube
Satellite nodules may be present
Peritoneal seeding common
Lymphatic spread to regional nodes
Hematogenous metastases may occur
Advanced stage at presentation typical.
Microscopic Description
Histological Features:
Signet ring cells with intracytoplasmic mucin displacing nucleus peripherally
Single cell infiltration pattern common
Mucin lakes with floating tumor cells
High nuclear grade with pleomorphism
High mitotic activity (>15 mitoses per 10 HPF)
Extensive lymphovascular invasion
Desmoplastic stromal reaction.
Cellular Characteristics:
Large cells with abundant intracytoplasmic mucin
Eccentric, compressed nuclei at cell periphery
Prominent nucleoli
Pleomorphic nuclear features
Mitotic figures including atypical forms
PAS-positive, diastase-resistant mucin
Clear cell boundaries.
Architectural Patterns:
Single cell infiltration is characteristic pattern
Indian file pattern similar to lobular breast carcinoma
Mucin lakes with scattered tumor cells
Minimal glandular formation
Sheet-like areas of signet ring cells
Targetoid pattern around normal structures
Perineural invasion may be present.
Grading Criteria:
High-grade carcinoma (Grade 3) by definition
Nuclear grade 3 (marked pleomorphism)
High mitotic count (>15 per 10 HPF)
Architectural disorganization
Extensive mucin production
Presence of necrosis
Aggressive growth pattern.
Immunohistochemistry
Positive Markers:
CK7 (positive in majority of cases)
PAX8 (nuclear, confirming müllerian origin)
CA125 (positive in cytoplasm)
MUC5AC (strongly positive in mucin)
MUC6 (may be positive)
CEA (may be positive)
EMA (epithelial membrane antigen).
Negative Markers:
CK20 (typically negative, helps exclude GI primary)
CDX2 (negative, excludes intestinal origin)
TTF-1 (negative, excludes lung origin)
ER/PR (typically negative)
WT1 (usually negative)
p63 (negative in tumor cells)
Inhibin (negative).
Diagnostic Utility:
PAX8 positivity confirms müllerian/gynecological origin
CK7+/CK20- pattern supports gynecological vs GI primary
Mucin markers (MUC5AC) confirm mucin production
Negative CDX2 helps exclude gastric/intestinal origin
Clinical correlation essential to exclude metastatic disease
Molecular studies may help determine primary site.
Molecular Subtypes:
Mucin-producing subtype (high MUC5AC expression)
ER/PR negative subtype (typically hormone receptor negative)
High proliferation subtype (elevated Ki-67)
p53 aberrant subtype (may show mutations)
Microsatellite stable subtype
Chromosomally unstable subtype.
Molecular/Genetic
Genetic Mutations:
TP53 mutations (present in 60-70% of cases)
KRAS mutations (more common than in typical tubal carcinomas)
PIK3CA mutations (may be present)
MUC gene alterations (affecting mucin production)
SMAD4 mutations (may be present)
BRCA1/2 mutations (no established association)
CDH1 mutations (E-cadherin, rare).
Molecular Markers:
p53 protein accumulation (correlates with mutations)
Ki-67 proliferation index (high, >50%)
MUC5AC overexpression (mucin production)
Loss of E-cadherin (may contribute to single cell pattern)
β-catenin alterations (may be present)
PD-L1 expression (variable)
Microsatellite stability (most cases).
Prognostic Significance:
Very poor prognosis (worse than conventional adenocarcinomas)
Advanced stage at diagnosis (majority Stage III-IV)
High metastatic potential
Rapid disease progression
Poor response to chemotherapy
Short overall survival (median 8-12 months)
TP53 mutation status may influence treatment response.
Therapeutic Targets:
Platinum-based chemotherapy (standard first-line)
Taxane combinations (paclitaxel with carboplatin)
Anti-angiogenic agents (bevacizumab)
Immunotherapy (limited efficacy)
Targeted therapy based on molecular profiling
HER2 testing (rarely positive)
Clinical trials for novel agents.
Differential Diagnosis
Similar Entities:
Metastatic signet ring cell carcinoma from GI tract (gastric, colorectal)
Lobular breast carcinoma metastasis (single cell pattern)
Primary peritoneal signet ring cell carcinoma
Krukenberg tumor (ovarian metastasis from GI)
Clear cell carcinoma with signetoid features
Mucinous adenocarcinoma with signet ring cells
Lymphoma with signet ring morphology.
Distinguishing Features:
Primary tubal vs GI metastasis: PAX8+/CDX2-, clinical history, endoscopic findings
Tubal vs breast metastasis: PAX8+, ER/PR status, mammography
Primary vs peritoneal: Site of origin, tubal involvement pattern
Carcinoma vs lymphoma: Epithelial markers vs lymphoid markers.
Diagnostic Challenges:
Determining primary site when signet ring cells present
Excluding metastatic disease from GI tract
Limited tissue for comprehensive workup
Clinical correlation essential
Imaging studies to identify primary site
Endoscopic evaluation may be needed.
Rare Variants:
Mixed signet ring and conventional adenocarcinoma
Signet ring with serous features
Signet ring with endometrioid pattern
Pleomorphic signet ring variant
Signet ring with neuroendocrine features
Micropapillary signet ring pattern
Signet ring with clear cell areas.
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 hysterectomy, fallopian tube measuring [size] cm with extensive tumor
Diagnosis
Signet ring cell carcinoma of fallopian tube
Classification
High-grade adenocarcinoma with signet ring cell features (Grade 3)
Histological Features
Shows signet ring cells with intracytoplasmic mucin, single cell infiltration pattern, and high-grade nuclear features
Signet Ring Cell Features
Signet ring morphology present in >50% of tumor cells, intracytoplasmic mucin (PAS-positive), eccentric nuclei
Extent of Disease
Size: [X] cm, Pattern: [infiltrative/single cell], Lymphovascular invasion: [extensive]
Mucin Studies
PAS: positive (intracytoplasmic mucin), Mucicarmine: positive, Alcian blue: positive
Special Studies
PAX8: positive (confirming müllerian origin), CK7: positive
CDX2: negative, CK20: negative (excluding GI primary)
MUC5AC: strongly positive, confirming mucin production
Molecular Features
p53: [aberrant pattern], Ki-67: [high proliferation index, >50%]
FIGO Staging
FIGO Stage: [II/III/IV] - [advanced stage at presentation]
Prognostic Factors
Signet ring cell carcinoma (very poor prognosis), High-grade (Grade 3), Advanced stage, Extensive LVI
Final Diagnosis
Primary fallopian tube signet ring cell carcinoma, FIGO Stage [II/III/IV]