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66 Benign Tumors, Pathology of the Fallopian Tube
https://t.me/med1917
Benign Tumors, Pathology of the Fallopian Tube,
Fig. 1 Medium-power view of an adenomatoid tumor,
smooth muscle fibers are admixed with microcystic spaces
lined by mesothelial cells
Benign Tumors, Pathology of the Fallopian Tube,
Fig. 2 Adenomatoid tumor with lymphatic-like channels
Clinical Features
• Incidence
In one consecutive series of fallopian tubes
unassociated with tubo-ovarian malignancy or
inflammatory disorders, adenofibromas were
found in 30% of cases. They are also seen in
10% of women with BRCA 1/2 mutations or a
strong family history of breast/ovarian carcinoma (Seidman et al. 2016).
• Age
The age range is from the third to the eighth
decade with a mean age of 49 years (AlvaradoCabrero et al. 1997; Khatib et al. 2015).
Benign Tumors, Pathology of the Fallopian Tube,
Fig. 3 Serous adenofibroma with broad fibrous papillae
projected above the fallopian tube surface
• Site
These tumors are mainly located in the fimbria
(Alvarado-Cabrero et al. 1997).
• Clinical Presentation
The majority of cases are an incidental finding,
although some adenofibromas may reach large
sizes (Tavares et al. 2020).
• Treatment
The standard treatment is surgical excision
(Bossuyt et al. 2008).
• Outcome
Serous adenofibroma is considered a benign
neoplasm (Bossuyt et al. 2008).
• Macroscopy
The majority of tumors are of microscopic size
(<0.3 cm). They are hard, white, predominantly fibromatous tumors (Khatib et al. 2015).
Microscopy
Serous adenofibroma has a biphasic architecture
with cellular fibromatous stroma lined by a single
layer of bland cuboidal epithelium (Seidman
et al. 2016).
Immunophenotype
Differential Diagnosis
Serous papillary adenofibromas should be distinguished from serous borderline tumors (SBT);
however, SBTs show stromal polypoid excrescences, glands, and papillae lined by stratified
Brenner Tumors, Pathology of the Ovary 67
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cuboidal to columnar epithelial cells (Bossuyt
et al. 2008) (Fig. 3).
Molecular Features
Not clinically relevant.
References and Further Reading
Alvarado-Cabrero, I., Navani, S. S., Young, R. H., &
Scully, R. E. (1997). Tumors of the fimbriated end of
the fallopian tube: A clinicopathologic analysis of
20 cases, including nine carcinomas. International
Journal of Gynecological Pathology, 16, 189–196.
Bossuyt, V., Medeiros, F., Drapkin, R., et al. (2008).
Adenofibroma of the fimbria: A common entity that is
indistinguishable from ovarian adenofibroma. Interna-
tional Journal of Gynecological Pathology, 27,390–397.
Goode, B., Joseph, N. M., Stevers, M., et al. (2018).
Adenomatoid tumors of the male and female genital
tract ar e defined by TRAF7 mutations that drive aberrant
NF-kB pathway activation. Modern Pathology, 31,
660–673.
Karpathiou, G., Hiroshima, K., & Peoc’h, M. (2020).
Adenomatoid tumor: A review of pathology with
focus on unusual presentations and sites, histogenesis,
differential diagnosis, and molecular and clinical
aspects with a historic overview of its description.
Advances in Anatomic Pathology, 27, 394–407.
Khatib, Y., Patel, R. D., Kashikar, A. S., & Chavan,
K. (2015). Serous papillary cystadenofibroma of the
fallopian tube: A case report and short review of the
literature. Indian Journal of Pathology & Microbiol-
ogy, 58, 524–527.
Sangoi, A. R., McKenney, J. K., Schwartz, E. J., et al.
(2009). Adenomatoid tumors of the female and male
genital tracts: A clinicopathological and immunohistochemical study of 44 cases. Modern Pathology, 22,
1228–1235.
Schwartz, E. J., & Longacre, T. A. (2004). Adenomatoid
tumors of the female and male genital tracts express
WT1. International Journal of Gynecological Pathol-
ogy, 23, 123–128.
