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What Is New In 5th Edition WHO-FGT

The WHO classification of tumours are a system specific fascicles, also commonly known as WHO blue books. The fifth edition of WHO blue books are revised & updated edition, under the leadership of Dr. Ian Cree. The aim is to provide a classification and a set of international standards which underpin the diagnosis of tumour worldwide.

The new classification emphasized on key molecular events that resulted in the discovery of new tumour types and in refinement to the categorization of common neoplasm like endometroid carcinoma. Importance is given to integrated morphological-molecular approach, with conventional pathology retaining its pivotal role in interpretation.

The specific organ wise updates of female genital tract WHO are reviewed below; Ovary: The histotype diagnosis is retained from 4th edition, with five main types of ovarian carcinoma having different risk factors, genetics, precursor lesions, immunophenotype, response to therapy and clinical outcome. Few changes in present edition include; reintroduction of mixed carcinoma category. Though rare, it is usually seen in background of endometriosis with clear cell and emdometrioid type. Rare ovarian carcinoma variants added includes mesonephric-like carcinoma and de-differentiated carcinoma (Endometrioid + undifferentiated carcinoma). Carcinosarcoma is now considered as carcinoma variant, rather than true mesenchymal and epithelial tumour. Seromucinous carcinoma has been removed, but is now included as morphological variant of emdometrioid carcinoma.

For non-epithelial ovarian neoplasm, category of gynandroblastoma (Male + female differentiation) has been reintroduced. Information regarding underlying molecular abnormality in sex-cord stromal tumours, such as FOXL2 mutations in adult granulosa tumours.
Tumours of Peritoneum and Fallopian tube: Well differentiated papillary mesothelioma has been renamed as “well differentiated papillary mesothelial tumour”, to signify its benign clinical course. The primary peritoneal HGSC which is exceedingly rare needs fallopian tube origin to be ruled out first. The origin of most extra uterine HGSCs as fallopian tube (FT) fimbrial end is accepted, and detailed recommendations how to designate the site of origin is outlined in 5th edition.

Another clarification is in regard to multiple HGSC, it was previously thought that they could arise at multiple sites through some form of the “Field effect.” However it is now convincingly proven that HGSC at multiple sites are clonal, with one site representing the primary and others being metastatic.

Tumors of uterine corpus: Two new morphologic types of endometrial carcinoma included are mesonephric-like-carcinoma and mucinous carcinoma intestinal type (changed to mucinous carcinoma-gastric type). Serous intraepithelial carcinoma is excluded from the classification, because such lesions, even in absence of any invasion may shed malignant cells and metastasize. The morphologic classifications is thus left unchanged, barring above mentioned changes. Molecular classification based on TCGA (the cancer genome atlas), whose four subtypes [POLEmut, MMRd p53abn, and no specific molecular profile], correspond to molecular subtypes identified on basis of genomic architecture. Four molecular subtypes are more reproducible than morphologic classification, & can be assigned on biopsy specimen to aid in initial treatment planning, provide prognostic information and predict response to treatment. This classification is particularly useful in prognostication of grade 3 endometrioid adenocarcinoma. (PROTEC-3 trial). Table 1 gives detailed Molecular classification of endometrial carcinoma. The POLEmut category is important, as these tumour have a favourable prognosis despite having high risk pathological features. Hence clinical trials are ongoing for de-escalating treatment. The p53abn has high levels of somatic copy number alteration just like ovarian HGSC, howevever association with BRCA 1 & 2 is less likely. The presence of Her2 amplification and HRD make them amenable to targeted therapy. They however respond better to Combined Chemo-radiation. The NSMP category contains hormone positive tumours and encompasses most conventional endometrioid carcinoma. MMRd category is amenable to check point inhibitors in metastatic setting. They have poorer prognosis outside lynch syndrome associated carcinoma. Thus this classification finds place in many international treatment guidelines like NCCN.

POLE-ultramutated EC MMR-deficient EC p53-mutant EC NSMP EC
> 100 mutations / Mb, SCNA very low, MSS 10-100 mutations / Mb, SCNA low, MSI < 10 mutations / Mb, SCNA high, MSS < 10 mutations/Mb, SCNA low, MSS, 30-
40% with CTNNB1 mutations
Often high-grade, ambiguous morphology
with scattered tumour giant cells,
prominent TILS
Often high-grade, prominent TILS,
mucinous differentiation, MELF-type
invasion, LVSI
Mostly high-grade with diffuse cytonuclear
atypia; glandular and solid forms exist
Mostly low-grade with frequent squamous
differentiation or morule, absence of TILS
Advanced stage at presentation Higher body mass index MMR-IHC: MLH1, MSH2, MSH6, and
PMS2; MSI assay; NGS
p53-IHC: mutant-like staining MMR-proficient, p53-wildtype, and
pathogenic POLE variant absent
Poor Intermediate to excellent May be associated with Lynch syndrome
Prognosis Excellent Intermediate

Table 1: Molecular classification of endometrial cancers

The other recommendation pertains to synchronous low grade endometrioid carcinoma of the endometrium and ovary are clonally related, with endometrial being the primary carcinoma.

