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Epithelial Tumors and Precursors, Type 2, Pathology of the Uterine Corpus 97
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Epithelial Tumors and
Precursors, Type 2, Pathology
of the Uterine Corpus
Eman Abdulfatah
University of Michigan, Ann Arbor, MI, USA
Serous Intraepithelial Carcinoma
Synonyms
Serous endometrial intraepithelial carcinoma
(EIC).
Definition
– Replacement of the surface epithelium/
endometrial glands with serous carcinoma
cells without invasion of the u nderlying
stroma.
E
98 Epithelial Tumors and Precursors, Type 2, Pathology of the Uterine Corpus
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– Proposed as a precursor lesion of serous carci-
noma, however, can be associated with extrauterine disease.
Clinical Features
• Age and epidemiology
Postmenopausal women, nonobese, estrogen
independent.
• Site
Uterine corpus; frequently arises on the surface
of an endometrial polyp in a background of
atrophic endometrium.
• Treatment
Surgical excision (hysterectomy).
• Outcome
Serous endometrial intraepithelial carcinoma
behaves as an adenocarcinoma that happens to
be growing along a surface, including the capability for metastasis to peritoneal sites.
Macroscopy
– Arising on the surfa ce of an endometrial polyp
or an irregular polypoid/papillary appearance
coating the endometrium.
Microscopy
– Very high-grade nuclear atypia and exfoliative
or hobnail cytomorphology, similar to serous
carcinoma cells (Fig. 1).
Immunophenotype
– Diffuse aberrant p53 expression.
Differential Diagnosis
• Metaplasia
– Cilia is present in tubal metaplasia.
– Papillary syncytial metaplasia is often asso-
ciated with stromal breakdown.
– Hobnail metaplasia shows mild nuclear
atypia and infrequent mitoses.
– p53 shows wild-type expression.
Serous Carcinoma
Synonyms
Serous adenocarcinoma; Uterine serous carcinoma; Serous papillary carcinoma.
Definition
High-grade endometrial carcinoma with complex
papillary and/or glandular architecture and
marked nuclear pleomorphism.
Clinical Features
• Incidence
Accounts for approximately 5–10% of endo-
metrial carcinomas.
• Age and epidemiology
Postmenopausal women (mean age: 60 years),
nonobese women, estrogen independent. More
often affects African American women with a
history of pelvic radiation or tamoxifen use
(Brinton 2013).
• Site
Uterine corpus; frequently arises on the surface
of an endometrial polyp in a background of at-
rophic endometrium (Clement and Young 2004).
• Treatment
Total abdominal hysterectomy and bilateral
salpingo-oophorectomy and surgical staging.
Adjuvant radiotherapy and/or chemotherapy.
• Outcome
An aggressive subtype of endometrial
carcinoma.
Overall survival rate 30–40%; survival up to
80% for small, low stage tumors (Clemet and
Young 2004).
High incidence of peritoneal and lymph node
metastases.
Macroscopy
– Normal-sized or small-sized uterus (since these
occur mostly in elderly).
– Tumor is often inconspicuous, arising on the
surface of an endometrial polyp or an irregular
polypoid/papillary appearance coating the
endometrium.
Microscopy
• Architecture (Figs. 2 and 3):
– Complex papillary architecture (most com-
monly) with or wi thout fibrovascular cores;
may have micropapillary component.
– Gland-like spaces may be observed.
– Solid growth.
– Slit-like spaces.