Seidman, J. D., Krishnan, J., Yemelyanova, A., et al.
(2016). Incidental serous tubal intraepithelial carcinoma and non-neoplastic conditions of the fallopian
tubes in grossly normal adnexa: A clinicopathologic
study of 388 completely embedded cases. International
Journal of Gynecological Pathology, 35, 423–429.
Tavares, M. A., Silva, R. C., Lourenço, M., & Ambrósio,
A. (2020). Giant serous adenofibroma of the fallopian
tube. BML Case Reports, 13, e234267.
Terada, T. (2012). An immunohistochemical study of
adenomatoid tumors of the uterus and fallopian tube.
Applied Immunohistochemistry & Molecular Morphology, 20, 173–176.
Wachter, D. L., Wünsch, P. H., Hartmann, A., et al. (2011).
Adenomatoid tumors of the female and male genital tract.
A comparative clinicopathologic and immunohistochemical analysis of 47 cases emphasizing their site-specific
morphologic diversity. V irchows Archiv, 458, 593–602.
B
Brenner Tumors, Pathology of
the Ovary
Simona Stolnicu
University of Medicine, Pharmacy, Sciences and
Technology “George E Palade” of Targu Mures,
Targu Mures, Romania
Benign Brenner Tumor
Definition
Benign Brenner tumor is a rare neoplasm with
unknown etiology, deriving through metaplasia of
the ovarian surface epithelium, from metaplastic
transitional epithelium (Walthard nests) located in
the hilar region of the ovary or beneath the serosa of
the fallopian tube or from a teratoma. Ben ign Brenner tumor is composed of bland transitional-type
epithelium, proliferating in a dense fibromatous
stroma.
Clinical Features
• Incidence
Benign Brenner tumor is a rare condition in the
ovary representing approximately 5% of all
benign epithelial tumors (Herrington et al. 2020).
• Age
The tumor usually occurs in adult patients
(fifth–seventh decade of life) but can develop
at any age (Herrington et al. 2020).
• Sex
Female.
• Site
Ovary.
• Treatment
Surgical excision is indicated and is curative.
• Outcome
The tumor has no risk of recurrence or
progression.
68 Brenner Tumors, Pathology of the Ovary
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Macroscopy
Benign Brenner tumor is usually unilateral (with
less than 10% being bilateral) and small (<2 cm),
being asymptomatic, and consequently found
incidentally when examining the ovary removed
for another lesion (Herrington et al. 2020). When
large in size, it may be associated with pain and
abdominal enlargement. Some tumors produce
hormones and are associated with endocrine
symptoms of estrogenic or, less often, androgenic
type. The tumor has a smooth external surface and
on the cut surface is solid, well-circumscribed,
with firm rubbery consistency, grey-white to pale
yellow color, and occasionally with small or large
cysts. In approximately 25% of cases, one can
Brenner Tumors, Pathology of the Ovary,
Fig. 1 Benign Brenner tumor associated with a mucinous
cystadenoma
identify a second neoplasm in contact with the
solid area (represented by the benign Brenner
tumor) that can contribute to the macroscopic
appearance, such as a mucinous or serous
cystadenoma or a dermoid cyst.
Microscopy
The tumor is composed of round to oval nests of
transitional/urothelial epithelium in a prominent
and dense stroma. The epithelial cells are oval,
with distinct cell membranes, pale cytoplasm,
and the oval nuclei occasionally present with
longitudinal groo ves (“coffee bean” nuclei),
fine chromatin, and small nucleoli. No areas of
atypicality or mitotic figures are identified. The
nests are usually solid and may also present with
squamous metaplasi a in the central area, but
some of them may show microcystic spaces
with eosinophilic or mucinous material and
surrounded by cubic or flat epithelium of transi-
Brenner Tumors, Pathology of the Ovary,
Fig. 2 Benign Brenner tumor associated with a mucinous
cystadenoma: higher magnification shows nests of transitional cells with eosinophilic cytoplasm but without atypia;
some nests present microcystic spaces with eosinophilic
material
tional, squamous, mucinous, or ciliated type. The
stroma is fibromatous and may harbor luteinized
cells, psammoma bodies, as well as areas of
hyalinization (Figs. 1 and 2).
