Case 1 10/2/17. Myxoid Soft Tissue Tumors & Tumor-like Lesions. Myxofibro- or Fibromyxo-?: Myxoid Soft Tissue Tumours We Are All Mixed Up About
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1 Myxoid Soft Tissue Tumors & Tumor-like Lesions Myxofibro- or Fibromyxo-?: Myxoid Soft Tissue Tumours We Are All Mixed Up About Rajiv M. Patel, M.D. RCPA NZ ASM 2017 (4:15-5:00pm, Saturday, ) Heterogenous grooup of lesions both benign & malignant characterized by abundant myxoid stroma Many have overlapping histologic and IHC features Their correct classification is important as many have significantly divergent biologic potential Talk will address the most common and/or clinically important myxoid lesions of soft tissue & the means by which they may be reliably identified Where appropriate the differential diagnosis & ancillary diagnostic methods needed for diagnosis will be addressed 2 Myxoid SST: Key features to evaluate Myxoid Soft Tissue Tumors & Tumor-like Lesions Cellularity Extremely low= myxoma, relatively high= fasciitis Arrangement of cells with respect to one another Little cell-cell contact= MLS, touching= ESMC Nuclear pleomorphism Absent= intramuscular myxoma, high degree of atypia= MFS Underlying vasculature Low vascularity= intramuscular myxoma, intricate vasculature= MLS & MFS (Alcian blue ph 2.5) evaluation of myxoid stroma (rarely) Hyaluronic acid-rich= intramuscular myxoma, MLS, MFS (pretreatment with hyaluronidase results in loss of positivity) Chondroitin sulfate-rich= ESMC & chordoma (hyaluronidase resistant positivity) Nodular fasciitis Intramuscular myxoma Angiomyxoma (aggressive angiomyxoma) Myxoid liposarcoma Myxofibrosarcoma Low-grade fibromyxoid sarcoma Extraskeletal myxoid chondrosarcoma 3 4 Case 1 20-year-old male with a right chest wall mass 6 1
2 7 8 Diagnosis? Tram-track SMA Clinical: Nodular fasciitis Nodular fasciitis Pseudosarcomatous, self-limiting, reactive process composed of fibroblasts and myofibroblasts Common, typically subcutaneous Young adults M=F Upper extremities, trunk, head & neck Rapidly growing, sometimes painful Imaging may reveal calcifications <2% local recurrence Simple excision 2
3 Histology: Nodular fasciitis Microcystic myxoid change Well circumscribe nodule (2-3 cm) Variably cellular, fascicular proliferation of fibroblasts & myofibroblasts Myxoid (early lesions) to collagenous (older lesions) Numerous mitoses especially in early lesions, not atypical forms Prominent inflammation around lesion Osteoclast-like giant cells in 10% of cases Postive for SMA, caldesmon, MSA & calponin (tram-track pattern); focal desmin; S100 negative Fasciitis Old fasciitis Differential: Nodular fasciitis Nodular fasciitis Myxomas Less cellular & mitotically active, finer more slender spindle cells with pyknotic nuclei Myxofibrosarcoma More atypia, mitoses with atypical forms, distinct curvilinear vessels MPNST More atypia, higher cellularity, SOX10 & S100 positive (typically focal) Myxoid DFSP CD34 positive with COL1A1-PDGFRB translocation Cellular FH Collagen trapping, foamy and hemosiderin laden macrophages, but may be indistinguishable from fasciitis Spindle cell carcinoma & melanoma Keratins and melanocytic markers, respectively Leiomyosarcoma Perinuclear vacuoles, stronger and more diffuse SMA and usually desmin positive 17 3
4 Ischemic fasciitis: zonation Granulation tissue surrouding areas of fibrinous & mxyoid change Reactive pseudosarcomatous myofibroblasts NF with USP6 Split Signal Case 2 33-year-old femal with a left thigh mass 4
5
6 Diagnosis? Intramuscular myxoma Clinical: Myxoma (intramuscular & juxta-articular) Benign mesenchymal tumor composed of bland spindled cells embedded in a hypovascular, frequently cystic, myxoid matrix Relatively common Intramuscular: more common in women; large muscles of thigh & buttock; may be associated with fibrous dysplasia (Mazabraud syndrome) Juxta-articular: more common in men with DJD; near knees, shoulders, hips Painless soft tissue mass Cured by complete excision Histopathology: Myxoma (intramuscular & juxta-articular) Well-circumscribed myxoid appearing mass, cystic Abundant Alcian blue positive, hyaluronidase-sensitive myxoid matrix Splaying apart of skeletal muscle Hypovascular, without well-developed arborizing vasculature Slender spindle cells with pyknotic nuclei, do not tend to touch Juxta-articular myxomas often show areas of increased cellularity, with partial fascicular growth pattern 6
