SOFT TISSUE PATHOLOGY by IHC001

FRCPath Course Manchester Soft Tissue Slide Seminar DR P Shenjere Consultant Histopathologist The Christie NHS Foundation Trust

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Case 1 • 15M; Lesion LT cheek

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SMA The Christie NHS Foundation Trust

DIAGNOSIS

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Case 10 • 19M; Neck mass

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DIAGNOSIS

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Nodular Fasciitis (NF): • • • • •

Common in young adults(20 to 40yrs) Most lesions grow rapidly and then stabilize Sites – usually upper extremity, trunk, head and neck Size – usually 2-3cm, almost never more than 5cm Anatomically – subcutaneous, fascial or intramuscular and rarely dermal

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Nodular Fasciitis (NF):

• Circumscribed or infiltrative, unencapsulated • Plump spindle cells which lack nuclear pleomorphism • Markedly cellular, but focally shows loose, myxoid, torn, feathery character. Formation of microcysts in some cases

• Spindle cells form S- or C- shaped fascicles • Mitotic figures may be numerous but no atypical forms seen • Extravasated RBC, mononuclear inflammatory cells and osteoclast-like GC – commonly seen

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NF (cont……): • Immuno-stains for SMA, MSA and calponin strongly positive; negative for desmin, CK, S100 protein, CD34 and h-Caldesmon. CD68 stains the osteoclast-like GC as well as some spindle cells • EM – myofibroblasts and fibroblasts • Variants: Intravascular, cranial and ossifying fasciitis

intradermal NF

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D/D of Nodular Fasciitis (NF) • • • • • • • •

Leiomyosarcoma Low grade myofibrosarcoma Low grade fibromyxoid sarcoma Low grade myxofibrosarcoma Myxoid DFSP Fibromatosis Benign fibrous histiocytoma Myxoma The Christie NHS Foundation Trust

• t(17;22(p13;q12.3) -cryptic • USP6-MYH9

• (ABC)

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Reactive/”transient neoplasia” • NF • Proliferative fasciitis • Proliferative myositis • Ischaemic fasciitis With heterotopic ossification • Fasciitis ossificans • fibro-osseous pseudotumour • Myositis ossificans • Heterotopic mesenteric ossification The Christie NHS Foundation Trust

Case 7 • 28F; vocal cord lesion

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ALK 1 The Christie NHS Foundation Trust

SMA The Christie NHS Foundation Trust

DIAGNOSIS

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Diagnosis • Inflammatory Myofibroblastic Tumour

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Inflammatory myofibroblastic tumour(IMT) • Mostly affect children and young adults • Common sites – lung, mesentery and omentum. Other sites – soft tissue, viscera, oral cavity and URT, GIT, GUT, breast and CNS • Systemic symptoms, anaemia, fever, polyclonal hypergammaglobulinaemia and raised ESR in some cases (probably related to IL-6 production) • Solitary or multinodular/multifocal

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Inflammatory myofibroblastic tumour • Size varies from 1 to 20cm • macro: firm and fleshy; may contain gelatinous areas with foci of hmg • Composed of a mixture of myofibroblasts, fibroblasts and mostly mononuclear inflammatory cells(B & T lymphocytes and polyclonal plasma cells). Compact fascicular or storiform growth pattern in cellular areas • Lymphoid follicles with germinal centres in some lesions • Large numbers of blood vessels mimicking granulation tissue may be seen • Variable myxoid and collagenized areas

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IMT • Ganglion-like myofibroblasts may be seen • Calcification and metaplastic bone rarely seen • Three patterns have been described, the first mimicking NF, the second LGMFS or LMS, and the third fibromatosis • Frankly malignant transformation in rare cases

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IMT • • • •

80-90% SMA +ve Desmin and calponin focally +ve in 60-70% 1/3 +ve for CK ALK +ve in 36-50%; positivity reliably predicts the presence of ALK gene rearrangement (Alk gene rearrangement can be detected by FISH) • 10% show ROS-1 rearrangement & are positive for ROS1 IHC • Rare cases show RET or PDGFB gene rearrangements

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• ETV6-NTRK3 Is expressed in a subset of ALK— ve IMTs Am J Surg Pathol 2016;40:1051–1061

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ALK Dual Colour Break Apart Probe; Abnormal Result

