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Melanocytic Tumors, Pathology of the Vulva 189
https://t.me/med1917
Melanocytic Tumors, Pathology of the Vulva,
Fig. 4 Genital melanotic macule epidermal acanthosis
with increased pigmentation of the basal layer and normal
Melanocytic Tumors, Pathology of the Vulva,
Fig. 3 AGN this example of a compound AGN demon-
strates a junctional component arranged as discohesive
nests, a band of dermal fibrosis and a dermal component
with atypia in the superficial dermis and bland morphology
with maturation sequence in the lower dermis
Melanocytic Tumors, Pathology of the Vulva,
Table 1 Criteria for differentiating AGN from vulvar
melanoma
AGN Vulvar melanoma
Age Premenopausal Postmenopausal
Size <1cm >1cm
Borders Circumscribed Poorly defined
Symmetry Symmetric Asymmetric
Shoulder Small or absent Extensive
Lentiginous
growth
Pagetoid
spread
Ulceration Absent Present
Dermal
mitoses
Maturation Present Absent
Minor Prominent
Rare, central Prominent
Rare,
superficial
More numerous,
deep, and atypical
number of junctional melanocytes
an incidence of about 7% in others (Rock et al.
1990). There appears to be an increased inci-
dence of genital melanosis in patients with
history of melanoma (Haugh et al. 2017).
• Age
Genital melanotic macules occur in adults with
an average age of about 40 years (Lenane
et al. 2000).
• Site
Medial aspect of labia majora and introitus are
most common sites (Kanj et al. 1992).
• Treatment
No treatment is usually necessary.
• Outcome
Genital melanotic macules are benign lesions.
They develop slowly, become stable, and may
finally regress. There are, however, rare reports
of melanoma developing in areas of melanosis
(Poggiali et al. 2010).
Macroscopy
Genital melanotic macules present as single
(genital melanotic macule) or multiple pigmented
Definition
A pigmented lesion on the vulvar mucosa characterized by increased pigmentation of basal
macules (genital melanosis) ranging from 0.5 to
2 cm in diameter (Lenane et al. 2000). They can be
irregular in size and color (Haugh et al. 2017).
keratinocytes with no or only minimal increase
in junctional melanocytes.
Microscopy
There is mild epidermal acanthosis with increased
Clinical Features
• Incidence
Reported incidence of genital melanotic macules varies from very uncommon in some studies (Barnhill et al. 1990; Lenane et al. 2000)to
pigmentation of the basal layer (Fig. 4). Melanocytes are normal in number or only slightly
increased and are not atypical (Fig. 5). In some
cases, the melanocytes have prominent dendritic
processes containing melanin pigment (Fig. 6 ).
M
190 Melanocytic Tumors, Pathology of the Vulva
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melanoma shows atypical melanocytes with confluent growth and pagetoid spread.
Vulvar Melanoma
Synonyms
Genital melanoma; Mucosal melanoma.
Definition
Melanocytic Tumors, Pathology of the Vulva,
Fig. 5 Genital melanotic macule high-power view show-
ing increased pigmentation of the basal layer and normal
number of junctional melanocytes
Melanocytic Tumors, Pathology of the Vulva,
Fig. 6 Genital melanotic macule this case shows slight
increased number of junctional melanocytes with
pigmented dendritic processes
Pigment incontinence and a mild perivascular
lymphocytic infiltrate can be seen in the upper
dermis (Kanj et al. 1992). Patients with history
of melanoma are more likely to show an increased
number of junctional melanocytes and some
pagetoid spread (Haugh et al. 2017).
Immunophenotype
Melanocytic markers including Melan-A, S100,
SOX10, and HMB45 show a normal or slightly
increased number of junctional melanocytes.
Melanoma occurring on the vulvar mucosa.
Clinical Features
• Incidence
Vulvar melanoma is rare, and only about
1.3–5% of melanomas are mucosal (Chang
et al. 1998; Rogers and Gibson 1997; Spencer
and Mehnert 2016; Tas et al. 2011).
• Age
Vulvar melanoma tends to affect the elderly;
the average age at diagnosis is in the fifth to
sixth decade of life (Chang et al. 1998;
Nagarajan et al. 2017).
