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Jeng, Y. M. (2015). Targeted next-generation sequenc-
ing of cancer genes identified frequent TP53 and ATRX
mutations in leiomyosarcoma. American Journal of
Translational Research, 7(10), 2072–2081. https://
www.ncbi.nlm.nih.gov/pubmed/26692951
Yao, X., Stewart, E. A., Laughlin-Tommaso, S. K., Heien,
H. C., & Borah, B. J. (2017). Medical therapies for
heavy menstrual bleeding in women with uterine
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cially insured population in the USA. BJOG, 124(2),
322–330. https://doi.org/10.1111/1471-0528.14383.
Yilmaz, A., Rush, D. S., & Soslow, R. A. (2002). Endo-
metrial stromal sarcomas with unusual histologic fea-
tures: A report of 24 primary and metastatic tumors
emphasizing fibroblastic and smooth muscle differen-
tiation. The American Journal of Surgical Pathology,
26(9), 1142–1150. https://doi.org/10.1097/00000478-
200209000-00004.
Ylisaukko-oja, S. K., Kiuru, M., Lehtonen, H. J., Lehtonen,
R., Pukkala, E., Arola, J., Launonen, V., & Aaltonen,
L. A. (2006). Analysis of fumarate hydratase mutations
in a population-based series of early onset uterine
leiomyosarcoma patients. International Journal of Can-
cer, 119(2), 283–287. https://doi.org/10.1002/ijc.21798.
Zhang, Q., Poropatich, K., Ubago, J., Xie, J., Xu, X.,
Frizzell, N., Kim, J., Kong, B., & Wei, J. J. (2018).
Fumarate hydratase mutations and alterations in
leiomyoma with bizarre nuclei. International Journal
of Gynecological Pathology, 37(5), 421–430. https://
doi.org/10.1097/PGP.0000000000000447.
Zivanovic, O., Jacks, L. M., Iasonos, A., Leitao, M. M., Jr.,
Soslow, R. A., Veras, E., Chi, D. S., Abu-Rustum,
N. R., Barakat, R. R., Brennan, M. F., & Hensley,
M. L. (2012). A nomogram to predict postresection
5 year overall survival for patients with uterine
leiomyosarcoma. Cancer, 118(3), 660–
doi.org/10.1002/cncr.26333.
Zou, Y., Turashvili, G., Soslow, R. A., Park, K. J., Croce,
S., McCluggage, W. G., Stewart, C. J. R., Oda, Y.,
Oliva, E., Young, R. H., Da Cruz Paula, A.,
Dessources, K., Ashley, C. W., Hensley, M. L., Yip,
S., Weigelt, B., Benayed, R., Antonescu, C. R., Lee,
C. H., & Chiang, S. (2020). High-grade transformation
of low-grade endometrial stromal sarcomas lacking
YWHAE and BCOR genetic abnormalities. Modern
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s41379-020-0535-y.
669. https://
Mesenchymal Tumors, Pathology of the Vagina 273
https://t.me/med1917
• Immunophenotype
Mesenchymal Tumors,
Pathology of the Vagina
Raji Ganesan
Birmingham Women’s and Children’s NHS Trust,
Birmingham, UK
The cells are positive for smooth muscle
markers – SMA, desmin, and h-caldesmon.
Leiomyomas tend to express hormone receptors.
• Differential Diagnosis
As discussed in smooth muscle tumors of the
uterine corpus.
Smooth Muscle Tumors
Definition
In similarity with smooth muscle tumors of the
uterine corpus, they are stratified as leiomyomas,
smooth musc le tumors of uncertain malignant
potential (STUMP), and leiomyosarcomas
(Swanson et al. 2020; Sayeed et al. 2018).
Clinical Features
They present as mass lesions with symptoms
including pain, dyspareunia, and abnormal vaginal bleeding (Zhao et al. 2003).
• Incidence
Very rare in the vagina.
• Age
Adult women.
• Site
None specified.
• Treatment
Surgical resection followed by adjuvant
treatment.
• Outcome
Leiomyomas have a benign outcome following
complete removal. STUMPs have been noted
to recur. Leiomyosarcomas are capable of distant spread.
• Macroscopy
They tend to be removed in pieces. Leiomyomas
tend to be nodular and rubbery, while leiomyosarcomas show hemorrhage and necrosis.
