Specialty Guide · Path-iQ Global Pathology Review

Gynaecological Pathology
The Complete Guide 2026

Gynaecological pathology covers the uterus, cervix, ovaries, fallopian tubes, vulva, and vagina — spanning endometrial carcinoma molecular classification, HPV-driven cervical neoplasia, ovarian tumour subtyping, and rare mesenchymal and trophoblastic tumours. The 2023 WHO Classification of Female Genital Tumours and the TCGA-derived molecular endometrial subgroups have transformed the prognostic and therapeutic landscape.

Updated 30 July 2026 · Path-iQ Editorial · About Path-iQ →

Endometrial Carcinoma — Molecular Classification (ProMisE / TCGA)

The TCGA (2013) identified four molecularly distinct endometrial carcinoma subgroups with markedly different prognoses. The ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) algorithm translates these into routine immunohistochemistry and sequencing, enabling molecular subgrouping without full RNA sequencing. The 2023 WHO classification and ESGO/ESTRO/ESP guidelines now recommend molecular classification for all endometrial carcinomas.

Molecular Subgroup	Frequency	Key Test	Histology	Prognosis	Therapy Implication
POLE ultramutated (POLEmut)	~7–12%	POLE exon 9/13 hotspot sequencing (P286R, V411L, S297F, A456P most common)	Usually endometrioid; high grade; prominent tumour-infiltrating lymphocytes (TILs); peritumoral lymphocytes	Excellent — 5-year DSS >95% regardless of grade or stage; "POLE paradox" (high grade, good prognosis)	Potential de-escalation of adjuvant therapy; high TMB → pembrolizumab responsive in recurrent setting; clinical trials ongoing for omitting radiation in POLEmut high-grade endometrioid
Mismatch repair deficient (MMRd)	~25–30%	IHC panel: MLH1, PMS2, MSH2, MSH6 — nuclear loss in tumour cells = dMMR; MLH1 loss → BRAF V600E/MLH1 promoter methylation to distinguish sporadic from Lynch	Any histotype; more common in endometrioid; heterogeneous grade; peritumoral lymphocytes	Intermediate; significantly worse than POLEmut; better than p53abn; Lynch syndrome patients require genetic counselling	Pembrolizumab approved for dMMR endometrial carcinoma (2nd-line and 1st-line combinations); dostarlimab (GARNET trial); Lynch syndrome cascade testing for family members
p53 abnormal (p53abn)	~25–30%	p53 IHC (DO-7): aberrant pattern = diffuse strong overexpression OR complete null pattern; confirm with TP53 sequencing if IHC equivocal	Serous carcinoma (~90% p53abn); high-grade endometrioid; clear cell; carcinosarcoma; undifferentiated; grade 3 endometrioid	Worst prognosis — 5-year DSS ~40–50% at advanced stage; resembles high-grade serous ovarian carcinoma molecularly	Carboplatin-paclitaxel ± trastuzumab (HER2+ serous); bevacizumab in recurrent; emerging PARP inhibitor trials (BRCAness)
No specific molecular profile (NSMP)	~35–40%	Absence of POLEmut + intact MMR + wild-type p53 pattern; diagnosis of exclusion	Mostly low-to-intermediate grade endometrioid; ER/PR positive in majority; mucinous	Intermediate; further risk stratification by CTNNB1 (beta-catenin) mutations (exon 3), L1CAM expression, and clinicopathological features	Endocrine therapy (medroxyprogesterone, letrozole) for low-risk/recurrent; CDK4/6 inhibitors in ER+ trials; clinical trial enrolment guided by concurrent biomarker profile

Priority Rule for Multiple Molecular Classifiers

A tumour may have more than one molecular alteration (e.g., POLEmut + MMRd; POLEmut + p53abn). Per ESGO/ESTRO/ESP 2023 guidelines, when multiple classifiers co-exist, apply this priority hierarchy:

