Soft tissue pathology is rapidly changing
Novel molecular findings
Tumors previously known under one rubric are reclassified with relative frequency
Lesions that for decades were thought to be reactive now are discovered to possess gene rearrangements
Features of previously unknown or incompletely described tumors are coalesced and synthesized into new entities
Relative rarity of soft tissue tumors only adds to the challenge
of keeping abreast of all of these advances
1. What’s new in soft tissue tumors ?
Moderator: Prof B D Radotra
2. Outline of class
• Soft tissue pathology is rapidly changing
• Novel molecular findings
• Tumors previously known under one rubric are reclassified with
relative frequency
• Lesions that for decades were thought to be reactive now are
discovered to possess gene rearrangements
• Features of previously unknown or incompletely described
tumors are coalesced and synthesized into new entities
Relative rarity of soft tissue tumors only adds to the challenge
of keeping abreast of all of these advances
5. Chondroid lipoma
• Nests and cords of
mature adipocytes
• Uni or
multivacuolated cells
• Embedded in a
prominent
myxohyaline matrix
6. Huang D, Sumegi J, Dal Cin P, et al. C11orf95-MKL2 is the resulting fusion oncogene of t(11;16)(q13;p13) in
chondroid lipoma. Genes Chromosomes Cancer 2010; 49: 810–8.
Chondroid lipoma
• DD:
• Myxoid liposarcoma
• Extraskeletal myxoid chondrosarcoma
• Extraskeletal chondroma
• Myoepithelioma/mixed tumor
• Benign adipose tissue tumor
• Does not recur locally or metastasize
• Proximal extremities and limb girdles
• Middle-aged adults, particularly females
• IHC : Vimentin (+) S-100p (+/-)
• t(11;16)(q13;p13)
• C11orf95-MKL2 fusion oncogene
7. Atypical Lipomatous Tumor/ Well-Differentiated
Liposarcoma
• Irregular fibrous
septa with finely
fibrillar collagen
• Enlarged
hyperchromatic
cells, within
septa
• Lipoblasts
usually rare or
absent
• Thick-walled
vessels with
intramural
hyperchromatic
cells
8. Atypical Lipomatous Tumor or
Well-Differentiated liposarcoma
•Sites at which margin-negative resection is often impossible
•Inguinal, paratesticular, retroperitoneal and mediastinal site
•Use “Well-differentiated liposarcoma’’
•Sites at which margin-negative resection is often possible
•Superficial and intramuscular tumors in extremities
•Use “Atypical lipomatous tumor’’
9. Atypical Lipomatous Tumor or
Well-Differentiated liposarcoma
•Giant ring and marker chromosomes
•Amplified sequences from 12q14-15, other parts of 12q, 1q
•Amplification of MDM2, CDK4, SAS, CPM and HMGIC
•Overexpression of MDM2, CDK4 and CPM may be detected by
IHC or FISH/CISH
11. Lochkern cells
• Enlarged adipocyte
nucleus
• Intranuclear
pseudovacuole
• Mimicking lipoblasts
• Usually in thick
sections
• May be positive for
MDM2 IHC
12. When Should You FISH Adipocytic Tumors?
• Recurrent fatty tumors
• Deep extremity tumors >10 cm in patients > 50 years of age
• Cases with “equivocal” atypia
• Fatty tumors of the retroperitoneum/pelvis/abdomen
14. • Median age: 56 years
• Tumors were well circumscribed
• No cytologic atypia
• Cytogenetic analysis: rearrangements of 12q15
• None showed ring or giant marker chromosomes
• FISH failed to identify amplification of MDM2, carboxypeptidase
M(CPM), SAS, CDK4, DDIT3, or HMGA2 in all cases
Macarenco RS, Erickson-Johnson M, Wang X, et al. Retroperitoneal lipomatous tumors without cytologic atypia: are they
lipomas? A clinicopathologic and molecular study of 19 cases. Am J Surg Pathol 2009; 33:1470–6.