Epithelial Tumors and Precursors, Type 2, Pathology of the Uterine Corpus 99
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E
Epithelial Tumors and Precursors, Type 2, Pathology
of the Uterine Corpus, Fig. 1 (a, c, and e). Serous
intraepithelial carcinoma frequently arises on the surface
of an endometrial polyp in a background of atrophic
endometrium. Higher magnification (d and f) shows
high-grade atypical nuclei with exfoliative morphology
and brisk mitotic activity. (b). p53 shows diffuse, aberrant
expression
100 Epithelial Tumors and Precursors, Type 2, Pathology of the Uterine Corpus
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Epithelial Tumors and Precursors, Type 2, Pathology
of the Uterine Corpus, Fig. 2 (a, c, and e). Serous
carcinoma with different architectural patterns including
gland-like spaces (in a), complex papillary architecture
(in c and e). Higher magnification (b, d, and f) shows
enlarged, hyperchromatic nuclei and brisk mitotic activity.
Psammoma calcifications are seen in B
Epithelial Tumors and Precursors, Type 2, Pathology of the Uterine Corpus 101
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E
Epithelial Tumors and Precursors, Type 2, Pathology
of the Uterine Corpus, Fig. 3 (a). Serous carcinoma
showing a solid architecture. (c and d) shows slit-like
spaces. (b and e). P53 aberrant expression. (f). p16 diffuse
expression
102 Epithelial Tumors and Precursors, Type 2, Pathology of the Uterine Corpus
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• Psammoma bodies may be present in up to
30% of cases.
• Tumor cells may appear discohesive with scant
cytoplasm.
• Nuclei are typically high-grade with pleomorphism, hyperchromasia, and prominent nucleoli.
• Brisk mitotic activity.
• Background endometrium, if present, is often
atrophic.
• May coexist with another high-grade subtype
of endometrial carcinoma.
Immunophenotype
– p53 and p16 are diffusely and strongly posi-
tive; p53 may be completely negative (“null
type” pattern).
– AE1/AE3 and CK7 positive.
– PAX8 positive.
– WT1 positive in 30% of cases.
– ER/PR often negative.
Molecular Features
– Often harbors mutations in TP53 but may show
alterations of PI3K/AKT/mTOR pathways
(Mahdi et al. 2015).
– May be seen in patients with breast carcinoma
(BRCA1/BRCA2 mutations) or Lynch
syndrome.
Differential Diagnosis
• Endometrioid carcinoma, villoglandullar
pattern
– Slender papillae with no branching.
– Cytologically bland.
– Squamous or mucinous metaplasia.
– ER/PR diffusely positive.
– p53 and p16 weak and patchy.
• Clear cell carcinoma
– Papillary, tubulocystic and solid architecture.
– Small papillae with hyalinized cores, lined
by a single layer of hobnailed cells.
– Clear to eosinophilic cytoplasm.
– HNF1B, Napsin A and AMACR positive.
– p53 and p16 weak and patchy.
• Secondary involvement of the endometrium
by tubo-ovarian carcinoma
– WT1 often strong and diffuse in extrauter-
ine serous carcinoma.
• Metaplasia
– Cilia is present in tubal metaplasia.
– Papillary syncytial metaplasia is often asso-
ciated with stromal breakdown.
– Hobnail metaplasia shows mild nuclear
atypia and infrequent mitoses.
– p53 shows wild-type expression.
Clear Cell Carcinoma
Synonyms
Clear cell adenocarcinoma.
Definition
Epithelial neoplasm composed of clear, ox yphil,
or hobnail cells arranged in papillary, tubulocystic
or solid patterns.
Clinical Features
• Incidence
Accounts for <1% of endometrial carcinomas.
• Age and epidemiology
Postmenopausal women (mean age late sixties).
More often affects African American women.
• Site
Uterine corpus.
• Treatment
Total abdominal hysterectomy and bilateral
salpingo-oophorectomy and surgical staging,
with or without adjuvant radiotherapy and/or
chemotherapy.
• Outcome
Overall 5-year survival rate < 50%.
Stage is most important prognostic factor.
Macroscopy
– Diffuse or polypoid mass.
