How the WHO 5th edition splits cervical squamous and glandular tumours by HPV status, the precursors of each, the p16 rules, Silva patterns, five whole slide images and MCQs.
- The big change: WHO 5th edition (2020) classifies cervical squamous cell carcinoma and adenocarcinoma as HPV-associated or HPV-independent
- Squamous: over 95% of squamous cell carcinomas are HPV-associated; morphological subtypes do not predict HPV status
- Glandular: usual-type adenocarcinoma is the commonest HPV-associated type; gastric-type is the commonest HPV-independent type
- Surrogate test: diffuse block-type p16 marks high-risk HPV; HPV ISH or PCR confirms
- Prognosis: HPV-independent tumours present later and behave worse
The WHO 5th edition approach
Persistent infection with high-risk HPV, above all types 16 and 18, causes most cervical cancers. The WHO Classification of Female Genital Tumours (5th edition, 2020) now puts HPV status first: each squamous cell carcinoma and adenocarcinoma is called HPV-associated or HPV-independent. The two groups differ in age, precursor lesion, behaviour and response to screening, and HPV vaccination will mostly prevent the first group.
| HPV-associated | HPV-independent | |
|---|---|---|
| Share of cases | Squamous: over 95%. Adenocarcinoma: about 85โ90% | Squamous: under 5%. Adenocarcinoma: about 10โ15% |
| Typical age | Younger, screening-detected | Older, often advanced at diagnosis |
| p16 | Diffuse block-type | Negative or patchy |
| Screening | Detected well by HPV testing and cytology | Often missed by HPV-based screening |
| Prognosis | Better, stage for stage | Worse |
Squamous precursors
The two-tier Lower Anogenital Squamous Terminology (LAST), adopted by WHO, replaces CIN 1โ3 with LSIL and HSIL.
Pathology MCQ| LSIL (CIN 1) | HSIL (CIN 2 and CIN 3) | |
|---|---|---|
| Morphology | Koilocytes; atypia confined to the lower third, maturation preserved | Atypical basaloid cells extend into the upper two-thirds or full thickness; mitoses above the basal layer |
| HPV types | Low-risk and high-risk | High-risk, especially HPV 16 and 18 |
| p16 | Negative or patchy (some block-positive) | Diffuse block-type |
| Natural history | Most regress | Significant risk of progression; treated by excision |
Use p16 to separate HSIL from mimics such as atrophy, immature squamous metaplasia and reactive change, and to sort a CIN 2 morphology into HSIL (block-positive) or LSIL (negative). Do not use it on clear LSIL or clear HSIL.
Pathology MCQHPV-independent squamous precursors are well defined in the vulva, where differentiated VIN precedes HPV-independent carcinoma, but they are rare and poorly characterised in the cervix.
Pathology MCQSquamous cell carcinoma
Invasive squamous cell carcinoma shows nests of atypical squamous cells with desmoplastic stroma, with or without keratin pearls and intercellular bridges.
Pathology MCQKeratinising, non-keratinising, basaloid, warty and papillary patterns do not tell you HPV status. Keratinising tumours can be HPV-associated, and basaloid and warty tumours usually are. WHO 5th edition asks for HPV status (p16 or HPV testing) rather than a morphological subtype.
Pathology MCQGlandular precursors and SMILE
| Lesion | HPV status | Key features |
|---|---|---|
| Adenocarcinoma in situ (AIS), usual type | HPV-associated | Pseudostratified columnar cells with enlarged, hyperchromatic nuclei, apical mitoses and apoptotic bodies, in normally placed glands; p16 block-positive |
| Stratified mucin-producing intraepithelial lesion (SMILE) | HPV-associated | Stratified epithelium with mucin vacuoles through its full thickness; p16 block-positive; regarded as a variant of AIS and managed the same way |
| Gastric-type AIS | HPV-independent | Columnar cells with abundant pale or eosinophilic cytoplasm and distinct borders, mild to moderate atypia; p16 negative or patchy, MUC6 positive |
Atypical glandular cells (AGC) is a cytology reporting category, not a histological precursor. An AGC result calls for colposcopy, endocervical and, depending on age, endometrial sampling.