• Microscopy
They are composed of intersecting fascicles of
smooth muscle. The diagnosis of malignancy
is based on the presence of mitoses, atypia, and
coagulative or tumor cell necrosis in the same
fashion as uterine smoo th muscle tumors
(Nucci and Lazar 2020).
Rhabdomyoma
Synonyms
Genital rhabdomyoma.
Definition
Benign tumor composed of skeletal muscle cells.
Clinical Features
They are usually discovered incidentally while
examination for other reasons.
• Incidence
Rare.
• Age
It usually occurs in women between the ages of
30 and 55 years.
• Site
Mostly in the vagina, rarely in cervix or vulva.
• Treatment
Local excision.
• Outcome
They are benign tumors.
• Macroscopy
They are typically polypoid or nodular.
• Microscopy
There is a patternless, subepithelial collection
of skeletal muscle cells. They have abundant
eosinophilic cytoplasm with identifiable cross
striation. No cytological atypia or mitoti c
activity is seen (Schoolmeester et al. 2018).
• Immunophenotype
The cells are desmin positive – this often high-
lights the cross striations. They also stain with
specific skeletal muscle markers – MyoD1 and
myogenin.
• Molecular Features
They lack the molecular abnormalities noted in
fetal rhabdomyomas associated with tuberous
sclerosis (Schoolmeester et al. 2018).
M
274 Mesenchymal Tumors, Pathology of the Vagina
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Mesenchymal Tumors, Pathology of the Vagina,
Fig. 1 Angiomyofibroblastoma (a) Low power view
showing alternating hypercellular and paucicellular areas.
• Differential Diagnosis
The morphological and immunohistochemical
features are distinctive.
Angiomyofibroblastoma
Definition
It is a benign, well-circumscribed myofibroblastic
neoplasm. It is seen more commonly in the vulva
but also seen in the vagina. It is believed to arise
from stromal cells distinctive to this anatomical
region.
Clinical Features
Painless mass mostly less than 5 cm and clinically
often diagnosed as a cyst (Nielsen et al. 1996).
• Incidence
Uncommon to rare.
• Age
Premenopausal adult women.
• Site
Lower third of the vagina.
• Treatment
Surgical excision.
• Outcome
Recurrences and metastasis are not described.
• Macroscopy
They are mostly well demarcated and have a
thin surrounding capsule.
(b) Neoplastic spindle cells characteristically swirl around
vessels
• Microscopy
Typically, there are hypercellular and hypo-
cellular areas. The tumor cells are spindle-
shaped, plasmacytoid, or epithelioid. They
lack atypia and mitotic activity is low. The
edematous stroma contains inflammatory
cells, especially lymphocytes and mast cells.
• Immunophenotype
The neoplastic cells are variably positive for
desmin, vimentin, SMA, and CD34. They do
not stain for keratin, S100, or CD68.
• Differential Diagnosis
Cellular angiofibroma is the main differential;
it is commoner in the vulva and is distin-
guished by its thick-walled blood vessels and
lack of desmin staining (Fig. 1).
References and Further Reading
Nielsen, G. P., Rosenberg, A. E., Young, R. H., Dickersin,
G. R., Clement, P. B., & Scully, R. E. (1996).
Angiomyofibroblastoma of the vulva and vagina. Mod-
ern Pathology, 9(3), 284–291.
Nucci, M., & Lazar, A. J. (2020).
Chapter 13: Mesenchymal tumors of the lower genital
tract. In WHO classification of tumors 5
Female genital tumors (pp. 477–526). Lyon: Interna-
tional Agency for Research on Cancer.
Patrelli, T. S., Franchi, L., Gizzo, S., Kiener, A., Berretta,
R., Piantelli, G., Caruana, P., Battista Nardelli, G., &
Bacchi Modena, A. (2012). Rhabdomyome du vagin.
Revue de la littérature à partir d'un cas clinique
[Rhabdomyoma of the vagina. Case report and short
th
edition.
Mesothelial Tumors, Pathology of the Peritoneum 275
https://t.me/med1917
literature review]. Annales de Pathologie, 32(1),
53–57. French.
Sayeed, S., Xing, D., J enkins, S. M., Weisman, P . S., Buehler ,
D., Warmke, L., Uram-Tuculescu, C., Bakkum-Gamez, J.
