Mimics of Soft Tissue Sarcoma
Savannah, GA
October 2019
Cyril Fisher MA MD DSc FRCPathConsultant Pathologist, University Hospitals Birmingham, UK
Professor Emeritus of Tumour Pathology
Institute of Cancer Research
University of London, UK
DiscrepanciesCases Dx % Grade %
1978 Baker US 130 32 -
1984 Tetu CAN 260 35 -
1986 Presant US SECSG 216 28 24
1986 Coindre FR panel 25 39 25
1989 Alvegaard SSG 240 25 40
1989 Shiraki US ECOG 488 26 -
1991 Harris UK 376 24 -
1995 Prescott UK 17 29 -
1999 Meis-K SSG 1000 20 25
2004 Randall US 104 37 25
2004 Van Dalen NE rpl 143 24 36
2009 Thway UK 349 22 23
2010 Lurkin FR 366 25 19
Benign/Malignant Discordance
2,425 patients
• 341(14%) had received discordant diagnoses.
• 124 benign tumors diagnosed as sarcomas
- 14 (11%) fasciitis
- 38 (31%) lipomas
• 77 non-sarcoma malignancies diagnosed as sarcomas
- 49 (64%) carcinoma
- 12 (16%) melanoma
Perrier at al PLOS ONE | https://doi.org/10.1371/journal.pone.0193330 April 5, 2018
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Mimics of Sarcoma
Reactive/‘transiently neoplastic’
• Nodular fasciitis
• Proliferative fasciitis
• Proliferative myositis
• Ischemic fasciitis
With heterotopic ossification
• Ossifying fasciitis
• Fibro-osseous pseudotumor
• Myositis ossificans
• Heterotopic mesenteric ossification
Massive localised lymphedema of
morbid obesity
Benign tumors with focal atypia
• Pleomorphic fibroma
• Leiomyoma with bizarre nuclei
• Atypical cutaneous FH
• Atypical neurofibroma
• Cellular schwannoma
• Spindle and pleomorphic lipoma
Benign tumors with diffuse atypia
• Pleomorphic hyalinising angiectatic t.
• Atypical fibroxanthoma
• Atypical intradermal smooth muscle t.
Non-mesenchymal tumors
• Sarcomatoid carcinoma
• Melanoma
Nodular Fasciitis
• Young adults
• Limbs, HN, trunk
• Rapidly growing
• Up to 5 cm
• Dermal
• S/c, fascial
• Intramuscular
• Does not recur
Nodular FasciitisNodular Fasciitis
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SMA SMA
h-caldesmoncalponin
Nodular Fasciitis
Nodular Fasciitis
• t(17;22)(p13;q12.3-13.1)
• USP6-MYH9 fusion
• USP6 rearranged in 74% of NF
• Other partners identified• RRBP1
• CALU
• CTNNB1
• MIR22HG
• SPARC
• TSBH2
• COL6A2
• CDH11
Erickson-Johnson 2011; Amary 2013; Oliveira 2014; Guo 2016; Patel 2017; Bekers 2018; Erber 2018
Nodular Fasciitis
• t(17;22)(p13;q12.3-13.1)
• USP6-MYH9 fusion
• USP6 rearranged in 74% of NF
• USP6 rearranged in• Cellular fibroma tendon sheath
• Myositis ossificans
• Aneurysmal bone cyst
• Giant cell reparative granuloma of hands, feet
• Fibro-osseous pseudotumor
Erickson-Johnson 2011; Amary 2013; Oliveira 2014; Guo 2016; Patel 2017; Bekers 2018; Erber 2018
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Metastasizing ‘Nodular Fasciitis’
Nodular Fasciitis
• Zonation
• Myxoid → cellular → fibrous
• Loose storiform, fascicular
• No nuclear pleomorphism
• Mitoses (normal)
• No necrosis
• Red blood cells, lymphocytes
• Small giant cells
Nodular Fasciitis
• Fibrous histiocytoma
• Fibromatosis
• Fibroma of tendon sheath
• Desmoplastic fibroblastoma
• Low grade myofibrosarcoma
• Leiomyosarcoma
• Myxofibrosarcoma
Differential Diagnosis
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Cutaneous Fibrous Histiocytoma
Fibromatosis
Beta-catenin
Fibroma of Tendon Sheath
• M 20-50
• Tendon, hands > feet
• Circumscribed, lobulated
• Sparse stellate cells
• Uniform collagen
• Fasciitis-like areas
• USP6 rearranged
• Pleomorphic variant
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Desmoplastic Fibroblastoma
• Slowly-growing
• Subcutis, rarely i/m.