Key; Red/Green Fusion Signal = Normal ALK gene. Red (3’) & Green (5’) signals flank the ALK breakpoint cluster region. The separate red and green signals indicate a Rearrangement of ALK

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IMT

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IMT

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IMT

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D/D of IMT • • • • • • • • •

NF Fibromatosis LGMFS Leiomyosarcoma SFT GIST FDRCT Retroperitoneal fibrosis Sarcomatoid carcinoma (in CK positive cases)

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Case 23 • 27F; Abdominal wall mass

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SMA

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ß-CATENIN The Christie NHS Foundation Trust

DIAGNOSIS • Fibromatosis

D/D • • • • • • • •

NF Desmoplastic fibroblastoma Perineurioma SFT LGMFS LGFMS LG-MPNST FS The Christie NHS Foundation Trust

Case 20 • 59M; vocal cord lesion

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AE1/3 The Christie NHS Foundation Trust

34BE12 The Christie NHS Foundation Trust

p63 The Christie NHS Foundation Trust

SMA The Christie NHS Foundation Trust

DIAGNOSIS

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Spindle Cell Carcinoma • Also called sarcomatoid carcinoma • M>F • Associated with drinking, smoking and previous radiotherapy treatment • Usually situated in the glottic region

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Macroscopy & Histology • Polypoid lesion • Usually ulcerated • Biphasic – sarcomatoid/spindle cell component & squamous cell component • Sarcomatoid component consist of spindle cells arranged in different patterns such as fascicles, myxoid, storiform etc • Foci of chondrosarcomatous/rhabdomyosarcomatous differentiation may be present • Neoplastic squamous component present in upto 81% - Either as an in-situ or invasive component

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IHC • CK +ve – broad spectrum ck e.g MNF116 & AE1/3, HMW CKs • p63 • Mesenchymal markers +ve in the sarcomatoid component

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Differential Diagnosis • Benign spindle cell lesions• Nodular fasciitis, ossifying & non ossifying fibro-osseous lesions, vocal cord nodule with stromal atypia, laryngeal contact ulcer/ granulation tissue, • SarcomasMPNST, synovial sarcoma,leiomyosarcoma, IMT, SFT, KS, etc • Spindle cell melanoma • Spindle cell myoepithelioma

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Case 4 • 62F; Perineal tumour

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CD34

BCL2 The Christie NHS Foundation Trust

DIAGNOSIS

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Solitary Fibrous Tumour • • • • • •

CD34 (95%) CD99 BCL2 EMA (33%) SMA (33%) Some cases may show focal S100, CK or desmin positivity

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SFT • NAB2-STAT6 gene fusion • inv(12)(q13q13) •

NAB2 exon 4 – STAT6 exon3 & NAB2 exon 6 – STAT6 exon 17 most common fusion variants

• Other fusion gene reported: STAT6- TRAPPC5 • Overexpression of STAT6

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Solitary Fibrous Tumour • • • • • •

CD34 (95%) CD99 BCL2 EMA (33%) STAT6 SMA (33%) Some cases may show focal S100, CK or desmin positivity • STAT6

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Malignant Solitary Fibrous Tumour Features associated with malignancy • >4 mitoses/10HPF • High cellularity • Pleomorphism • necrosis

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“Dedifferentiated” SFT

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SFT Differential diagnosis • Sarcomatoid mesothelioma • Sarcomatoid carcinoma • Synovial sarcoma • Dedifferentiated LPS • Low grade fibromyxoid sarcoma • Cellular schwannoma • MPNST The Christie NHS Foundation Trust

Case 8 • 29F; Thigh mass

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DIAGNOSIS

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Monophasic Synovial Sarcoma

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IHC • Most cases show positivity for CK and EMA • EMA expressed more often and more widely • EMA consistently +ve in epithelial elements of biphasic SS • Other markers- TLE1 (85-97%), CD99 • Focal positivity for S100 in ≈40% • CD34 positivity – very rare

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Synovial Sarcoma • SS18 (18q11.2) • SSX (Xp11.21-23) types 1, 2, 4 (of 5)

• SS18/SSX fusion genes 60% SSX1, 40% SSX2,<1% SSX4 •

Rare variants e.g. t(X;20)(p11.23;q13.33) (SS18L1-SSX)