7 Differential: Myxoma (intramuscular & juxta-articular) Myxofibrosarcoma Curvilinear vessels, atypia Myxoid liposarcoma Chicken wire vasculature, lipoblasts, t(12;16)(q13;p11) resulting in FUS- DDIT3 (CHOP) gene fusion ESMC Multinodular, cording and stranding of cells, NR4A3 gene fusions Myxoid nodular fasciitis Less myxoid, more cellular, multinucleated giant cells, extravasated RBCs Myxoid fibromatosis More cellular and fascicular, spindle cells have pinpoint nucleoli, lymphs scattered around distinct vessels Case 3 30-year-old female with a vaginal wall mass 40 Desmin ER
8 Diagnosis? Aggressive angiomyxoma Clinical: Aggressive angiomyxoma Rare, distinctive myxoid tumor of the genital region, most often seen in women of reproductive age (F:M ratio 6:1) Perineum, pelvis, genital region in women of reproductive age Scrotum, spermatic cord, and pelvis in adult men Benign, deep-seated, slow-growing neoplasm with significant potential for local recurrence given myxoid nature & infiltrative growth Wide local excision with free margins No know role for adjuvant therapy Pathology: Aggressive angiomyxoma Variably circumscribed, but infiltrative Large (up to 60cm) May have a grenz zone if near skin/mucosa Abundantly myxoid Bland spindled to stellate cells Prominent hyalinized vasculature Small smooth muscle aggregates near vessels Lymphod aggregates and mast cells Desmin, SMA, ER/PR, CD34+; CK & S100- Involvement of HMGA2 gene at 12q
9 Aggressive angiomyxoma: Desmin Aggressive angiomyxoma: PR 50 Differential: Aggressive angiomyxoma Angiomyofibroblastoma Angiomyofibroblastoma Plumper cells, not extensively myxoid Myxoid leiomyoma Better circumscribed, larger areas of typical smooth muscle, larger vessels Other myxomas Genital stromal polyps No grenz zone, more cellular variability, higher cellularity Myxofibrosarcoma Atypia, curvilinear vessels 52 Myxoid leiomyoma Case 4 41-year-old male with popliteal deep soft tissue mass 53 9
10 Diagnosis? 59 10
11 Clinical: Myxoid liposarcoma Myxoid liposarcoma Variably cellular, plexiform vasculature, myxoid, spindled or round cells, monovacuolated lipoblasts 30% liposarcoma; 10% of all sarcomas Slow-growing mass in deep soft tissues of limbs; may be multifocal M=F; peak incidence 4 th decade 90% overall 5 yr survival purely myxoid lesions, 40% for highgrade round cell lesions Adjuvant chemotherapy followed by wide excision Histopathology: Myxoid liposarcoma Multinodular, well-demarcated, gelatinous mass Proliferation of evenly distributed, monomorphic spindle cells, with little cell-to-cell contact Rich vascularized chicken wire vasculature Monovacuolated lipoblasts Abundant myxoid stroma Myxoid liposarcoma Plexiform vasculature 64 MLS MLS 11
12 MLS Monovacuolated lipoblasts High-grade myxoid (round cell) liposarcoma M/RCLS Ancillary Studies S-100 protein + t(12;16)(q13;p11) fusing DDIT3 with TLS t(12;22)(q13;q11) fusing DDIT3 and EWS DDIT3 (12q13) translocated DDIT3 (12q13) intact DDIT3[CHOP] (12q13) Break-Apart Probe 12
13 Differential: Myxoid liposarcoma Low-grade myxofibrosarcoma Distinct curvilinear vessels Pleomorphic tumor cells demonstrating perivascular condensation Lacks DDIT3 (CHOP)-TLS and DDIT3(CHOP)-EWS gene fusions ESMC Cording and stranding of cells end to end Inconspicuous vasculature NR4A3 gene fusions Case 5 A 4-year-old male presented with a flank mass 13
14 Diagnosis? EMA MUC4 -ve for CD34, h-caldesmon, and SMA +ve for EMA (focal) and MUC4 Low grade fibromyxoid sarcoma(lgfms) Low-Grade Fibromyxoid Sarcoma (Evans tumor) 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 Clinical: LGFMS 21 patients recurrences after intervals up to 15 years (median 3.5 yrs) 15 with metastasis after periods up to 45 years (median 5 yrs) 14 patients DOD Patients need lifelong follow-up Primarily affects young to middle-aged adults (median 35 yrs) 10-20% of cases present in children Predominantly present as deep soft tissue mass 20% present as superficial tumors of dermis or subcutis Superficial tumors relatively common in children (~40% of superficial tumors) Local recurrence 10%, metastasis in 5-10% Adverse factors: incomplete excision, possibly higher grade areas Wide excision with free margins, adjuvant radiotherapy Am J Surg Pathol Oct;35(10):
