Deep Soft Tissue tumors

1.
Interactive
Microscopy
Session:
Deep
Soft
Tissue
Tumors
III:
Spindle
Cell
Tumors
Jason
L.
Hornick,
M.D.,
Ph.D.

2. I
2
Interactive
Microscopy
Session
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Deep Soft Tissue Tumors III: Spindle Cell Tumors
Jason
l.
Hornick,
M.D.,
Ph.D.
Soft Tissue Tumor Pathology: An Anatomic and Pattern-­Based Approach
USCAP Interactive Center, Palm Springs, CA
DEEP SOFT TISSUE TUMORS III: SPINDLE CELL TUMORS
Jason L. Hornick, M.D., Ph.D.
Brigham and Women’s Hospital and Harvard Medical School, Boston, MA USA
jhornick@partners.org
Case 1A. 32-­year-­old man with a tumor in the lower right thigh.
Case 1B. 44-­year-­old woman with a chest wall mass.
Diagnosis: Monophasic Synovial Sarcoma.
Synovial sarcoma includes monophasic, biphasic, and poorly differentiated variants;;
monophasic is the most common. This relatively common sarcoma type (10-­15% of
adult sarcomas) has a wide anatomic distribution but has a predilection for the deep soft
tissues of the extremities, often adjacent to the knee or hip. Compared to other adult
spindle cell sarcomas, synovial sarcoma is relatively sensitive to chemotherapy.
Histology and Ancillary Studies:
Monophasic synovial sarcoma is composed of highly cellular fascicles and sheets of
uniform spindle cells with limited cytoplasm and indistinct cell borders (giving the
impression of overlapping nuclei). Some tumors contain tight, intersecting fascicles with
a fibrosarcoma-­like appearance. Wiry stromal collagen fibers, scattered mast cells, and
dilated, branching, thin-­walled blood vessels (hemangiopericytoma-­like) are
characteristic features. By immunohistochemistry, most tumors show strong and diffuse
nuclear staining for TLE1 and patchy expression of EMA;; keratin expression is usually
limited to few scattered cells. CD99 is positive in more than 50% of synovial sarcomas,
usually with a cytoplasmic pattern. S100 protein is positive in around 30% of cases. The
pathognomonic t(X;;18) translocation resulting in an SS18-­SSX1 or SS18-­SSX2 fusion is
highly specific for synovial sarcoma;; FISH for SS18 (formerly known as SYT), which can
be performed on paraffin sections, is helpful to confirm the diagnosis.

3.
3
Interactive
Microscopy
Session
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Deep Soft Tissue Tumors III: Spindle Cell Tumors
Jason
l.
Hornick,
M.D.,
Ph.D.
Differential Diagnosis:
The differential diagnosis for monophasic synovial sarcoma includes malignant
peripheral nerve sheath tumor (MPNST), solitary fibrous tumor (SFT), and spindle cell
rhabdomyosarcoma. MPNST typically contains alternating hypercellular and
hypocellular areas with patchy myxoid stroma, perivascular accentuation of cellularity,
and some nuclear variability (as opposed to the remarkable uniformity of synovial
sarcoma). There is considerable immunophenotypic overlap, although strong and
diffuse nuclear TLE1 favors synovial sarcoma over MPNST (of note, 20% of MPNST
cases are also strongly positive). SOX10 is positive (usually in a limited number of cells)
in around 40% of MPNST cases but is consistently negative in synovial sarcoma. Loss
of nuclear staining for the recently developed marker H3K27me3 (see below under
MPNST) is highly specific for MPNST. SS18 gene rearrangement is specific for synovial
sarcoma. Although hemangiopericytoma-­like vessels are common in both synovial
sarcoma and SFT, SFT usually lacks the fascicular architecture of synovial sarcoma
and shows more nuclear variability. CD34 is typically strong positive in SFT but is rarely
expressed in synovial sarcoma. EMA may be positive in around 20% of SFT cases.
Nuclear staining for STAT6 is highly specific for SFT. Spindle cell rhabdomyosarcoma
shows diffuse staining for desmin and MYOD1 and more limited staining for myogenin.
“Fibrosarcoma” is a diagnosis of exclusion (that you should probably never make!);;
nearly all tumors that were formerly diagnosed as fibrosarcoma can now be classified
as monophasic synovial sarcoma, MPNST, or the fibrosarcomatous (higher grade)
variant of dermatofibrosarcoma protuberans (DFSP).
References:
1. Bahrami A, Folpe AL. Adult-­type fibrosarcoma: A reevaluation of 163 putative
cases diagnosed at a single institution over a 48-­year period. Am J Surg Pathol.
2010 Oct;;34(10):1504-­13.
2. Terry J, Saito T, Subramanian S, Ruttan C, Antonescu CR, Goldblum JR,
Downs-­Kelly E, Corless CL, Rubin BP, van de Rijn M, Ladanyi M, Nielsen TO.
TLE1 as a diagnostic immunohistochemical marker for synovial sarcoma
emerging from gene expression profiling studies. Am J Surg Pathol. 2007
Feb;;31(2):240-­6.
3. Thway K, Fisher C. Synovial sarcoma: defining features and diagnostic evolution.
Ann Diagn Pathol. 2014 Dec;;18(6):369-­80.