• Site
Vulvar melanoma accounts for 80–85% of
genital melanoma cases with labia majora and
clitoris being the most common site. Less com-
monly, it can occur in vagina, distal urethra,
and rarely the cervix.
• Treatment
Complete excision with negative margins and
sentinel lymph node biopsy depending on the
depth is the treatment of choice.
• Outcome
Vulvar melanoma in situ has a relatively good
prognosis after complete excision; however, inva-
sive vulvar melanoma is an aggressive disease
with a median disease-specific survival of
72.3 months and 5– and 10-year survival rates
of 58.2% and 35.8%, respectively (Moxley et al.
2011; Nagarajan et al.2017; Tcheung et al.2012).
Mitotic activity and tumor depth have been found
to be the strongest predictors of outco me.
Differential Diagnosis
The main differential diagnosis is with melanoma,
and sometimes a biopsy is required to differentiate
between them. On histologic examination,
Macroscopy
Vulvar melanoma presents with flat, raised, or
polypoid pigmented or amelanotic lesions. Ulceration may be present.
Melanocytic Tumors, Pathology of the Vulva 191
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Microscopy
Vulvar melanomas are usually broad, poorly
circumscribed, and asym metric. In the mucosa,
the melanocytes are present predominantly as single cells with irregular distribution, confluent
growth, and prominent pagetoid spread involving
the entire breadth of the lesion (Fig. 7). If there is
an invasive component, it usually shows a nodular
growth pattern without nesting or maturation
(Fig. 8). The melanocytes show cytologic a typia
including enlarged nuclei with prominent nucleoli
and mitotic activity (Fig. 9).
Immunophenotype
Similar to other melanocytic tumors, vulvar melanomas express melanocytic markers including
Melanocytic Tumors, Pathology of the Vulva,
Fig. 7 Melanoma in situ showing an intraepidermal pro-
liferation of atypical melanocytes predominantly as single
cells with irregular distribution, confluent growth, and
prominent pagetoid spread
Melan-A, SOX10, and S100. HMB-45 shows diffuse or patchy staining without the gradual loss of
staining with depth expected in a nevus, Ki-67
shows increased labeling index in the dermis or
lamina propria, and p16 may show areas of
diffuse loss.
Molecular Features
Vulvar melanomas demonstrate mutations in
NRAS, KIT, and TP53 genes. In contrast, genital
nevi exhibit predominantly BRAF gene mutations
(Rouzbahman et al. 2015; Yelamos et al. 2016).
Differential Diagnosis
The main differential diagnosis is with benign
melanocytic lesions including atypical genital
nevi and melanotic macules. Table 1 from atypical
genital nevus section outlines the differentiating
features. In contrast to melanomas, nevi tend to
occur in younger women. On histologic examination, they show a predominantly nested pattern in
the junction and maturation with dermal descent in
the lamina propria and none or only rare mitotic
figures limited to the superficial dermis or lamina
propria. Genital melanotic macules show only pigmentation of basal layer with minimal increase in
the number of melanocytes. Since melanomas may
demonstrate focal areas with histologic features of
melanotic macules, complete excision of any melanotic macule that extends to peripheral margin or
is part of an incompletely removed melanocytic
tumor is advised. Another differential diagnosis is
M
Melanocytic Tumors, Pathology of the Vulva,
Fig. 8 Invasive melanoma showing a nodular growth
pattern with lack of maturation and no nesting
Melanocytic Tumors, Pathology of the Vulva,
Fig. 9 Vulvar melanoma at higher magnification the
cells show cytologic atypia including enlarged nuclei
with prominent nucleoli and mitotic activity
192 Melanocytic Tumors, Pathology of the Vulva
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with extramammary Paget disease (EMPD).
EMPD shows characteristically a pagetoid pattern,
and the pigmented variant also demonstrates melanin pigment mimicking melanoma in situ (Hilliard
et al. 2009). As opposed to melanoma, EMPD is
positive for pan-cytokeratin, CK7, and CEA.