Pathology MCQ
Pathology MCQAdenocarcinoma
| Group | Types | Notes |
|---|---|---|
| HPV-associated | Usual type (most common); mucinous NOS, intestinal, signet-ring cell; invasive stratified mucin-producing carcinoma (iSMC) | Block p16; usual type has apical mitoses and apoptoses; villoglandular is a growth pattern of usual type |
| HPV-independent | Gastric type (most common in this group), clear cell, mesonephric, endometrioid | p16 negative or patchy; gastric type is aggressive, MUC6 and HIK1083 positive, and linked to Peutz-Jeghers syndrome (STK11) |
| Clear cell | HPV-independent | Historically linked to in-utero diethylstilboestrol; most current cases are sporadic; napsin A and HNF1ฮฒ positive |
| Mesonephric | HPV-independent | Arises from mesonephric remnants; GATA3 and luminal CD10 positive, ER and PR negative |
Pathology MCQSilva pattern classification
For HPV-associated adenocarcinoma, the pattern of invasion predicts nodal spread better than depth alone:
| Pattern | Invasion | Risk |
|---|---|---|
| A | Well-demarcated glands, no destructive stromal invasion or lymphovascular invasion | Nodal metastasis essentially absent; conservative surgery may be possible |
| B | Early destructive invasion from pattern A glands: small clusters or single cells, with or without lymphovascular invasion | Low nodal risk, mainly with lymphovascular invasion |
| C | Diffuse destructive invasion, confluent growth or solid areas | Higher nodal and recurrence risk |
Immunohistochemistry
| Marker | Use |
|---|---|
| p16 | Block-type staining as a surrogate for high-risk HPV; distinguishes HPV-associated from HPV-independent tumours and HSIL from mimics |
| HPV ISH or PCR | Confirms high-risk HPV when p16 is equivocal |
| ER and PR | Usually negative or weak in endocervical adenocarcinoma; strong in endometrial endometrioid carcinoma |
| MUC6, HIK1083 | Gastric-type differentiation |
| GATA3, CD10 | Mesonephric carcinoma |
| Napsin A, HNF1ฮฒ | Clear cell carcinoma |
| p53 | Often aberrant in HPV-independent tumours, especially gastric type |
Endocervical versus endometrial origin: block p16 with ER and PR negative or weak favours an HPV-associated cervical primary; patchy p16, strong ER and PR, PTEN loss and nuclear ฮฒ-catenin favour endometrial endometrioid carcinoma.
Virtual slides
Follow the HPV-associated pathway from cytology to invasion. On annotated slides, tap a region and the viewer zooms to it.
Practice questions
Four quick questions on the points examiners test most.
How does the WHO 5th edition (2020) primarily classify cervical squamous cell carcinoma?
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A cervical biopsy shows atypia extending to the middle third (CIN 2 morphology). Which result supports a diagnosis of HSIL?
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Which cervical adenocarcinoma is HPV-independent, aggressive and associated with Peutz-Jeghers syndrome?
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An HPV-associated adenocarcinoma shows well-demarcated glands with no destructive stromal invasion and no lymphovascular invasion. What is its Silva pattern and nodal risk?
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Work through the gynaecological pathology MCQs with virtual slides and the cytopathology reporting MCQs.
- WHO 5th edition classifies cervical carcinomas by HPV status first.
- Over 95% of squamous cell carcinomas are HPV-associated; morphological subtypes do not predict HPV status.
- Use p16 for CIN 2 morphology and HSIL mimics, not for clear LSIL or HSIL.
- SMILE is a variant of AIS; gastric-type is the main HPV-independent adenocarcinoma and behaves badly.
- Silva pattern A adenocarcinoma has essentially no nodal spread.
WHO Classification of Tumours Editorial Board. Female Genital Tumours. WHO Classification of Tumours, 5th ed. Lyon: IARC; 2020 ยท Darragh TM, Colgan TJ, Cox JT, et al. The Lower Anogenital Squamous Terminology Standardization Project for HPV-associated lesions. Arch Pathol Lab Med 2012;136:1266โ1297 ยท Stolnicu S, Barsan I, Hoang L, et al. International Endocervical Adenocarcinoma Criteria and Classification (IECC). Am J Surg Pathol 2018;42:214โ226 ยท Roma AA, Diaz De Vivar A, Park KJ, et al. Invasive endocervical adenocarcinoma: a new pattern-based classification system. Am J Surg Pathol 2015;39:667โ672
High-Yield, Board-Style Image MCQs & Interactive Whole Slide Images
High-resolution virtual microscopy with questions aligned to ABP, FRCPath, NEET-SS, DM Hematopathology and MD/DNB.
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