N., Howitt, B. E., Cortese, C., Park, K. J., & Schoolmeester, J. K. (2018). Criteria for risk stratification of
vulvar and vaginal smooth muscle tumors: An evaluation
of 71 cases comparing proposed classification systems.
American Journal of Surgical Pathology, 42(1), 84–94.
Schoolmeester, J. K., Xing, D., Keeney, G. L., & Sukov,
W. R. (2018). Genital Rhabdomyoma of the lower
female genital tract: A study of 12 cases with molecular
cytogenetic findings. International Journal of Gyneco-
logical Pathology, 37(4), 349–355.
Swanson, A. A., Howitt, B. E., & Schoolmeester, J. K.
(2020). Criteria for risk stratification of vulvar and
vaginal smooth muscle tumors: A follow-up study
with application to leiomyoma variants, smooth muscle
tumors of uncertain malignant potential, and
leiomyosarcomas. Human Pathology, 103,83–94.
Zhao, Y., Li, Y., & Xu, Y. (2003). Clinico-pathologic anal-
ysis of 26 cases of leiomyoma of the vagina. Beijing Da
Xue Xue Bao Yi Xue Ban, 35(1), 37–40. Chinese.
Mesothelial Tumors,
Pathology of the Peritoneum
Ben Davidson
1
Department of Pathology, Norwegian Radium
Hospital, Oslo University Hospital, Oslo, Norway
2
University of Oslo, Faculty of Medicine, Institute
1,2
and Bojana Djordjevic
of Clinical Medicine, Oslo, Norway
3
Division of Anatomic Pathology, Department of
Laboratory Medicine and Molecular Diagnostics,
Sunnybrook Health Sciences Centre, Toronto,
ON, Canada
4
Department of Laboratory Medicine and
Pathobiology, University of Toronto, Toronto,
ON, Canada
3,4
• Age
Middle-aged patients, 28–68 years.
• Sex
Female and male.
• Site
In the female, adenomatoid tumors most commonly occur in the myometrium and the
fallopian tube wall, but may rarely arise in the
ovary, the omentum, the bowel mesentery, and
the peritoneum. In the male, adenomatoid
tumors may be located in the epididymis and
less commonly in the sperm atic cord, prostate,
and ejaculatory ducts.
• Treatment
Usually an incidental finding at surgery for
other indications.
• Outcome
This is a benign tumor.
Macroscopy
Well circumscribed and usually not exceeding
2 cm in size. Typically located subjacent to serosal
surfaces.
Microscopy
Composed of pseudoglandular and pseudovascular
spaces lined by flat to cuboidal cells (Fig. 1). The
spaces may be small and anastomosing or large and
pseudocystic. Occasionally, adenomatoid tumors
may assume papillary architecture.
Immunophenotype
Tumors express mesothelial markers including
calretinin, CK5/6, D2–40, and WT-1. Estrogen
M
Adenomatoid Tumor
Definition
Benign tumor of mesothelial origin.
Clinical Features
• Incidence
Infrequent. Adenomatoid tumors may disproportionately occur in immunocompromised patients.
Mesothelial Tumors, Pathology of the Peritoneum,
Fig. 1 Adenomatoid tumor composed of flattened meso-
thelial cells forming small pseudoglandular spaces
276 Mesothelial Tumors, Pathology of the Peritoneum
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receptor and PAX8 may be focally expressed.
Epithelial markers like BerEP4 and claudin-4 are
negative. Unlike in many mesotheliomas, BAP1
expression is retained.
Molecular Features
Similar to well-differentiated papillary mesothelial tumors, adenomatoid tumors harbor somatic
missense mutations in the TRAF7 gene. Unlike
mesothelioma, adenomatoid tumors lack BAP1,
CDKN2A, and NF2 mutations or deletions.
Differential Diagnosis
The differential diagnosis of adenomatoid tumor
includes well-differentiated papillary mesothelial
tumor, peritoneal inclusion cysts, lymphangioma,
and adenocarcinoma with signet ring morphology.
Well-Differentiated Papillary
Mesothelial Tumor
Synonyms
Well-differentiated papillary mesothelioma.
Microscopy
Well-differentiated papillary mesotheli al tumors
do not exhibit stromal invasion. The most common architectural pattern is the papillary pattern,
but others, including tubulopapillary, corded,
and adenomatoid-like, may be found. The papillae are lined by flat to cuboidal cells with bland
nuclear features and infrequent mitoses (Figs. 2,
3,and4).