Differential Diagnosis
When the benign Brenner tumor is solid, an endometrioid type of adenofibroma with squamous
differentiation must be excluded, based on the
Immunophenotype
The tumor cells are positive for p63, GATA3,
CK7, AR, uroplakin, and thrombomodulin and
negative for CK20, PAX8, ER, and PR (Esheba
et al. 2009).
epithelial component that looks different. When
a benign Brenner tumor is cystic in appearance, it
needs to be differentiated from other benign cystic
neoplasm of ovarian origin, especially from a
mucinous cystadenoma. Also, benign Brenner
tumor can mimic an insular granulosa cell tumor
Molecular Features
Not clinically relevant.
or a carcinoid tumor but the particular and benign
microscopic appearance of Brenner tumor
Brenner Tumors, Pathology of the Ovary 69
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together with immunohistochemical stains
may help.
Borderline Brenner Tumor
Definition
Borderline Brenner tumor is represented by a proliferation of transitional epithelium without stromal invasion, resembling a low-grade papillary
urothelial neoplasm of the urothelial tract. The
tumor is thought to arise from a benign Brenner
tumor. It may also be associated with a mucinous
cystic tumor, similar to benign Brenner tumor of
the ovary.
Clinical Features
• Incidence
This is a very rare and unusual tumor. The
patients present with abdominal mass and pain.
• Age
Patients with borderline Brenner tumor are
usually over age of 50 (Herrington et al. 2020).
• Sex
Female.
• Site
Ovary.
• Treatment
Conservative surgical excision is
recommended.
• Outcome
Excellent, with rare cases of local recurrence
but no risk of progression.
type stratified epithelium, with usually uniform
but elongated nuclei, fine chromatin, and visible
nucleoli (Figs. 3, 4, and 5). Sometimes, however,
nuclear pleomorphism and mitotic figures can be
encountered as well as areas of mucinous or squamous metaplasia and areas of necrosis. Areas of
benign Brenner tumor are always identified, usually at the periphery and in the form of solid nests
(sometimes compressed and difficult to be recognized). Microscopic grading of these tumors is no
longer recommended. Stromal invasion is lacking
by definition.
Brenner Tumors, Pathology of the Ovary,
Fig. 3 Borderline Brenner tumor: papillary growth pattern
with papillary projections lined by transitional-type stratified epithelium
B
Macroscopy
The tumor is usually unilateral, large in size
(15-20 cm), and present with cystic (unilocular
or multilocular) admixed with solid areas
(Herrington et al. 2020). On cut surface, friable
polypoid projections are seen within the lumina of
cystic component (borderline areas), while the
solid areas are of white color and represent the
benign Brenner component.
Microscopy
Microscopically, the tumor shows a papillary
growth pattern with papillary projections (which
are sometimes confluent) lined by transitional-
Brenner Tumors, Pathology of the Ovary,
Fig. 4 Borderline Brenner tumor: transitional-type strati-
fied epithelium, with usually uniform but elongated nuclei
is lining the papillary projections
70 Brenner Tumors, Pathology of the Ovary
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Clinical Features
• Incidence
The tumor is extremely rare, with only case
reports in published literature.
• Age
Patients with malignant Brenner tumor are over
the age of 50 years old (Herrington et al. 2020).
• Sex
Female.
• Site
Ovary.
• Treatment
Surgical and oncologic treatment are
Brenner Tumors, Pathology of the Ovary,
Fig. 5 Borderline Brenner tumor: high-power magnifica-
tion shows a transitional-type stratified epithelium lacking
atypia; note that the elongated nuclei present with longitudinal grooves (“coffee bean” nuclei), fine chromatin, and
small nucleoli
recommended (debulking and adjuvant chemotherapy), similar to other epithelial ovarian
cancers.
• Outcome
The prognosis is better in FIGO stage I than in
advanced stages (Nasioudis et al. 2016).
Immunophenotype
The tumor is positive for p63 and GATA3 and
negative for ER, PR, and WT1, while p53 is of
wild type (Esheba et al. 2009).