4. I
4
Interactive
Microscopy
Session
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Deep Soft Tissue Tumors III: Spindle Cell Tumors
Jason
l.
Hornick,
M.D.,
Ph.D.
Case 2A. 72-­year-­old man with a paraspinal mass.
Case 2B. 66-­year-­old man with a left thigh mass.
Diagnosis: Malignant Peripheral Nerve Sheath Tumor.
Malignant peripheral nerve sheath tumor (MPNST) may arise sporadically or in patients with
type 1 neurofibromatosis (NF1); around 10% of MPNST cases arise following therapeutic
radiation. Deep soft tissues of the proximal extremities and paraspinal region are the most
common anatomic sites. This aggressive sarcoma type is associated with a high metastatic rate
and poor outcomes with limited chemotherapeutic options. MPNST with heterologous
rhabdomyoblastic differentiation (malignant Triton tumor) is more aggressive than conventional
high-grade MPNST.
Histology and Ancillary Studies:
MPNST typically shows a fascicular architecture and contains alternating hypercellular
and hypocellular areas, the latter often with myxoid stroma. Perivascular accentuation of
cellularity is a characteristic and diagnostically helpful feature. The spindled tumor cells
are often relatively uniform with hyperchromatic, tapering or buckled nuclei and palely
eosinophilic cytoplasm with indistinct cell borders;; occasional more pleomorphic cells
may be seen. Low-­grade tumors may be difficult to distinguish from neurofibromas;;
areas of increased cellularity, nuclear atypia, and mitotic activity are clues to the
diagnosis of MPNST. Around 10-­15% of MPNSTs contain heterologous elements, most
often rhabdomyoblasts. MPNST with rhabdomyoblastic differentiation is widely known
as malignant Triton tumor. By immunohistochemistry, less than 50% of MPNSTs are
positive for S100 protein, SOX10, and/or GFAP;; when positive, each of these markers
typically shows only limited (focal or patchy) staining. Loss of nuclear staining for
H3K27me3 (histone H3 with lysine 27 trimethylation), a result of inactivation of the
polycomb repressive complex 2 (PRC2) secondary to SUZ12 or EED mutations, is
highly specific for MPNST and is observed in more than 90% of high-­grade tumors (loss
of H3K27me3 is much less common in low-­grade MPNST).
Differential Diagnosis:
The differential diagnosis for MPNST includes monophasic synovial sarcoma, spindle
cell melanoma, leiomyosarcoma, and spindle cell rhabdomyosarcoma. Monophasic
synovial sarcoma is typically more uniform in both architecture and cytology than
MPNST and contains overlapping nuclei. SOX10 expression is specific for MPNST in
this differential diagnosis (although not a sensitive marker), whereas strong and diffuse
TLE1 favors synovial sarcoma. Loss of H3K27me3 is highly specific for MPNST, and
SS18 gene rearrangement is specific for synovial sarcoma. Spindle cell melanoma is
typically found at superficial locations and in the distribution of lymph nodes (such as

5.
5
Interactive
Microscopy
Session
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Deep Soft Tissue Tumors III: Spindle Cell Tumors
Jason
l.
Hornick,
M.D.,
Ph.D.
the axilla or groin);; melanoma typically shows more striking nuclear atypia than MPNST
including large nucleoli, at least a minor component of more epithelioid cells, and a
vaguely nested architecture. Strong and diffuse staining for S100 protein and SOX10 is
typical of melanoma and is almost never observed in MPNST. MART1 and HMB-­45 are
generally not helpful in this distinction, since spindle cell melanomas are rarely positive
for these markers. Leiomyosarcomas typically contain broad, blunt-­ended nuclei and
brightly eosinophilic cytoplasm (at least focally);; SMA, desmin, and caldesmon are
typically positive. MPNST with heterologous rhabdomyoblastic differentiation is a close
histologic mimic of spindle cell rhabdomyosarcoma;; the skeletal muscle markers desmin
and MYOD1 are positive in the rhabdomyoblastic component of such MPNST cases, as
opposed to the diffuse staining pattern for these markers in spindle cell
rhabdomyosarcoma. Loss of H3K27me3 is specific for MPNST in this differential
diagnosis.
References:
1. Le Guellec S, Decouvelaere AV, Filleron T, Valo I, Charon-­Barra C, Robin YM,
Terrier P, Chevreau C, Coindre JM. Malignant peripheral nerve sheath tumor is a
challenging diagnosis: a systematic pathology review, immunohistochemistry,
and molecular analysis in 160 patients from the French Sarcoma Group
database. Am J Surg Pathol. 2016 Jul;;40(7):896-­908.
2. Prieto-­Granada CN, Wiesner T, Messina JL, Jungbluth AA, Chi P, Antonescu
CR. Loss of H3K27me3 expression is a highly sensitive marker for sporadic and
radiation-­induced MPNST. Am J Surg Pathol. 2016 Apr;;40(4):479-­89.
3. Schaefer IM, Fletcher CD, Hornick JL. Loss of H3K27 trimethylation distinguishes
malignant peripheral nerve sheath tumors from histologic mimics. Mod Pathol.
2016 Jan;;29(1):4-­13.
Case 3A. 56-­year-­old woman with a mass in the left thigh.
Case 3B. 75-­year-­old man with a mass in the right upper arm.
Diagnosis: Leiomyosarcoma.
Leiomyosarcoma is the most common sarcoma type (approximately 25% of all
sarcomas). The anatomic distribution is wide;; the most common sites include uterus,
retroperitoneum, and deep soft tissues of the proximal extremities and trunk. Origin from
a vein can sometimes be identified. Leiomyosarcoma is the most common sarcoma
type to metastasize to the skin (most often scalp).