• Circumscribed
• Sparse stellate cells
• Uniform collagen
• Rare SMA
• t(2;11)(q35;q13)
Evans 1995; Nishio 2011
Low-grade Myofibrosarcoma
Various copy number changes
No specific rearrangement
Nodular Fasciitis Leiomyosarcoma
h-Caldesmon
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Nodular Fasciitis Myxofibrosarcoma
Fasciitis: Subtypes
• Usual
• nodular
• cranial
• intravascular
• Proliferative
• Ischemic
Intravascular Fasciitis
• 80% <30 yrs, M = F
• Extremities (U > L)
head, neck, trunk
• Veins or arteries
• Transmural, luminal
• Multinodular
• Benign: 2 recurred
Patchefsky 1981
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Proliferative Fasciitis
• Adults 40-70, M = F
• Forearm, thigh
• Rapid growth
• < 5cm
• Trauma in 30%
• Self-limiting
Proliferative Myositis
• Desmin negative
• CK negative
• S100pr negative
• CD34 negative
• CD31 negative
Proliferative Fasciitis/Myositis
• Carcinoma
• Rhabdomyosarcoma
• Melanoma
• Epithelioid sarcoma
• ES-like (pseudomyogenic)
hemangioendothelioma
Differential Diagnosis
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Ischemic Fasciitis
• F =M, 15-95 years
• Immobilization, trauma
• Shoulder, back, buttock
• Sacrum, greater trochanter
• No ulcer – deep subcutis
• Painless mass 1 – 8 cm
• Rarely recurs
Montgomery 1992; Perosio 1993; Liegl 2008
Ischemic Fasciitis
Ischemic Fasciitis
• Lobular, zonal
• Fibrinoid necrosis
• Myxoid stroma
• Ectatic thin vessels
• Atypical fibroblasts
• SMA, desmin, CD34
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Mimics of Sarcoma
Reactive/‘transiently neoplastic’
• Nodular fasciitis
• Proliferative fasciitis
• Proliferative myositis
• Ischemic fasciitis
With heterotopic ossification
• Ossifying fasciitis
• Fibro-osseous pseudotumor
• Myositis ossificans
• Heterotopic mesenteric ossification
Massive localised lymphedema of
morbid obesity
Benign tumors with focal atypia
• Pleomorphic fibroma
• Leiomyoma with bizarre nuclei
• Atypical cutaneous FH
• Atypical neurofibroma
• Cellular schwannoma
• Spindle and pleomorphic lipoma
Benign tumors with diffuse atypia
• Pleomorphic hyalinising angiectatic t.
• Atypical fibroxanthoma
• Atypical intradermal smooth muscle t
Non-mesenchymal tumors
• Sarcomatoid carcinoma
• Melanoma
Ossifying Fasciitis
Fibro-osseous Pseudotumor of Digits
• Adults, history of trauma
• Fingers (I,M)> toes, prox phalanx
• Rarely other sites e.g. wrist
• Dermis, subcutis
• NF-like background, mitoses
• Bony trabeculae, cartilage
• Can stabilise or regress
• USP6 rearranged
Dupree 1986; De Silva 2003; Moosavi 2008; Chaudhry 2010; Flucke 2018
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Fibro-osseous Pseudotumour of Digits
Fibro-osseous Pseudotumor
Myositis Ossificans
• Young adults, M>F
• Rapid growth, trauma history
• Proximal limbs, trunk
• Zoning – peripheral bone
• Metaplastic bone, giant cells, cartilage
• USP6-COL1A1 fusion – ABC of soft tissue
De Silva 2003; Sukov 2008; Bekres 2018; Flucke 2018
Myositis Ossificans
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Extraskeletal Osteosarcoma
• Older adults, extremities
• Some post radiation
• Some in DDL, MPNST, carcinoma
• Subcutaneous or subfascial
• Aggressive
• Histologic subtypes as in bone
Extraskeletal Osteosarcoma
• Adults, mean 47 years
• Mean body weight 186 kg (409 lbs)
• Thigh, leg, genitalia, abdominal wall
• Some had lymphadenectomy
• Ill-defined mass, mean 33cm, 7.4 kg
• Can persist or recur
• Rarely ➔ angiosarcoma
Farshid 1998; Manduch 2009; Shon 2011
Massive Localised Lymphedema of Morbidly Obese
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Massive Localised Lymphedema of Morbidly Obese
Atypical Lipomatous Tumor/WDL
• Lobules of mature fat
• Expanded connective tissue septa
• fine, fibrillary collagen
• edema fluid
• uniformly distributed fibroblasts
• Capillaries at interface
• No atypia
Massive Localised Lymphedema of Morbidly Obese
Atypical Cutaneous Fibrous Histiocytoma
• Extremities
• Polypoid nodule, plaque
• Dermis, superficial subcutis
• Focal pleomorphism
• Atypical mitoses
• Focal SMA, rarely CD34
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Atypical Cutaneous FHAtypical Cutaneous Fibrous Histiocytoma
Atypical Fibroxanthoma/PDS
Atypical Fibroxanthoma/PDS
CD10+
SMA focally +CD10+
SMA focally +
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Pleomorphic Dermal Sarcoma
• M>F, sun-damaged skin, head.
