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Clear Cell Tumors, Pathology of the Ovary 77
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mismatch repair protein expression is seen in the
setting of either Lynch syndrome or sporadic
(nongermline) loss.
Molecular Features
Approximately 40–50% of clear cell carcinomas
show loss of function mutations in ARID1A,
which is thought to be an early molecular event
in tumor progression (Wiegand et al. 2010).
PIK3CA mutations are also common and are usually seen in tandem with ARID1A loss (Chandler
et al. 2015). Mutations may also be seen in KRAS
(10%), TP53 (<10%), TERT (<10%), and in mismatch repair genes (up to 6%).
Clear cell borderline tumors that are seen in
association with clear cell carcinoma show a similar mutational profile to the malignant component,
including ARID1A and PIK3CA abnormalities.
Differential Diagnosis
Clear Cell Borderline Tumor
The morphological appearances of clear cell borderline tumor are rather distinctive, but confusion
may arise between this entity and struma ovarii
with cytoplasmic clearing, based on the presence
of tubular architecture and dense eosinophilic
secretions. The presence of additional
teratomatous elements in addition to expression
of TTF-1 and Thyrogobulin will support the diagnosis of struma ovarii in this scenario.
Clear Cell Carcinoma
Although clear cells are the hallmark of clear cell
carcinoma, they can be seen in other tumor types.
The diagnosis of clear cell carcinoma therefore
rests on a combination of cytologic and architectural features, supplemented by immunohistochemistry if necessary.
High-grade serous carcinoma (HGSC) with
foci of clear cell change may show morphologic
overlap with clear cell carcinoma. However,
HGSC will show areas of conventional architectural patterns, including large papillae, tufting/
budding (rather than hobnailing), and slit-like
spaces. The nuclei of HGSC are high-grade but
exhibit marked pseudostratification, a greater
degree of nuclear pleomorphism (in a more diffuse distribution), and a much higher mitotic rate
than clear cell carcinoma. HGSC is more often
advanced stage at diagnosis, with significant
involvement of pelvic and extrapelvi c sites. Associated serous tubal intraepithelial carcinoma
(STIC) may also be seen in the fallopian tube.
Expression of WT1 and ER are especially helpful
in distinction from clear cell carcinoma, in addition to aberrant p53 expression.
A serous borderline tumor (SBT) or low-grade
serous carcinoma (LGSC) may resemble clear cell
carcinoma with a papillary predominant growth
pattern. However, the papillae of SBT/LGSC are
larger and more bulbous, with nuclear stratification and tufting/budding. Similarly to HGSC,
expression of WT1 and ER aid in the distinction
from clear cell carcinoma.
Endometrioid-type ovarian carcinoma may
also contain foci of clear cell change, which may
represent secretory vacuoles within glandular epithelium or glycogenation of squamous morules.
The oxyphilic variant of endometrioid ovarian
carcinoma may also be confus ed with clear cell
carcinoma. In both scenarios, however, areas of
conventional endometrioid morphology, including glandular +/ cribriform and solid growths
patterns, should also be seen. Atypia is low-grade
and luminal borders are smooth, in contrast to
those of clear cell carcinoma-bearing hobnail
cells. Positivity with ER and PR together with
absent/focal expression of clear cell markers is
of use in this differential diagnosis. A cautious
approach with the latter markers is advised, however, as the immunoprofile of clear cell change
may overlap with that of clear cell carcinoma; in
this regard, Napsin A is a more specific marker
than HNF1β to refute or substantiate the diagnosis
of clear cell carcinoma.
Ovarian germ cell tumors such as
dysgerminoma or yolk sac tumor (YST) may
also be included in the differential diagnosis,
particularly in the setting of frozen section.
Patients with these tumors are typically younger,
however, and may show elevated serum biomarkers. Close attention to morphologic features
C
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(including primitive cells arranged in nests and
reticular architecture in dysgerminoma and YST,
respectively) and the absence of the architectural
and cytologic features typical of clear cell carcinoma should clarify the diagnosis. An immunohistochemistry panel including both germ cell
tumor markers (SALL4, PLAP, OCT3/4, AFP,
and Glypican-3) and clear cell markers will
contribute.