6. I
6
Interactive
Microscopy
Session
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Deep Soft Tissue Tumors III: Spindle Cell Tumors
Jason
l.
Hornick,
M.D.,
Ph.D.
Histology and Ancillary Studies:
Leiomyosarcomas are composed of intersecting fascicles of spindle cells with variably
broad, blunt-­ended nuclei, brightly eosinophilic cytoplasm, and well-­defined cell borders.
High grade leiomyosarcomas show more nuclear variability;; the characteristic nuclear
features should be carefully sought since they are so helpful to make the diagnosis.
Mitotic activity is highly variable. By immunohistochemistry, leiomyosarcomas are nearly
always positive for SMA;; expression of desmin and caldesmon is usually seen as well
(although poorly differentiated tumors may show limited staining or occasionally be
negative). Keratin and EMA expression is relatively common, found in 30-­40% of cases.
Differential Diagnosis:
The differential diagnosis for low-­grade leiomyosarcoma includes the very rare deep
leiomyoma and angioleiomyoma. The differential diagnosis for higher grade
leiomyosarcomas includes low-­grade myofibroblastic sarcoma, spindle cell
rhabdomyosarcoma, and malignant peripheral nerve sheath tumor (MPNST). Although
uterine-­type leiomyomas of the retroperitoneum and pelvis may show some mitotic
activity, leiomyomas of deep somatic soft tissue are devoid of mitotic figures;; deep
leiomyomas show no nuclear atypia. Even rare mitotic figures in a well-­differentiated
smooth muscle neoplasm of deep somatic soft tissue should lead to a diagnosis of low-­
grade leiomyosarcoma. Angioleiomyomas arise in the subcutis and show perivascular
growth. Low-­grade myofibroblastic sarcoma typically shows infiltrative margins, as
opposed to the relative circumscription of most soft tissue sarcomas (including
leiomyosarcoma). Low-­grade myofibroblastic sarcoma contains spindle cells with more
tapering nuclei and palely eosinophilic (as opposed to brightly eosinophilic) cytoplasm.
Both tumor types often express SMA and desmin;; staining for caldesmon is relatively
specific for leiomyosarcoma in this differential diagnosis. Spindle cell
rhabdomyosarcoma is also diffusely positive for desmin, although SMA is usually
negative;; expression of skeletal muscle transcription factors MYOD1 and myogenin are
specific for rhabdomyosarcoma. MPNST typically shows alternatively hypocellular and
hypercellular areas and perivascular accentuation of cellularity;; tapering (as opposed to
broad, blunt-­ended) nuclei are characteristic of MPNST. Although not a sensitive marker
for MPNST, SOX10 expression is not seen in leiomyosarcomas. Loss of nuclear
H3K27me3 is specific for MPNST in this differential diagnosis.
References:
1. Hornick JL, Fletcher CD. Criteria for malignancy in nonvisceral smooth muscle
tumors. Ann Diagn Pathol. 2003 Feb;;7(1):60-­6.
2. Miettinen M. Smooth muscle tumors of soft tissue and non-­uterine viscera:
biology and prognosis. Mod Pathol. 2014 Jan;;27 Suppl 1:S17-­29.