Immunophenotype
Tumors express mesothelial markers including calretinin, CK5/6, D2–40, and WT-1.
Estrogen receptor and PAX8 may be focally
expressed. CEA and CD15 (Leu M1) are negative. BerEP4 and MOC 31 may show focal
staining. Unlike in mesoth elioma, BAP1
expression is retained.
Definition
Benign papillary tumor of mesothelial origin.
Clinical Features
• Incidence
Uncommon.
• Age
23–75 years.
• Sex
Females, rare in males.
• Site
Abdominal and pelvic peritoneum.
• Treatment
Usually an incidental finding at surgery for
other indications. Some pati ents may present
with pain.
• Outcome
This is a benign tumor.
Macroscopy
Papillary or nodular lesions, usually less than
2 cm in largest dimension. They may be multiple,
but they are more commonly solitary.
Mesothelial Tumors, Pathology of the Peritoneum,
Fig. 2 Well-differentiated papillary mesothelial tumor
growing on the surface of the ovary
Mesothelial Tumors, Pathology of the Peritoneum,
Fig. 3 Well-differentiated papillary mesothelial tumor
growing on the surface of the omentum
Mesothelial Tumors, Pathology of the Peritoneum 277
https://t.me/med1917
Mesothelioma
Synonyms
Malignant mesothelioma.
Definition
Malignant tumor of mesothelial origin.
Clinical Features
• Incidence
30 cases per 1 million in industrialized nations.
Mesothelial Tumors, Pathology of the Peritoneum,
Fig. 4 Well-differentiated papillary mesothelial tumor
composed of papillae with at most secondary branching.
The papillae are lined by cuboidal cells with bland nuclei.
Some of the papillae contain psammoma bodies
Molecular Features
Well-differentiated papillary mesothelial tumors
have a distinct genetic profile from malignant
mesothelioma. They have mutations in genes
including TRAF7,EHD1, ATM, and TP73. Unlike
mesothelioma, they lack BAP1, CDKN2A, NF2,
and SMARCC1 gene alterations.
Differential Diagnosis
The differential diagnosis includes mesothelioma and a serous borderline tumor. Unlike
some mesotheliomas, differentiated papillary
mesothelial tumors r etain expression of BAP1
and express L1CAM. Diagnostic pitfalls may
involve mesotheliomas which do retain BAP1
expression as well as noninvasive regions of
mesotheliomas, especially in biopsy specimens.
Correlation with imaging and clinical presentation may be required. With regard to serous
borderline tumor, morphologic resemblance to
well-differentiated papillary mesothelial tumor
may be striking. Although the latter can express
ER, PR, BerEp4, MOC31, and CD15 (LeuM1),
this is typically focal rather than diffuse. In
addition, a large majority of serous borderline
tumors will be associated with an ovarian mass,
whereas well-differentiated papillary mesothelial tumors will only involve the ovarian surface. Primary peritoneal serous borderline
tumors (without stromal invasion) are
exceedingly rare.
• Age
20–84 years, median 52 years. Rarely, it may
also occur in children. Exposure to asbestos is
a significant risk factor.
• Sex
Approximately two-thirds of the patients
are male.
• Site
Abdominal and pelvic peritoneum. 15% of
mesotheliomas are peritoneal.
• Treatment
Most common modalities of treatment are
cytoreductive surgery and chemotherapy.
Radiation therapy is used sometimes. Trials
involving multimodal therapy with immunotherapy are ongoing.
• Outcome
Mesothelioma is an aggressive tumor with a
poor prognosis. Untreated patients have a 6–9month life expectancy, and the 3-year survival
rate of treated patients is 9–15%. Women with
peritoneal mesotheliomas may have longer
survival.
Macroscopy
Plaques and nodules of tumors involve the peritoneal surfaces.
Microscopy
Morphologic mesothelioma variants include epithelioid (Fig. 5), sarcomatoid, biphasic, and deciduoid.
