MINI-SYMPOSIUM: UPDATE ON PATHOLOGY OF FEMALE GENITAL TRACT TUMOURS
Endometrial carcinoma:
changes to classification
(WHO 2020)
Mariam Masood
Naveena Singh
Abstract
Since the 2014 WHO classification of Female Genital Tract tumour,
there have been significant improvements in our understanding of
the genomic basis of endometrial carcinoma, largely based on the
seminal findings from The Cancer Genome Atlas analysis, which
have been befittingly included in the newest edition for the subcatego-
rization of endometrioid carcinomas. Nevertheless, morphological
classification, with or without the aid of immunohistochemistry, re-
mains paramount to diagnosis and correct patient management, in
addition to retaining the global outreach of the 5th Classification in
the absence of universal access to molecular testing. In addition to
this change in subclassification of endometrioid carcinomas, four
new entities have been included within the endometrial carcinoma
classification: mesonephric adenocarcinoma, mesonephric-like
adenocarcinoma, squamous cell carcinoma and mucinous carcinoma,
intestinal type. The subject of Neuroendocrine neoplasia has merited a
separate chapter under “Neuroendocrine Neoplasia of Female Genital
Tract” in congruence with other body sites. This streamlines the clas-
sification and aids management of patients consistently. Additionally,
more nuanced information has been included in most other subsec-
tions, including novel immunohistochemical markers and relevant
prognostic factors. In this short review, we aim to describe the up-
dates to endometrial carcinoma classification in the latest WHO
edition.
Keywords classification; endometrial carcinoma; histology; the
Cancer Genome Atlas
Introduction
Recent years have seen an exponential improvement in our un-
derstanding of the pathogenetic basis of endometrial carcinomas
(EC). The molecular characterization by The Cancer Genome
Atlas (TCGA)1 has led to a paradigm shift from the traditional
dualistic model of Type 1 and Type 2 EC to a classification that
reflects its much more heterogeneous nature.2 The diagnosis of
Mariam Masood BSc MBBS FRCPath Consultant Histopathologist, St
George’s University Hospitals NHS Foundation Trust, London, UK.
Conflicts of interest: The authors have no conflicts of interest to
declare.
Naveena Singh MBBS MD MRCPath Consultant Histopathologist,
Department of Cellular Pathology, The Royal London Hospital,
London, UK. Conflicts of interest: The authors have no conflicts of
interest to declare.
DIAGNOSTIC HISTOPATHOLOGY 27:12
certain histotypes of endometrial tumours has been plagued with
suboptimal reproducibility,3 which may consequently have an
adverse impact on clinical management. Future adoption of a
molecular basis of categorization would improve accuracy and
reproducibility in diagnosis and prognostication, in addition to
holding promise for personalized treatment and improved patient
outcomes.
The new WHO classification, published in 2020, acknowl-
edges these molecular developments in the subclassification of
EC.4 However, in accordance with WHO’s international
approach, the new edition continues to classify the tumours
based on morphology with the aid of immunohistochemistry, as
some molecular techniques remain fairly inaccessible globally.
Furthermore, while the molecular classification applies to all
histotypes of EC, its impact on risk categorization of the rarer
non-endometrioid tumours, independent of histotype, requires
further prospective research data. Clinical decision-making still
hinges on the primary binary distinction of endometrioid from
non-endometrioid carcinomas and for this reason a thorough
recognition of all EC histotypes and the distinction of endome-
trioid from non-endometrioid carcinomas is vital for clinical
management.
In this article, we aim to highlight the significant changes that
have occurred since the previous (2014)5 WHO classification
(Table 1) with an emphasis on clinical impact.