7.
7
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Deep Soft Tissue Tumors III: Spindle Cell Tumors
Jason
l.
Hornick,
M.D.,
Ph.D.
3. Weiss SW. Smooth muscle tumors of soft tissue. Adv Anat Pathol. 2002
Nov;;9(6):351-­9.
Case 4. 56-­year-­old woman with a subcutaneous nodule on the right arm.
Diagnosis: Angioleiomyoma.
Angioleiomyoma is a benign smooth muscle tumor that arises in the subcutaneous
tissues of the extremities. This tumor type often presents as a painful nodule. In the
most recent WHO classification, leiomyomas have been grouped together with other
perivascular neoplasms (i.e., myopericytoma/myofibroma and glomus tumor);;
occasional angioleiomyomas show morphologic overlap with myopericytomas.
Angioleiomyomas only very rarely recur after surgical excision.
Histology and Ancillary Studies:
Angioleiomyomas are sharply circumscribed and are composed of fascicles of well-­
differentiated smooth muscle cells with vesicular chromatin and brightly eosinophilic
cytoplasm, at least focally arranged around blood vessels in a concentric fashion. The
presence of prominent blood vessels (most often veins) is a helpful clue to the
diagnosis. Angioleiomyomas may show limited (degenerative) nuclear atypia and
occasional mitotic figures. Although immunohistochemistry is generally unnecessary
given the well-­differentiated histology, the tumor cells are usually diffusely positive for
SMA, desmin, and caldesmon.
Differential Diagnosis:
Given the presence of mild nuclear atypia and occasional mitotic figures in some
examples of angioleiomyoma, the possibility of a low-­grade leiomyosarcoma (primary or
metastatic) might be entertained. The diagnosis of angioleiomyoma is relatively
straightforward once the vascular component and the focally concentric arrangement of
tumor cells around blood vessels are recognized. It is critical to recognize the vascular
component, since any mitotic activity in a smooth muscle tumor of the subcutis (other
than angioleiomyoma) is diagnostic of leiomyosarcoma.
References:
1. Matsuyama A, Hisaoka M, Hashimoto H. Angioleiomyoma: a clinicopathologic
and immunohistochemical reappraisal with special reference to the correlation
with myopericytoma. Hum Pathol. 2007 Apr;;38(4):645-­51.

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Deep Soft Tissue Tumors III: Spindle Cell Tumors
Jason
l.
Hornick,
M.D.,
Ph.D.
2. Mentzel T, Dei Tos AP, Sapi Z, Kutzner H. Myopericytoma of skin and soft
tissues: clinicopathologic and immunohistochemical study of 54 cases. Am J
Surg Pathol. 2006 Jan;;30(1):104-­13.
3. Miettinen M. Smooth muscle tumors of soft tissue and non-­uterine viscera:
biology and prognosis. Mod Pathol. 2014 Jan;;27 Suppl 1:S17-­29.
Case 5A. 42-­year-­old man with a right neck mass.
Case 5B. 31-­year-­old woman with a left thigh mass.
Diagnosis: Spindle Cell/Sclerosing Rhabdomyosarcoma.
It has recently been recognized that spindle cell rhabdomyosarcoma and sclerosing
rhabdomyosarcoma are histologic variants of a single tumor type with the same
molecular genetic alteration (see below). Although pediatric spindle cell
rhabdomyosarcomas have an excellent prognosis, spindle cell/sclerosing
rhabdomyosarcomas in adults are aggressive with significant metastatic potential. This
tumor type has a predilection for the head and neck but also arises on the extremities
and trunk.
Histology and Ancillary Studies:
Spindle cell rhabdomyosarcoma is composed of intersecting fascicles of spindle cells
with elongated nuclei, vesicular chromatin, and palely eosinophilic, indistinct cytoplasm.
Occasional cells show a more rounded appearance, and rhabdomyoblasts with brightly
eosinophilic cytoplasm can usually be identified in small numbers. Sclerosing
rhabdomyosarcoma contains abundant hyalinized collagenous stroma, within which
nests of ovoid or short spindle cells are embedded, sometimes with a pseudovascular
appearance. Many tumors show both spindle cell and sclerosing patterns. By
immunohistochemistry, the tumor cells are diffusely positive for desmin, muscle-­specific
actin, and MYOD1;; myogenin typically shows more limited staining. Spindle
cell/sclerosing rhabdomyosarcomas often harbor MYOD1 (L122R) mutations (especially
tumors arising in adults and older children);; congenital and infantile spindle cell
rhabdomyosarcomas harbor various gene fusions.
Differential Diagnosis:
The differential diagnosis for spindle cell/sclerosing rhabdomyosarcoma includes
leiomyosarcoma, malignant peripheral nerve sheath tumor (MPNST) with heterologous
rhabdomyoblastic differentiation, and monophasic synovial sarcoma. The tumor cells in
leiomyosarcoma usually contain broader, blunt-­ended nuclei and brightly eosinophilic