1st — POLEmut (dominant; overrides all others; excellent prognosis applies regardless of other features)
2nd — MMRd (if no POLE hotspot; overrides p53 status)
3rd — p53 abnormal (if POLE WT and MMR-intact)
4th — NSMP (if all three above negative)

Ovarian Tumour Classification — WHO 2020

Tumour	Frequency	Histology	Key Molecular Feature	IHC	Clinical Behaviour
High-grade serous carcinoma (HGSC)	~70% of ovarian carcinomas	Papillary, solid, cribriform; marked nuclear atypia; high mitotic rate; psammoma bodies; slit-like spaces	TP53 mutation ~96%; BRCA1/2 germline or somatic 15–20%; HRD (homologous recombination deficiency) ~50%	WT1+, PAX8+, p53 aberrant, ER+/−; CK7+; CA-125 elevated clinically	Aggressive; stage III–IV at diagnosis in ~75%; exquisitely platinum-sensitive; PARP inhibitor maintenance (olaparib, niraparib, rucaparib) in BRCA-mutated and HRD
Low-grade serous carcinoma (LGSC)	~5%	Uniform small cells; micropapillary or papillary; low nuclear grade; psammoma bodies; no necrosis; precursor: serous borderline (atypical proliferative serous tumour)	KRAS or BRAF mutation (~35–40%); NRAS, NF2 mutations; MAPK pathway; wild-type TP53	WT1+, PAX8+, p53 wild-type (normal pattern); ER+	Indolent course but platinum-resistant; MEK inhibitor (trametinib) approved for recurrent LGSC (NCI GOG-0281); endocrine therapy (letrozole) active
Endometrioid carcinoma	~10%	Glandular architecture resembling endometrial carcinoma; squamous differentiation; often low grade; associated with endometriosis	CTNNB1 (beta-catenin) mutations; PTEN loss; MMRd in ~10–13%; PIK3CA; ARID1A	PAX8+, ER+, PR+; WT1−; beta-catenin nuclear staining (CTNNB1-mutated)	Better prognosis than HGSC; usually stage I–II; BRCA2 association; molecular subgrouping as endometrial (POLEmut, MMRd, p53abn, NSMP) now applied
Clear cell carcinoma	~10%	Hobnail cells; clear cytoplasm; tubulocystic, papillary, or solid; hyalinised stroma; associated with endometriosis	ARID1A loss (~50%); PIK3CA; TERT promoter; HNF1B amplification; usually TP53 wild-type	HNF1B+, Napsin A+, PAX8+; p53 wild-type; ER−/PR−; WT1−	Platinum-resistant; ARID1A loss may be therapeutic target; mTOR inhibitors under investigation; immunotherapy in ARID1A-deficient subset
Mucinous carcinoma (primary ovarian)	~3%	Expansile or infiltrative mucinous glands; intestinal-type cells; stratified mucinous epithelium; diagnosis requires exclusion of GI/appendiceal metastasis	KRAS mutation (~75%); HER2 amplification; CDX2+	CK20+, CDX2+, CK7+, PAX8 weak/−; must exclude appendiceal primary (CK20+++ and CK7− favours appendix)	Stage I: excellent prognosis after surgery. Stage III–IV: poor; chemotherapy response minimal; HER2-targeted therapy in HER2-amplified cases
Granulosa cell tumour (GCT)	Most common malignant sex cord–stromal tumour	Adult type: Call-Exner bodies (small follicle-like spaces); grooved "coffee-bean" nuclei; low mitotic rate; associated with oestrogenic effects (endometrial hyperplasia/carcinoma)	FOXL2 C402G mutation: pathognomonic for adult GCT (present in ~97%)	Inhibin A+, Calretinin+, SF-1+; WT1+; EMA−; CK weak/focal	Indolent; late recurrence (5–20 years); inhibin as tumour marker; bevacizumab, aromatase inhibitors for recurrent disease

Cervical Cancer — Pathology and HPV Classification

The 2020 WHO Classification introduced a major conceptual shift: stratifying cervical squamous and glandular lesions by HPV-association status rather than purely by morphology. This has implications for pathological diagnosis, risk assessment, and the interpretation of p16 IHC.