Macroscopy
Most cases are unilateral, however about 15–20%
may be bilateral (Herrington et al. 2020). Tumor is
associated with pelvic pain, abdominal mass, and
Molecular Features
Not clinically relevant.
sometimes with vaginal bleeding. On cut surface
the tumor is large, has solid admixed with cystic
areas and a white color.
Differential Diagnosis
Differential diagnosis includes malignant Brenner
tumor, which in contrast to borderline tumor is
associated with stromal invasion. Also, granulosa
cell tumor with a papillary architecture may
resemble borderline Brenner tumor, but identifying more typical morphologic patterns of
granulosa cell tumor together with immunohistochemical stains may help the diagnosis.
Microscopy
The tumor is represented by irregular nests of
tumor cells of transitional/urothelial type, sometimes with squamous differentiation in a
desmoplastic stroma. Cellular atypia is present
with hyperchromatic pleomorphic nuclei and visible nucleoli, eosinophilic cytoplasm, and variable mitotic activity. Areas of benign and
borderline Brenner tumor are present, but sometimes are difficult to be identified and extensive
Malignant Brenner Tumor
sampling is recommended.
Definition
This is a very rare ovarian tumor with unknown
etiology, resembling an invasive urothelial carcinoma but always associated with a benign and a
borderline Brenner component. Also, in some cases,
a mucinous adenocarcinoma component may be
present.
Immunophenotype
The tumor cells are positive for p63 and GATA
3 and negative for ER, PR, WT1, and p16 (Esheba
et al. 2009).
Molecular Features
Not clinically relevant.
Brenner Tumors, Pathology of the Ovary 71
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Differential Diagnosis
High-grade serous or endometrioid adenocarcinoma with transitional-like differentiation should
be ruled out from malignant Brenner tumors, based
on the presence of a benign or borderline component in malignant Brenner tumor as well as on the
immunohistochemical profile. The presence of an
endometrioid cyst is in favor of an endometrioid
adenocarcinoma, while the presence of an associated mucinous cyst is in favor of a Brenner tumor.
Metastatic papillary urothelial carcinoma is another
differential diagnosis, and clinical information is
crucial to differentiate between the two tumors.
References and Further Reading
Esheba, G. E., Longacre, T. A., Atkins, K. A., et a l.
(2009). Expression of the urothelial differentiation
markers GATA3 and placental S100 (S100P) in
female genital tract transitional cell proloferation.
The American Journal of Surgical Pathology, 33(3),
347–353.
Herrington, C. S., Kim, K. R., Kong, C., et al. (2020).
Tumours of the uterine cervix. W. C. o. T. E. B. F. g.
tumours (pp. 336–389). Lyon: International Agency for
Research on Cancer.
Nasioudis, D., Sisti, G., Holcomb, K., et al. (2016).
Malignant Brenner tumors of the ovary; A populationbased analysis. Gynecologic Oncology, 142(1),
44–49.
B
C
https://t.me/med1917
Clear Cell Tumors, Pathology
of the Ovary
Nairi Tchrakian
Department of Cellular Pathology, The Royal
London Hospital, Barts Health NHS Trust,
London, UK
Definition
• Clear cell cystadenoma and adenofibroma:
Benign epithelial neoplasm composed of simple small to medium-sized glands lined by
bland clear or oxyphilic cells with accompanying fibromatous stroma.
• Clear cell borderline tumor: An epithelial
neoplasm compo sed of crowded glands
and/or cysts lined by clear or oxyphilic cells
with low-grade nuclear atypia set within fibromatous stroma, without stromal invasion.
• Clear cell carcinoma: A malignant epithelial
neoplasm showing tubulocystic, papillary,
and/or solid architecture, composed of clear
(or oxyphilic) cuboidal and hobnail cells.
Clinical Features
• Incidence
Benign clear cell tumors are extremely rare,
with only small case series described in the
literature (Zhao et al. 2011). Pure clear cell
borderline tumors are rare, comprising <1%
of all ovarian borderline tumors (Uzan et al.
2012). They are more commonly seen accom-
panying a clear cell carcinoma than as the
exclusive element in a tumor. Clear cell carcinoma accounts for 10–12% of ovarian carcinomas in North America (Peres et al. 2019). The
tumor is seen at a higher prevalence in Asia –
particularly in Japan, where it accounts for up
to 27% of all ovarian carcinomas (Machida
et al. 2019).