9.
9
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Microscopy
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Deep Soft Tissue Tumors III: Spindle Cell Tumors
Jason
l.
Hornick,
M.D.,
Ph.D.
(as opposed to pale) cytoplasm;; expression of SMA and caldesmon favors
leiomyosarcoma, whereas MYOD1 and myogenin are specific for rhabdomyosarcoma.
A history of NF1 or origin from a large nerve should suggest MPNST. The
rhabdomyoblastic component in some cases of MPNST is usually a focal finding;;
alternating hypocellular and hypercellular areas, patchy myxoid stroma, and
perivascular hypercellularity favor MPNST. Loss of H3K27me3 is specific for MPNST in
this differential diagnosis. Monophasic synovial sarcoma shows more uniform
cytomorphology than spindle cell rhabdomyosarcoma and is negative for desmin and
MYOD1.
References:
1. Agaram NP, Chen CL, Zhang L, LaQuaglia MP, Wexler L, Antonescu CR.
Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell
rhabdomyosarcomas: evidence for a common pathogenesis. Genes
Chromosomes Cancer. 2014 Sep;;53(9):779-­87.
2. Alaggio R, Zhang L, Sung YS, Huang SC, Chen CL, Bisogno G, Zin A, Agaram
NP, LaQuaglia MP, Wexler LH, Antonescu CR. A molecular study of pediatric
spindle and sclerosing rhabdomyosarcoma: identification of novel and recurrent
VGLL2-­related fusions in infantile cases. Am J Surg Pathol. 2016 Feb;;40(2):224-­
35.
3. Nascimento AF, Fletcher CD. Spindle cell rhabdomyosarcoma in adults. Am J
Surg Pathol. 2005 Aug;;29(8):1106-­13.
4. Szuhai K, de Jong D, Leung WY, Fletcher CD, Hogendoorn PC. Transactivating
mutation of the MYOD1 gene is a frequent event in adult spindle cell
rhabdomyosarcoma. J Pathol. 2014 Feb;;232(3):300-­7.
Case 6. 26-­year-­old woman with a left ankle mass.
Diagnosis: Clear Cell Sarcoma.
Clear cell sarcoma is a translocation-­associated sarcoma showing melanocytic
differentiation. This tumor type shows a marked predilection for the distal extremities,
especially the ankle and foot, and usually arises in deep soft tissues, involving tendons
or aponeuroses. Clear cell sarcoma usually affects adolescents and young adults. A
protracted clinical course is typical, with metastases to lymph nodes and lung,
sometimes decades after primary tumor excision;; long-­term follow-­up is critical.

10. I
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Deep Soft Tissue Tumors III: Spindle Cell Tumors
Jason
l.
Hornick,
M.D.,
Ph.D.
Histology and Ancillary Studies:
Clear cell sarcoma is composed of nests and short fascicles of uniform spindle (or
sometimes epithelioid) cells with abundant, usually palely eosinophilic cytoplasm,
vesicular nuclei, and prominent nucleoli. Clear cytoplasm is less common. The nests
are separated by dense collagenous stroma. Occasional multinucleated wreath-­like
tumor giant cells are a distinctive and diagnostically helpful feature. By
immunohistochemistry, clear cell sarcoma is positive for S100 protein, SOX10, HMB-­45,
and melan A. HMB-­45 is usually more strongly positive than S100 protein. Nearly all
clear cell sarcomas harbor a t(12;;22) translocation, resulting in the EWSR1-­ATF1 gene
fusion. FISH for EWSR1 can be used to confirm the diagnosis.
Differential Diagnosis:
Once the immunophenotypic findings are established, the key differential diagnostic
consideration for clear cell sarcoma is metastatic melanoma. The clinical presentation
as an infiltrative deep-­seated mass in the distal extremities, along with the uniform
cytomorphology, is helpful to support the diagnosis of clear cell sarcoma. Most
metastatic melanomas show marked nuclear atypia and pleomorphism. Detection of
EWSR1 rearrangement by FISH is specific for clear cell sarcoma in this differential
diagnosis.
References:
1. Kosemehmetoglu K, Folpe AL. Clear cell sarcoma of tendons and aponeuroses,
and osteoclast-­rich tumour of the gastrointestinal tract with features resembling
clear cell sarcoma of soft parts: a review and update. J Clin Pathol. 2010
May;;63(5):416-­23.
2. Meis-­Kindblom JM. Clear cell sarcoma of tendons and aponeuroses: a historical
perspective and tribute to the man behind the entity. Adv Anat Pathol. 2006
Nov;;13(6):286-­92.
3. Thway K, Fisher C. Tumors with EWSR1-­CREB1 and EWSR1-­ATF1 fusions: the
current status. Am J Surg Pathol. 2012 Jul;;36(7):e1-­e11.
Case 7A. 50-­year-­old man with a left neck mass.
Case 7B. 48-­year-­old woman with a right chest wall mass.