• NOTCH1/2, FAT1 mutations
• Pleomorphic spindle and polygonal cells
• Atypical mitoses, necrosis
• Invasive into deep s/c, fascia, muscle
• Perineurial, lymphatic invasion
• 28% recurred, 10% metastasised
• Margin status predictive
Miller 2012
Neurofibroma with Atypia
Malignancy in Neurofibroma
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Neurofibroma with Atypia
• Atypia alone not significant
• Atypia with
• High cellularity
• Loss of architecture
• Mitoses >1/50 but <3/10 hpf
• 2 or more = Atypical
neurofibromatous neoplasms of
uncertain biologic potential
(ANNUBP)
• P53+, p16-, Ki67+ can occur
Cellular Schwannoma
• Middle aged females
• Mediastinum, R/P, pelvis
• Visceral locations
• Not associated with NF-1
• Attached to nerve
• Encapsulated, up to 19 cm
• Erodes bone, can recur
Woodruff 1981; White et al, 1990; Casadei et al, 1995
Cellular Schwannoma
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S100pr
EMA
S100pr
GFAPCK
Malignant Peripheral Nerve Sheath Tumor
Cellular Schwannoma vs MPNST
• Not associated with NF-1
• Capsule
• Atypia focal
• S100 protein & SOX10 uniformly +
• EMA+ perineurial cells
• H3K27Me3 retained
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Malignancy in Schwannoma
• Atypical epithelioid cells
• abundant cytoplasm
• vesicular chromatin
• prominent nucleoli
• single, cluster, nodule
• Epithelioid MPNST
• S100 protein +
• SOX10 +
• H327Kme3 +
• INI loss (50%)
• Angiosarcoma (epithelioid)
Woodruff, 1994; Trassard, 1996; Mentzel, 1999; Ruckert, 2000; McMenamin 2001
Epithelioid MPNSTAngiosarcoma in Schwannoma
Lipoma
• Normal-looking fat
• Some anisocytosis
• No atypia or mitoses
• MDM2 negative
• HMGIC-PPAP2B/LLP
• HMGA1-PPAP2B
Spindle Cell Lipoma
• Males >45 years
• Deep subcutis
• Rarely in muscle
• Thin capsule
• Yellow/gray
• Scalp
• Neck
• Shoulder
• Orbit
• Eyelid
• Mouth
• Larynx
• Foot
• Perineum
• Skin
• Muscle
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Spindle Cell Lipoma
Spindle Cell Lipoma
Spindle Cell Lipoma
• Fatty areas: like lipoma
• Cells bland, scanty cyto
• CD34, bcl-2
• Collagen, mast cells
• Myxoid stroma
• Loss of 13q14, 16q13
• Lack of Rb expression
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Spindle Cell Lipoma
• Pseudoangiomatous
• Myxoid
• Low-fat
• Fat-free
• With pleo lipoma
• Atypical
Billngs 2007; Marino-Enriquez 2017; Ko 2017
Myxoid SCL vs Myxoid Liposa
• Location
• Vascular pattern
• Lipoblasts
• Rb loss
• DDIT3 rearrangement
Atypical Spindle Cell Lipomatous Tumor
• Spindle cell liposarcoma, atypical spindle cell
lipoma, fibrosarcoma-like lipomatous neoplasm
• Rare tumor of limbs, adults, M>F
• Ill-defined margin
• Variably cellular spindle cell component
• Scattered nuclear atypia
• Differentiated adipose tissue
• uni- or multivacuolated lipoblasts
• Rb loss 57%
Dei Tos et al, AJSP 1996; Mentzel 2010; Deyrup 2013; Creytens 2014; Marino-Enriquez 2017
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Atypical Spindle Cell Lipomatous Tumor
• CD34 64%
• S100 protein 40%
• Desmin 22%
• MDM2 6%
• CDK4 5%
• Rb loss 57%
• MDM2 FISH 0%
Mariño-Enriquez 2017
Atypical Spindle Cell Lipomatous Tumor
• Distinct lesion?