References and Further Reading
Barnhill,R.L.,Albert,L.S., Shama, S. K., Goldenhersh,
M. A., Rhodes, A. R., & Sober, A. J. (1990). Genital
lentiginosis: A clinical and histopathologic study. Journal
of the American Academy of Dermatology, 22(3),
453–460. https://doi.org/10.1016/0190-9622(90)
70064-o.
Brenn, T. (2011). Atypical genital nevus. Archives of
Pathology & Laboratory Medicine, 135(3), 317–320.
https://doi.org/10.1043/2009-0382-RA.1.
Cengiz, F. P., Emiroglu, N., & Wellenhof, R. H. (2015).
Dermoscopic and clinical features of pigmented skin
lesions of the genital area. Anais Brasileiros de
Dermatologia, 90(2) , 178–183. https://doi.org/10.
1590/abd1806-4841.20153294.
Chang, A. E., Karnell, L. H., & Menck, H. R. (1998). The
National Cancer Data Base report on cutaneous and
noncutaneous melanoma: A summary of 84,836 cases
from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer, 83(8), 1664–1678. https://doi.org/
10.1002/(sici)1097-0142(19981015)83:8<1664::aidcncr23>3.0.co;2-g.
Christensen, W. N., Friedman, K. J., Woodruff, J. D., &
Hood, A. F. (1987). Histologic characteristics of vulvar
nevocellular nevi. Journal of Cutaneous Pathology,
14(2), 87–91. https://doi.org/10.111 1/j.1600-0560.1987.
tb00478.x.
Clark, W. H., Jr., Hood, A. F., Tucker, M. A., & Jampel,
R. M. (1998). Atypical melanocytic nevi of the genital
type with a discussion of reciprocal parenchymalstromal interactions in the biology of neoplasia.
Human Pathology, 29(1 Suppl), 1–24. https://doi.org/
10.1016/s0046-8177(98)80028-2.
Cohen, Y., Rosenbaum, E., Begum, S., Goldenberg, D.,
Esche, C., Lavie, O., Sidransky, D., & Westra, W. H.
(2004). Exon 15 BRAF mutations are uncommon in
melanomas arising in nonsun-exposed sites. Clinical
Cancer Research, 10(10), 3444–3447. https://doi.org/
10.1158/1078-0432.CCR-03-0562.
Gleason, B. C., Hirsch, M. S., Nucci, M. R., Schmidt,
B. A., Zembowicz, A., Mihm, M. C., Jr., McKee,
P. H., & Brenn, T. (2008). Atypical genital nevi.
A clinicopathologic analysis of 56 cases. The American
Journal of Surgical Pathology, 32(1), 51–57. https://
doi.org/10.1097/PAS.0b013e318068420c.
Haugh, A. M., Merkel, E. A., Zhang, B., Bubley, J. A.,
Verzi, A. E., Lee, C. Y., & Gerami, P. (2017). A clinical,
histologic, and follow-up study of genital melanosis in
men and women. Journal of the American Academy of
Dermatology, 76(5), 836–840. https://doi.org/10.1016/
j.jaad.2016.11.003
Hilliard, N. J., Huang, C., & Andea, A. (2009). Pigmented
extramammary Paget’s disease of the axilla mimicking
melanoma: Case report and review of the literature.
Journal of Cutaneous Pathology, 36(9), 995–1000.
https://doi.org/10.1111/j.1600-0560.2009.01174.x.
Hosler, G. A., Moresi, J. M., & Barrett, T. L. (2008). Nevi
with site-related atypia: A review of melanocytic nevi
with atypical histologic features based on anatomic site.
Journal of Cutaneous Pathology, 35(10), 889–898.
https://doi.org/10.1111/j.1600-0560.2008.01041.x.
Kanj, L. F., Rubeiz, N. G., Mroueh, A. M., & Kibbi, A. G.
(1992). Vulvar melanosis and lentiginosis: a case
report. Journal of the American Academy of Dermatol-
ogy, 27(5 Pt 1), 777–778. https://doi.org/10.1016/
s0190-9622(08)80232-0.