11.
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Deep Soft Tissue Tumors III: Spindle Cell Tumors
Jason
l.
Hornick,
M.D.,
Ph.D.
Diagnosis: Solitary Fibrous Tumor.
First recognized in the pleura, solitary fibrous tumor (SFT) is an anatomically ubiquitous
fibroblastic neoplasm, which, in its conventional form, belongs to the WHO managerial
category with tumors of intermediate biologic potential (rarely metastasizing);; the 5-­10%
of SFTs with increased mitotic activity (see below) are clinically malignant with
significant metastatic potential (20-­30%). The tumors formerly known as
“hemangiopericytoma” are now recognized to represent cellular examples of SFT;; this
term is no longer used. SFT has a predilection for middle-­aged adults;; the most
common anatomic locations are the pleura, retroperitoneum, proximal extremities, trunk,
and head and neck.
Histology and Ancillary Studies:
SFTs most often show alternating hypocellular and hypercellular areas, with prominent
collagenous stroma, a “patternless” or haphazard architecture, and dilated, thin-­walled,
branching (“staghorn”) or more rounded and hyalinized blood vessels. The tumor cells
are ovoid or short spindled with fine chromatin and indistinct cytoplasm. Cellular
examples of SFT are more histologically uniform with more limited stroma. Occasional
cases show adipocytic differentiation. The most reliable criterion for malignancy in SFT
is mitotic activity;; tumors with 4 or more mitoses per 10 HPF are designated malignant
SFTs. Such tumors are often (though not invariably) hypercellular, sometimes with more
notable nuclear atypia and pleomorphism. By immunohistochemistry, SFTs are positive
for CD34 (in 95% of cases) and CD99 (in around two-­thirds of cases), although these
markers lack specificity. The most specific diagnostic marker for SFT is STAT6;; nuclear
staining reflects the presence of the pathognomonic NAB2-­STAT6 gene fusion, found in
almost all cases. Around 20% of SFTs are at least focally positive for EMA, a potential
diagnostic pitfall.
Differential Diagnosis:
The differential diagnosis for SFT is broad and varies based on tumor cellularity;; the
most important diagnostic considerations include spindle cell lipoma, low-­grade
fibromyxoid sarcoma (LGFMS), monophasic synovial sarcoma, and malignant
peripheral nerve sheath tumor (MPNST). Spindle cell lipomas are almost exclusive to
the shoulders, upper back, neck and face. Ropy collagen bundles are a distinctive
feature. Although both spindle cell lipomas and SFTs are strongly positive for CD34,
only SFTs are positive for STAT6. Loss of expression of RB1 (retinoblastoma) favors
spindle cell lipoma. In contrast to SFT, LGFMS is strongly positive for MUC4 and almost
always negative for CD34. Cellular (and malignant) examples of SFT show significant
histologic overlap with monophasic synovial sarcoma, including staghorn blood vessels;;
STAT6 and CD34 are consistently negative in synovial sarcoma, whereas strong and
diffuse TLE1 favors synovial sarcoma (although TLE1 is not specific). Similar to synovial
sarcoma, SFTs may express EMA. Detection of SS18 gene rearrangement by FISH is

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Deep Soft Tissue Tumors III: Spindle Cell Tumors
Jason
l.
Hornick,
M.D.,
Ph.D.
specific for synovial sarcoma. MPNST typically shows a more fascicular architecture
than SFT and perivascular accentuation of cellularity;; SOX10 expression and loss of
nuclear staining for H3K27me3 are specific for MPNST in this differential diagnosis.
References:
1. Cheah AL, Billings SD, Goldblum JR, Carver P, Tanas MZ, Rubin BP. STAT6
rabbit monoclonal antibody is a robust diagnostic tool for the distinction of solitary
fibrous tumour from its mimics. Pathology. 2014 Aug;;46(5):389-­95.
2. Demicco EG, Park MS, Araujo DM, Fox PS, Bassett RL, Pollock RE, Lazar AJ,
Wang WL. Solitary fibrous tumor: a clinicopathological study of 110 cases and
proposed risk assessment model. Mod Pathol. 2012 Sep;;25(9):1298-­306.
3. Doyle LA, Vivero M, Fletcher CD, Mertens F, Hornick JL. Nuclear expression of
STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod Pathol.
2014 Mar;;27(3):390-­5.
4. Robinson DR, Wu YM, Kalyana-­Sundaram S, Cao X, Lonigro RJ, Sung YS,
Chen CL, Zhang L, Wang R, Su F, Iyer MK, Roychowdhury S, Siddiqui J, Pienta
KJ, Kunju LP, Talpaz M, Mosquera JM, Singer S, Schuetze SM, Antonescu CR,
Chinnaiyan AM. Identification of recurrent NAB2-­STAT6 gene fusions in solitary
fibrous tumor by integrative sequencing. Nat Genet. 2013 Feb;;45(2):180-­5.
5. Yoshida A, Tsuta K, Ohno M, Yoshida M, Narita Y, Kawai A, Asamura H,
Kushima R. STAT6 immunohistochemistry is helpful in the diagnosis of solitary
fibrous tumors. Am J Surg Pathol. 2014 Apr;;38(4):552-­9.
Case 8A. 23-­year-­old woman with an abdominal wall mass.
Case 8B. 31-­year-­old man with a left shoulder mass.
Diagnosis: Desmoid-­Type Fibromatosis.
Desmoid fibromatosis usually affects young to middle-­aged adults and may arise in the
abdominal wall, in the abdominal cavity (especially the mesentery of the small intestine),
and at extra-­abdominal sites, most often the deep soft tissues of the limb girdles, chest
wall, back, head and neck, and proximal extremities. Desmoid tumors usually present
as painless, slow-­growing, poorly demarcated masses. Although desmoid fibromatosis
can recur locally, recurrence is unpredictable: incompletely excised tumors sometimes
regress, and widely excised tumors sometimes recur. There has been a significant shift
in clinical practice over the past 5 years, such that a watchful waiting approach is now