•

(SS18L1-SSX)

•Ladanyi 2002; Allander 2002; Guillou 2004; Baird 2005; Storlazzi 2007; Amary 2007; Nakayama 2007

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Fusion proteins • SS18 protein - transcriptional coactivator • SSX protein

- transcriptional corepressors

• Fusion protein - functions of both targets include: IGF2, CD44, EGR1, JUNB, WNT

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D/D • • • • •

Fibrosarcoma Leiomyosarcoma Clear cell sarcoma Fibromatosis carcinoma

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Biphasic SS

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Poorly Differentiated SS

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Hemangiopericytic Growth Pattern Stout & Murray: “Hemangiopericytoma: a vascular tumor featuring Zimmerman’s pericytes” Annals of Surgery, 1942.

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Tumours with Haemangiopericytic Pattern • • • • • •

SFT Myofibroma Synovial sarcoma Mesenchymal chondrosarcoma Some MPNST ESS

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Case 27 • 35M; Shoulder lesion

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IHC • Diffusely positive for CD34

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DIAGNOSIS • DFSP

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Dermatofibrosarcoma Protuberans (DFSP) • • • • •

Dermal and subcutaneous tumour Atrophic epidermis Cytologically bland and uniform Prominent storiform pattern Lace-like or honeycomb pattern of infiltration of subcutaneous fat • Infiltrates along septa of adipose tissue • Rarely has giant cell fibroblastoma component

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IHC • Diffusely positive for CD34 • Rare examples –ve for CD34 • SMA+/Other superficial spindle cell tumours +ve for CD34: 1. 2. 3. 4. 5. 6.

Myxoinflammatory fibroblastic sarcoma Cellular angiofibroma Superficial acral fibromyxoma Spindle cell lipoma SFT Mammary type myofibroblastoma The Christie NHS Foundation Trust

Morphological Variants • Pigmented (Bednar tumour) • Myxoid • Granular cell and atrophic variants also described

Myxoid DFSP

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Occasionally contain myoid whorls/bodies

CD34

SMA The Christie NHS Foundation Trust

DFSP with Fibrosarcomatous Transformation

• DFSP rarely undergoes fibrosarcomatous change (<5%) • Occur de novo or in recurrences • Gradual or abrupt • Cellular with associated nuclear atypia, increased mitoses • Cells arranged in fascicles producing a herringbone pattern • 10-15% metastasise The Christie NHS Foundation Trust

DFSP Molecular Pathology • t(17;22)(q22;q13) - most common • Supernumerary ring chromosomes containing material from 17q22 and 22q13 → fusion of COL1a1 and PDGFβ Fusion protein processed into functional PDGF-β

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When is FISH Required? • Not in classical cases • Useful in unusual histologic patterns & in cases with fibrosarcomatous transformation & metastases • Small punch biopsies

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Tumours with a storiform growth pattern • Other fibrohistiocytic tumours (BFH, PDS/pleomorphic undifferentiated sarcoma) • Perineurioma • Occasional cases of MPNST • Occasional cases of spindle cell carcinoma • Some cases of SFT • Nodular Fasciitis

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Low grade fibromyxoid sarcoma(LGFMS) Originally described by Harry Evans in 1987 (n=2) • Both originally diagnosed as benign • Both locally recurred and eventually metastasized • One patient died from disease Follow-up study by Evans in 1993 (n=10) • 10 new cases • 8/10 diagnosed retrospectively after recurrence / metastasis • 7/10 recurred • 5/10 metastasized (some late) • 4/10 died of disease

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LGFMS

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LGFMS

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Low-grade Fibromyxoid Sarcoma

Giant collagenous rosettes in some cases

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LGFMS – IHC & Molecular Pathology • • • • • • •

Vimentin + EMA -/+ (30%) SMA +/S100 -/+ CD34 – rarely focally +ve Desmin – neg. MUC4 +ve - most useful marker

•

LGFMS/SEF

•

EWSR1-CREB3L1 rearrangements harbored by a smaller number of LGFMS

t(7;16)(q33;p11); t(11;16)(p13;p11) FUS-CREB3L1; FUS-CREB3L2

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•MUC4

•EMA

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LGFMS – D/D • • • • • •

Neurofibroma Perineurioma Nodular fasciitis Fibromatosis LG MFS Myxofibrosarcoma

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Case 6 • 52F; Thigh lesion

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CD34 CD34

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DIAGNOSIS • Benign Fibrous Histiocytoma