Mesenchymal tumours are better defined using molecular perturbations. 2020 WHO now includes molecularly defined entities like; High-grade endometrial stromal sarcomas associated with YWHAE- NUTM2A/B or BCOR genetic abnormalities, undifferentiated sarcomas associated with SMARCA4 mutation, Sarcomas associated with NTRK rearrangements. This will result in diminution of the category of undifferentiated sarcomas.

Cervical and lower genital tract epithelial neoplasm: Squamous & Adenocarcinoma are divided into HPV associated and independent, clear, mesonephric and gastric type included in later. The classification across lower genital tract sites is harmonized, including for vaginal and vulvar carcinoma. In vagina no HPV- independent lesion is defined. p16 immunostaining or HPV testing is required for this categorization. (Table 2A, 2B)

There is no difference in treatment between HPV-associated and HPV-independent tumours as of today. There is no evidence that an HPV-independent squamous precursor lesion exists, and squamous intraepithelial lesions are therefore grouped into a single, HPV-associated, category. Thus, Squamous are all HPV associated whereas adenocarcinoma are divided into HPV associated and independent.

Table 2A. Comparison of the 2014 and 2020 World Health Organization (WHO) classifications of cervical squamous cell carcinoma
WHO 2014 WHO 2020
Squamous cell carcinoma,
usual type
Squamous cell carcinoma,
Keratinising type HPV-associated
Non-keratinising type Squamous cell carcinoma,
Papillary type HPV-independent
Basaloid type Squamous cell carcinoma, NOS
Warty type
Verrrucous type
Squamotransitional type
Lymphoepithelioma-like type
HPV, Human papillomavirus; NOS, not otherwise specified.
Table 2B. Comparison of the 2014 and 2020 World Health Organization (WHO) classifications of cervical adenocarcinoma
WHO 2014 WHO 2020
Endocervical adenocarcinoma,
usual type
HPV-associated cervical
adenocarcinoma (includes several subtypes; see text)
Mucinous carcinoma, NOS HPV-independent cervical adenocarcinoma
Mucinous carcinoma, gastric
Gastric type
Mucinous carcinoma, intestinal
Mesonephric type
Mucinous carcinoma, signet
ring cell type
Clear cell type
Villoglandular carcinoma Other adenocarcinomas
Mesonephric carcinoma
Serous carcinoma
Clear cell carcinoma
Endometrioid carcinoma
HPV, Human papillomavirus; NOS, not otherwise specified.

Trophoblastic tumours : 5th edition WHO, Tabulates the different categories of trophoblast and the benign and malignant lesions arising from each category. The category of gestational trophoblastic neoplasms (GTNs) has been expanded to include mixed trophoblastic tumour. Diagnosis of molar and non-molar pregnancies has been given a more detailed description. Exaggerated placental site reaction and placental site nodule / plaque (PSN) are classified as tumour-like lesions (in the 4th edition, these were grouped as non-neoplastic lesions)

Conclusion : The new WHO classification addresses numerous issues and incorporates recent developments in the field. However because of large number of authors, some inconsistencies have crept in the text. The WHO has released the erratum to take care of some of these issues.

The online version with Whole slide images is a welcome change in this series.

References :
1. WHO Classification of tumours series, 5th edition; vol.4, 2020
2. Cree, I A, White, V A, Indave, B I & Lokuhetty, D Revising the WHO classification: female genital tract tumours; (2020) Histopathology 76, 151– 156.
3. McCluggage, WG. Progress in the pathological arena of gynecological cancers. Int J Gynecol Obstet. 2021; 155(Suppl. 1): 107– 114
4. McCluggage WG, Singh N, Gilks CB. Key changes to the World Health Organization (WHO) classification of female genital tumours introduced in the 5th edition (2020). Histopathology. 2022 Apr; 80(5):762-778.

Dr. Gurudutt Gupta
Sr. Consultant & Head – Histopathology, RGCIRC, Rohini

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