Molecular classes of endometrial carcinoma
EC fall into four non-overlapping molecular categories: (i) those
harbouring mutations in the gene encoding the (exonuclease
domain of the) enzyme DNA Polymerase epsilon (POLEmut EC),
also known as ultramutated owing to the exceptionally high rates
of mutations within tumour cells; (ii) those that are mismatch
repair deficient (MMRd EC), also known as hypermutated as
these too show high rates of mutations in tumour cells; (iii) those
showing mutations in the oncogene TP53 (p53abn EC), also
known as copy number-high owing to the high numbers of so-
matic copy number alterations; and (iv) those having none of
these 3 molecular defects, a diagnosis of exclusion, known as No
Specific Molecular Profile (NSMP EC).1,6 This molecular catego-
rization leads to better prediction of clinical outcomes than that
afforded by morphology and traditional risk parameters such as
stage and the presence of lymphovascular space invasion
(LVSI).7 Furthermore it serves to screen for patients with an
underlying genetically inherited risk of cancer; approximately
10% of MMRd EC occurs as part of Lynch Syndrome and if
correctly diagnosed, appropriate surveillance and prophylactic
strategies can be put in place for patients as well as their family
members.8
Clinicians and pathologists are widely aware of the poor
prognosis of grade 3 endometrioid and high-grade serous carci-
noma of the endometrium. The TCGA analysis and subsequent
studies have shown that all p53abn EC, including serous, grade 3
endometrioid as well as other histotypes, and also some
morphologically low-grade endometrioid carcinomas, have
complex genomic abnormalities with extensive somatic copy
number alterations.9,10 Clinically, these patients have a poor
prognosis and should undergo similar treatment, especially if
diagnosed at an advanced stage. The British Gynaecological
493 Ó 2021 Published by Elsevier Ltd.
 MINI-SYMPOSIUM: UPDATE ON PATHOLOGY OF FEMALE GENITAL TRACT TUMOURS

Cancer Society (BGCS) recommends treatment at a cancer centre, grade morphology, occur in association with obesity, nulli-
and consideration of further imaging and adjuvant therapy.11 parity and diabetes mellitus, and their behaviour ranges from
While MMRd EC often show high-grade morphology, the excellent to intermediate.4
prognosis is intermediate in comparison with p53abn and The TCGA molecular categories of EC can be replicated in
POLEmut EC.1,6 Morphologically, MELF pattern of invasion, practice using surrogate markers: MMR and p53 immunohis-
mucinous differentiation and tumour infiltrating lymphocytes tochemistry (IHC) and sequencing for POLE.7 These must be
may suggest this histotype.4 Ultimately, this should be confirmed interpreted using a particular algorithm as the 2 categories
with immunohistochemistry for the MMR proteins MLH1, PMS2, characterized by high mutational rates, POLEmut and MMRd
MSH2 and MSH6.7 This is relevant clinically as these patients EC, can show multiple mutations and adherence to the algo-
may have underlying Lynch Syndrome, with a predisposition to rithm ensures correct interpretation of MMR and p53 IHC
colorectal and ovarian carcinoma, thereby opening the door to (Figure 1).4,6
genetic counselling if required.12 Ultimately, the WHO classification aims to provide uniform
The novel category of POLEmut EC was identified by the terminology to aid communication globally. Since some molec-
TCGA study, revolutionizing our understanding of endometrioid ular techniques may not be available worldwide, the diagnostic
carcinoma. These occur in younger women with no metabolic process continues to rest on histomorphology, with adjunct
predisposition such as obesity and, despite showing high-grade immunohistochemistry if available.4
morphology, these cancers have excellent prognosis.13
Lastly, the subcategory of NSMP EC carries few somatic copy
Endometrioid carcinoma
number alterations and low numbers of mutations. PTEN,
CTNNB1, PIK3CA, ARID1A and KRAS mutations have been Endometrioid carcinoma is by far the most commonly encoun-
identified in this category.1 These tumours typically have low- tered malignant epithelial uterine tumour. This remains defined
as a carcinoma with varying architecture that may be glandular,
papillary or solid, composed of tumour cells showing endome-
trioid differentiation, typically arising in a background of atypical
Classification of endometrial carcinoma in WHO 2014 hyperplasia. Nuclear atypia tends to be mild to moderate and
and WHO 2020 squamous differentiation is common. Mucinous change may be
seen to varying degree and its presence does not define a sepa-
WHO 2014 classification of WHO 2020 classification of
rate category even when extensive, as long as the newly
endometrial carcinoma endometrial epithelial tumours
described (non-endometrioid) intestinal-type mucinous carci-
Endometrioid carcinoma Endometrioid carcinoma noma is excluded (see below). The list of morphological varia-
Squamous differentiation POLE-ultramutated tions of endometrioid carcinoma has been expanded to include
endometrioid carcinoma microglandular, spindle cell, sertoliform, sex cord-like and hya-
Villoglandular Mismatch repair-deficient linized patterns and endometrioid EC with small non-villous
endometrioid carcinoma papillae. A secretory pattern, which was previously recognized,
Secretory P53-mutant endometrioid may be focal or widespread, and can mimic clear cell carcinoma.