Metastatic clear cell renal cell carcinoma
(CCRCC) may resemble ovarian clear cell carcinoma morphologically. Clinical and macroscopic
features (renal mass, bilateral and multinodular
ovarian involvement) as well as the chicken-wire
vascular pattern typical of CCRCC may suggest
this diagnosis, in addition to expression of CD10,
RCC, and CA-IX.
References and Further Reading
Bennett, J. A., Dong, F., Young, R. H., & Oliva, E. (2015).
Clear cell carcinoma of the ovary: Evaluation of prog-
nostic parameters based on a clinicopathological anal-
ysis of 100 cases. Histopathology, 66(6), 808–815.
https://doi.org/10.1111/his.12514.
Chandler, R. L., Damrauer, J. S.,Raab, J. R., Schisler, J. C.,
Wilkerson, M. D., Didion, J. P., Starmer, J., Serber, D.,
Yee, D., Xiong, J., Darr, D. B., Pardo-Manuel de
Villena, F., Kim, W. Y., & Magnuson, T. (2015). Coex-
istent ARID1A-PIK3CA mutations promote ovarian
clear-cell tumorigenesis through pro-tumorigenic
inflammatory cytokine signalling. Nature Communica-
tions, 6, 6118. https://doi.org/10.1038/ncomms7118.
Lim, D., Ip, P. P., Cheung, A. N., Kiyokawa, T., & Oliva,
E. (2015). Immunohistochemical comparison of ovarian
and uterine Endometrioid carcinoma, Endometrioid car-
cinoma with clear cell change, and clear cell carc inoma.
The American Journal of Surgical Pathology, 39(8),
1061– 1069. https://doi.org/10.1097/PAS.
0000000000000436.
Machida, H., Matsuo, K., Yamagami, W., Ebina, Y.,
Kobayashi, Y., Tabata, T., Kanauchi, M., Nagase, S.,
Enomoto, T., & Mikami, M. (2019). Trends and characteristics of epithelial ovarian cancer in Japan between
2002 and 2015: A JSGO-JSOG joint study. Gyneco-
logic Oncology, 153(3), 589–596. https://doi.org/10.
1016/j.ygyno.2019.03.243.
Parra-Herran, C., Bassiouny, D., Lerner-Ellis, J., Olkhov-
Mitsel, E., Ismiil, N., Hogen, L., Vicus, D., & NofechMozes, S. (2019). p53, mismatch repair protein, and
POLE abnormalities in ovarian clear cell carcinoma: An
outcome-based Clinicopathologic analysis. The Ameri-
can Journal of Surgical Pathology, 43(12), 1591–1599.
https://doi.org/10.1097/PAS.0000000000001328.
Peres, L. C., Cushing-Haugen, K. L., Kobel, M., Harris,
H. R., Berchuck, A., Rossing,M. A., Schildkraut, J. M.,
& Doherty, J. A. (2019). Invasive epithelial ovarian
cancer survival by Histotype and disease stage. Journal
of the National Cancer Institute, 111(1), 60–68. https://
doi.org/10.1093/jnci/djy071.
Uzan, C., Dufeu-Lefebvre, M., Fauvet, R., Gouy, S.,
Duvillard, P., Darai, E., & Morice, P. (2012). Management and prognosis of clear cell borderline ovarian
tumor. International Journal of Gynecological Cancer,
22(6), 993– 999. https://doi.org/10.1097/IGC.
0b013e3182534acf.
Wiegand, K. C., Shah, S. P., Al-Agha, O. M., Zhao, Y., Tse,
K., Zeng, T., Senz, J., McConechy, M. K., Anglesio,
M. S., Kalloger, S. E., Yang, W., Heravi-Moussavi, A.,
Giuliany, R., Chow, C., Fee, J., Zayed, A., Prentice, L.,
Melnyk, N., Turashvili, G., ... Huntsman, D. G.
(2010). ARID1A mutations in endometriosisassociated ovarian carcinomas. The New England Jour-
nal of Medicine, 363(16), 1532–1543. https://doi.org/
10.1056/NEJMoa1008433.