Lenane, P., Keane, C. O., Connell, B. O., Loughlin, S. O.,
& Powell, F. C. (2000). Genital melanotic macules:
Clinical, histologic, immunohistochemical, and ultra-
structural features. Journal of the American Academy of
Dermatology, 42(4), 640–644. Retrieved from https://
www.ncbi.nlm.nih.gov/pubmed/10727311
Moxley, K. M., Fader, A. N., Rose, P. G., Case, A. S.,
Mutch, D. G., Berry, E., Schink, J. C., Kim, C. H., Chi,
D. S., & Moore, K. N. (2011). Malignant melanoma of
the vulva: An extension of cutaneous melanoma?
Gynecologic Oncology, 122(3), 612–617. https://doi.
org/10.1016/j.ygyno.2011.04.007.
Nagarajan, P., Curry, J. L., Ning, J., Piao, J., Torres-Cabala,
C. A., Aung, P. P., Ivan, D., Ross, M. I., Levenback,
C. F., Frumovitz, M., Gershenwald, J. E., Davies,
M. A., Malpica, A., Prieto, V. G., & Tetzlaff, M. T.
(2017). Tumor thickness and mitotic rate robustly pre-
dict melanoma-specific survival in patients with pri-
mary vulvar melanoma: A retrospective review of
100 cases. Clinical Cancer Research, 23(8),
2093–2104. https://doi.org/10.1158/1078-0432.CCR-
16-2126.
Poggiali, S., Biagioli, M., Bilenchi, R., & Rubegni,
P. (2010). Malignant melanoma of the vulva and
melanosis. Minerva Ginecologica, 62(2), 169–170.
Retrieved from https://www.ncbi.nlm.nih.gov/
pubmed/20502427
Rock, B., Hood, A. F., & Rock, J. A. (1990). Prospective
study of vulvar nevi. Journal of the American Academy
of Dermatology, 22(1), 104–106. https://doi.org/10.
1016/0190-9622(90)70017-c.
Rogers, R. S., 3rd, & Gibson, L. E. (1997). Mucosal,
genital, and unusual clinical variants of melanoma.
Mayo Clinic Proceedings, 72(4), 362–366. https://doi.
org/10.4065/72.4.362.
Rouzbahman, M., Kamel-Reid, S., Al Habeeb, A., Butler,
M., Dodge, J., Laframboise, S., Murphy, J., Rasty, G.,
& Ghazarian, D. (2015). Malignant melanoma of vulva
and vagina: A histomorphological review and mutation
analysis–a single-center study. Journal of Lower
.
Mesenchymal Benign and Malignant Tumors, Pathology of the Cervix 193
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Genital Tract Disease, 19(4), 350–353. https://doi.org/
10.1097/LGT.0000000000000142.
Spencer, K. R., & Mehnert, J. M. (2016). Mucosal mela-
noma: Epidemiology, biology and treatment. Cancer
Treatment and Research, 167, 295–320. https://doi.org/
10.1007/978-3-319-22539-5_13.
Tas, F., Keskin, S., Karadeniz, A., Dagoglu, N., Sen, F.,
Kilic, L., & Yildiz, I. (2011). Noncutaneous melanoma
have distinct features from each other and cutaneous
melanoma. Oncology, 81(5–6), 353–358. https://doi.
org/10.1159/000334863.
Tcheung, W. J., Selim, M. A., Herndon, J. E., 2nd,
Abernethy, A. P., & Nelson, K. C. (2012). Clinicopathologic study of 85 cases of melanoma of the female
genitalia. Journal of the American Academy of Derma-
tology, 67(4), 598–605. https://doi.org/10.1016/j.jaad.
2011.11.921.
Tseng, D., Kim, J., Warrick, A., Nelson, D., Pukay, M.,
Beadling, C., Heinrich, M., Selim, M. A., Corless,
C. L., & Nelson, K. (2014). Oncogenic mutations in
melanomas and benign melanocytic nevi of the female
genital tract. Journal of the American Academy of Der-
matology, 71(2), 229–236. https://doi.org/10.1016/j.
jaad.2014.03.033.