carcinoma None of these patterns reflect biological behaviour and these are
No specific molecular profile regarded as part of the same entity, rather than clinically sig-
(NSMP) endometrioid nificant variants.
carcinoma The most significant change to subclassification of endome-
Mucinous carcinoma trioid EC is the recognition of the 4 molecular subtypes; it is
Serous endometrial intraepithelial Serous carcinoma NOS recommended that endometrioid EC, in particular high-grade
carcinoma endometrioid EC, should be classified into molecular subtypes,
Serous carcinoma as described above, where resources permit.4
Clear cell carcinoma Clear cell adenocarcinoma NOS While grading of endometrioid carcinomas remains un-
Neuroendocrine tumours changed; some additional details that alter prognostication have
Low-grade been recommended. FIGO grading, as previously, is based on the
High-grade extent of solid, non-squamous architecture: < 5%, 6e50% and
Mixed cell adenocarcinoma Mixed cell adenocarcinoma >50% defining grades 1, 2 and 3 respectively (Figure 2a). With
Undifferentiated carcinoma Carcinoma, undifferentiated, NOS regard to solid architecture, the International Society of Gyne-
Dedifferentiated carcinoma cological Pathologists (ISGyP) endorses the interpretation of
Squamous cell carcinoma NOS confluent microacinar growth pattern as ‘solid’ despite the
Mesonephric adenocarcinoma presence of small acinar spaces (Figure 2b).14 Binary grading is
Mesonephric-like adenocarcinoma recommended, with FIGO grades 1 and 2 constituting low-grade
Mucinous carcinoma, intestinal endometrioid EC and grade 3 tumours constituting high-
type grade.4,14
The correlation between microcystic, elongated and frag-
Carcinosarcoma NOS mented (MELF) invasion pattern and lymphovascular invasion
has been recognized.4,15 Furthermore, for the distinction be-
Table 1 tween focal and extensive lymphovascular invasion, a cut-off of

DIAGNOSTIC HISTOPATHOLOGY 27:12 494 Ó 2021 Published by Elsevier Ltd.

 MINI-SYMPOSIUM: UPDATE ON PATHOLOGY OF FEMALE GENITAL TRACT TUMOURS
<5 and 5 respectively has been suggested to correlate with risk
of metastasis and guide clinical management4; more recently a
criterion of ‘> 4 LVSI-involved vessels in at least one H&E sec-
tion” has been proposed to define clinically relevant LVSI.16
Guidance has been provided to aid the conundrum of syn-
chronous ovarian and endometrial endometrioid carcinomas. It
has been shown that this combination of tumours represents a
primary carcinoma of likely endometrial origin with ovarian
metastasis, but it is recommended that these are treated
conservatively if the tumours are low-grade and stage IA (organ
confined at both sites), with no evidence of lymphovascular in-
vasion or metastasis, as such cases have been shown in the
literature to demonstrate indolent behaviour.17 It is advised that
such tumours are managed as independent low-stage primary
tumours of the uterus and ovary until further data accrue.
Serous carcinoma
Serous carcinoma is the second commonest endometrial carci-
noma, accounting for approximately 10% of all cases.4 This is
characterized by diffuse and striking nuclear pleomorphism, and
typically exhibits papillary and/or glandular growth patterns,
though solid architecture may be encountered (Figure 3a). This
carcinoma is not graded as it is high-grade by definition. This
typically arises in a background of atrophy and some cases may
be microscopic or confined to the epithelium of a polyp; despite
this they retain potential to metastasize via the tubes and are
classified and staged as carcinomas despite their size or absence
of stromal invasion.18
The vast majority of serous EC demonstrate TP53 mutations19
and additional common genomic changes are mutations affecting
PIK3CA, PPP2R1A, and FBXW7.1 About one-third of cases show
Figure 1 Algorithm for interpretation of POLE sequencing, MMR IHC and p53 IHC for accurate mo-
lecular categorization of endometrial carcinoma.
DIAGNOSTIC HISTOPATHOLOGY 27:12
ERBB2 (HER2) amplification.4,20 With regard to molecular class,
all serous EC cases included in the TCGA analysis were classified
as copy number-high.1 These tumours almost invariably show
aberrant, mutation-type p53 IHC expression, most commonly
diffuse nuclear over-expression or complete absence of staining.