Zhao, C., Wu, L. S., & Barner, R. (2011). Pathogenesis of
ovarian clear cell adenofibroma, atypical proliferative
(borderline) tumor, and carcinoma: Clinicopathologic
features of tumors with endometriosis or
adenofibromatous components support two related
pathways of tumor development. Journal of Cancer,
2,94–106. https://doi.org/10.7150/jca.2.94.
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Endometrioid Tumors,
Pathology of the Ovary
Naveena Singh
Department of Cellular Pathology, The Royal
London Hospital, Barts Health NHS Trust,
London, UK
Definition
Endometrioid
cystadenoma/
adenofibroma
Endometrioid
borderline
tumor
Endometrioid
carcinoma
Clinical Features
• Incidence
Benign and borderline endometrioid tumors
are rare (Mink et al. 2002). Endometrioid
Benign epithelial tumors with
endometrioid differentiation;
some examples may represent
endometriotic cysts in which
stroma and evidence of cyclical
bleeding is inapparent.
An epithelial tumor in which
there is a proliferation of
endometrioid glands without
confluent or destructive
invasion.
A malignant epithelial tumor
with endometrioid
differentiation and variable
glandular, papillary, and solid
architecture.
carcinoma accounts for approximately 10% of
ovarian tumors (Köbel et al. 2009; Peres
et al. 2019).
• Age
The mean patient age in cases of borderline
endometrioid tumor and endometrioid carcinoma is 46–55 years and 55 years, respectively
(Bell and Kurman 2000; Roth et al. 2003;
Rambau et al. 2018).
• Sex
Female.
• Site
Ovary.
• Clinical Associations/Risk Factors
Endometriosis is a predisposing factor for the
spectrum of ovarian endometrioid tumors.
Endometrioid carcinoma may occur in the context of Lynch syndrome (Chui et al. 2014;
Niskakoski et al. 2018) and its incidence is
increased in those receiving hormone therapy
and/or with a first-degree family history of
breast cancer (Wentzensen et al. 2016).
• Treatment
Treatment is based on grade and stage, with
surgery alone being sufficient for low-grade
(grade 1 or 2) and stage IA cases.
• Outcome
Endometrioid cystadenoma and adenofibroma
are benign lesions. Malignant behavior has not
been described in endometrioid borderline
tumor and it therefore carries an excellent
prognosis (Bell and Kurman 2000; Roth et al.
2003). Outcome in endometrioid carcinoma is
© Springer Nature Switzerland AG 2023
S. Stolnicu, R. Ali-Fehmi (eds.), Gynecologic Pathology, Encyclopedia of Pathology,
https://doi.org/10.1007/978-3-030-97378-0
80 Endometrioid Tumors, Pathology of the Ovary
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dependent upon stage at diagnosis (Rambau
et al. 2017). The 5-year survival rates for local-
ized (FIGO stage IA/IB), regional (FIGO stage
IC/II), and distant (FIGO stage III/IV) disease
are 87%, 84%, and 45%, respectively (Peres
et al. 2019). Staging the rare carcinomas that
simultaneously involve the endometrium and
ovary is problematic. These have been demon-
strated to be clonally related, thereby
representing metastasis from one (probably
endometrium) to other (probably ovary) site
(Anglesio et al. 2016; Schultheis et al. 2016).
Despite this, their indolent behavior supports
conservative management if the following
criteria are met: low-grade endometrioid carci-
noma at both sites; <50% myometrial inva-
sion; absence of any other disease site; and
absence of lymphovascular space invasion
(Gilks and Singh 2018).
Macroscopy
Endometrioid Cystadenoma/Adenofibroma
Endometrioid cystadenomas appear as unilocular
cysts. Adenofibromas are predominantly solid
with a white cut surface that may be punctuated
by small cysts. Endometrioid adenofibroma may
appear in continuity with an endometriotic cyst.
Endometrioid Borderline Tumor
Endometrioid borderline tumors tend to be unilateral (3–10% are bilateral) and large, with a mean
maximum dimension of 9 cm (Bell and Kurman
2000; Roth et al. 2003). They have smooth sur-
faces and may be solid, cystic, or a combination of
the two. The cyst lumen may contain hemorrhagic
material.