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Deep Soft Tissue Tumors III: Spindle Cell Tumors
Jason
l.
Hornick,
M.D.,
Ph.D.
preferred by most experts;; surgery is avoided unless patients experience pain,
functional impairment, or impingement on vital structures.
Histology and Ancillary Studies:
Desmoid fibromatosis is composed of bland, uniform spindle cells with tapering nuclei,
indistinct or small nucleoli, and indistinct palely eosinophilic cytoplasm with ill-­defined
cell borders, arranged in long sweeping fascicles. Collagenous stroma is common.
Some tumors contain myxoid stroma with stellate tumor cells. Between the fascicles,
medium-­sized blood vessels with muscular walls and variable perivascular edema are a
characteristic and diagnostically helpful feature. In some tumors, the collagenous
stroma shows keloidal hyalinization. Mitotic activity is variable and sometimes
prominent. At the tumor periphery, desmoid fibromatosis typically infiltrates into adjacent
skeletal muscle with scattered atrophic myocytes. By immunohistochemistry, desmoid
fibromatosis is usually at least focally positive for SMA;; desmin is occasionally positive
in limited numbers of tumor cells. Nuclear staining for β-­catenin is observed in around
90% of cases, reflecting the presence of CTNNB1 mutations (or in patients with familial
adenomatous polyposis, APC germline mutations).
Differential Diagnosis:
The differential diagnosis for desmoid fibromatosis may be broad, depending upon the
cellularity and stromal characteristics. For cellular examples, the differential diagnosis
includes monophasic synovial sarcoma, low-­grade fibromyxoid sarcoma (LGFMS), and
low-­grade myofibroblastic sarcoma. Monophasic synovial sarcoma typically contains
more closely apposed (overlapping) nuclei and shorter fascicles;; EMA, keratin, and
TLE1 expression favors synovial sarcoma over desmoid fibromatosis, whereas nuclear
β-­catenin staining favors desmoid fibromatosis. LGFMS shows a more whorled (as
opposed to fascicular) growth pattern and is diffusely positive for MUC4, whereas
desmoid tumors are consistently negative for this marker. The tumor cells in low-­grade
myofibroblastic sarcoma usually show more notable nuclear atypia and variability than
desmoid fibromatosis;; diffuse desmin expression is common. Hypocellular and myxoid
examples of desmoid fibromatosis may be confused with nodular fasciitis. Rapid growth,
superficial location, and small tumor size favor nodular fasciitis;; nuclear β-­catenin is
helpful to make this distinction. Particularly in core biopsy specimens and in patients
with prior surgery, desmoid fibromatosis can be difficult to distinguish from scar tissue;;
again, nuclear β-­catenin can be used to confirm the diagnosis of desmoid fibromatosis.
References:
1. Carlson JW, Fletcher CD. Immunohistochemistry for beta-­catenin in the
differential diagnosis of spindle cell lesions: analysis of a series and review of the
literature. Histopathology. 2007 Oct;;51(4):509-­14.

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Deep Soft Tissue Tumors III: Spindle Cell Tumors
Jason
l.
Hornick,
M.D.,
Ph.D.
2. Gronchi A, Raut CP. Optimal approach to sporadic desmoid tumors: from radical
surgery to observation. Time for a consensus? Ann Surg Oncol. 2012
Dec;;19(13):3995-­7.
3. Lazar AJ, Hajibashi S, Lev D. Desmoid tumor: from surgical extirpation to
molecular dissection. Curr Opin Oncol. 2009 Jul;;21(4):352-­9.
4. Montgomery E, Folpe AL. The diagnostic value of beta-­catenin
immunohistochemistry. Adv Anat Pathol. 2005 Nov;;12(6):350-­6.
Case 9. 64-­year-­old man with a tongue mass.
Diagnosis: Low-­Grade Myofibroblastic Sarcoma.
Low-­grade myofibroblastic sarcoma is a rare sarcoma type with a wide anatomic
distribution and a predilection for the head and neck, including the tongue. Owing to
infiltrative margins, this sarcoma type has a significant risk for local recurrence but low
metastatic potential (only around 5%).
Histology and Ancillary Studies:
Low-­grade myofibroblastic sarcoma is composed of relatively uniform spindle cells with
tapering nuclei, mild nuclear atypia, variably prominent nucleoli, and palely eosinophilic
cytoplasm with ill-­defined cell borders, arranged in long fascicles;; areas with prominent
stromal collagen are commonly seen. Unlike many other spindle cell sarcomas, low-­
grade myofibroblastic sarcoma typically shows infiltrative margins. By
immunohistochemistry, low-­grade myofibroblastic sarcoma is usually strongly positive
for SMA or desmin (or both);; around 30% of cases show nuclear β-­catenin staining.
Differential Diagnosis:
The differential diagnosis for low-­grade myofibroblastic sarcoma includes desmoid
fibromatosis, leiomyosarcoma, and spindle cell rhabdomyosarcoma. Low-­grade
myofibroblastic sarcoma typically shows more diffusely infiltrative margins than desmoid
fibromatosis;; nuclear atypia and variability are the most helpful features to diagnosis
low-­grade myofibroblastic sarcoma. Diffuse desmin expression favors low-­grade
myofibroblastic sarcoma;; nuclear β-­catenin is not specific in this differential diagnosis.
The tumor cells in leiomyosarcoma contain broader, blunt-­ended nuclei, more brightly
eosinophilic cytoplasm, and more conspicuous cell borders than low-­grade
myofibroblastic sarcoma. Leiomyosarcoma lacks the stromal collagen typical of low-­
grade myofibroblastic sarcoma. Caldesmon is specific for leiomyosarcoma in this
differential diagnosis. Spindle cell rhabdomyosarcoma is more highly cellular than low-­
grade myofibroblastic sarcoma, as the tumor cells contain less cytoplasm. The