A small minority may show the recently described cytoplasmic
staining pattern or indeed normal, wild-type expression.21
These tumours are staged as other EC. Correct diagnosis is
vital for these clinically aggressive tumours that are responsible
for 40% of all deaths due to EC. With the exception of tumours
limited to the endometrium, these carry a high risk of recurrence
and death regardless of stage and presence or absence of LVSI.
This aggressive behaviour often merits adjuvant radiotherapy
with chemotherapy.22 In the future, targeted treatments related
to HER2 amplification, defects in the homologous recombination
repair pathway of DNA repair and immune checkpoint inhibition
may prove to be effective therapies.6
Clear cell carcinoma
Clear cell carcinoma is a subtype with imprecise diagnostic
criteria and likely variation in diagnostic thresholds.23 For these
reasons its exact frequency is not known; this represents <10%
and likely around 2% of all EC. The tumour is defined as a
carcinoma composed of variably pleomorphic cells that may be
polygonal, cuboidal, flat or hobnail and show clear or eosino-
philic cytoplasm (Figure 3b). The cells may be arranged in
papillary, tubulocystic, and/or solid architectural patterns. This
loose definition results in significant overlap with endometrioid
and serous carcinomas. In terms of the molecular profile, these
tumours are heterogeneous and contain a mixture of TCGA
subtypes.24,25
495 Ó 2021 Published by Elsevier Ltd.
 MINI-SYMPOSIUM: UPDATE ON PATHOLOGY OF FEMALE GENITAL TRACT TUMOURS
Figure 2 (a) Endometrioid carcinoma: glandular and solid architecture. (b) Endometrioid carcinoma: confluent microacinar architecture should be
considered as ‘solid’.
In addition to the previously recognized positivity for
HNF1beta in endometrial clear cell carcinoma, the new edition
also endorses positive Napsin-A and AMACR, which are more
readily available, to be diagnostically useful. The tumours are
typically negative for estrogen and progesterone receptors (ER
and PR), and most show wild-type p53 immunoreactivity; those
that show mutation-pattern p53 IHC expression are arguably
better considered to be variants of serous carcinoma.4
Undifferentiated and dedifferentiated carcinoma
Undifferentiated and dedifferentiated carcinomas are clinically
aggressive EC histotypes. The morphological criteria remain the
same as previously. These tumours are defined as epithelial tu-
mours showing no specific lineage differentiation. They are
characterized by a relatively monotous population of small to
intermediate-sized tumour cells arranged in solid sheets. There is
no gland, trabecular or nest formation. Foci of abrupt keratini-
zation can be present. There is often necrosis and invariably high
mitotic activity. The majority of cases are monomorphic, how-
ever, about 40% of these show an admixture of carcinoma that is
usually of grade 1 or 2 endometrioid type (Figure 4), but rarely
grade 3 endometrioid or even serous. The two components vary
widely in proportion and in the nature of the interface.4
These tumours are associated with mismatch repair deficiency
in 50e75% of cases.26 A significant proportion of these tumours
contain inactivating mutations in core genes of the SWI/SNF
complex.27 This is manifested immunohistochemically by loss of
expression in SMARCA4 (BRG1), SMARCB1 (INI1), ARID1A or
ARID1B.4 Other useful immunohistochemistry includes negative
or very occasional perinuclear dot like positivity for EMA and
pancytokeratins. It is recommended to use two epithelial markers
Figure 3 (a) High grade uterine serous carcinoma. (b) Clear cell carcinoma of the endometrium.
DIAGNOSTIC HISTOPATHOLOGY 27:12
to exclude other EC subtypes. Some tumours may show
expression of neuroendocrine markers, synaptophysin and
chromogranin, but this is usually focal. ER, PR, PAX8 and e-
cadherin are typically negative in the undifferentiated compo-
nent. The negative staining for most markers is a useful diag-
nostic feature, in conjunction with typical morphology.