Microscopy
Endometrioid Cystadenoma/Adenofibroma
Endometrioid cystadenomas are cysts lined by
endometrioid epithelium. They are distinct from
endometriotic cysts in that they lack supporting
endometrial-like stroma. In endometrioid
adenofibromas, endometrioid glands are embedded within a fibromatous stroma. The glands are
widely spaced, without evidence of crowding
(Norris 1993).
Endometrioid Borderline Tumor
Adenofibromatous
This is the most common growth pattern in endometrioid borderline tumor (Bell and Kurman
2000; Roth et al. 2003; Zhang et al. 2018). The
features are as per adenofibroma, but the glands
are crowded and irregular with mild to moderate
nuclear atypia, recapitulating atypical hyperplasia
of the endometrium, albeit with a vaguely lobular
architecture (Fig. 1). Squamous metaplasia, particularly in the form of morules, is common.
Intracystic
This growth pattern is characterized by a papillary
proliferation that projects into the lumen of an
endometriotic cyst.
In both patterns, the presence of more than
5 mm of confluent growth (back-to-back
Endometrioid Carcinoma
Endometrioid carcinomas are unilateral and
large with a mean maximum dimension of
11 cm (Rambau et al. 2017). They may be
solid, cyst ic, or a combination of the two with
varying degrees of hemorrhage and necrosis.
They may appear in continuity with an endometriotic cyst, presenting as a solid nodule that
projects into the cyst lumen.
Endometrioid Tumors, Pathology of the Ovary,
Fig. 1 Endometrioid borderline tumor typically shows
lobular growth comprising areas resembling atypia or
non-atypical endometrial hyperplasia
Endometrioid Tumors, Pathology of the Ovary 81
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glandular proliferation without intervening
stroma) or destructive stromal invasion should
trigger a diagnosis of endometrioid carcinoma.
Endometrioid Carcinoma
Endometrioid carcinoma of the ovary demonstrates the same spectrum of appearances as its
uterine counterpart and, in some instances, is seen
in continuity with benign and borderline
adenofibromatous components. It typically com-
prises a confluent proliferation of irregularly shaped
glands with smooth luminal contours, though papillary and solid components may be present in varying degrees and invasion may be overtly destructive
with associated desmoplasia. Generally, the tumor
cell nuclei are mild-moderately atypical and round/
ovoid, with open chromatin, though more pronounced atypia may be evident. Squamous and
mucinous differentiation are common features.
Some tumors show cytoplasmic clearing and others
secretory change with subnuclear vacuolation. Less
commonly, tumors may exhibit sex cord-stromallike growth with cells arranged in small tubules,
nests, or cords; prominent spindled morphology;
oxyphilic cytoplasm; ciliated change; and a corded
and hyalinized pattern (Pitman et al. 1994; Tornos
et al. 1995; Eichhorn and Scully 1996; Murray
et al. 2005).
Immunophenotype
KRAS, and ARID1A mutations seen in 53%, 40%,
17%, 33%, and 30%, respectively) (Wu et al.
2007; McConechy et al. 2014; Köbel et al.
2019). More recently it has been demon strated
that the four molecular groups identified by the
Cancer Genome Atlas (TCGA) are also seen
within ovarian endometrioid carcinomas, with
similar prognostic, and potentially therapeutic,
correlates (Krämer et al. 2020).
E
Differential Diagnosis
Endometrioid cystadenoma/adenofibroma: Serous
cyst-/adenofibroma, clear cell cyst-/adenofibroma,
mucinous cyst-/adenofibroma, endometriotic cyst,
and endometrioid borderline tumor.
Endometrioid borderline tumor: Endometrioid
carcinoma, endometrioid adenofibroma, mucinous
borderline tumor, and serous borderline tumor.
Endometrioid carci noma: High-grade serous
carcinoma (vs. grade 3 endometrioid carcinoma),
clear cell carcinoma (vs. endometrioid carcinoma
with clear cells), metastatic endometrial endometrioid carcinoma, metastatic colorectal carcinoma, metastatic endocervical adenocarcinoma,
Sertoli-Leydig cell tumor, adult granulosa cell
tumor, yolk sac tumor, mesonephric-like carcinoma, and carcinosarcoma (vs. grade 3 endometrioid carcinoma) (Fig. 2).