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Benign Fibrous Histiocytoma • PRKCB-PDPN t(1;16)(p36;p11) • PRKCD-LAMTOR1 t(3;12)(p21;q13) • PRKCD-RDH5 t(3;12)(p21;q13)

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Case 11 • 33F; Middle finger lesion

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DIAGNOSIS

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Atypical Fibrous Histiocytoma • Extremities of young patients, non sun damaged skin • Low power view resembles ordinary BFH • High power view reveals foci of severe cytological atypia, high mitotic count, necrosis • Characterised by frequent local recurrence, rare mets • Rx- complete excision and follow up

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D/D • • • • • •

BFH AFX Spindle cell Ca Leiomyosarcoma Melanoma Spindle cell Sarcoma NOS (MFH)

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Variants of FH • • • •

Cellular Aneurysmal Atypical Deep

• • • • • • • • •

Epithelioid fibrous histiocytoma Clear Cell Granular cell Keloidal Lipidized Atrophic Myxoid Palisading Myofibroblastic

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Case 19 • 70M; Forehead lesion

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DIAGNOSIS

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Diagnosis • Spindle cell sarcoma NOS • Not AFX because of subcutaneous extension, and necrosis

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Case 25 • 80M; Scalp lesion

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IHC • +ve for CK14, CK5, p63 • No mucin on PAS

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DIAGNOSIS • Spindle cell carcinoma/sarcomatoid carcinoma

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Case 22 • 69M; Forehead lesion

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CD34

CD31 Fli-1

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DIAGNOSIS

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Angiosarcoma (AS) • Conventional (idiopathic) • Lymphoedema assoc. • Post radiation

Conventional AS • • • •

Elderly pts Sun-damaged skin Head & neck M>F

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Epithelioid AS

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Epithelioid AS

CD31

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Clear Cell/Signet Ring Cell AS

Am. J. Dermatopathol.2013; 35; 671–675 Histopathology 2015, 66, 856–863

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Clear Cell/Signet Ring Cell AS

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Other Morphological Variants of Epithelioid AS • Foamy cell • Granular cell

Dermatopathol. 2014; 36; 669–672 J. Cutan. Pathol. 2010; 37; 901–906 J. Cutan. Pathol. 2012; 39; 476–478, 475

Histopathology 2015, 66, 856–863

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AS • Can be mostly epithelioid/spindled • Vasoformation can be inconspicuous, usually seen at the periphery • Can be easily mistaken for other tumours if index of suspicion low!

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AS IHC • Use more than one endothelial marker • CD34, CD31, Podoplanin, Fli-1, FVIIIRA

• CD31 – not entirely specific, also expressed by histiocytes • CD34 – less sensitive than CD31 & not specific • Fli-1 – poor specificity; expressed by carcinomas, AFX/PDS, MM The Christie NHS Foundation Trust

ERG • • • •

ERG = ETS-related gene ETS family of transcription factor Expressed in normal endothelial cells Expressed by haemangiomas, lymphangiomas, almost all angiosarcomas, EHE and PMHE • Also +ve in AML, subset of EWS + some prostatic adenocarcinoma

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ERG

CD31

ERG The Christie NHS Foundation Trust

D/D of cutaneous Spindle Cell Tumour with cellular pleomorphism • • • • • •

Atypical Fibroxanthoma (AFX) Spindle Cell Carcinoma Melanoma Leiomyosarcoma Angiosarcoma Atypical Fibrous Histiocytoma

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IHC in D/D of Pleomorphic Cutaneous Spindle Cell Tumours Tumour

AE1/3 or MNF116

34BE12

CK5

p63

SMA

Desmin

S100

CD31

SpCC

+/-

AFX

-/+

LMS

-/+

+/-

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Case 12 • 61M; Groin mass

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SMA The Christie NHS Foundation Trust

DIAGNOSIS

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Intravascular Leiomyosarcoma • Most commonly involve IVC/PA D/D • Intimal sarcoma

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Case 17 • 31F; Bladder tumour

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SMA

Desmin

h-caldesmon The Christie NHS Foundation Trust

DIAGNOSIS • Leiomyosarcoma • Pt Rxd for retinoblastoma in childhood Ref: Soft tissue, pelvic, and urinary bladder leiomyosarcoma as second neoplasm following hereditary retinoblastoma. Venkatraman L, Goepel JR, Steele K, Dobbs SP, Lyness RW, McCluggage WG. J Clin Pathol. 2003 Mar;56(3):233-6.

