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Mesenchymal Benign and Malignant Tumors, Pathology of the Cervix 199
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Mesenchymal Benign and Malignant Tumors,
Pathology of the Cervix, Table 1 Diagnostic criteria
for leiomyosarcoma of the uterus
Variant Diagnostic criteria
Mesenchymal Benign and Malignant Tumors,
Pathology of the Cervix, Fig. 8 Leiomyosarcoma
showing hypercellularity and hyperchromasia compared
to the background myometrial smooth muscle cells
Conventional
(spindle cell)
Epithelioid One or more of the following:
Myxoid One or more of the following:
Two or more of the following:
Marked cytologic atypia
Tumor cell necrosis
Four mitoses/mm
10 HPF of 0.55 mm in diameter and
0.24 mm
HPF of 0.55 mm in diameter and
0.24 mm
HPF of 0.55 mm in diameter and
0.24 mm
2
in area)
Moderate to severe nuclear atypia
Tumor cell necrosis
1.6 mitoses/mm
2
in area)
Moderate to severe nuclear atypia
Tumor cell necrosis
0.4 mitoses/mm
2
in area)
Infiltrative borders
2
(10 mitoses/
2
(4 mitoses/10
2
(>1 mitoses/10
Mesenchymal Benign and Malignant Tumors,
Pathology of the Cervix, Fig. 9 Leiomyosarcoma
showing enlarged nuclei and brisk mitotic activity
in leiomyoma (40% vs 78%) (Leitao et al.
2004). Abnormal p53 and positive block-like
p16 are seen in about half of cases (Schaefer
et al. 2017).
Molecular Features
Complex numerical and structural chromosomal
aberrations and mutations in known cancer genes
such as TP53 and ATRX are seen (Makinen et al.
2016). MDM2 overexpression is seen in a minor-
ity of leiomyosarcomas but not in leiomyomas
(Hall et al. 1997). MED12 mutation and
HMGA2 overexpression are infrequent in
leiomyosarcomas, but might suggest that a subset
of uterine leiomyosarcomas arise from
leiomyomas (Makinen et al. 2017).
Differential Diagnosis
Leiomyoma will not show atypia, tumor-type
necrosis, and brisk mitotic activity.
Inflammatory myofibroblastic tumor has a
myxoid appearance and is positive for ALK
immunohistochemistry.
Endometrial stromal sarcoma contains uniform
nuclear morphology and low mitotic activity.
CD10 usually positive and caldesmon is negative.
Perivascular epithelioid cell tumor (PEComa)
has epithelioid morphology. HMB45 and
Melan-A are positive.
NTRK-Rearranged Cervical Sarcoma
Synonyms
NTRK-rearranged cervical sarcoma; NTRKrearranged cervical sarcoma with features of
fibrosarcoma.
Definition
Spindle cell sarcoma characterized by
rearrangements of NTRK gene.
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200 Mesenchymal Benign and Malignant Tumors, Pathology of the Cervix
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Clinical Features
• Incidence
Rare. Recently molecularly defined in 2018
(Chiang et al. 2018). Other case series (Croce
et al. 2019; Solomon et al. 2020) and case
reports exist.
• Age
23–44 years (Chiang et al. 2018; Croce
et al. 2019).
• Sex
Female.
• Site
Cervix.
• Treatment
These tumors might benefit from TRK inhibitors (larotrectinib and entrectinib). Both drugs
are FDA approved for solid tumors harboring
NTRK gene fusion (Demetri et al. 2020).
• Outcome
Limited data available. Variable outcomes;
metastasis, recurrence, and progression have
been reported (Chiang et al. 2018).
Macroscopy
Firm to fleshy mass located mainly in the cervix or
lower uterine segment.
Microscopy
The tumor has an infiltrative border and is composed of spindle cells with mild to moderate
nuclear atypia, arranged in a diffuse herringbone
or storiform architecture. Mitotic activity is variable, but usually brisk.
Immunophenotype
S100 positive and CD34 is variable (Chiang et al.