Endometrioid epithelium is typically positive for
CK7, hormone receptors ER and PR (81–85%),
and PAX8 (85%). Endometrioid carcinomas are
generally WT1 negative (10–14% of tumors will
express WT1 to some degree) and napsin
A negative (positivity observed in 3–8% of cases,
particularly in areas of secretory change). They
typically exhibit wild-type immunoreactivity with
p53 (but see below) (Köbel et al. 2016, 2019).
Molecular Features
Ovarian endometrioid carcinomas typically show
alterations in the WNT/β-catenin signaling, PI3K
and MAPK pathways (CTNNB1, PIK3CA, PTEN,
Endometrioid Tumors, Pathology of the Ovary,
Fig. 2 Endometrioid ovarian carcinoma resembles its
endometrial counterpart and similar rules apply for diagnosis and grading
82 Endometrioid Tumors, Pathology of the Ovary
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References and Further Reading
Anglesio, M. S., Wang, Y. K., Maassen, M., Horlings,
H. M., Bashashati, A., Senz, J., Mackenzie, R., Grewal,
D. S., Li-Chang, H., Karnezis, A. N., Sheffield, B. S.,
McConechy, M. K., Kommoss, F., Taran, F. A.,
Staebler, A., Shah, S. P., Wallwiener, D., Brucker, S.,
Gilks, C. B., Kommoss, S., & Huntsman, D. G. (2016).
Synchronous endometrial and ovarian carcinomas:
Evidence of clonality. Journal of the National Cancer
Institute, 108(6), djv428.
Bell, K. A., & Kurman, R. J. (2000). A clinicopathologic
analysis of atypical proliferative (borderline) tumors
and well-differentiated endometrioid adenocarcinomas
of the ovary. The American Journal of Surgical Pathol-
ogy, 24(11), 1465–1479.
Chui, M. H., Ryan, P., Radigan, J., Ferguson, S. E., Pollett,
A., Aronson, M., Semotiuk, K., Holter, S., Sy, K.,
Kwon, J. S., Soma, A., Singh, N., Gallinger, S., Shaw,
P., Arseneau, J., Foulkes, W. D., Gilks, C. B., & Clarke,
B. A. (2014). The histomorphology of Lynch
syndrome-associated ovarian carcinomas: Toward a
subtype-specific screening strategy. The American
Journal of Surgical Pathology, 38(9), 1173–1181.
Eichhorn, J. H., & Scully, R. E. (1996). Endometrioid
ciliated-cell tumors of the ovary: A report of five
cases. International Journal of Gynecological Pathol-
ogy, 15(3), 248 –25 6. https://doi.org/10.1097/
00004347-199607000-00010. Erratum in: Int
J Gynecol Pathol 1996;15(4):369.
Gilks, C. B., & Singh, N. (2018). Synchronous carcinomas
of endometrium and ovary: A pragmatic approach.
Gynecologic Oncology Reports, 27,72–73.
Köbel, M., Kalloger, S. E., Carrick, J., Huntsman, D.,
Asad, H., Oliva, E., Ewanowich, C. A., Soslow,
R. A., & Gilks, C. B. (2009). A limited panel of
immunomarkers can reliably distinguish between
clear cell and high-grade serous carcinoma of the
ovary. The American Journal of Surgical Pathology,
33(1), 14–21.
Köbel, M., Rahimi, K., Rambau, P. F., Naugler, C., Le
Page, C., Meunier, L., de Ladurantaye, M., Lee, S.,
Leung, S., Goode, E. L., Ramus, S. J., Carlson, J. W.,
Li, X., Ewanowich, C. A., Kelemen, L. E.,
Vanderhyden, B., Provencher, D., Huntsman, D., Lee,
C. H., Gilks, C. B., & Mes Masson, A. M. (2016). An
immunohistochemical algorithm for ovarian carcinoma
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Köbel, M., Luo, L., Grevers, X., et al. (2019). Ovarian
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Krämer, P., Talhouk, A., Brett, M. A., Chiu, D. S., Cairns,
E. S., Scheunhage, D. A., Hammond, R. F. L., Farnell,
D., Nazeran, T. M., Grube, M., Xia, Z., Senz, J., Leung,
S., Feil, L., Pasternak, J., Dixon, K., Hartkopf, A.,
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P., Kommoss, F. K. F., Sinn, H. P., Heublein, S.,
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Kroon, C. D., Nijman, H. W., de Bruyn, M., Thompson,
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Journal of Ovarian Research, 11(1), 67.