Squamous Lesions

Lesion	Old Terminology	HPV Status	p16 IHC	Clinical Significance
LSIL (low-grade squamous intraepithelial lesion)	CIN 1	HPV-associated (any type)	Negative or focal/patchy (not block positive)	High spontaneous regression (>80% regress in 2 years); conservative management; HPV typing guides follow-up
HSIL (high-grade squamous intraepithelial lesion)	CIN 2 / CIN 3	HPV-associated (predominantly HPV16, 18)	Block-positive (diffuse basal to surface, ≥2/3 epithelial thickness)	Significant cancer risk if untreated; LEEP / cold-knife cone excision; CIN 3 / HSIL extending to margins requires re-excision or hysterectomy
Squamous cell carcinoma (SCC) — HPV-associated	—	HPV16 (~60%), HPV18, HPV31, HPV33	Block-positive (diffuse strong)	Most common cervical malignancy globally; keratinising or non-keratinising morphology; radiosensitive; concurrent cisplatin + radiation standard of care for locally advanced disease
Squamous cell carcinoma — HPV-independent	—	HPV-negative; often TP53-mutated	Negative (wild-type p53 pattern)	Older women; aggressive; keratinising; worse prognosis than HPV-associated SCC; rare; may arise in background of lichen sclerosus or vulvar differentiated VIN

p16 IHC Interpretation Rules

Block-positive (diagnostic positive): diffuse strong nuclear and cytoplasmic staining involving ≥2/3 of epithelial thickness from the basal layer — required for HSIL diagnosis when morphology is borderline; always present in HPV-associated SCC and endocervical adenocarcinoma (usual type)
Negative: completely absent OR patchy/focal staining — consistent with HPV-independent lesion, LSIL, or reactive process; negative p16 in a morphological HSIL-appearing lesion warrants HPV ISH confirmation or reclassification
Aberrant pattern: strong nuclear-only staining without cytoplasmic component — seen in endometrial stromal sarcoma; not interpreted as HPV-positive

Vulvar Pathology — Two Pathway Model

Vulvar squamous cell carcinoma arises via two distinct pathways with different risk factors, morphologies, and patient demographics:

Pathway	Precursor	HPV Status	p16	p53	Typical Patient
HPV-associated pathway	uVIN (usual vulvar intraepithelial neoplasia) / HSIL	HPV-positive (16, 18, 31, 33)	Block-positive	Wild-type pattern	Younger women (40s–50s); smoking history; cervical HSIL often concurrent
HPV-independent pathway	dVIN (differentiated VIN); lichen sclerosus → dVIN → SCC	HPV-negative	Negative	Overexpression or null pattern (TP53-mutated)	Older women (70s–80s); lichen sclerosus; more aggressive biology; worse prognosis

Leading Gynaecological Pathologists — Global 2026

Jaime Prat

Ovarian & Gynaecological Tumour Classification

Hospital de la Santa Creu i Sant Pau, Barcelona

Past president of the International Society of Gynecological Pathologists (ISGyP); co-editor of WHO Classification of Female Genital Tumours (5th edition, 2020). International authority on ovarian tumour dualistic model, borderline tumours, and endometrioid carcinoma classification.

Lora Hedrick Ellenson

Endometrial Carcinoma Molecular Pathology

Memorial Sloan Kettering Cancer Center

Authority on endometrial carcinoma molecular classification, TCGA integration into pathological reporting, and the pathological basis of Lynch syndrome-associated endometrial cancer. Expert on mismatch repair IHC interpretation in gynaecological tumours.

C. Blake Gilks

Ovarian Cancer & ProMisE Classification

University of British Columbia / Vancouver General Hospital

Co-developer of the ProMisE molecular classifier for endometrial carcinoma; world authority on HGSC pathology, HRD testing in ovarian cancer, and the integration of molecular data into gynaecological pathology reporting for clinical trial eligibility.