Mixed carcinoma of the uterine corpus
The designation of “mixed carcinoma of the uterine corpus”
applies when two discrete histological types are identified, at
least one of which is either serous or clear cell.4 The new edition
strictly advocates that the two components should be unambig-
uously distinct histotypes of endometrial carcinoma; these
should be distinct morphologically as well as immunohis-
tochemically. Dedifferentiated EC and carcinosarcoma that are
mixed by definition are excluded from this diagnosis. The arbi-
trary threshold of 5% of a serous component in a mixed tumour
has been removed, since there is evidence to suggest that any
percentage of high-grade carcinoma, serous or clear cell, confers
a worse prognosis. These account for about <10% of all EC, a
percentage that is even lower with application of strict criteria,
and their behaviour is generally determined by the worst
component.4,28,29
New entities
The new classification has seen the introduction of four new
entities: Mesonephric adenocarcinoma, mesonephric-like
adenocarcinoma, squamous cell carcinoma and mucinous car-
cinoma, gastrointestinal type. In each of these it is important to
rule out extension from the cervix as this is overwhelmingly the
more common site of a primary carcinoma with this morphology.
496 Ó 2021 Published by Elsevier Ltd.
 MINI-SYMPOSIUM: UPDATE ON PATHOLOGY OF FEMALE GENITAL TRACT TUMOURS
Figure 4 Dedifferentiated carcinoma: in this example islands of low-
grade endometrioid carcinoma with glandular architecture are seen
within a diffuse population of discohesive ‘rhabdoid’-appearing un-
differentiated carcinoma cells.
Immunohistochemistry is of limited use and, in cases
involving both endometrium and cervix, distinguishing between
endometrial and cervical origin will require extensive sampling
at grossing and correlating with radiological findings. It is ex-
pected that with increased recognition, we will develop a better
understanding of these rare tumours in the future.
Mesonephric and mesonephric-like adenocarcinoma
Both these tumours share many morphological, immunohisto-
chemical and molecular similarities, however mesonephric car-
cinoma shows definite evidence of mesonephric remnants, which
is not identifiable in mesonephric-like carcinoma. The aetiology
remains enigmatic but KRAS and ARID1A mutations have been
described in both tumours.30,31
Typically these tumours show small tubules with dense
eosinophilic colloid-like material in close association with a
diverse array of morphologies including papillary, ductal, reti-
form, solid and spindled architecture (Figure 5).
In keeping with the mesonephric origin/differentiation, these
tumours typically show diffuse positivity for GATA-3. Calretinin
and CD10 positivity has also been described. ER and PR are
negative, and p53 shows wild-type staining.
Squamous cell carcinoma, NOS
Primary squamous cell carcinoma of the endometrium is well
recognized but was inadvertently excluded in the 4th edition.
Like the mesonephric carcinomas, squamous cell carcinoma is
exceedingly rare in the uterine corpus. Risk factors include
chronic inflammatory conditions, previous irradiation, and HPV
infections. Morphologically, these are identical to SCC seen
elsewhere in the body, but may exhibit less cytological atypia,
and have broad invasive fronts.4
Mucinous carcinoma, gastrointestinal type
Primary mucinous endometrial carcinoma of gastric (gastroin-
testinal) type has only been recently described as previously the
focus was on those tumours of this morphology arising in the
DIAGNOSTIC HISTOPATHOLOGY 27:12
cervix, where it is more common.32 Histologically, this is char-
acterized by glandular architecture with mucin-secreting epithe-
lium that may include goblet cells. The tumour cells are typically
ER and PR negative, unlike endometrioid EC with mucinous
differentiation. Their correct recognition is important, firstly to
exclude cervical or gastrointestinal tract origin, and, secondly, as
these are reported to be associated with aggressive clinical
behaviour, and should therefore not be misdiagnosed as low-
grade endometrioid EC (Figure 6).4
Carcinosarcoma
Recategorization of carcinosarcoma as an endometrial carcinoma
as opposed to a mixed epithelial and mesenchymal malignancy
has been one of the most important changes.4 Next generation
sequencing has proven that the sarcomatous elements are
transdifferentiated from carcinoma during tumour evolution.33
While the high frequency of TP53 mutations has been docu-
mented in both editions; with the advent of TCGA classification,
78% or more of carcinosarcomas are classified as p53abn, 22
e38% as NSMP and <5% as POLEmut or MMRd.34
Its aggressive nature is highlighted and furthermore, it has
been noted that most of the metastases appear to morphologi-
cally resemble the carcinomatous component. While stage re-
mains the most important prognostic factor, several other
parameters have been included in this new edition, which
include size of >5 cm, lymphovascular invasion and sarcoma-
tous predominance. The presence of rhabdomyoblastic elements
is considered to be associated with poor prognosis according to
various large studies. Both editions cite that the presence of se-
rous component is associated with poor prognosis.35,36
Clinical implications
The WHO classification remains the gold standard for catego-
rizing EC. The latest edition provides more detailed under-
standing of each entity with an explanation for the molecular
underpinnings. We are currently in a very exciting phase of
translating molecular findings to clinical practice.