According to World Health Organization (WHO), in
2018 approximately 382,000 patients were diagnosed with endometrial carcinoma worldwide. Traditionally , the pathogenesis of endometrial
carcinoma has been based on a dualistic model
that defines two broad categories of endometrial
carcinoma (Bokhman 1983). Ty pe 1 tumors are
defined as low grade, estrogen dependent, relatively
indolent neoplasms, and Type 2 tumors, arising
independent of estrogenic stimulation , typically
associated with p53 mutations and an aggressive
clinical course. This dichotomous categorization of
endometrial carcinoma is conceptually still relevant,
however, seems to be an oversimplification for routine clinical practice where increasing clinical, morphologic, immunophenotypic, and molecular
overlap exists. With advances in the understanding
of endometrial carcinoma at the genomic and proteomic levels came the molecular classification, in the
2013 landmark paper by Th e Cancer Genome Atlas
(TCGA) that defined four types of endometrial carcinoma. As the overall understanding of endometrial carcinoma evolves, accurate histologic typing
of endometrial carcinoma continues to be a challenge in the routine sign out of cases (Clement and
Young 2002).
Precursor Type 1
Endometrioid Intraepithelial Neoplasia (EIN)/
Atypical Hyperplasia (AH)
See text below.
E
Epithelial Tumors and
Precursors, Type 1, Pathology
of the Uterine Corpus
Sanam Husain
Henry Ford Health System, Detroit, MI, USA
Definition
Endometrial carcinoma is the most common malignancy of the uterine corpus in the western world
with a global increase in the incidence of new cases.
Definition
An increase in the ratio of endometrial glands to
stroma accompanied by cytologic alteration in the
glandular epithelium defines atypical hyperplasia
(AH) of the endometrium and is synonymous with
endometrioid intraepithelial neoplasia (EIN). The
concept has evolved over many years and is primarily based on the architectural and cytologic
and histopathologic patterns of endometrial
glands and stroma. It is now well established that
this histopathologic pattern represents a clonal
alteration of the endometrium driven by underlying mutations, most ly observed in the PTEN and
PAX2 genes, and microsatellite instability.
84 Epithelial Tumors and Precursors, Type 1, Pathology of the Uterine Corpus
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Unopposed estrogen production plays a key role
in the pathogenesis of AH/EIN and subsequently
that of endometrioid adenocarcinoma by estrogenic stimulation of the endometrial lining.
Clinical Features
Although most prevalent in postmenopausal
females, endometrial hyperplasia is being
observed with increasing frequency in the premenopausal patient population due to the
increased incidence of diseases associated with
excess estrogen worldwide such as obesity, hypertension, and type II diabetes mellitus. As such,
AH/EIN is seen in up to 25% of premenopausal
women with less than 5% presenting at age
40 or less.
Up to 30% of patients with AH/EIN diagnoses
who undergo definitive surgery with immediate
follow-up will have endometrioid adenocarcinoma
identified in the hysterectomy specimen. With the
increased incidence of AH/EIN in premenopausal
patients, there is a growing demand for fertility
preserving, nonsurgical treatment options. Hormonal treatment with progesterone is a viable
option for this patient population with high doses
of progestins administered either orally or as a
component of intrauterine devices (IUD). High
dose progesterone treatment is also an alternative
to surgery in patients who are not surgical candidates. Surveillance endometrial sampling after
6 months of progestin therapy is recommended,
with the biopsy results categorized as resolution
(no residual AH/EIN), persistent AH/EIN
(residual disease in endometrial biopsy), and progression (morphologic evidence of endometrial
adenocarcinoma). Histologic evidence of exogenous hormone therapy effect is often present. The
overall outcome of AH/EIN is excellent,like that of
early-stage low grade endometrial carcinoma.
ratio by greater than 50% and typically a maximum linear extent of at least 1 mm. The crowded
glands may have cribriform configuration, papillary infoldings, or cystic dilatation (Fig. 1). The
distinctive feature of AH/EIN, however, is the
cytologic alteration of the endometrial glandular
epithelium within the area of architectural complexity. The nuclear features in the focus of glandular crowding can vary; however, most
commonly the lesional cells display relatively
large, round to ovoid vesicular nuclei, inconspicuous nucleoli, loss of polarity, and variable
mitotic activity (Fig. 2). It is of pivotal importance
to acknowledge that the cellular changes in
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 1 Atypical hyperplasia/
endometrioid intraepithelial neoplasia (AH/EIN).