15.
15
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Microscopy
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Deep Soft Tissue Tumors III: Spindle Cell Tumors
Jason
l.
Hornick,
M.D.,
Ph.D.
presence of occasional rhabdomyoblasts and expression of MYOD1 and myogenin are
specific for spindle cell rhabdomyosarcoma in this differential diagnosis.
References:
1. Carlson JW, Fletcher CD. Immunohistochemistry for beta-­catenin in the
differential diagnosis of spindle cell lesions: analysis of a series and review of the
literature. Histopathology. 2007 Oct;;51(4):509-­14.
2. Mentzel T, Dry S, Katenkamp D, Fletcher CD. Low-­grade myofibroblastic
sarcoma: analysis of 18 cases in the spectrum of myofibroblastic tumors. Am J
Surg Pathol. 1998 Oct;;22(10):1228-­38.
Case 10A. 48-­year-­old woman with a right thigh mass.
Case 10B. 33-­year-­old man with a left forearm mass.
Diagnosis: Soft Tissue Perineurioma.
Perineuriomas are uncommon benign peripheral nerve sheath tumors that usually
present as painless subcutaneous masses in the extremities of middle-­aged adults,
although the age range and anatomic distribution are wide, and a subset of cases arises
in deep soft tissue.
Histology and Ancillary Studies:
Soft tissue perineurioma is usually composed of bland, slender spindle cells with
elongated, bipolar cytoplasmic processes;; some tumors contain ovoid nuclei with less
obvious cytoplasmic processes. A whorled or storiform architecture is characteristic.
Tumor cellularity is highly variable, although most tumors show moderate cellularity.
Hypocellular tumors may have either collagenous or myxoid stroma. Occasional tumors
contain scattered atypical, pleomorphic cells with degenerative nuclear atypia (similar to
“ancient” schwannoma and atypical neurofibroma). By immunohistochemistry, EMA
expression is the defining feature of soft tissue perineurioma, although the extent and
intensity of staining are highly variable;; some tumors show very limited, weak staining,
which can only be visualized at high magnification. EMA often highlights the delicate
cytoplasmic processes of tumor cells. CD34 is positive in around two-­thirds of cases,
often more strongly and diffusely than EMA. The tight junction-­associated protein
claudin-­1 is positive in up to 50% of cases. S100 protein and MUC4 are consistently
negative.

16. I
16
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Microscopy
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Deep Soft Tissue Tumors III: Spindle Cell Tumors
Jason
l.
Hornick,
M.D.,
Ph.D.
Differential Diagnosis:
The differential diagnosis for soft tissue perineurioma includes low-­grade fibromyxoid
sarcoma (LGFMS), solitary fibrous tumor (SFT), low-­grade malignant peripheral nerve
sheath tumor (MPNST), and, for superficial, hypercellular examples,
dermatofibrosarcoma protuberans (DFSP). LGFMS can be extremely difficult (if not
impossible) to distinguish from soft tissue perineurioma on histologic grounds,
especially in limited biopsy material;; EMA expression is not helpful to make this
distinction, since the majority of LGFMS cases are also positive. MUC4 expression and
FUS gene rearrangement are both specific for LGFMS in this differential diagnosis. SFT
lacks the storiform or whorled architecture and distinctive cytomorphology of soft tissue
perineurioma;; nuclear staining for STAT6 is specific for SFT. Low-­grade MPNST shows
more fascicular architecture and nuclear atypia than soft tissue perineurioma. Although
both soft tissue perineurioma and DFSP show a storiform architecture, perineuriomas
rarely show marked hypercellularity;; diffuse infiltration of subcutaneous adipose tissue
typical of DFSP is not a feature of soft tissue perineurioma.
References:
1. Doyle LA, Möller E, Dal Cin P, Fletcher CD, Mertens F, Hornick JL. MUC4 is a
highly sensitive and specific marker for low-­grade fibromyxoid sarcoma. Am J
Surg Pathol. 2011 May;;35(5):733-­41.
2. Hornick JL, Fletcher CD. Soft tissue perineurioma: clinicopathologic analysis of
81 cases including those with atypical histologic features. Am J Surg Pathol.
2005 Jul;;29(7):845-­58.