• Age
Most patients with clear cell carcinoma are perior postmenopausal, but tumors may arise at a
younger age in patients with Lynch syndrome.
• Sex
Female individuals.
• Site
Ovary; almost all cases are unilateral and may
present with symptoms related to an ovarian/
pelvic mass. Bilateral tumors account for <4%
of clear cell carcinomas.
• Clinical Associations/Risk Factors
Benign, borderline, and malignant clear cell
ovarian tumors have been reported in varying
degrees to arise in association with endometriosis (Zhao et al. 2011). In clear cell carcinomas
in particular, endometriosis is associated with
up to 74% of tumors (Parra-Herran et al. 2019).
Lynch syndrome predisposes to clear cell carcinoma (Parra-Herran et al. 2019).
© 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
74 Clear Cell Tumors, Pathology of the Ovary
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• Treatment
All clear cell ovarian tumors are treated with
surgical resection. Typically, hysterectomy,
bilateral salpingo-oophorectomy, omentectomy,
and staging peritoneal biopsies are undertaken
for clear cell carcinoma, with or without adjuvant chemoradiotherapy.
• Outcome
The outcome for benign and borderline clear
cell tumors is excellent, with no recurrences
reported in the latter (Uzan et al. 2012).
For clear cell carcinoma, stage is the most
important prognostic factor (Bennett et al.
2015), whereby a favorable outcome is typi-
cally seen in stage I tumors with negative peritoneal washings, and a poor prognosis is seen
in advanced stage (III/IV) tumors (87% and
24% cause-specific 5-year survival rates,
respectively) (Peres et al. 2019).
Macroscopy
Clear cell cystadenoma and adenofibroma:
Solid, smooth-surfaced fibromatous mass,
often containing small cysts. The reported
size range is 3.5 - 26 cm.
Clear cell borderline tumor: Solid or predomi-
nantly solid fibromatous mass with a smooth,
lobulated surface, and a firm to spongy
tan/white/yellow cut surface with variably sized
cysts containing watery fluid. The reported size
range is 2 - 23 cm (mean size: 6 cm).
Clear cell carcinoma: Varies from solid, mixed
solid, and cystic to mainly cystic on cut surface. Carcinoma is often seen as one or multiple pale fleshy exophytic nodules arising from
an endometriotic cyst wall, commonly associated with necrosis or hemorrhage. Some solid
foci may correspond histologically to a borderline adenofibromatous component rather than
carcinoma. Surface involvement should be
noted as being present or absent. A wide size
range is seen (mean size: 13 cm).
Microscopy
Clear cell cystadenoma and adenofibroma:
These tumors are composed of small to
medium-sized glands, well-spaced and typically round in shape, embedded in fibromatous
stroma. The lining of the glands is 1–2 cells
thick, and composed of bland flat or low cuboidal cells with clear or eosinophilic cytoplasm.
Nuclei are typically small and uniform, with
evenly dispersed chromatin and lacking nucleoli. Mitotic figures are usually not identified.
Eosinophilic secretions may be seen within
glandular lumina. By definition, glandular
crowding and nuclear atypia are absent. Endometriosis may be seen in association with the
neoplasm.
Clear cell borderline tumor: These tumors are
composed of variably sized, irregularly
shaped, and crowded glands with an accompanying dense and fibromatous stroma. Small,
solid nests of cells without associated
desmoplasia can be seen in between glands,
which may be mistaken for invasion. The
lesional cells have clear or eosinophilic
cytoplasm and variably atypical nuclei (with
low-grade atypia) which may show mild
hyperchromatism or small nucleoli. Nuclear
stratification may be seen but should be no
more than mild in degree. Mitotic figures may
be seen, but overall mitotic activity is low.
Eosinophilic secretions may be seen within
glandular lumina. Complex architecture is not
permitted. Associated endometriosis is
often seen.
