1
same neoplasm.
• Nearly all LGSCs arise in a background of
ovarian benign or borderline serous tumors.
• Most HGSCs are believed to arise from a
precursor lesion, STIC (serous tubal intraepi-
thelial carcinoma), in the tubal mbriae.
• New criteria for primary site assignment in
HGSC include:
- Fallopian tube: STIC present, or mucosal
HGSC present, or part or all of the fallopian
tube is inseparable from tubo-ovarian mass.
- Ovary: both fallopian tubes are separate from
ovarian mass, and no STIC or mucosal HGSC
present in either fallopian tube.
- Tubo-ovarian: fallopian tubes and ovaries are
unavailable for complete examination, and
pathologic ndings are consistent with
extrauterine HGSC.
- Peritoneal (exceedingly rare): both fallopian
tubes and ovaries are fully examined using a
SEE-FIM (Sectioning and Extensively
Examining the FIMbriated end) protocol,
and no gross or microscopic evidence of STIC
or HGSC present in either fallopian tube or
ovary.
- These criteria classify approximately 80% of
HGSCs as primary tubal.
• Serous borderline tumor is the sole recom-
mended term:
- Obsolete terminology no longer recommend-
ed includes atypical proliferative serous
tumor, serous tumor of low malignant
potential, semimalignant serous tumor and
non-invasive LGSC / micropapillary serous
borderline tumor (the latter no longer consid-
ered denitionally synonymous with non-
invasive LGSC).
NON-SEROUS EPITHELIAL
TUMORS
• The following terminology is no longer
recommended:
- Atypical proliferative tumor or tumor of low
malignant potential for all epithelial tumors
(mucinous, endometrioid, seromucinous,
clear cell, Brenner).
Issue 15 || September 2021
WHAT’S NEW
IN GYNECOLOGIC
PATHOLOGY 2021:
OVARY AND
FALLOPIAN TUBE
Gulisa Turashvili
1
and Ricardo Lastra
2
1
Department of Pathology and Laboratory Medicine,
Sinai Health System and University of Toronto, Toronto,
ON, Canada
2
Department of Pathology, University of Chicago Medical
Center, Chicago, IL, USA
Corresponding Author: Gulisa Turashvili, MD, PhD
Department of Pathology and Laboratory Medicine
Sinai Health System and University of Toronto
Toronto, Ontario, Canada
E-mail: Gulisa.Turashvili@sinaihealth.ca
ORCID
Gulisa Turashvili
https://orcid.org/0000-0001-6125-5865
Ricardo Lastra
https://orcid.org/0000-0003-0691-5685
Abstract
The 5th edition of the World Health Organiza-
tion (WHO) Classication of Female Genital
Tumors was published in 2020. Although the
classication of ovarian and fallopian tube
neoplasms is largely unchanged from the prior
(4th) edition, this newsletter compiles the most
important renements in these organ sites,
including serous and non-serous epithelial
tumors, and sex cord-stromal tumors.
SEROUS NEOPLASMS
• The 4th edition divided serous carcinoma into
low grade (LGSC) and high grade (HGSC) vari-
ants.
• LGSC and HGSC are best considered two
fundamentally different tumors based on their
distinct biology, rather than variants of the
SEROMUCINOUS CARCINOMA
• Previously dened as a carcinoma composed
predominantly of serous and endocervical-type
mucinous epithelium, often with foci showing
clear cells, endometrioid or squamous differen-
tiation.
• Now considered a subtype of endometrioid
adenocarcinoma with mucinous differentiation
(Fig. 1).
NEW VARIANTS OF EPITHELIAL
TUMORS
• Mesonephric-like adenocarcinoma:
- Composed of multiple architectural patterns
(tubular, glandular/pseudoendometrioid,
ductal, papillary, solid), intraluminal eosino-
philic colloid-like material, dense or vesicular
chromatin, inconspicuous nucleoli and
nuclear crowding, and lacking squamous or
mucinous differentiation.
- Positive for GATA3, TTF1, CD10 (luminal)
and PAX8, and negative for hormone
receptors and WT1, with wild-type p53
expression.
- Usually unilateral and diagnosed at stage I in
postmenopausal women.
- May arise from paraovarian mesonephric
remnants or Müllerian carcinomas displaying
secondary mesonephric transdifferentiation.
- May be associated with endometriosis,
cystadenomas, adenobromas, borderline
tumors and LGSC.
Fig. 1. Endometrioid adenocarcinoma with mucinous
differentiation.
WHAT’S NEW
IN PATHOLOGY?
Sponsored by an unrestricted grant from Bio-Techne
2
Dr. Turashvili has been part of the Pathology
Outlines editorial board since 2020. She is
originally from Georgia and pursued her
pathology training in Canada and USA. She is
currently afliated with Mount Sinai Hospital
and the University of Toronto as a gynecologic
and breast pathologist and Assistant Professor.