Yelamos, O., Merkel, E. A., Sholl, L. M., Zhang, B., Amin,
S. M., Lee, C. Y., Guitart, G. E., Yang, J., Wenzel, A. T.,
Bunick, C. G., Yazdan, P., Choi, J., & Gerami,
P. (2016). Nonoverlapping clinical and mutational patterns in melanomas from the female genital tract and
atypical genital nevi. The Journal of Investigative Der-
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j.jid.2016.05.094.
Clinical Features
• Incidence
Very rare. About 5% of all cervical sarcomas
(Fedare 2006).
• Age
Wide range. Mean age 37 years
(Schoolmeester et al. 2017).
• Sex
Female.
• Site
Cervix, uterine corpus, vagina, and vulva.
• Treatment
Surgical resection is the mainstay of therapy,
as chemotherapy and/or radiotherapy have lim-
ited benefit. There has been some success with
tyrosine kinase inhibitors.
• Outcome
It is usually a localized tumor at presentation
with slow progression. Metastases can occur
later, most commonly to lungs, brain, and
bone. Alveolar soft part sarcoma of the gyne-
cologic tract shows better prognosis than other
sites (Nielsen et al. 1995).
M
Macroscopy
It is a soft, friable tumor with white-yellow cut
surface. Some may show necrosis and/or
hemorrhage.
Mesenchymal Benign and
Malignant Tumors, Pathology
of the Cervix
Nissreen Mohammad2and Lynn Hoang
1
Anatomical Pathology, Vancouver General
Hospital, Vancouver, BC, Canada
2
University of British Columbia, Vancouver,
BC, Canada
Alveolar Soft Part Sarcoma
Definition
A mesenchymal neoplasm of uncertain histogenesis defined by a specific translocation der(17)t
(X;17)(p11.2q25) resulting in ASPSCR1-TFE3
gene fusion (Ladanyi et al. 2001).
1,2
Microscopy
The tumor has a uniform appearance and is
divided into compartments of variable sizes,
which are subdivided into defined nests of large
polygonal cells with granular eosinophilic cytoplasm and round-oval nuclei with prominent
nucleoli and may show binucleation. The cells
show degeneration, necrosis, and loss of cohesion
at the center of the nest resulting in an “alveolar”
pattern (Figs. 1 and 2).
Immunophenotype
TFE3 is positive in the tumor nuclei
(Schoolmeester et al. 2017). It is negative for
HMB45, melan-A, desmin, and SMA . PAS
stains the rhomboid crystals in majority of cases
(Fig. 3).
194 Mesenchymal Benign and Malignant Tumors, Pathology of the Cervix
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fusion causing activation of MET signaling.
(Ladanyi et al. 2001).
Differential Diagnosis
Perivascular epithelioid cell tumor (PEComa) also
shows polygonal cells with abundant granular
cytoplasm. By immunohistochemistry PEComa
will show a “ myomelanocytic” phenotype with
variably positive HMB45, melan-A, desmin,
and/or SMA.
Mesenchymal Benign and Malignant Tumors,
Pathology of the Cervix, Fig. 1 Alveolar soft part sar-
coma shows polygonal cells with granular eosinophilic
cytoplasm forming an “alveolar” pattern, low power
COL1A1-PDFRB Fusion Cervical Sarcoma
Synonyms
Dermatofibrosarcoma protuberans; Fibrosarcoma.
Definition
Spindle cell sarcoma characterized by
rearrangements of fusion of COL1A1-PDFRB.
Mesenchymal Benign and Malignant Tumors,
Pathology of the Cervix, Fig. 2 Alveolar soft part sar-
coma shows polygonal cells with granular eosinophilic
cytoplasm forming an “alveolar” pattern, high power
Mesenchymal Benign and Malignant Tumors,
Pathology of the Cervix, Fig. 3 Alveolar soft part sar-
coma is positive for a PAS stain
Clinical Features
• Incidence
Rare. Only two reports in the cervix and one in
the uterine corpus have been described so far
(Croce et al. 2019).
• Age
48 and 60 years (Croce et al. 2019).
• Sex
Female.
• Site
Cervix. They can also occur in the uterine
corpus.