• Morphologic spectrum
• ?related to spindle cell lipoma
• Not related to atypical lipomatous tumor/WDL
• Intermediate (10-15% local recurrence, no mets)
• Rare dedifferentiation
Dei Tos et al, AJSP 1996; Mentzel 2010; Deyrup 2013; Creytens 2014; Marino-Enriquez 2017
Pleomorphic Lipoma
• Clinically like SCL – rarer
• Encapsulated
• Lipomatous areas
• Spindle cells in collagen
• Multinucleated/floret cells
• Lipoblasts
• Atypical mitoses
• Rb loss
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Atypical Pleomorphic Lipoma
• Subcutaneous > deep
• Poor circumscription
• Atypical spindle cells
• Pleomorphism
• lipoblasts
• Multinucleation
Creytens 2017
Pleomorphic LipomaDifferential Diagnosis
• Atypical lipomatous tumor
• Atypical fibroxanthoma
• Myxoid DFSP
• GC fibroblastoma
• Pleomorphic fibroma
Well-differentiated Liposarcoma
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Atypical Lipomatous Tumor/WD Liposarcoma
• Supernumerary chromosomes
- ring, giant rod
• Amplified sequences of 12q14-15
- MDM2, CPM at 12q15
- HMGIC at 12q14.3 coamplified
- CDK4, SAS/TSPAN31 at 12q14.1
G1 checkpoint
CDK4 MDM2
More sens and spec than IHC
Array CGH
MDM2, CDK4, P16 Thway 2012
Fat Necrosis Lochkerne
Size of Fat Cells
• Small in atrophic adipose tissue
• Variation not diagnostic
• Range wider in ALT than in
lipoma or spindle cell lipoma
Bean 2018
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Dysplastic Lipoma
• M>F, neck, shoulders, s/c
• Can be multiple
• retinoblastoma
• Variable adipocyte size
• Single cell fat necrosis
• Focal nuclear atypia
• Rb1 total (22/32) or partial loss
• MDM2 not amplified
• P53 overexpressed
Evans 2015 (anisometric cell); Agaimy 2016; Michal 2018 from Michal et al AJSP 2018
Dysplastic Lipoma
• M>F, neck, shoulders, s/c
• Can be multiple
• retinoblastoma
• Variable adipocyte size
• Single cell fat necrosis
• Focal nuclear atypia
• RB1 Total or partial loss
• MDM2 not amplified
• P53 overexpressed
from Michal et al AJSP 2018Evans 2015 (anisometric cell); Agaimy 2016; Michal 2018; Creytens 2018
Sarcomatoid Carcinoma vs Sarcoma
• Organ-based – not sarcoma!
• In situ component
• Epithelial component
• Heterologous elements
• CK positive CK
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Synovial Sarcoma vs Sarcomatoid Ca
• No in situ component
• Not pleomorphic
• CK more focal
• Bcl-2, CD56 positive
• Mast cells
• SS18 rearrangement on FISH
CKCK
Spindle Cell Melanoma vs MPNST
• Junctional component
• S100pr, SOX10 widespread
• Both lack melanoma Ags
• BRAF, NRAS mutation
CKSOX10
Conclusions
• Be aware of the clinical history
• location
• duration
• rate of growth
• antecedent event
• Be familiar with the diagnostic possibilities
• Seek a further opinion
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THE END
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