Robert Soslow

Uterine Sarcoma & Endometrial Pathology

Memorial Sloan Kettering Cancer Center

International authority on uterine smooth muscle tumours (STUMP), endometrial stromal tumours, and the WHO 2020 classification of uterine mesenchymal neoplasms. Expert in molecular reclassification of uterine sarcomas — including SMARCA4-deficient tumours and NTRK-fused spindle cell neoplasms.

Naveena Singh

Cervical & Endometrial Pathology

Barts Health NHS Trust / Queen Mary University of London

Leading UK gynaecological pathologist; expert on endocervical adenocarcinoma classification (Silva pattern), HPV-independent cervical lesions, p16 IHC standardisation, and the two-tier cervical glandular intraepithelial neoplasia grading system.

Ie-Ming Shih

Ovarian Carcinogenesis & Serous Carcinoma

Johns Hopkins School of Medicine

Fundamental discoverer of the fallopian tube origin of high-grade serous carcinoma; pioneer in STIC (serous tubal intraepithelial carcinoma) as the precursor of HGSC. Contributions to LGSC KRAS/BRAF mutation biology and the dualistic model of ovarian carcinogenesis.

Frequently Asked Questions

What does POLE-mutated endometrial cancer mean for treatment?

POLE (polymerase epsilon) hotspot mutations cause an ultramutator phenotype — an extraordinarily high tumour mutational burden (TMB typically >100 mutations/Mb) resulting from defective proofreading of DNA replication. Despite often being high-grade on histology, POLEmut endometrial carcinomas have a paradoxically excellent prognosis — greater than 95% 5-year disease-specific survival even in stage III–IV disease. This has prompted ESGO/ESTRO/ESP 2023 guidelines to recommend that adjuvant therapy decisions consider molecular subgroup: POLEmut tumours may not require radiation or chemotherapy that would be standard for morphologically similar tumours. In the recurrent setting, POLEmut tumours are exceptionally immunogenic and highly responsive to checkpoint inhibitor therapy (pembrolizumab), which is consistent with their extremely high neo-antigen burden.

Is high-grade serous ovarian carcinoma related to BRCA mutations?

BRCA1 or BRCA2 germline mutations occur in approximately 15–20% of all HGSC patients and confer a 44–46% (BRCA1) and 12–13% (BRCA2) lifetime ovarian cancer risk. An additional 5–8% have somatic (tumour-acquired, non-inherited) BRCA1/2 mutations. Furthermore, approximately 50% of HGSC have HRD (homologous recombination deficiency) through other mechanisms (BRCA1 promoter methylation, RAD51C, RAD51D, PALB2, BRIP1 mutations). All three groups — germline BRCA, somatic BRCA, and non-BRCA HRD — show clinically meaningful benefit from PARP inhibitor maintenance therapy (olaparib, niraparib, rucaparib) after platinum response, as shown in SOLO-1, PRIMA, and ARIEL-3 trials. All patients with newly diagnosed HGSC should receive germline BRCA testing and tumour HRD testing.

How should Lynch syndrome be evaluated in endometrial carcinoma?

Universal MMR IHC testing (MLH1, PMS2, MSH2, MSH6) is recommended for all endometrial carcinomas regardless of age or family history — endorsed by ESGO, SGO, and CAP guidelines. When MLH1 loss is found, reflex MLH1 promoter methylation testing distinguishes sporadic hypermethylation (most common) from Lynch syndrome (no methylation = likely germline MLH1 mutation → genetic referral). Loss of MSH2, MSH6, or PMS2 without concomitant MLH1 loss, or loss of MSH2+MSH6 together, is highly suspicious for Lynch syndrome and triggers germline genetic counselling regardless of methylation. Lynch syndrome diagnosis has implications not only for the patient (annual endometrial surveillance, coloscopy, urological surveillance) but for all first-degree relatives.