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Case 16 • 68F; Lt buttock lesion

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S100 The Christie NHS Foundation Trust

DIAGNOSIS • Schwannoma

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Cystic change The Christie NHS Foundation Trust

Plexiform Schwannoma The Christie NHS Foundation Trust

Case 21 • 76M; Lt knee lesion

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IHC • Dot-like paranuclear positivity for CK20 and cam 5.2 • Positive for Chr, Synapt and NF • -ve for TTF-1

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DIAGNOSIS • Merkel cell Carcinoma

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D/D • PNET, lymphoma, small cell melanoma, metastatic small cell carcinoma, rhabdomyosarcoma and other SRBCTs

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PAS+/-DIASTASE

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CD99 Synaptophysin S100

MNF116 Chrom A CD45 Tdt

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DESMIN The Christie NHS Foundation Trust

Myo-D1

Myogenin

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CD56 The Christie NHS Foundation Trust

Diagnosis • Rhabdomyosarcoma (solid variant of alveolar subtype)

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Case 24 • 85F; Breast mass

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DIAGNOSIS • Sarcomatoid carcinoma

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Case 26 • 34F; Thigh mass • (Microscope)

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DIAGNOSIS • • • • •

EMC Pos for S100+/-, (EMA, Chr, Synap) 75% have EWSR – t(9;22), variant translocations seen in others D/D: MFS, Myxoid Liposarc, Myoepithelial tumour, carcinoma

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EMC • • • • •

M=F Extremities Slow growing Multinodular Most low grade

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Case 13 • 79M; Perineal lesion

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DIAGNOSIS

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Cellular Angiofibroma

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Soft Tissue Tumours of the Genital Tract • • • •

AA Smooth muscle tumours Fibroepithelial polyp (cellular) Angiomyofibroblastoma

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Case 2 • 40M; Thigh lesion

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DIAGNOSIS

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Cellular Myxoma • • • •

Involves deep soft tissues May have intramuscular component >20% cellular areas Cytologically bland

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D/D • • • • • •

Aggressive angiomyxoma Myxoid NF LGFS Myxoid liposarc Low grade myxofibrosarcoma Intramuscular myxoma

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Case 5 • 61M; Mass adherent to stomach

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DOG 1.1 The Christie NHS Foundation Trust

Case 15 • 20F; Gastric Mass

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IHC • Positive for CD34, CD117, DOG1.1, SMA and hcaldesmon

• DOG1 The Christie NHS Foundation Trust

DIAGNOSIS • GIST

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Case 29 • 29F; Parotid mass

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DIAGNOSIS • Spindle cell lipoma

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Case 9 • 64F; Shoulder mass

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DIAGNOSIS

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Spindle Cell Lipoma (SCL) (1)

• Usually involve head, neck and shoulder regions of middle aged men • Present as a painless, mobile, solitary mass within the superficial soft tissues (often with a long history) • Rare cases described elsewhere (limbs, oral cavity, breast, larynx, spermatic cord etc) and also in the dermis • Very rarely multiple and familial • Usually less than 5.0 cms in diameter & circumscribed • Oval or discoid, yellowish or greyish-white, may be mucoid

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SCL(3) • IHC: spindle cells strongly +ve for CD34. Also CD10, Bcl2+ve(50%) Adipocytes + ve for S100 protein AR positivity in both spindle and adipocytic cells in almost all cases (Syed S et al. Arch. Pathol. Lab. Med. 2008;132;81-3)

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Variants of SCL • Myxoid • Pseudoangiomatous • Angiomatous (haemangiopericytic, cavernous/capillary or curvilinear +/- perivascular hyalinization) • Low fat or fat free (Billings SD & Folpe AL Am. J. Dermatopathol. 2007;29;437-442) • Fibrous/collagenous • Plexiform • Composite • ? Inflammatory