MMR testing is increasingly being undertaken for EC,
regardless of histotype. This aids recognition not only of MMRd
EC, which have an intermediate behaviour, but may also high-
light patients with Lynch Syndrome.7,8,12 Such patients if young
may not be suitable candidates for hormonal therapy.37
Her-2 testing in serous EC has been suggested in the new
edition,4 though HER2 status correlates more strongly with
p53abn EC than serous histology.38 Studies have shown that
approximately 30% of these tumours show HER-2 over-
expression and/or gene expression leading to the suggestion of
adding trastuzumab to carboplatin and paclitaxel regimen in
suitable patients with recurrent or advanced stage carcinoma.6
Currently the BGCS and European Society for Medical
Oncology (ESMO) advocate an algorithmic approach based on
FIGO grade and staging.39 There is a risk of “overtreatment” and
“undertreatment” in a minority of cases since morphology alone
may not truly represent clinical behaviour. This is particularly
true of POLEmut and p53abn EC. For this reason, the recently
published joint guidelines of the European Societies of Gynae-
cological Oncology, Pathology, and Radiotherapy and Oncology
have risk categorization algorithms both with and without
497 Ó 2021 Published by Elsevier Ltd.
 MINI-SYMPOSIUM: UPDATE ON PATHOLOGY OF FEMALE GENITAL TRACT TUMOURS
Figure 5 Mesonephric-like carcinoma: low-power view to show variety
of architectural patterns. Courtesy of Dr Elizabeth Euscher, MD
Anderson Cancer Centre, Houston, Texas, USA.
Figure 6 Gastric (gastro-intestinal) type endometrial carcinoma: note
the deceptively low-grade nuclear morphology that belies the
aggressive behaviour reported to be typical of this rare tumour.
molecular classification.37 The prognostic value of the TCGA
subtypes has been validated by numerous retrospective studies.
Ongoing prospective clinical trials in this field will improve our
understanding of the clinical utility of the TCGA classification.
Key to the exciting new application of molecular genomics in
diagnosis and management of EC is the correct interpretation of
MMR and p53 IHC,40 as well as wider availability of POLE mu-
tation testing.
Summary and conclusions
The diagnosis of endometrial tumours continues to show
interobserver variability. The new WHO classification provides
useful morphological, immunohistochemical and molecular
diagnostic features to avoid discrepancies. It also aims to pro-
vide uniform nomenclature in order to facilitate communication
globally.
There has been an introduction of four new entities: meso-
nephric adenocarcinoma, mesonephric-like adenocarcinoma,
squamous cell carcinoma and mucinous carcinoma, intestinal
type. Neuroendocrine neoplasms have been separated from the
endometrial carcinoma chapter.
DIAGNOSTIC HISTOPATHOLOGY 27:12
The new WHO classification emphasises the importance of
histology supported by adjunct immunohistochemistry. This is
particularly important for accurate distinction of endometrioid
from non-endometrioid EC. As our understanding of the molec-
ular basis of EC continues to increase, we anticipate further
evolution within the WHO classification in future editions. It is
also hoped that the dawn of personalized medicine leads to the
introduction of targeted molecular therapies in the treatment of
EC with improved patient outcomes. A
REFERENCES
1 Cancer Genome Atlas Research Network. Kandoth C, Schultz N,
et al. Integrated genomic characterization of endometrial carci-
noma. Nature 2013; 497: 67e73.
2 Casey L, Singh N. POLE, MMR, and MSI testing in endometrial
cancer: proceedings of the ISGyP Companion Society Session at
the USCAP 2020 Annual Meeting. Int J Gynecol Pathol 2021; 40:
5e16.
3 Gilks CB, Oliva E, Soslow RA. Poor interobserver reproducibility in
the diagnosis of high-grade endometrial carcinoma. Am J Surg
Pathol 2013; 37: 874e81.
4 WHO Classification of Tumours Editorial Board. Female genital
tumours. 5th edn. Lyon (France): International Agency for
Research on Cancer, 2020.
5 WHO classification of tumors of the Female reproductive organs.
4th edn. Lyon: International Agency for Research on Cancer
(IARC), 2014.