Retroperitoneal lipoma
16. Round cell liposarcoma
Hypercellular and high grade areas in myxoid
liposarcoma
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO Classification of Tumours of Soft Tissue and Bone.
Pathology and Genetics of Tumours of Soft Tissue and Bone. 4th ed. Lyon: IARC Press, 2013.
18. Unusual examples of dedifferentiated
liposarcoma
Mixed-type liposarcoma
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO Classification of Tumours of Soft Tissue and Bone.
Pathology and Genetics of Tumours of Soft Tissue and Bone. 4th ed. Lyon: IARC Press, 2013.
20. • Dedifferentiated liposarcoma
(DDLPS) is traditionally defined as a
non-lipogenic high-grade sarcoma
arising from a well-differentiated
liposarcoma
• DDLPSs with lipoblastic
differentiation
• Cellularity and mitosis (5 per 10 hpf)
• Positive CDK4, MDM2 and p16ink4a
immunostains and amplification of the
MDM2 locus
• Metastatic potential
Liau JY, Lee JC,Wu CT, Kuo KT, Huang HY, Liang CW. Dedifferentiated liposarcoma with homologous lipoblastic differentiation:
expanding the spectrum to include low-grade tumours. Histopathology 2013; 62: 702–10.
Dedifferentiated liposarcoma with homologous
lipoblastic differentiation
21. Fibrosarcoma-like lipomatous neoplasm
• low-grade spindle
cell component
resembling
fibrosarcoma
• mixture of bland
fibroblastic cells
resembling the
preadipocyte and
early-adipocyte
stage of embryonic
fat
22. DD
• (low-grade) dedifferentiated LPS
• Myxoid LPS
• Uniform fibroblast-like spindle cells arranged in parallel
• Myxoid background with arborizing thin vessels
• Wide range of lipoblasts, including signet ring and spindled
univacuolated/bivacuolated cells
• No identifiable chromosomal gains or losses
• No recurrences or metastases
Deyrup AT, Chibon F, Guillou L, Lagarde P, Coindre JM, Weiss SW. Fibrosarcoma-like lipomatous neoplasm: a
reappraisal of so-called spindle cell liposarcoma defining a unique lipomatous tumor unrelated to other
Fibrosarcoma-like lipomatous neoplasm
24. Nodular fasciitis
• Fibrous or myxoid
• Plump, immature-
appearing
fibroblasts and
myofibroblasts
• Tissue culture or
granulation tissue
• Mitotic figures
• Atypical mitoses are
virtually never seen
25. • Considered to be a reactive process
• Misinterpreted as a sarcoma in active
growth phase
• Clonal neoplasm
• MYH9-USP6, 17p13 and 22q13.1
• Novel model of ‘transient neoplasia’
Erickson-Johnson MR, Chou MM, Evers BR, et al. Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-USP6
gene fusion.Lab Invest 2011; 91: 1427–33.
Nodular fasciitis
26. Spindle cell and
pleomorphic lipoma
Mammary-type
myofibroblastoma
Cellular
angiofibroma
13q del (Rb Gene), Loss of nuclear expression of Rb on IHC
Chen BJ, Marino-Enriquez A, Fletcher CD, Hornick JL. Loss of retinoblastoma protein expression in spindle cell/pleomorphic lipomas and
cytogenetically related tumors: an immunohistochemical study with diagnostic implications. Am J Surg Pathol 2012; 36: 1119–28.
28. DD
• Undifferentiated pleomorphic sarcoma
• Myxofibrosarcoma
• Adults
• Slow-growing supra-fascial mass of 10
cm or less
• Most commonly in the lower extremity
• Diffuse CD34 expression
• Focal CK+ve
• Do not recur or metastasize
• Intermediate malignancy
Carter JM, Weiss SW, Linos K, et al. Superficial CD34-positive fibroblastic tumor: report of 18 cases of a distinctive low-grade
mesenchymal neoplasm of intermediate (borderline) malignancy. Mod Pathol 2014;27:294–302.