2018; Croce et al. 2019). ER, PR, and desmin are
negative. panTRK immunohistochemistry has
poor sensitivity and specificity in sarcomas (80%
and 74.4% respectively) (Solomon et al. 2020). It
can show false positivity in smooth muscle differentiation and stromal sarcomas with BCOR/
BCORL1 alteration. False negatives occur in
NTRK3 fusion sarcomas. Therefore, molecular
testing is the definitive diagnostic method when
NTRK-rearranged sarcoma is suspected.
Molecular Features
This tumor is defined by oncogenic fusions occurring in one of three neurotrophic tyrosine receptor
kinase genes NTRK1, NTRK2, or NTRK3 with a
wide variety of fusion partners.
Differential Diagnosis
Leiomyosarcoma is positive for caldesmon,
SMA, and desmin, while S100 negative.
Leiomyosarcoma can show false positive
panTRK staining.
Low-grade or high-grade uterine stromal sarcomas defined by other molecular fusions will
show CD10, ER, and PR positivity, and variable
cyclin D1 and BCOR staining. It might show false
positive panTRK staining. Molecular testing is
ideal if morphologically or immunop henotypically inconclusive.
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Mesenchymal Tumors and
Mixed Epithelial and
Mesenchymal Tumors,
Pathology of the Vulva
Scott C. Bresler1and Aleodor Andea
1
Pathology, University of Michigan, Ann Arbor,
MI, USA
2
Department of Pathology, University of
Michigan, Ann Arbor, MI, USA
Aggressive Angiomyxoma
Definition
Aggressive angiomyxoma (AAM) is a rare, locally
aggressive, and deep-seated neoplasm that occurs
most commonly in the genital and pelvic regions of
reproductive-aged females. The tumor has a high
potential for recurrence; however, distant metastasis is rare (Blandamura et al. 2003).
Clinical Features
• Incidence
Rare.
• Age
Patients in the fourth decade of life are most
commonly involved (Fetsch et al. 1996). How-
ever, the reported age range is wide: 11–77 years
(Chan et al. 2000; Sutton and Laudadio 2012).
• Sex
The female to male ratio is reported to be 6.6:1
(Chan et al. 2000).
• Site
Perineum, pelvis, vulva, vagina, and less com-
monly in males at corresponding sites (Iezzoni
et al. 1995).
• Treatment
Surgical treatment is the mainstay of therapy,
with wide local excision (at least 1 cm margins)
preferred due to the infiltrative nature of the
tumor and tendency for local recurrence.
• Outcome
Local recurrences are frequent, occurring in
30–50% of cases (Amezcua et al. 2005; Chan
et al. 2000; Fetsch et al. 1996; Granter et al.
1997; Iezzoni et al. 1995; Steeper and Rosai
2
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva 203
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1983). Patients with involved margins follow-
ing resection have a slightly increased risk for
local recurrence after 10 years (Chan et al.
2000). Distant metastases are exceptional but
have been reported (McCluggage et al. 2010).
Macroscopy
Clinically, AAM is often mistaken clinically for a
Bartholin gland cyst. Lesions generally are large
and irregularly shaped (Fig. 1) with ill-defined
borders and a shiny, gelatinous appearance in
addition to areas of hemorrhage (Fig. 2).
Microscopy
Histologic examination reveals a multilobulated,
infiltrative tumor in most cases (Fig. 3), although a
minority of cases are circu mscribed (Granter et al.
1997). Numerous interspersed blood vessels are
present of varying caliber from small to large and
muscular, the latter of which is a distinguishing
feature (Fig. 4 ). Tumors have a myxoid background with collagen fibers concentrated around
blood vessels. Entrapment of normal adipose
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 1 Aggressive angiomyxoma – macroscopic features.
Gross image revealing an irregularly shaped mass that is
adherent to skeletal muscle and fibroadipose tissue
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 2 Aggressive angiomyxoma – macroscopic features.
Serial sections reveal an infiltrative, gelatinous appearing
tumor with a glistening surface showing areas of hemorrhage
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 3 Aggressive angiomyxoma – microscopic features.