6 Vermij L, Smit V, Nout R, Bosse T. Incorporation of molecular
characteristics into endometrial cancer management. Histopa-
thology 2020; 76: 52e63.
7 Talhouk A, McConechy MK, Leung S, et al. Confirmation of
ProMisE: a simple, genomics-based clinical classifier for endo-
metrial cancer. Cancer 2017; 123: 802e13.
8 Crosbie EJ, Ryan NAJ, Arends MJ, et al. The Manchester Inter-
national Consensus Group recommendations for the manage-
ment of gynecological cancers in Lynch syndrome. Genet Med
2019; 21: 2390e400.
9 Bosse T, Nout RA, McAlpine JN, et al. Molecular classification of
grade 3 endometrioid endometrial cancers identifies distinct
prognostic subgroups. Am J Surg Pathol 2018; 42: 561e8.
10 Leo
n-Castillo A, de Boer SM, Powell ME, et al. Molecular classi-
fication of the PORTEC-3 trial for high-risk endometrial cancer:
impact on prognosis and benefit from adjuvant therapy. J Clin
Oncol 2020; 38: 3388e97.
11 Sundar S, Balega J, Crosbie E, et al. BGCS Uterine Cancer
Guidelines: Recommendations for Practice. https://www.bgcs.
org.uk/wp-content/uploads/2019/05/BGCS-Endometrial-
Guidelines-2017.pdf. Accession date May 1, 2021.
12 Diagnostics guidance [DG42] Published. Testing strategies for Lynch
syndrome in people with endometrial cancer. 28 October 2020,
https://www.nice.org.uk/guidance/dg42 (accessed 1 May 2021).
13 McAlpine JN, Chiu DS, Nout RA, et al. Evaluation of treatment
effects in patients with endometrial cancer and POLE mutations:
an individual patient data meta-analysis. Cancer 2021; 127:
2409e22.
14 Soslow RA, Tornos C, Park KJ, et al. Endometrial carcinoma
diagnosis: use of FIGO grading and genomic subcategories in
clinical practice: recommendations of the International Society of
498 Ó 2021 Published by Elsevier Ltd.
 MINI-SYMPOSIUM: UPDATE ON PATHOLOGY OF FEMALE GENITAL TRACT TUMOURS
Gynecological Pathologists. Int J Gynecol Pathol 2019; 38:
S64e74.
15 Dogan Altunpulluk M, Kir G, Topal CS, Cetiner H, Gocmen A. The
association of the microcystic, elongated and fragmented (MELF)
invasion pattern in endometrial carcinomas with deep myometrial
invasion, lymphovascular space invasion and lymph node
metastasis. J Obstet Gynaecol 2015; 35: 397e402.
16 Peters E, Leo
n-Castillo A, Smit VTHMD, et al. Defining substantial
lymphovascular space invasion in endometrial cancer. Int J
Gynecol Pathol, 2021. published online: https://doi.org/10.1097/
PGP.0000000000000806.
17 Blake Gilks C, Singh N. Synchronous carcinomas of endometrium
and ovary: a pragmatic approach. Gynecol Oncol Rep 2018; 27:
72e3.
18 Schultheis AM, Martelotto LG, De Filippo MR, et al. TP53 muta-
tional spectrum in endometrioid and serous endometrial cancers.
Int J Gynecol Pathol 2016; 35: 289e300.
19 Buza N, Hui P. Marked heterogeneity of HER2/NEU gene ampli-
fication in endometrial serous carcinoma. Genes Chromosomes
Cancer 2013; 52: 1178e86.
20 Baergen RN, Warren CD, Isacson C, Ellenson LH. Early uterine
serous carcinoma: clonal origin of extrauterine disease. Int J
Gynecol Pathol 2001; 20: 214e9.
21 Singh N, Piskorz AM, Bosse T, et al. p53 immunohistochemistry is
an accurate surrogate for TP53 mutational analysis in endometrial
carcinoma biopsies. J Pathol 2020; 250: 336e45.
22 de Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemo-
radiotherapy versus radiotherapy alone in women with high-risk
endometrial cancer (PORTEC-3): patterns of recurrence and post-
hoc survival analysis of a randomised phase 3 trial. Lancet Oncol
2019; 20: 1273e85.
23 Murali R, Davidson B, Fadare O, et al. High-grade endometrial
carcinomas: morphologic and immunohistochemical features,
diagnostic challenges and recommendations. Int J Gynecol Pathol
2019; 38: S40e63.