Superficial CD34-positive fibroblastic tumor
29. Solitary fibrous tumor
• Round to fusiform
cells
• Indistinct
cytoplasmic borders
• Arranged around an
elaborate
vasculature
• Dividing sinusoidal
vessels have a
staghorn or antler-
like configuration
30. • Omission ‘Haemangiopericytoma’
• inv12(q13q13), NAB2-STAT6 fusion
• Overexpression of STAT6 especially in CD34-negative cases
Doyle LA, Vivero M, Fletcher CD, Mertens F, Hornick JL. Nuclear expression of STAT6 distinguishes solitary fibrous tumor from
histologic mimics. Mod Pathol. 2015 28, 1324–1335
Solitary fibrous tumor
31. • Bland spindle cells
infiltrating adipose
tissue in a
honeycomb pattern
• Small nodules
• Prominent
hemosiderin
deposition
Hemosiderotic fibrolipomatous tumor
32. Myxoinflammatory fibroblastic sarcoma
• Multinodular and
poorly circumscribed
• Dense inflammatory
infiltrate
• Merging with myxoid
or hyaline zones
• Scattered atypical
cells
33. Elco CP, Marino-Enriquez A, Abraham JA, Dal evidenceCin P, Hornick JL. Hybrid myxoinflammatory fibroblastic sarcoma/hemosiderotic
fibrolipomatous tumor: report of a case providing further for a pathogenetic link. Am J Surg Pathol 2010; 34: 1723–7.
Hemosiderotic fibrolipomatous tumor
Myxoinflammatory fibroblastic sarcoma
DD
• Infectious or inflammatory
process
• Tumours of uncertain
differentiation
• Common around the
ankle
• IHC : CD68, CD34 SMA
• t(1;10)(p22;q24)
TGFBR3-MGEA5 and
non random involvement
of chromosome 3
34. Low grade fibromyxoid sarcoma
• Alternating fibrous
and myxoid areas
• Bland spindle and
stellate cells in a
whorled growth
pattern within a
myxoid stroma
• Hyalinized collagen
rosette surrounded
by tumor cells with
round to-epithelioid
morphology
35. DD
• Benign (perineurioma, cellular myxoma, neurofibroma, SFT)
• Locally aggressive behavior (Desmoid fibromatosis)
• Sarcomas (Low-grade MPNST, low-grade myxofibrosarcoma,
myxoid DFSP, extraskeletal myxoid chondrosarcoma or
synovial sarcoma with prominent myxoid stroma)
• Deep soft tissues of the proximal extremities or trunk
• (7;16) translocation, FUS and CREB3L2
• EMA 43% to 91%
• GPE shows upregulation of Mucin 4
• MUC4 sensitive and specific IHC marker
Doyle LA, Moller 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; 35: 733–41
Low grade fibromyxoid sarcoma
37. • MUC4 is positive in 70%
• Morphologic and molecular overlap with LGFMS
• FUS-CREB3L1 translocation
Doyle LA, Moller 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; 35: 733–41
Sclerosing epithelioid fibrosarcomas
41. Tenosynovial giant cell tumour
• Sheets of rounded
synovial-like cells
• Admixed with
multinucleated giant
cells and xanthoma
cells with
hemosiderin
42. • Pigmented villonodular synovitis
• Tenosynovial Giant cell tumor
• Reciprocal translocations CSF
(1p13], with COL6A3 [2q37]
• CSF1 IHC present diffusely
throughout within the
mononuclear cells
• Reactive synovitis, staining
showed a linear pattern that
highlighted the synovial lining
Cupp JS, Miller MA, Montgomery KD, et al. Translocation and expression of CSF1 in pigmented villonodular synovitis,
tenosynovial giant cell tumor, rheumatoid arthritis and other reactive synovitides. Am J Surg Pathol 2007; 31: 970–6.