Scanning magnification image showing a multinodular
growth pattern and overall hypocellularity
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 4 Aggressive angiomyxoma – microscopic features.
Prominent thick-walled vessels and hypocellularity are
typical features. Tumors have a myxoid background with
collagen fibers concentrated around blood vessels
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204 Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva
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tissue is a common occurrence (Fig. 5). Tumors
are typically composed of bland spindled to stellate cells with delicate cytoplasmic processes
without nuclear atypia but showing hyperchromasia (Fig. 6) (Granter et al. 1997). Mitotic
activity is rare.
Immunophenotype
Tumors are typically diffusely positive for ER and
PR, suggesting a role for hormone receptors in the
growth or development of these tumors. AAM is
also typically positive for smooth muscle markers
such as smooth muscle actin (SMA) and desmin.
HMGA2 is a sensitive immunohistochemical
marker for this neoplasm, in part likely due to
overexpression resulting from rearrangements at
12q15 which include its encoding gene (see
Molecular Features below). However, expression
of HMGA2 is not entirely specific for AAM and is
seen in other neoplasms with potentially similar
histologic features including leiomyoma,
fibroepithelial stromal polyp, and nodular fasciitis
(McCluggage et al. 2010). Tumors also often
express CDK4; however, MDM2 expression by
immunohistochemistry is usually absent (Van
Roggen et al. 2005).
Molecular Features
Structural rearrangements involving HMGA2 at
12q15 are found in approximately 30% of
AAMs (Medeiros et al. 2007). HMGA2 protein
expression status does not always correlate with
the presence or absence of a translocation involving its encoding gene (Rabban et al. 2006).
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 5 Aggressive angiomyxoma – microscopic features.
Entrapment of adipose tissue is a common feature
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 6 Aggressive angiomyxoma – microscopic features.
Tumor cells are spindled to stellate in appearance with
hyperchromatic nuclei, indistinct nucleoli, and delicate
cytoplasmic processes
Differential Diagnosis
Angiomyofibroblastoma, superficial angiomyxoma,
and fibroepithelial stromal polyp are the most
important differential diagnoses. In particular,
aggressive angiomyxoma can show considerable
morphologic overlap with angiomyofibroblastoma, which some authors consider to be
part of the same morphologic spectrum (Granter
et al. 1997). This notion is supported by the presence of spindle cells containing brightly eosinophilic cytoplasm and cigar-shaped nuclei in most
cases, which tend to be concentrated around blood
vessels. Additionally, many cases of aggressive
angiomyxoma show immunohistochemical reactivity for desmin and SMA. Angiomyofibroblastoma, however, in contrast to aggressive
angiomyxoma, is typically sharply circumscribed
and occurs in the subcutis rather than in deep
soft tissue (Granter et al. 1997). Superficial
angiomyxoma occurs more superficially in the
dermis and/or subcutaneous tissue and shows a
lobulated growth pattern. Other potential histologic mimics include myxoid lipoma, myxoid
embryonal rhabdomyosarcoma (“sarcoma
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva 205
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botryoides”), myxoid leiomyoma, and
myxofibrosarcoma.
Angiomyofibroblastoma
Definition
Angiomyofibroblastoma is a benign neoplasm
with myofibroblastic differentiation that occurs
primarily in the subcutaneous tissue of the vulva
and vagina of reproductive-aged women.
Clinical Features
• Incidence
Rare. Descriptions of angiomyofibroblastoma
are limited to small case series and case reports.
• Age
Almost exclusively occurs in reproductiveaged women. Rarely occurs in pediatric
patients or in postmenopausal women.
• Sex
More common in females, but also described
in men. Cases resembling angiomyofibroblastoma occurring in males have sometimes
been termed “ angiomyofibroblastoma-like
tumors” (Laskin et al. 1998); however, these
are histologically identical to cellular
angiofibroma (Iwasa and Fletcher 2004).
• Site
Vulva and vagina are the most commonly
affected sites. Lesions occurring in the perineum and inguinal region have also been
reported (Laskin et al. 1997).
• Treatment
Simple surgical excision is the mainstay of
therapy.
• Outcome
Minimal risk of local recurrence.