Increased glandular density and cytologic demarcation
compared to inactive endometrial gland in the center
Macroscopy
The endometrial lining most commonly appears
to be thickened or vaguely polypoid, without discrete lesions, however, may appear unremarkable.
Microscopy
The architectural abnormality in AH/EIN is
defined by an increase in the gland to stroma
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 2 AH/EIN. Cytologic
atypia in AH/EIN with adjacent benign glands
Epithelial Tumors and Precursors, Type 1, Pathology of the Uterine Corpus 85
https://t.me/med1917
type with microsatellite instability, and mutations
in PTEN, PIK3CA, and CTNNB1.
Differential Diagnosis
The dif ferential diagnosis o f AH/EIN includes common benign and malignant diseases of the endometrium. Of the benign entities, non-atypical
hyperplasia, endometrial polyp, and various types
of endometrial metaplasia are most important. Nonatypical or benign endometrial hyperplasia is characterized by increased glandular density similar to
AH/EIN; however, there is no cytologic demarca-
Epithelial Tumors and Precursors, Type 1, Pathology
of the Uterine Corpus, Fig. 3 Marked AH/EIN. The
presence of stroma between the atypical glands argues
against a diagnosis of endometrial adenocarcinoma
tion in non-atypical hyperplasia with the crowded
glands displaying features similar to those in the
non-crowded glands (Kurman et al. 1985). Endometrial polyps often show irregular glands with
variable degrees of cystic dilatation and may show
AH/EIN can be often subtle and are considered
sufficient for a definitive diagno sis of AH/EIN if
they are distinct from the adjoining non-crowded
endometrium. This cytologic demarcation is the
most reliable and distinguishing feature of
AH/EIN. In addition to the nuclear atypia, the
cells in AH/EIN may demonstrate tubal, mucinous, secretory, papillary, eosinophilic, and squamous morular metaplasia. The presence of
epithelial metaplasia in an area of increased glandular density, therefore, does not exclude AH/EIN
(Fig. 3).
glandular crowding. Comparing the cytology to the
adjacent glands will reveal a similar morphology;
however, it is important to know that AH/EIN can
involve endometrial polyps and the cytomorphologic features will be those of typical AH/EIN
seen in non-polypoid areas. Endometrial metaplasia
including tubal, secretory, and eosinophilic types
can be focal changes mimicking cytologic demarcation. The increase in gland to stroma ratio, higher
degree of cytologic atypia, and comparison to the
non-crowded areas in the endometrium can be helpful (McKenney and Longacre 2009).
Distinguishing AH/EIN from well-
Immunohistochemistry
Estrogen receptor (ER) and progesterone receptor
(PR) are frequently diffusely positive in AH/EIN.
The vast majority of AH/EIN (approximately
98%) shows intact expression of mismatch repair
proteins. When present in association MMRdeficient endometrial carcinoma, the focus of
AH/EIN often displays similar absent immunohistochemical staining. Loss of PTEN by
immunoperoxidase staining is frequently
differentiated endometrial carcinoma can be challenging especially in biopsy/curetting specimens.
Confluent, anastomosing glands or cribriform
architecture are patterns of endometrial adenocarcinoma. Size criteria of 2.1 mm may be used to
make the distinction. When the features for adenocarcinoma are equivocal, a diagnosis of “at
least AH/EIN” with a comment explaining that
the atypical hyperplasia borders onto well differentiated adenocarcinoma is reasonable.
observed in AH/EIN similar to endometrioid adenocarcinoma. Absent PAX2 expression has been
proposed as a marker for AH/EIN (Quick
Endometrioid Carcinoma
See text below.
et al. 2012).