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D/D of Spindle Cell Lipoma • Spindle cell liposarcoma and ALT (those with pleomorphic lipoma component) • Dendritic fibromyxolipoma (Suster S. et al. Ann. Diagn. Pathol. 1998;2:111-20)

• • • • •

Peripheral nerve sheath tumour Mammary type myofibroblastoma Cellular angiofibroma Myxoid liposarcoma ( myxoid SCL) Lipomatous hemangiopericytoma

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Myxoid SCL vs. Myxoid Liposarcoma(MLS) • Difference in sites (neck, upper back and shoulder for SCL; extremities and trunk for MLS) • Subcutaneous (SCL) vs deep (MLS) • Cells are spindly in SCL; round, oval or stellate in MLS. Also lipoblasts in MLS • Prominent chicken wire vascularity in MLS

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Myxoid SCL vs Myxoid Liposarcoma(MLS) - cont • Microcystic lymphangioma-like areas in many MLS; not seen in SCL • CD34 more strongly and diffusely positive in SCL; only a small number of CD34 +ve cells in MLS (Suster S, Fisher C. Am. J. Surg. Pathol. 1997;21;195-200) • CHOP/DDIT3 and FUS or EWS gene fusion t(12;16) or t(12;22) in MLS

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MLS

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Case 28 • 48M; Retroperitoneal mass

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DIAGNOSIS • Spindle cell liposarcoma

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Mostly Superficial Myxoid Soft Tissue Tumours • • • • • • • • • •

“Ganglion” Myxoid NF Myxoid Nodular Fasciitis Myxoid Spindle cell lipoma Myxoid Neurothekeoma Sup. Angiomyxoma OFMT Myoepithelioma Agg. Angiomyxoma Digital myxoma

• Myxofibrosarcoma • Myxoid DFSP

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Mostly Deep Myxoid Soft Tissue Tumours • Intramuscular myxoma • Cellular myxoma • Juxta-articular myxoma

• • • • • •

Myxoid Liposarcoma EMC LGFS Chordoma Myxoid MPNST Myxopapillary Ependymoma • Myxoid Leiomyosarcoma • Synovial sarcoma • Solitary Fibrous Tumour The Christie NHS Foundation Trust

Case 30 • 68M; Mediastinal mass

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DIAGNOSIS • Dedifferentiated Liposarcoma

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Case 14 • 66F; Retroperitoneal mass

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CD34

DOG 1.1

CD117

h-Caldesmon The Christie NHS Foundation Trust

DIAGNOSIS • GIST

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GIST

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GIST

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Rhabdomyosarcomatous differentiation in GIST post tyrosine kinase inhibitor therapy

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GIST Immunohistochemistry • • • • • • • • • •

DOG1 (99%) CD117 (95%) CD34 (70%) PKC theta (96%) SMA (30-40%) S100 (5%) h-caldesmon (80%) Desmin (<1%) CK (<1%) MUC4 -ve The Christie NHS Foundation Trust

DOG1 positivity in LGFMS Thway K et al. Int J Surg Pathol. 23(6):454-60

• 5/11 showed varying amounts of DOG1 expression, ranging from weakly in approximately 5% of cells to strongly in up to 100% of cells

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Features of Lipoblasts • Cytoplasmic vacuoles (one or more): large round empty

• Nucleus indented

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Lipoblasts

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GIST

EMC

CARCINOMA

MYXOFIBROSARCOMA

LMS

CHORDOMA

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Case 18# • 56 Female – parametrial mass

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• h-caldesmon

• SMA

• Melan-A The Christie NHS Foundation Trust

DIAGNOSIS

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Angiomyolipoma • PEComas -

AML Clear cell “sugar” tumour of the lungs LAM PEST(primary extrapulmonary sugar tumour) Clear cell myomelanocytic tumour

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PEComas • Ass. With tuberous sclerosis complex (– usually multiple AMLs) • Criteria for malignancy - >/=70% atypical epithelioid cells - >/=2mitoses per 10HPFs - Atypical mitotic figures - necrosis

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Case 3 • 61M; sacral tumour

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Galectin

S100 The Christie NHS Foundation Trust

DIAGNOSIS

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Chordoma • 50% sacrococcygeal region • 35% base of skull Variants Chondroid Chordoma Dedifferentiated Chordoma

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D/D • Chondrosarcoma • Myxopapillary ependymoma • Parachordoma

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