Microscopy
• Architecture (Fig. 4):
Epithelial Tumors and Precursors, Type 2, Pathology of the Uterine Corpus 103
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E
Epithelial Tumors and Precursors, Type 2, Pathology
of the Uterine Corpus, Fig. 4 (a, b, e). Clear cell carci-
noma showing papillary, solid, and tubulocystic architectural patterns, respectively. (c). Papillae with hyalinized
stroma. (d). Tumor cells with abundant clear cytoplasm.
(f). Tumor cells with eosinophilic cytoplasm and hobnail
cells
104 Epithelial Tumors and Precursors, Type 2, Pathology of the Uterine Corpus
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– Papillary, solid, and tubulocystic patterns.
– Papillae are often short and branching with
hyalinized stroma.
• Polygonal cells with moderate to abundant
clear or eosinophilic cytoplasm.
• Frequent hobnail cells.
• Nuclei are hyperchromatic with prominent
nucleoli.
• Occasional psammoma bodies, eosinophilic
extracellular globules, or hyaline bodies.
• Background endometrium is atrophic, may
arise within an endometrial polyp.
• May coexist with another high-grade subtype
of endometrial carcinoma.
Immunophenotype
– HNF1B, Napsin A and AMACR positive in
most cases.
– CK7 positive.
– ER and PR usually negative.
– Rarely overexpresses p53.
Molecular Features
– Somatic mutations of TP53 have been reported
in 30–40% of cases.
– Low incidence of KRAS, PIK3CA mutations
and mismatch repair deficiency.
Differential Diagnosis
• Endometrioid carcinoma, with clear cell or
secretory changes
– Well-formed endometrioid type-glands.
– Often low-grade nuclear features.
– ER/PR diffusely positive.
• Serous cell carcinoma
– Papillary, tubulocystic, and solid
architecture.
– Striking nuclear pleomorphism.
– p53 aberrant expression.
• Arias-Stella reaction
– Younger age.
– Associated with pregnancy.
– Partial involvement of endometrial
glands.
– Normal glandular architecture.
– Low mitotic activity and proliferative
index.
• Secondary involvement of the endometrium
by tubo-ovarian clear cell carcinoma or cervical clear cell carcinoma
– Distinction is based on tumor site; morpho-
logically indistinguishable.
• Metastatic clear cell renal cell carcinoma
– History of renal cell carcinoma.
– ER, PR, and CK7 negative.
Squamous Cell Carcinoma
Definition
Epithelial neoplasm composed of malignant squamous epithelium.
Clinical Features
• Incidence
Rare, accounts for <0.5% of endom etrial
carcinomas.
• Age and epidemiology
Postmenopausal women (mean age late
sixties).
HPV-unrelated.
Chronic pyometra, cervical stenosis, uterine
prolapse, squamous metaplasia and prior history of pelvic radiation are predisposing
factors.
• Site
Uterine corpus.
• Treatment
Total abdominal hysterectomy with or without
bilateral salpingo-oophorectomy with adjuvant
radiotherapy and/or chemotherapy.
• Outcome
Overall survival is 70–80% for stage I tumors,
but only 20–25% for stage III disease.
Worse prognosis than endometrioid carcinoma
(stage by stage).
Macroscopy
– Sometimes have a papillary/ condylomatous
appearance.
– White cut surfaces.
Microscopy
– Diagnostic criteria:
– No coexisting endometrioid adenocarcinoma.
Epithelial Tumors and Precursors, Type 2, Pathology of the Uterine Corpus 105
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Differential Diagnosis
• Endometrioid carcinoma with extensive
squamous differentiation
– Scattered endometrioid type-glands.
– ER/PR diffusely positive.
• Extension from cervical squamous cell
carcinoma
– Mass originating in the cervix.
– p16 and HPV positive.
• Extensive squamous metaplasia
– No atypia.
– No invasion.
Undifferentiated Carcinoma
Definition
Malignant epithelial neoplasm with no differentiation (glandular or squamous).