Tenosynovial giant cell tumour
45. Malignant glomus tumours:
• Marked nuclear atypia and
• Any level of mitotic activity or having atypical mitotic figures
Glomus tumor of uncertain malignant potential
• 2.0cm and
• Location in a deep site
Genetics
• Neurofibromatosis-1, BRAF (V600E), KRAS, Notch
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO Classification of Tumours of Soft Tissue and Bone.
Pathology and Genetics of Tumours of Soft Tissue and Bone. 4th ed. Lyon: IARC Press, 2013.
Malignant glomus
Glomus tumor of uncertain malignant potential
46. • Bland uniform spindle
cells with minimal
atypia
• Variably myxoid and
collagenous
background
• Numerous branching
thin-walled blood
vessels
Angiofibroma of soft tissue
47. DD
• Solitary fibrous tumor, myxofibrosarcoma, low-grade
fibromyxoid sarcoma, and myxoid liposarcoma
• Slowly enlarging, painless mass, extremities
• Subfascial, deep-seated or subcutaneous
• benign neoplasm
• t(5;8) AHRR-NCOA2 gene fusion
Edgar MA, Lauer SR, Bridge JA, et al. Soft tissue angiofibroma: report of 2 cases of a recently described tumor. Hum Pathol
2013;44:438–41.
Angiofibroma of soft tissue
49. • Relatively uniform
spindle-shaped cells
deposited in a myxoid
stroma
• Arranged in irregular
fascicules
• Scattered
rhabdomyoblasts
Spindle cell rhabdomyosarcoma
50. Children
• Uncommon, paratesticular region
• Good prognosis
• NCOA2 Translocations
Adults
• Rare, head and neck
• Poorer outcome, 50% recurrence and metastasis
Nascimento AF, Fletcher CD. Spindle cell rhabdomyosarcoma in adults. Am J Surg Pathol 2005; 29: 1106–13.
Spindle cell rhabdomyosarcoma
51. • Lobules, small nests,
microalveoli, and
single-file arrays
• Abundantly
hyalinized,
eosinophilic to
basophilic matrix
Sclerosing rhabdomyosarcoma
52. DD
• Extraskeletal osteosarcoma, chondrosarcoma
• Limbs in both adults and children
• Some spindle cell rhabdomyosarcomas show sclerosing
morphology in proportions – morphological continuum
Folpe AL, McKenney JK, Bridge JA, Weiss SW. Sclerosing rhabdomyosarcoma in adults: report of four cases
of a hyalinizing, matrix-rich variant of rhabdomyosarcoma that may be confused with osteosarcoma,
chondrosarcoma, or angiosarcoma. Am J Surg Pathol 2002; 26: 1175–83.
Sclerosing rhabdomyosarcoma
59. DD
Atypical vascular proliferation
• MYC gene amplification with co-
amplification of FLT4 in a quarter of
cases
• Helpful in challenging cases where
atypical post-radiation vascular
proliferation
Mentzel T, Schildhaus HU, Palmedo G, Buttner R, Kutzner H. Postradiation cutaneous angiosarcoma after treatment of breast carcinoma is characterized by MYC
amplification in contrast to atypical vascular lesions after radiotherapy and control cases: clinicopathological, immunohistochemical and molecular analysis of 66
cases. Mod Pathol 2012; 25:75–85.
Angiosarcoma
63. • More common in neurofibromatosis-1 patients
• EMA and claudin-1 for perineurial cells
• S-100 for schwann cells and neurofibroma cells
• CD34 and NFP for neurofibromatous component
Hornick JL, Bundock EA, Fletcher CD. Hybrid schwannoma/perineurioma: clinicopathologic analysis of 42 distinctive benign nerve sheath tumors. Am J Surg Pathol 2009; 33:
1554–61. Harder A, Wesemann M, Hagel C, et al. Hybrid neurofibroma/schwannoma is overrepresented among schwannomatosis and neurofibromatosis patients. Am J Surg
Pathol 2012; 36: 702–9.
