Definition/General
Introduction:
Ovarian borderline tumors (BOT), also known as tumors of low malignant potential (LMP), represent a unique category of epithelial ovarian neoplasms
They constitute 10-15% of all epithelial ovarian tumors
These tumors show epithelial proliferation and atypia without destructive stromal invasion
They have an excellent prognosis compared to invasive carcinomas.
Origin:
Originate from the surface epithelium of the ovary or inclusion cysts
Develop through adenoma-borderline-carcinoma sequence
Show intermediate features between benign adenomas and invasive carcinomas
Lack the capacity for destructive stromal invasion
May progress to invasive carcinoma in small percentage of cases.
Classification:
Classified by WHO 2020 guidelines
Serous borderline tumor (most common, 65%)
Mucinous borderline tumor (25-30%)
Endometrioid borderline tumor (rare)
Clear cell borderline tumor (rare)
Brenner borderline tumor (rare)
Mixed types possible.
Epidemiology:
Peak incidence in 4th-5th decades (younger than invasive carcinomas)
Reproductive age predominance
Better prognosis than invasive carcinomas
Serous BOT: Mean age 45 years
Mucinous BOT: Mean age 40 years
Indian population shows similar age distribution with good outcomes.
Clinical Features
Presentation:
Pelvic mass (most common presentation)
Abdominal pain and distension
Asymptomatic discovery during routine examination
Urinary symptoms (pressure effects)
Irregular menstruation
Early satiety
Better performance status compared to invasive carcinomas
Incidental finding during imaging.
Symptoms:
Pelvic or abdominal pain (mild to moderate)
Abdominal bloating
Urinary frequency
Feeling of fullness
Mild nausea
Change in bowel habits
Pelvic pressure
Usually no constitutional symptoms (weight loss, fatigue)
Fertility concerns in young women.
Risk Factors:
Nulliparity
Infertility
Late menopause
Early menarche
Family history of ovarian/breast cancer
BRCA1/2 mutations (less common than in invasive carcinomas)
Endometriosis (for endometrioid BOT)
Hormone replacement therapy
Pregnancy may be protective.
Screening:
No specific screening protocols
Pelvic examination
Transvaginal ultrasound
CA-125 (may be elevated but usually <200 U/mL)
HE4 (human epididymis protein 4)
ROMA index (Risk of Ovarian Malignancy Algorithm)
Imaging studies: CT, MRI for characterization.
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Gross Description
Appearance:
Variable size ranging from 5-30 cm
Unilateral or bilateral (bilateral more common than in invasive carcinomas)
Serous BOT: Multilocular cystic with papillary projections
Mucinous BOT: Large, multilocular, mucin-filled cysts
Surface may show papillary excrescences
Smooth external surface (no surface involvement usually).
Characteristics:
Serous BOT: Gray-white papillary projections, clear fluid
Mucinous BOT: Thick mucoid content, multilocular appearance
Cut surface shows complex papillary architecture
No obvious necrosis or hemorrhage typically
Firm consistency
Intact capsule in most cases.
Size Location:
Size typically 10-20 cm (smaller than invasive carcinomas)
Bilateral involvement: Serous BOT (25-50%), Mucinous BOT (5-10%)
Both ovaries may be involved synchronously
Unilateral predominance in mucinous type
Peritoneal implants possible (especially serous).
Multifocality:
Bilateral disease more common in serous BOT
Peritoneal implants in 25-30% of serous BOT
Lymph node involvement rare but possible
Omental involvement may occur
Multifocal growth within same ovary common
Surface involvement less common than invasive carcinomas.
Microscopic Description
Histological Features:
Epithelial proliferation with stratification and atypia
Papillary architecture with fibrovascular cores
Nuclear atypia (mild to moderate)
Mitotic activity (variable but usually <10/10 HPF)
No destructive stromal invasion
Serous BOT: Hierarchical branching, tufting
Mucinous BOT: Intestinal or endocervical type epithelium.
Cellular Characteristics:
Epithelial cells show enlarged nuclei with mild to moderate atypia
Increased nuclear:cytoplasmic ratio
Prominent nucleoli
Loss of polarity (focal)
Mitotic figures present but not excessive
Apoptotic bodies may be seen
Ciliated cells (serous type)
Goblet cells (mucinous intestinal type).
Architectural Patterns:
Complex papillary pattern with hierarchical branching
Cribriform areas (epithelial proliferation)
Solid epithelial buds without stromal cores
Serous pattern: Fine papillae, psammoma bodies
Mucinous pattern: Villous architecture, intestinal-type epithelium
No microinvasion or destructive invasion.
Grading Criteria:
BOT are not graded like invasive carcinomas
Assessment focuses on degree of epithelial proliferation
Nuclear atypia (mild to moderate)
Architectural complexity
Absence of stromal invasion is key diagnostic criterion
Microinvasion (<5 mm) may be present but prognosis remains excellent.