Macroscopy
Like aggressive angiomyxoma (AAM),
angiomyofibroblastoma is most often confused
clinically with a Bartholin gland cyst. Tumors
typically arise in subcutaneous tissue; however,
superficial variants have also been described,
which present as a pedunculated mass
(Schoolmeester and Fritchie 2015). Lesions are
usually painless and well circumscribed (Fig. 7)
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 7 Angiomyofibroblastoma – macroscopic features.
Tumors are well circumscribed and often multilobulated
M
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 8 Angiomyofibroblastoma – macroscopic features.
The cut surfaces are tan-white with both firm and gelatinous areas
with rubbery, tan-white cut surfaces containing
edematous areas (Fig. 8). The overall size is typically less than 5 cm in greatest dimension
(Schoolmeester and Fritchie 2015).
Microscopy
Tumors are typically well demarcated with defined
borders (Fig. 9). There is regional variability in
cellularity, and an alternating edematous to collagenous background is characteristic (Fig. 10).
Numerous thin-walled, capillary-sized vessels are
present. The tumor is typically composed of plump
spindled to epithelioid cells that vary from loosely
206 Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva
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Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 9 Angiomyofibroblastoma – microscopic features.
Tumors are well demarcated without infiltration of surrounding normal subcutaneous tissue
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 10 Angiomyofibroblastoma – microscopic features.
Regions of varying cellularity can be seen at scanning
magnification. Lipomatous change is a common finding
dispersed to contained in small clusters, usually in
the vicinity of blood vessels (Figs. 11 and 12).
Tumor cells can also show a plasmacytoid
cytomorphology and can be bi- or multinucleated
(Schoolmeester and Fritchie 2015). The presence
of infiltrating mast cells is a typical feature
(Fig. 12). Lipomatous change is common, and
tumors with a predominant lipomatous appearance
have been described (Fig. 13) (Laskin et al. 1997;
Luis et al. 2015). Mitoses are rare or absent, and
cytologicatypiaisnotafeature.
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 11 Angiomyofibroblastoma – microscopic features.
In regions of higher cellularity, clusters of tumor cells often
coalesce around background prominent thin-walled blood
vessels. Tumor cells are cytologically bland and are plump
spindled to epithelioid in appearance
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 12 Angiomyofibroblastoma – microscopic features.
In hypocellular areas with prominent background edema,
mast cells are often present. Multinucleation can be seen
Immunophenotype
Although immunohistochemistry has somewhat
limited utility in the diagnosis of soft tissue
tumors of the lower genital tract, angiomyofibroblastoma typically expresses desmin (Fig. 14)
(Nielsen et al. 1996). Interestingly, smooth muscle
actin (SMA) is typically negative despite classification as a myofibroblastic neoplasm (Fletcher
et al. 1992). Like AAM, angiomyofibroblastoma
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Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 13 Angiomyofibroblastoma – microscopic features.
The lipomatous variant can be mistaken for lipoma, spindle
cell lipoma, or even well-differentiated liposaroma
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 14 Angiomyofibroblastoma – immunohistochemical
features. Expression of desmin can usually be demonstrated. Tumor cells typically do not express smooth muscle actin
typically expresses the hormone receptors ER and
PR (Fig. 15). Expression of CD34 is typically
lacking (Schoolmeester and Fritchie 2015).
Molecular Features
Unlike cellular angiofibroma, mammary-type
myofibroblastoma (MTMF), and spindle cell
lipoma (SCL), angiomyofibroblasoma does not
show deletion of 13q14 (Magro et al. 2014).
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 15 Angiomyofibroblastoma – immunohistochemical
features. Expression of ER is typically present, as in
aggressive angiomyxoma
Differential Diagnosis
The principal alternative diagnostic consideration
is AAM, which is typically infiltrative and has a
high potential for local recurrence. AAM usually
contains thick-walled vessels in contrast to the
prominent thin-walled vessels characteristic of
angiomyofibroblastoma. AAM also contains
abundant stromal mucin, whereas in angiomyofibroblastoma, the stroma is edematous and does
not actually contain mucin (Fletcher et al. 1992).