Hybrid nerve sheath tumors
65. Malignant gastrointestinal
neuroectodermal tumor
• Clear cell sarcoma-like
tumor of the GI tract with
osteoclast-like giant cells
• Epithelioid/polygonal
cells with variable
amount of eosinophilic
cytoplasm
• Vesicular nuclei with
chromatin margination
and scattered
intranuclear cytoplasmic
inclusions
66. DD
• GIST, monophasic synovial sarcoma,
primary or metastatic malignant
melanoma, Clear cell sarcoma
• Middle-aged adults
• Highly malignant neoplasm
• S100, SOX10, and neuroendocrine
markers positive
• EWSR1 translocation
Stockman DL, Miettinen M, Suster S, Spagnolo D, Dominguez-Malagon H, Hornick JL, Adsay V, Chou PM, Amanuel B, VanTuinen P, Zambrano EV. Malignant
gastrointestinal neuroectodermal tumor: clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis of 16 cases with a reappraisal of
clear cell sarcoma-like tumors of the gastrointestinal tract. The American journal of surgical pathology. 2012 Jun 1;36(6):857-68.
Malignant gastrointestinal
neuroectodermal tumor
68. • Proliferation of spindle-
shaped or stellate-
shaped cells
• Palely eosinophilic
cytoplasm
• Random or loosely
fascicular growth pattern
Acral fibromyxoma
69. DD
• Neurofibroma, myxoma, fibroma, low-
grade fibromyxoid sarcoma,
dermatofibroma, superficial
angiomyxoma or DFSP
• Benign lesion occurs in
subungual/periungual sites
• Positive for CD34
• Low rate of recurrence
• No risk of metastasis has been
reported
Hollmann TJ, Bovee JV, Fletcher CD. Digital fibromyxoma (superficial acral fibromyxoma): a detailed characterization of 124
cases. Am J Surg Pathol 2012; 36: 789–98.
Acral fibromyxoma
70. • Mild to severe solar
elastosis is regularly
encountered adjacent
to the tumor
• Cells have moderate to
severe pleomorphism
• Spindle, epithelioid, or
multinucleated forms
• Atypical mitotic figures
Atypical fibroxanthoma
71. DD
• Poorly differentiated variants of SCC,
melanoma, cutaneous
leiomyosarcoma, and atypical fibrous
histiocytoma
• Malignant tumor
• CD68, CD10 positive
• High Ki67 index
• Shares 9p and 13q deletions with
undifferentiated pleomorphic sarcomas
López L, Vélez R. Atypical fibroxanthoma. Archives of Pathology and Laboratory Medicine. 2016 Apr;140(4):376-9.
Atypical fibroxanthoma
72. • Hypocellular to
moderately cellular
proliferation of bland,
spindled to stellate cells
• Tumor matrix calcifies
in a distinctive grungy
or flocculent pattern
Phosphaturic mesenchymal tumour
73. DD
• SFT, hemangiomas, Giant cell
tumors, spindle cell lipomas, and
various cartilaginous tumors
• Adults, wide anatomical distribution
• Association with osteomalacia
• Over-expression of FGF23
• Osteomalacia typically resolves after
resection
Phosphaturic mesenchymal tumour
74. • Multinodular or lobular
architecture
• Cells arranged in
reticular, trabecular,
nested, and solid
patterns
• epithelioid, clear cell,
spindle cell, or
plasmacytoid
Myoepithelial carcinoma
75. DD
• High-grade extraskeletal myxoid
chondrosarcoma, epithelioid
MPNST, poorly differentiated
synovial sarcoma, epithelioid
sarcoma, undifferentiated carcinoma,
Ewing sarcoma/PNET
• Aggressive clinical course in both
children and adults
• EWSR1 Translocations
• Cytokeratin and EMA positive
• Functional loss of material on
chromosome 22q, SMARCB1/INI1
expression is lost
Gleason BC, Fletcher CD. Myoepithelial carcinoma of soft tissue in children: an aggressive neoplasm analyzed in a series of 29
cases. Am J Surg Pathol 2007; 31: 1813–24.