Definition
Molecular Features
AH/EIN may demonstrate a molecular phenotype
similar to endometrial carcinoma, endometrioid
Endometrioid carcinoma is the prototype of
estrogen-driven type I neoplasms, and is by far
the most common histologic type, comprising
E
86 Epithelial Tumors and Precursors, Type 1, Pathology of the Uterine Corpus
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greater than 90% of all epithelial malignancies.
Most frequently encountered in postmenopausal
women, the incidence of endometrioid adenocarcinoma in the premenopausal patient population is
increasing, similar to its precursor AH/EIN.
Excess estrogen, either endogenous or exogenous,
plays a key role in the development of the endometrial neoplasm. Obesity, polycystic cystic
ovary syndrome (PCO), early menarche, late
menopause, and estrogen-pr oducing tumors such
as adult granulosa cell tumor are predisposing
conditions. Exogenous unopposed estrogen and
tamoxifen are established risk factors for the
development of endometrial neoplasia. Endometrial carcinoma is associated with hereditary diseases, of which Lynch syndrome and Cowden
syndrome are most common.
Clinical Features
By far the most common presenting symptom of
endometrial carcinoma is abnormal uterine bleeding. Less freque ntly, patients may present with
pelvic and or abdominal symptoms. Serologic
markers are not of particular use in this setting;
however, CA-125 can be elevated in patients with
advanced stage disease.
Treatment
Low grade endometrioid adenocarcinomas less
than 2 cm in greatest dimension that are superficially invasive without lymph vascular space
invasion are treated with simple hysterectomy
and bilateral salpingo-oophorectomy. High grade
endometrioid histology, size larger than 2 cm,
lymph-vascular space invasion, and deep
myometrial invasion typically warrant chemotherapy, radiation therapy, or hormonal treatment.
Current guidelines based on molecular profiles
are evolving and are likely to play an important
role in the future management of disease.
Outcome
Generally, the endometrioid type of endometrial
carcinoma has an indolent course with early-stage
carcinomas showing an excellent prognosis. The
overall 5-year survival rate of stage is 90%, with a
significant drop to30–50% forstage 2endometrial
carcinomas. The prognosis for high stage
endometrial carcinoma (stages 3 and 4) is dismal
with a 20% 5-year survival.
Staging parameters are of paramount importance in determining the prognosis of endometrial
carcinoma. Tumors limited to the endometrium
(stage 1a) have an excellent prognosis with a
5-year survival of greater than 90%.
Endometrial carcinoma that invades cervical
connective tissue or destructive stromal invasion
has an adverse outcome compared to tumors that
involve endocervical glandular mucosa only. This
distinction is important and additional sampling of
the isthmus-cervical junction may be necessary to
definitively establish tumor extension into cervical
stroma. Occasionally, endometrial carcinoma
involving the endocervical stroma may present as
a distinct lesion and can be misdiagnosed as an
independent cervical primary. The tumors may
exhibit relatively bland histologic features and
may be misinterpreted as benign endocervical
glandular proliferations (Tambouret et al. 2003).
Tumors that involve ovarian parenchyma and
fallopian tube have a decreased overall survival
(5-year disease-free survival of 37%). Detached
tumor cells identified intraluminally in the
fallopian tubes are not considered bona fide
adnexal involvement. Presence of endometrioid
adenocarcinoma in the ovary raises the question
whether this is spread from the endometrial primary or a synchronous ovarian primary. Lower
grade histology, myometrial invasion less than
50%, and absent angiolymphatic invasion are features that argue against metastasis to the ovary
(Connell et al. 1999). The presence of endometriosis within the ovary is an important feature along
with absent surface involvement that favors a synchronous primary. Typically, only unilateral ovarian involvement is present in such cases. The
abovementioned parameters are in general helpful
in making the decision of independent primaries
versus metastasis from organ to the other. However, in some cases it may not be possible to do so
with certainty. Generally, when this occurs in a
metastatic setting it is the endometrial tumor
involving the ovary with transtubal spread and
less likely from the ovary to the endometrium,
although in rare instances it can occur. Additionally, when there is secondary involvement of either
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