Immunohistochemistry
Positive Markers:
CK7 (cytokeratin 7, positive in most BOT)
PAX8 (Müllerian origin)
WT1 (serous BOT, strong nuclear staining)
p53 (wild-type pattern, scattered positive cells)
ER/PR (hormone receptors, variable)
CA-125 (serous BOT)
CDX2 (mucinous BOT, intestinal type).
Negative Markers:
CK20 (negative in serous, may be positive in mucinous)
TTF-1 (thyroid transcription factor)
CDX2 (negative in serous BOT)
p16 (usually negative, unlike HGSC)
Vimentin (variable)
Inhibin (sex cord-stromal tumors)
Chromogranin (neuroendocrine).
Diagnostic Utility:
WT1 distinguishes serous BOT from other types
p53 wild-type pattern (unlike HGSC with mutant pattern)
CDX2 helps identify intestinal-type mucinous BOT
PAX8 confirms Müllerian origin
CK7/CK20 profile aids in subtyping
Low Ki-67 proliferation index typically.
Molecular Subtypes:
KRAS mutations (mucinous BOT, 50-70%)
BRAF mutations (serous BOT, 15-30%)
PIK3CA mutations (mucinous BOT, 20%)
ARID1A mutations (endometrioid BOT)
p53 mutations (rare, unlike invasive carcinomas)
Microsatellite stability (most cases).
Molecular/Genetic
Genetic Mutations:
KRAS mutations (mucinous BOT, 50-70%)
BRAF mutations (serous BOT, 15-30%)
PIK3CA mutations (20-30%)
ARID1A mutations (endometrioid BOT)
CTNNB1 mutations (rare)
p53 mutations (rare, <5%)
BRCA1/2 mutations (uncommon)
POLE mutations (rare).
Molecular Markers:
p53 expression (wild-type pattern, scattered cells)
Ki-67 proliferation index (low, <20%)
PTEN expression (usually retained)
MLH1/MSH2/MSH6/PMS2 (intact expression)
ARID1A expression (loss in endometrioid BOT)
β-catenin (membranous pattern)
Cyclin D1 (variable).
Prognostic Significance:
Excellent prognosis overall (95-98% survival)
KRAS mutations do not affect prognosis in BOT
BRAF mutations associated with serous histology
Peritoneal implants (invasive vs non-invasive important)
Bilateral disease does not worsen prognosis significantly
Young age associated with better outcome.
Therapeutic Targets:
Surgical management is primary treatment
Conservative surgery in young patients desiring fertility
MAPK pathway (potential target for KRAS/BRAF mutated cases)
PI3K/AKT pathway inhibitors
Hormone therapy (anti-estrogens for ER+ cases)
Targeted therapy generally not required due to excellent prognosis.
Differential Diagnosis
Similar Entities:
Invasive serous carcinoma (especially low-grade)
Invasive mucinous carcinoma
Benign serous cystadenoma
Benign mucinous cystadenoma
Metastatic adenocarcinoma (especially appendiceal, colorectal)
Brenner tumor
Clear cell carcinoma.
Distinguishing Features:
BOT: No destructive stromal invasion
BOT: p53 wild-type pattern
BOT: Low Ki-67
Invasive carcinoma: Destructive invasion
Invasive carcinoma: Higher grade atypia
Benign adenoma: No epithelial proliferation
Metastases: Clinical history and organ-specific markers
Brenner: Transitional epithelium.
Diagnostic Challenges:
Distinguishing BOT from invasive carcinoma (stromal invasion assessment)
Microinvasion vs destructive invasion
Implants classification (invasive vs non-invasive)
Frozen section diagnosis accuracy
Sampling adequacy (extensive sampling required)
Mixed patterns within same tumor.
Rare Variants:
Micropapillary variant (serous BOT with worse prognosis)
Cribriform variant
Borderline Brenner tumor
Atypical proliferative clear cell tumor
Atypical proliferative endometrioid tumor
Mixed borderline tumor
Borderline tumor with microinvasion.
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 specimen, [left/right/bilateral], measuring [size] cm
Diagnosis
Ovarian borderline tumor (tumor of low malignant potential), [subtype]
Classification
WHO 2020: Borderline tumor, [specific subtype]
Histological Features
Shows epithelial proliferation and atypia without stromal invasion
Size and Extent
Size: [X] cm, [unilateral/bilateral]
Surface and Capsule
Surface involvement: [present/absent], capsule: [intact/breached]
Stromal Invasion
Destructive stromal invasion: [absent/present], microinvasion: [absent/present]
Special Studies
IHC: CK7 [+/-], WT1 [+/-], p53 [wild-type/mutant pattern]
Molecular: [test performed]: [result]
Staging
FIGO Stage: [stage], peritoneal implants: [absent/present]
Prognostic Factors
Excellent prognosis, Stage: [stage], Bilaterality: [yes/no]
Final Diagnosis
Ovarian borderline tumor, [complete subtype]