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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