Angiomyofibroblastoma morphologically closely
resembles the group of tumors that are characterized by 13q14 deletion, specifically cellular
angiofibroma, MTMF, and SCL. These tumors
can be distinguished by Rb immunohistochemistry, as this nuclear marker is retained in angiomyofibroblastoma and lost in cellular angiofibroma,
MTMF, and SCL (Chen et al. 2012). Moreover,
cellular angiofibroma contains thicker vessels that
are often hyalinized. Additionally, cellular
angiofibroma, which expresses CD34, is uniformly densely cellular, whereas angiomyofibroblastoma usually shows regional variation in
cellularity. The lipomatous variant of angiomyofibroblastoma can be confused for lipoma, which
typically lacks expression of ER and PR. The
lipomatous variant can potentially also be confused with well-d ifferentiated liposarcoma. In
contrast to well-differentiated liposarcoma, however, angiomyofibroblastoma lacks cytologic
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atypia or nuclear hyperchromasia. Fluorescence
in situ hybridization to detect MDM2 amplification or immunohistochem istry to detect MDM2
protein overexpression can be employed to differentiate these entities in difficult cases or small
biopsy specimens (Weaver et al. 2009). Myxoid
leiomyoma usually shows expression of SMA.
Myxofibrosarcoma usually contains prominent
curvilinear vessels, which are not observed in
angiomyofibroblastoma. Glomus tumor, which
also often shows perivascular accentuation, differs from angiomyofibroblastoma in that it displays a round cell cytomorphology and clinically
presents as a painful mass. Additionally, SMA is
usually positive in glomus tumor. Solitary fibrous
tumor, which may also closely resemble
angiomyofibroblastoma, diffusely expres ses
STAT6 by immunoh istochemistry due to characteristic translocations involving STAT6 often pre-
sent in this tumor type (Doyle et al. 2014).
Cellular Angiofibroma
Definition
Benign tumor that occurs most commonly in the
vulva of middle-aged women. As cellular
fibroma, as its name suggests, is typically moderately cellular in appearance, recognition of this
entity is important as it can be confused for more
aggressive neoplasms.
• Treatment
Simple excision is typically curative.
• Outcome
Local recurrence is rare.
Macroscopy
Cellular angiofibroma typically presents as a subcutaneous or dermal-based mass that is small in
size [average 3.9 cm; (Iwasa and Fletcher 2004)].
Many cases are “shelled out” without accompanying skin (Iwasa and Fletcher 2004).
Microscopy
Microscopic examination reveals a wellcircumscribed tumor based in the dermis or superficial subcutaneous tissue (Fig. 16). An infiltrative
border is seen in a small minority of tumors (Iwasa
and Fletcher 2004). A prominent feature is numerous small to medium-sized background blood
vessels, which sometimes show hyalinization
(Fig. 17). Lesions are composed of a moderately
cellular proliferation of short, bland spindle cells
in a collagenous background arranged in short
fascicles or without a particular architectural pattern. Occasional cases show a prominent fascicular arrangement and can resemble schwannoma
(Iwasa and Fletcher 2004). Tumor cells usually
do not show cytologic atypia, with oval nuclei and
indistinct nucleoli (Fig. 18). Thin, delicate collagen fibers are seen in the background. Mast cells
Clinical Features
• Incidence
Uncommon.
• Age
Middle-aged females are the most commonly
affected group of patients. Affected men tend
to be older than women (Iwasa and Fletcher
2004).
• Sex
The tumor has marked female predilection.
Examples also rarely occur in men and have
been termed “ angiomyofibroblastoma-like
tumor” (Iwasa and Fletcher 2004; Laskin
et al. 1998).
• Site
Vulva is the most common anatomic site.
Mesenchymal Tumors and Mixed Epithelial and Mesenchymal Tumors, Pathology of the Vulva,
Fig. 16 Cellular angiofibroma – microscopic features.
At scanning magnification, this example of a cellular
angiofibroma shows a grenz zone and well-circumscribed
dermal mass that is uniformly cellular
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