• Treatment
These tumors might benefit from tyrosine
kinase inhibitors such as imatinib.
• Outcome
Limited data available. The tumors presented at
FIGO stage IB and IIIB. One died of disease
after 60 months and one was alive with no evi-
dence of disease after 10 months of follow-up.
One patient had a previous dermatofibrosarco ma
protuberans.
Molecular Features
Unbalanced translocation der(17)t(X;17)
(p11.2q25) resulting in ASPSCR1-TF E3 gene
Macroscopy
They are large (5–8 cm) tumors with infiltrative
margins.
Mesenchymal Benign and Malignant Tumors, Pathology of the Cervix 195
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Microscopy
The tumors were cellular and exhibited storiform
and herringbone archi tecture, similar to fibrosarcomas and dermatofibrosarcoma protuberans as
described elsewhere in the body. The cells were
uniform, had ovoid/spindled nuclei, scant cytoplasm, and indistinct cell borders. Nuclear atypia
was mild to moderate and mitotic activity was
high. Necrosis is variable.
Immunophenotype
The tumors diffusely expressed CD34 and were
negative for ER, PR, desmin, S100, and Trk. They
were negative for BCOR but expressed
Cyclin D1.
Molecular Features
This tumor is defined by the presence of a
COL1A1-PDFRB oncogenic fusion.
Differential Diagnosis
The differential diagnosis includes NTRKrearranged cervical sarcoma, leiomyosarcoma,
and undifferentiated cervical sarcoma. Molecular
testing is likely needed for a definitive diagnosis.
Embryonal Rhabdomyosarcoma
Synonyms
Sarcoma botryoides.
Definition
Rhabdomyosarcoma is a malignant mesenchymal
neoplasm with skeletal muscle differentiation. It is
divided into distinct subtypes: embryonal/
botryoid, alveolar, pleomorphic, and spindle cell/
sclerosing. Embryonal rhabdomyosarcoma represents more than 75% of rhabdomyosarcomas of
the lower female genital tract with a propensity for
the cervix and the vagina (Nasioudis et al. 2017).
The other subtypes are very unlikely to involve
the cervix.
Clinical Features
• Incidence
Sarcomas constitute 1% of cervical malignancies, and embryonal rhabdomyosarcoma
accounts for the majority of those sarcomas
(64%) (Fedare 2006).
• Age
Children and adolescents. Rare in patients
older than 40 (Dehner et al. 2012).
• Sex
Female.
• Site
Vagina in children and cervix in adolescents
(Dehner et al. 2012).
• Treatment
Chemotherapy and surgery.
• Outcome
Overall 5 year survival is 70% (Nasioudis et al.
2017). Anaplasia is associated with a worse
prognosis.
Macroscopy
These are fleshy polypoid or submucosal grapelike (from Greek botrys, meaning a bunch of
grapes) masses.
Microscopy
The tumor cells resemble the different stages of
skeletal muscle embryogenesis with variable
range of differentiation. Benign surface epithelium or entrapped glands can be seen at the
surface of the tumor. Botryoid rhabdomyosarcoma is characterized by a cambium layer,
where subepithelial condensation of tumor cells
are separated from the surface epithelium by a
layer of loose hypocellular stroma. There is variable cellularity with hypocellular loose myxoid
areas and hypercellular areas of packed
undifferentiated small round or spindle cells
(Fig. 4). Rhabdomyoblasts may or may not be
present. Cross-striations, chondromyxoid
matrix, or cartilage nodules seen in half of cases
(Dehner et al. 2012). There is usually brisk
mitotic activity. Anaplasia i n the form of large
lobated hyperchromatic nuclei three times the
size of neighboring cells with or without atypical
mitotic figures can be seen (Qualman et al.
2008).
Immunophenotype
MYOD1, myogenin, and desmin are positive
(maybe variable or focal). SMA is negative.
M
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• Age
Premenopausal women. Median age 31 years
(Xiao et al. 2014).
• Sex
Female.
• Site
Can be seen throughout the female genital
tract, cervix, vulva, vagina, uterus, and ovaries
(Xiao et al. 2014).