Myoepithelial carcinoma
76. • Multilobular growth
pattern
• Partial encapsulation by
a thick fibrous shell
• Characteristic
ossification
• Reticular and cord-like
growth of round-to
ovoid tumor cells
• Embedded in a
fibromyxoid background
Ossifying fibromyxoid tumours
77. DD
• Epithelioid neurofibroma, Epithelioid
schwannoma, epithelioid malignant
peripheral nerve sheath tumor, chondroid
syringoma, myxoid chondrosarcoma,
epithelioid smooth muscle tumors
• IHC- S100p and Vimentin
• Recurrent rearrangement of PHF1, located
on 6p21
• Risk stratification – Typical, Atypical and
Malignant
• High nuclear grade, high cellularity, mitotic
activity >2 per 50 hpf, and atypical ossification
within tumour nodules
Gebre-Medhin S, Nord KH, Moller E, et al. Recurrent rearrangement of the PHF1 gene in ossifying fibromyxoid tumors. Am J
Pathol 2012; 181:1069–77.
Ossifying fibromyxoid tumours
79. • Risk stratification (Benign, Uncertain and
Malignant) 2 or more worrisome features:>5
cm, infiltrative, high nuclear grade, high
cellularity, mitotic activity greater than 1 MF/50
HPF, necrosis, vascular invasion
• Sclerosing variant characterized by densely
collagenous stroma in which cords of tumour
cells are embedded (Retroperitoneum)
• Express both myoid and melanocytic markers,
a small percentage of tumours are negative for
mitf, mart-1, and HMB-45;
• These harbour a TFE3 gene fusion and are in
turn immunopositive for TFE3.
Argani P, Aulmann S, Illei PB, et al. A distinctive subset of PEComas harbors TFE3 gene fusions. Am J Surg Pathol 2010; 34: 1395–
406.
PEComa
80. • Cellular spindle cell
neoplasm
• Uniform, elongated
nuclei
• An infiltrative growth
pattern, rare mitosis
• Benign proliferation of
respiratory epithelium
Low-grade sinonasal sarcoma with
neural and myogenic features
81. DD
Schwannoma, MPNST, monophasic
synovial sarcoma, glomangiopericytoma,
solitary fibrous tumorsPositivity for S100 ,
SMA, MSA
• Adults
• Rarely: rhabdomyoblastic differentiation,
Hemangiopericytic vascular pattern
• t(2;4) PAX3-MAML3 fusion
• Locally aggressive
Lewis JT, Oliveira AM, Nascimento AG, et al. Lowgrade sinonasal sarcoma with neural and myogenic features: a clinicopathologic
analysis of 28 cases. Am J Surg Pathol 2012;36:517–25.
Low-grade sinonasal sarcoma with
neural and myogenic features
83. • Comprise up to 20% of all pleomorphic soft tissue sarcomas
• All recognisable lines of differentiation have been excluded
• Subclassified according to predominant morphological patterns:
round cell, spindle cell, pleomorphic, and epithelioid
Fletcher CD, Gustafson P, Rydholm A, Willen H, Akerman M. Clinicopathologic re-evaluation of 100 malignant fibrous
histiocytomas: prognostic relevance of subclassification. J Clin Oncol 2001; 19: 3045–50.
Undifferentiated/unclassified sarcomas
A, Low-grade spindle cell sarcoma with immature adipocytes and non-pleomorphic lipoblasts in the low-grade dedifferentiated component (case 1). B, Within the same tumour,
high-grade spindle cell sarcoma containing lipoblasts with variable nuclear pleomorphism (case 1). C, Lipogenic low-grade myxoid liposarcoma-
like to (inset) high-grade round cell liposarcoma-like area (case 2). D, Conventional pleomorphic liposarcoma-like DDLPS showing
scattered pleomorphic lipoblasts in a spindle cell to pleomorphic sarcoma (case 17); and E,F epithelioid pleomorphic liposarcoma-like
DDLPS composed of sheets of epithelioid (E, case 4) to bizarre (F, case 3) lipoblasts