E
Epithelial Tumors and Precursors, Type 2, Pathology
of the Uterine Corpus, Fig. 5 ( a and b). Nests of squa-
mous cell carcinoma invading into the myometrium with
keratin pearls and intercellular bridges. No coexisting
endometrioid adenocarcinoma and no connection between
the tumor and cervical squamous epithelium
– No connection between the tumor and cervical
squamous epithelium.
– No prior or concomitant cervical squamous
cell carcinoma.
– Keratinization and intercellular bridges
(Fig. 5).
– Some tumors have spindled appearance
(sarcomatoid).
Immunophenotype
– p63 and p40 positive.
– ER and PR negative.
– p16 negative.
Molecular Features
– Somatic mutations of TP53 have been reported
in 30–40% of cases.
– Low incidence of KRAS, PIK3CA mutations
and mismatch repair deficiency.
Clinical Features
• Incidence
Uncommon, <5% of endometrial carcinomas.
• Age and epidemiology
Median age 55 years.
• Site
Uterine corpus.
• Treatment
Total abdominal hysterectomy and bilateral
salpingo-oophorectomy with adjuvant radiotherapy and/or chemotherapy.
• Outcome
Adverse outcome.
More than 50% present as high-stage disease.
Disease related death rate (41–75%), mostly in
the first 5 years.
Macroscopy
– Fungating/fleshy polypoid masses with exten-
sive hemorrhage and necrosis.
Microscopy
– Sheets of discohesive monotonous medium to
large cells (Fig. 6).
– Vesicular nuclei with prominent nucleoli,
marked nuclear pleomorphism.
106 Epithelial Tumors and Precursors, Type 2, Pathology of the Uterine Corpus
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Differential Iagnosis
• Endometrioid carcinoma, FIGO grade 3
– <50% of the tumor has glandular areas.
– High-grade component is cohesive.
– Strong expression of epithelial markers.
• Undifferentiated endometrial stromal
sarcoma
– Focal spindled cells.
– Epithelial markers are negative.
– CD10 focally positive.
• Large cell neuroendocrine carcinoma
– Strong expression of neuroendocrine
markers.
• Lymphoma
– Positive for CD45, CD5, CD20.
Dedifferentiated Carcinoma
Definition
Malignant epithelial neoplasm composed of
undifferentiated endometrial carcinoma and a jux-
Epithelial Tumors and Precursors, Type 2, Pathology
of the Uterine Corpus, Fig. 6 (a and b).
Undifferentiated component showing sheets of discohesive
medium to large cells with vesicular chromatin and prominent nucleoli. Rhabdoid cells with eccentric nuclei are
seen in (a)
– Tumor cells with scant or abundant clear or
vacuolated cytoplasm.
– Rhabdoid cells may be seen.
– Myxoid background may be focally present.
– Necrosis is common.
Immunophenotype
– EMA, CAM5 .2, and AE1/AE3 focally
positive.
– CK 18 is the most helpful epithelial marker.
– p53 and p16 positive in 50% of the cases.
– Vimentin positive.
– Neuroendocrine markers (synap tophysin,
chromogranin, and CD56) focally positive.
– ER and PR negative.
Molecular Features
– May be associated with mismatch repair defici-
ency (more frequently MLH1/PMS2 mutations).
taposed c omponent of either FIGO grade 1 or
2 endometrioid carcinoma.
Clinical Features
• Incidence
Uncommon, <5% of endometrial carcinomas.
• Age and epidemiology
Median age 55 years.
• Site
Uterine corpus but may involve the lower uterine segment.
• Treatment
Total abdominal hysterectomy and bilateral
salpingo-oophorectomy with adjuvant radiotherapy and/or chemotherapy.
• Outcome
Aggressive tumors, with recurrence or death
from tumor in 55–95% of women.
Macroscopy
– Large, polypoid masses with extensive hemor-
rhage and necrosis.
Microscopy
– Undifferentiated endometrial carcinoma with a
juxtaposed FIGO grade 1 or 2 endometrioid
carcinoma (Figs. 7 and 8).
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