24 Hoang LN, McConechy MK, Meng B, et al. Targeted mutation
analysis of endometrial clear cell carcinoma. Histopathology 2015;
66: 664e74.
25 DeLair DF, Burke KA, Selenica P, et al. The genetic landscape of
endometrial clear cell carcinomas. J Pathol 2017; 243: 230e41.
€ S, Cristo

bal-Lana E, et al. Molecular
26 Rosa-Rosa JM, Leskela
genetic heterogeneity in undifferentiated endometrial carcinomas.
Mod Pathol 2016; 29: 1390e8.
27 Karnezis AN, Hoang LN, Coatham M, et al. Loss of switch/-
sucrose non-fermenting complex protein expression is associated
with dedifferentiation in endometrial carcinomas. Mod Pathol
2016; 29: 302e14.
28 Quddus MR, Sung CJ, Zhang C, Lawrence WD. Minor serous and
clear cell components adversely affect prognosis in ’’mixed-type’’
endometrial carcinomas: a clinicopathologic study of 36 stage-I
cases. Reprod Sci 2010; 17: 673e8.
29 Li W, Li L, Wu M, Lang J, Bi Y. The prognosis of stage IA mixed
endometrial carcinoma. Am J Clin Pathol 2019; 152: 616e24.
DIAGNOSTIC HISTOPATHOLOGY 27:12
30 Howitt BE, Nucci MR. Mesonephric proliferations of the female
genital tract. Pathology 2018; 50: 141e50.
31 Mirkovic J, McFarland M, Garcia E, et al. Targeted genomic
profiling reveals recurrent KRAS mutations in mesonephric-like
adenocarcinomas of the female genital tract. Am J Surg Pathol
2018; 42: 227e33.
32 Wong RW, Ralte A, Grondin K, Talia KL, McCluggage WG.
Endometrial gastric (Gastrointestinal)-type mucinous lesions:
report of a series illustrating the spectrum of benign and malignant
lesions. Am J Surg Pathol 2020; 44: 406e19.
33 McConechy MK, Hoang LN, Chui MH, et al. In-depth molecular
profiling of the biphasic components of uterine carcinosarcomas.
J Pathol Clin Res 2015; 1: 173e85.
34 Cherniack AD, Shen H, Walter V, et al. Integrated molecular
characterization of uterine carcinosarcoma. Cancer Cell 2017; 31:
411e23.
35 Matsuo K, Takazawa Y, Ross MS, et al. Significance of histologic
pattern of carcinoma and sarcoma components on survival out-
comes of uterine carcinosarcoma. Ann Oncol 2016; 27: 1257e66.
36 Kurnit KC, Previs RA, Soliman PT, et al. Prognostic factors
impacting survival in early stage uterine carcinosarcoma. Gynecol
Oncol 2019; 152: 31e7.
37 Concin N, Matias-Guiu X, Vergote I, et al. ESGO/ESTRO/ESP
guidelines for the management of patients with endometrial car-
cinoma. Int J Gynecol Cancer 2021; 31: 12e39.
38 Vermij L, Horeweg N, Leon-Castillo A, et al. HER2 status in high-risk
endometrial cancers (PORTEC-3): relationship with histotype, mo-
lecular classification, and clinical outcomes. Cancers 2020; 13: 44.
39 Colombo N, Creutzberg C, Amant F, et al. ESMO-ESGO-ESTRO
consensus conference on endometrial cancer: diagnosis, treat-
ment and follow-up. Ann Oncol 2016; 27: 16e41.
40 Wong RW-C, Palicelli A, Hoang L, Singh N. Interpretation of p16,
p53 and mismatch repair protein immunohistochemistry in
gynaecological neoplasia. Diagn Histopathol 2020; 26: 257e77.
Practice points
C Morphology remains crucial in typing and grading endometrial
carcinomas.
C It is crucial for correct management to accurately distinguish be-
tween endometrioid and non-endometrioid histotypes; for this
reason it is vital to be aware of and recognize the variants of
endometrioid carcinoma and the growing list on non-
endometrioid histotypes.
C The molecular classification of endometrial carcinoma applies to
all histotypes but is most clinically relevant in the distinction of
endometrioid carcinomas, particularly those that are high-grade
(grade 3).
499 Ó 2021 Published by Elsevier Ltd.