The epithelioid pattern is the most common and
exhibits tubular, papillary, and solid patterns. Pap illae exhibit n onhierarchica l branching and hyalinized
cores. The cells are cuboidal in shape and have
eosinophilic to amphophilic cytoplasm. There is
typically only mild cellular atypia. While mitotic
M
278 Mesothelial Tumors, Pathology of the Peritoneum
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However, the latter are small and focal. Furthermore, they uniformly retain expression of BAP
1 and also express L1CAM. Adenocarcinomas
with diffuse peritoneal involvement, particularly
high-grade serous and clear cell carcinomas, are
an important consideration in the differential diagnosis of mesothelioma. Immunohistochemical
stains that can help in this situation are discussed
above and should be used as part of a panel. Mesotheliomas may focally exhibit variably sized vacuoles, reminiscent of an adenomatoid tumor. Unlike
Mesothelial Tumors, Pathology of the Peritoneum,
Fig. 5 Mesothelioma. The tumor cells grow in epithelioid
sheets and invade underlying soft tissue. On the surface of
the tumor, there is focal formation of papillae without
fibrovascular cores. Cytologic atypia is notable but is not
severe. Mitotic figures are notable but not numerous
mesothelioma, adenomatoid tumors retain BAP1
expression. Florid mesothelial hyperplasia may
prompt differential diagnostic consideration. The
most important distinguishing feature is the
absence of a mass-forming lesion in mesothelial
hyperplasia, along with an immunohistochemical
figures are present, they are not numerous.
Lymphoplasmacytic inflammation, foamy histio-
lack of EMA expression but positive expression of
desmin.
cytes, and psammoma bodies may be present in
some cases. Invasion into subperitoneal tissues is
usually seen. The epithelioid subtype has the best
References and Further Reading
prognosis.
Alakus, H., Yost, S. E., Woo, B., French, R., Lin, G. Y.,
Immunophenotype
Tumors express mesothelial markers including
calretinin, CK5/6, mesothelin D2–40, CK7, and
WT-1. In contrast to carcinomas, they will not
stain for claudin-4, CD15 (LeuM1), and B72.3.
BerEP4, MOC 31, estrogen receptor, and PAX8
may be focally expressed. Approximately 50% of
mesotheliomas have loss of expression of BAP1.
Molecular Features
Approximately 40–80% of mesotheliomas have
biallelic somatic mutation or homozygous deletion
of the BAP1 tumor suppressor gene. Less frequent
genetic alterations include CDKN2A homozygous
deletion and mutations of NF2, SETD2,and
DDX3X. In children and young adults, mesotheliomas often lack BAP1 or NF2 inactivation but
show recurrent ALK or EWSR1/FUS-ATF1 gene
fusions. Ten percent of mesotheliomas are associated with germline BAP1 mutations.
Differential Diagnosis
Noninvasive areas of mesothelioma may resemble
well-differentiated papillary mesothelial tumor.
Jepsen, K., Frazer, K. A., et al. (2015). BAP1 mutation
is a frequent somatic event in peritoneal malignant
mesothelioma. Journal of Translational Medicine,
13, 122.
Alexander, H. R., Jr., Li, C. Y., & Kennedy, T. J. (2018).
Current management and future opportunities for peritoneal metastases: Peritoneal mesothelioma. Annals of
Surgical Oncology, 25, 2159–2164.
Andrici, J., Jung, J., Sheen, A., D’Urso, L., Sioson, L.,
Pickett, J., Parkhill, T. R., et al. (2016). Loss of BAP1
expression is very rare in peritoneal and gynecologic
serous adenocarcinomas and can be useful in the differential diagnosis with abdominal mesothelioma.
Human Pathology, 51,9–15.
Baker, P. M., Clement, P. B., & Young, R. H. (2005).
Malignant peritoneal mesothelioma in women:
A study of 75 cases with emphasis on their morphologic spectrum and differential diagnosis. American
Journal of Clinical Pathology, 123, 724–737.
Berzenji, L., & Van Schil, P. (2018). Multimodality treat-
ment of malignant pleural mesothelioma.
F1000Research, 7, F1000 Faculty Rev-1681. https://
doi.org/10.12688/f1000research.15796.1.
Cerruto, C. A., Brun, E. A., Chang, D., & Sugarbaker, P. H.
(2006). Prognostic significance of histomorphologic
parameters in diffuse malignant peritoneal mesothelioma. Archives of Pathology & Laboratory Medicine,
130, 1654–1661.
Chen, X., Sheng, W., & Wang,J. (2013). Well-differentiated
papillary mesothelioma: A clinicopathological and
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