• Treatment
Combination of surgery and/or radiotherapy
Mesenchymal Benign and Malignant Tumors,
Pathology of the Cervix, Fig. 4 Embryonal rhabdo-
myosarcoma. A cellular proliferation of undifferentiated
small round blue cells
and systemic chemotherapy.
• Outcome
The 10 year survival for localized disease is
75%. The outcomes are worse for older
patients, extraosseous and metastatic disease
Molecular Features
(Krasin et al. 2005; Baldini et al. 1999).
There is a high prevalence of DICER1 mutations
(up to 95% of cases) (de Kock et al. 2020).
Macroscopy
Multilobulated soft mass with grey-yellow or tan cut
Differential Diagnosis
surface. Hemorrhage and necrosis might be seen.
Adenosarcoma is the main differential especially
when it has rhabdomyosarcomatous differentiation or sarcomatous overgrowth. Adenosarcoma
can also “less commonly” have a DICER1 mutation. Adenosarcoma will show a phyllodes-like
growth pattern and periglandular condensation.
The patients are usually older.
Microscopy
There are solid sheets or lobules of uniform round
cells. The nuclei are round or ovoid with fine powdery chromatin (Figs. 5 and 6). The nucleoli might
be small or inconspicuous. The cytoplasm is scant
or pale due to intracellular glycogen. A minority
of cases might show rosettes, most commonly
Homer-Wright rosettes. This feature corresponds
Ewing Sarcoma
to the old designation of PNET. Mitotic activity is
variable. Tumor necrosis shows a “filigree pattern”
Synonyms
with zones of necrotic ghost cells.
Primitive neuroectodermal tumor (PNET).
Immunophenotype
Definition
Undifferentiated small round blue cell sarcoma
characterized by the presence of translocations
leading to the fusion of EWSR1 gene on 22q12
with one of several members of the ETS family of
transcription factors (Lin et al. 1999).
CD99 shows strong and diffuse membranous positivity. It is highly sensitive for Ewing sarcoma,
but is also positive in other small blue round cell
tumors.
FLI1 stain is positive in up to 94% of Ewing
sarcomas, but is not specific(Folpeetal.2005).
NSE, CD57, and synaptophysin can be positive.
Clinical Features
• Incidence
A proportion of Ewing sarcomas will show aberrant keratin expression (Folpe et al. 2005).
Extremely rare in the cervix. Only rare case
reports detail Ewing’s sarcoma of the uterine
cervix (Mashriqi et al. 2015; Kyriazoglou et al.
2019).
Molecular Features
Translocations leading to the fusion of EWSR1
gene on 22 q12 with one of several members of
Mesenchymal Benign and Malignant Tumors, Pathology of the Cervix 197
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Leiomyoma of the Uterine Cervix
Synonyms
Fibroid; Myoma.
Definition
Benign mesenchymal tumor with smooth muscle
differentiation.
Clinical Features
Mesenchymal Benign and Malignant Tumors,
Pathology of the Cervix, Fig. 5 Ewing sarcoma. Solid
sheets of uniform round cells with round/ovoid nuclei with
fine powdery chromatin and inconspicuous nucleoli, low
power
Mesenchymal Benign and Malignant Tumors,
Pathology of the Cervix, Fig. 6 Ewing sarcoma. Solid
sheets of uniform round cells with round/ovoid nuclei with
fine powdery chromatin and inconspicuous nucleoli, high
power
the ETS family of transcription factors is
characteristic (Lin et al. 1999). The most common
translocation is t(11;22)(q24;q12) resulting in the
EWSR1-FLI1 gene fusion.
Differential Diagnosis
Undifferentiated endometrial carcinoma has a
discohesive and small blue round cell morphology.
One-third are mismatch repair (MMR) deficient
and may show loss of one of the SWI/SNF proteins.
Primary cervical neuroendocrine (small cell)
carcinoma is HPV driven and is p16 positive.
Metastatic tumors such as melanoma, neuroendocrine carcinoma, or lymphoma can have a blue
cell appearance.
• Incidence
Unlike the uterine corpus, leiomyomas of the
cervix are rare. They are the most common
benign mesenchymal tumor of the cervix, but
account for about 5% (0.6–10%) of uterine
leiomyomas (Tiltman 1998; Okamoto
et al. 2003).