Clear cell carcinoma: Clear cell carcinoma dis-
plays complex architectural patterns – typically papillary, tubulocystic, and solid –
which are often admixed (Fig. 1). The papillary
growth pattern is characterized by simple, nonbranching papillae – often with hyalinized
stroma – without significant hierarchical
branching (Fig. 2). Psammoma bodies are
rare. The tubulocystic pattern comprises variably sized rigid tubules and cysts, which may
contain dense eosinophilic secretions (Fig. 3).
The solid pattern shows sheets of tumor cells
separated by min imal stroma or delicate
septations. Stroma may be fibromatous,
hyalinized, or edematous/myxoid. The tumor
cells lining papil lae, tubules, and cysts are typically present in a single layer and range from
flat to cuboid al to hobnailed in appearance
Clear Cell Tumors, Pathology of the Ovary 75
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C
Clear Cell Tumors, Pathology of the Ovary,
Fig. 1 Ovarian clear cell carcinoma showing characteris-
tic admixture of architectural patterns – papillary (left) and
tubulocystic (right)
Clear Cell Tumors, Pathology of the Ovary,
Fig. 2 Ovarian clear cell carcinoma, papillary growth pat-
tern – simple nonbranching papillae with hyalinized cores
lined by a single layer of tumor cells
Clear Cell Tumors, Pathology of the Ovary,
Fig. 3 Ovarian clear cell carcinoma with a predominantly
cystic growth pattern
Clear Cell Tumors, Pathology of the Ovary,
Fig. 4 Ovarian clear cell carcinoma – infiltrative glands
lined by “hobnailed” cells, the nuclei of which protrude
into glandular lumina
(Fig. 4). Cytoplasm is typically clear but may
be eosinophilic in the less common oxyphilic
variant of the tumor. “Targetoid” cells with a
signet ring-like appearance may be seen, and
hyaline bodies may also be present (Fig. 5).
Nuclear pleomorphism is typically variably
distributed within the tumor, rather than diffusely present. Some foci of the tumor may
appear deceptively benign, owing to bland
cytologic features; elsewhere, however, cytologic atypia will be seen in the form of
enlarged, monomorphic nuclei with angulated
contours, marked hyperchromasia and prominent nucleoli (Fig. 6). Nuclear pseudoinclusions may be seen rarely. Mitotic activity
is variable but is typically low. Some tumors
display a peritumoral or tumor-infiltrating
chronic inflammatory cell infiltrate, which
may be more prominent in a mismatch repair
protein-deficient (MMRd) setting. More often
than not, the tumor arises in association with
endometriosis, often in the form of an
76 Clear Cell Tumors, Pathology of the Ovary
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Clear Cell Tumors, Pathology of the Ovary,
Fig. 5 Ovarian clear cell carcinoma – hyaline bodies are
often present (center)
Clear Cell Tumors, Pathology of the Ovary,
Fig. 6 Ovarian clear cell carcinoma demonstrating typical
cytonuclear features of clear cytoplasm, nuclear hyperchromasia, angulated nuclei, and variable pleomorphism
endometriotic cyst (Fig. 7). Carcinoma may
also be seen to arise from a borderline clear
cell adenofibroma. Mixed clear cell carcinoma
and endometrioid carcinoma may be seen,
especially in the setting of endometriosis or
Lynch syndrome.
Immunophenotype
Like other Müllerian tumors, clear cell carcinoma shows expression o f CK7 and PAX8.
Clear Cell Tumors, Pathology of the Ovary,
Fig. 7 Ovarian clear cell carcinoma (upper) arising in
association with an endometriotic cyst (lower)
Clear Cell Tumors, Pathology of the Ovary,
Fig. 8 Positive HNF1β expression in ovarian clear cell
carcinoma – strong, crisp nuclear staining is seen
Expression of Napsin A, HNF1 β,andAMACR
(Racemase) are also used to support the diagnosis. HNF1β is a highly sensitive marker for clear
cell carcinoma (Fig. 8) but is less specificthan
Napsin A or AMACR. ER, PR, and WT1 are
negative, which may be helpful to exclude other
differential diagnoses (see below) (Lim et al.
2015). Most tumors show wild-type expression
of p53, but a proportion may show aberrant
expression. Loss of ARID1a may be seen on
immunohistochemical staining, which correlates
with ARID1A loss of function mutation. Loss of
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