Dr. Lastra has been part of the Pathology
Outlines editorial board since 2020. He is
currently an Associate Professor of pathology
at the University of Chicago Medical Center,
where he also serves as the gynecologic pathol-
ogy fellowship program director.
Meet the Authors
The authors did not receive any
compensation from Bio-Techne.
- The most common molecular alterations
include KRAS mutations, 1p loss and 1q
gain, while NRAS or PIK3CA mutations are
rare.
- Tumors with coexisting serous neoplasms
show shared molecular alterations (KRAS or
NRAS mutations).
- Clinical outcome is unknown due to rarity.
• Dedifferentiated carcinoma:
- A biphasic tumor composed of an undifferen-
tiated carcinoma (sheet-like growth of
monotonous, discohesive, round, rhabdoid to
spindle cells with brisk mitoses, often
necrosis and abundant tumor-inltrating
lymphocytes) and a differentiated (usually
low grade endometrioid adenocarcinoma,
rarely serous carcinoma) component, often
with abrupt interface in between (Fig. 2).
- Undifferentiated areas are focally positive for
EMA, pan-keratin and CK18, focally positive
to negative for PAX8, and negative for
hormone receptors and E-cadherin, with
common loss of SMARCA4 (BRG1), SMAR-
CA2 (BRM), SMARCB1 (INI1) or ARID1A,
DNA mismatch repair deciency in one-
third of cases and typically wild-type p53
expression.
- Usually diagnosed at advanced stages, with
pelvic and para-aortic lymph node involve-
ment and poor prognosis.
• Carcinosarcoma:
- A biphasic neoplasm composed of high grade
carcinomatous and sarcomatous elements.
- Now considered a variant of carcinoma rather
than a true mixed epithelial-mesenchymal
tumor.
• Mixed carcinoma:
- True mixed carcinomas are uncommon.
- Should only be diagnosed when at least two
tumor types are clearly recognizable on hema-
toxylin-eosin-stained sections, with distinct
morphologic and preferably immunopheno-
typic differences.
- Each histotype with their percentages should
be reported (no minimum percentage
requirement).
- Endometriosis-associated histotypes are most
common, e.g. endometrioid and clear cell
carcinomas (Fig. 3).
ANCILLARY TESTING
• Aberrant p53 expression refers to three immu-
nostaining patterns associated with TP53
mutation:
- Overexpression (strong nuclear expression in
>80% of tumor cells).
- Complete absence of nuclear staining (with
satisfactory controls).
- Unequivocal cytoplasmic expression.
SEX CORD-STROMAL TUMORS
• Most (>90%) adult-type granulosa cell tumors
(GCTs) exhibit somatic FOXL2 mutations.
• Sertoli-Leydig cell tumors (SLCTs) may harbor
DICER1 or FOXL2 mutations and are now
classied into three molecular subtypes:
- DICER1-mutant tumors show somatic
(~50%) or germline (69%) hotspot muta-
tions in the RNase IIIb domain of DICER1,
an endoribonuclease involved in microRNA
processing and gene expression regulation.
• Occur in younger patients and induce
androgenic symptoms.
• Moderately or poorly differentiated with
retiform or heterologous elements (the latter
two predict DICER1 mutations) (Fig. 4).
- FOXL2-mutant tumors show c.402C>G
(p.Cys134Trp) mutations that upregulate
CYP19A1 encoding aromatase.
• Occur in postmenopausal patients and
induce estrogenic symptoms.
• Moderately or poorly differentiated lacking
retiform or heterologous elements.
• Reported in 0-22% of cases.
• FOXL2 and DICER1 mutations are
mutually exclusive.
- DICER1-FOXL2 wild-type tumors:
• Occur in patients with intermediate age.
• Well-differentiated lacking retiform or
heterologous elements.
• Microcystic stromal tumors exhibit CTNNB1
or, less frequently, APC mutations and may
represent an extracolonic manifestation of
familial adenomatous polyposis.
• Small cell carcinomas of hypercalcemic type
exhibit deleterious germline or somatic
mutations in SMARCA4, part of the SWI/SNF
complex, resulting in loss of SMARCA4
protein expression.
• Gynandroblastoma has been reintroduced (Fig. 5 ).
- Dened as a sex cord-stromal tumor with an
admixure of female (adult-type or juvenile
GCT) and male (Sertoli cell tumor or SLCT)
elements.
- Most commonly composed of a predominant
SLCT component and a smaller component
of juvenile GCT, both expressing sex cord-
stromal markers, sometimes with shared
DICER1 mutations.
Fig. 2. Dedifferentiated carcinoma composed of
undifferentiated carcinoma and low-grade endome-
trioid adenocarcinoma.
Fig. 4. Moderately differentiated Sertoli-Leydig cell
tumor with heterologous elements (intestinal-type
glands) and somatic
DICER1
mutation.
Fig. 3. Mixed carcinoma composed of clear cell
carcinoma and endometrioid adenocarcinoma.
Fig. 5. Gynandroblastoma composed of Sertoli-
Leydig cell tumor and adult-type granulosa cell tumor.