• Age
Fourth and fifth decade.
• Sex
Female.
• Site
Uterine cervix.
• Treatment
Myomectomy or observation. They are less
amenable to uterine artery embolization than
those of the uterine corpus (Kim et al. 2012).
• Outcome
They have a benign course but can recur after
myomectomy.
Macroscopy
Well circumscribed nonencapsulated with whitetan whorled surface, similar to the uterine corpus.
Microscopy
Leiomyomas have intersecting fascicles of spindle cells with moderate pink cytoplasm and cigarshaped nuclei (Fig. 7). A few mitotic figures can
be seen. Mostly have a distinct border from surrounding cervical stroma, but maybe less defined
than uterine leiomyomas. They may show v ariable amounts of collagenous matrix or dystrophic
calcification.
The histologic variants of leiomyomas seen in
the uterine corpus have not been well documented
in the cervix. Fumarate hydratase (FH)-deficient
leiomyoma show ribbon-like arrangement of
M
198 Mesenchymal Benign and Malignant Tumors, Pathology of the Cervix
https://t.me/med1917
Leiomyosarcoma of the Uterine
Cervix
Definition
Malignant mesenchymal tumor with smooth muscle differentiation.
Clinical Features
• Incidence
Sarcomas of the uterine cervix constitute 1% of
Mesenchymal Benign and Malignant Tumors,
Pathology of the Cervix, Fig. 7 Leiomyomas with
bland spindled cells containing eosinophilic cytoplasm
tumor cells, prominent eosinophilic nuclei with
perinucleolar halos, eosinophilic globules
(rhabdoid), cytoplasmic inclusions, prominent
nuclear atypia and multinucleated cells, and
staghorn vessels. (Miettinen et al. 2016).
The criteria for malignanc y are the same as for
smooth muscle neoplasms of the uterine corpus.
Immunophenotype
Leiomyomas are positive for H-caldesmon, SMA,
desmin, and ER. Fumarate hydratase staining is
lost in most patients with germline or sporadic FH
mutations. Cases with missense mutations can
show retained staining. Presence of 2SC staining
is more sensitive and specific for detection of FH
aberrations (Joseph et al. 2015).
Molecular Features
It is presumed to by the same as seen in the uterine
corpus. They can harbor MED12 mutations and
HMGA2 rearrangements (80–90% of all
leiomyomas) (Mehine et al. 2014), less frequently
HMGA1 rearrangements and COL4A5 and
COL4A6 rearrangements (Mehine et al. 2014).
They can have FH mutations.
Differential Diagnosis
Leiomyosarcomas have marked atypia, mitoses
>10 per 10 HPFs, and coagulative tumor necrosis.
Inflammatory myofibroblastic tumor will have
myxoid matrix, mixed inflammatory cell infiltrate,
and positive ALK immunohistochemistry.
malignancies involving the cervix.
Leiomyosarcoma is the second most common
sarcoma of the uterine cervix (14% of all sarcomas) (Fadare 2006).
• Age
Fourth to sixth decade.
• Sex
Female.
• Site
Uterine cervix.
• Treatment
Variable; hysterectomy.
• Outcome
Due to its rarity and differing therapeutic measures, prognostic and predictiv e factors have
not been well established.
Macroscopy
Tumors are poorly circumscribed, white-tan, and
fleshy. May show a variegated hemorrhagic,
necrotic, or myxoid surface. They may expand
the cervix or protrude into the endocervical
canal.
Microscopy
Leiomyosarcomas comprise of intersecting fascicles of atypical spindle cells. They show
coagulative necrosis, increased mitotic activity,
and/or atypical mitotic figures (Figs . 8 and 9).
Variants and criteria for malignancy are inferred
from uterine corpus criteria as cervical
leiomyosarcomas are rare and not well studied.
See Table 1 from the WHO classification of
female genital tumors, 5th Edition (2020).
Immunophenotype
H-caldesmon, SMA, and desmin are positive.
ER expression in leiomyosarcoma is less than
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