15 Histopathology: LGFMS Admixture of collagenous and myxoid zones, with abrupt transitions from one to the other Bland spindle cells with oval nuclei and pale eosinophilic cytoplasm Sweeping fascicles or storiform arrangement of cells Arcuate vessels, prominent in myxoid zones Low mitotic activity No necrosis Hypo- & hypercellular zones Curvilinear vessels 15
16 Bland spindle cells Giant collagenous rosettes in some cases (hyalinizing spindle cell tumor with giant rosettes) 16
17 51 prospectively diagnosed as LGFMS 0 metastases 0 DOD LGFMS clinically behaves as low-grade sarcoma if accurately diagnosed. Caveat: short follow-up Histologic features: LGFMS/HSCT LGFMS/HSCT IHC & Molecular Pathology Vimentin + EMA -/+ (30%) SMA +/- S100 -/+ CD34 rarely focally +ve Desmin neg. MUC4 +ve - most useful marker (>90%) t(7;16)(q33;p11) FUS-CREB3L1; t(11;16)(p13;p11) FUS-CREB3L2 EWSR1-CREB3L1 rearrangements harbored by a smaller number of LGFMS FUS FISH Differential: LGFMS Perineurioma MUC4-; no FUS-CREB3L1, FUS-CREB3L2 or EWSR1-CREB3L1 Neuroblastoma-like schwannoma (for HSCTGR) S100+, MUC4-; FUS-CREB3L1, FUS-CREB3L2 or EWSR1-CREB3L1 Myxoid DFSP Strong and diffuse CD34, COL1A1-PDGFRB translocation Downs-Kelly et al Am J Surg Pathol 2008;32:
18 Soft tissue perineurioma EMA Myxoid DFSP 18
19 Key points: LGFMS Sarcoma of children and young adults Deep soft tissues of proximal extremities Deceptively bland histologic features Overlapping features between LGFMS/HSCT Both lesions demonstrate a t(7;16) reciprocal translocation Treatment: complete excision with tumor-free margins with adjuvant radiotherapy Outcome: low rate of recurrence and rare late metastases Sclerosing Epithelioid Fibrosarcoma (SEF) Rare mesenchymal fibroblastic malignant tumour Affects middle aged and elderly patients Deep soft tissue of limbs and limb girdle > trunk > head & neck Aggressive clinical behaviour: Local recurrence in 50% of cases Metastasis in upto 80% of cases Overall mortality of 25-57% Sclerosing epithelioid fibrosarcoma Sheets, nests and cords of monomorphic epithelioid fibroblastic cells embedded in a densely sclerotic collagenous matrix Myxoid change, calcification and metaplastic bone formation in places Haemangiopericytoma-like vasculature (focally) Conventional fibrosarcomatous areas or LGFMS may be present 19
20 SEF - Immunohistochemistry EMA positive in 50% of cases MUC4 +ve in upto 65% t(7;16)(q33-34;p11), FUS-CREB3L2 in 38% of MUC4-positive cases Case 6 73-year-old male with a history of an enlarging mass of the left distal posterior leg Gisselsen 1998; Donner 2000; Jiao 2002; Ogose 2004; Guillou 2007; Doyle
21 Diagnosis? 123 Myxofibrosarcoma Myxofibrosarcoma Fibroblastic lesion with pleomorphic cells, variable myxoid stroma & distinct vascular pattern One of the most common sarcomas of the elderly (50-70 yrs), no sex predilection Slow growing, painless mass, limbs & limb girdles; 2/3 in subcutis & lower dermis, 1/3 deep soft tissues Recurrences 50% to 60%, regardless of grade Metastases 20% to 35%, only in intermediate to high-grade lesions (lungs, bone, lymph nodes) Complete excision +/- adjuvant therapy based on grade and margin status 21
22 Myxofibrosarcoma: Pathologic Features Atypical cells with enlarged, hyperchromatic, pleomorphic nuclei Variable myxoid stroma Lipoblast-like cells Low mitotic activity Prominent arcuate vascular with condensation of atypical cells Grades 1-3 Complex karyotype
23 MFS Myxofibrosarcoma: Differential Low-grade Nodular fasciitis Myxomas Myxoid spindle cell lipoma Dermal nerve sheath myxoma Myxoid liposarcoma Extraskeletal myxoid chondrosarcoma* Low-grade fibromyxoid sarcoma High-grade Myxoinflammatory fibroblastic sarcoma* Pleomorphic liposarcoma High-grade MPNST Metastatic carcinoma & melanoma CD Angiomyxoma Angiomyxoma 23
24 Myxoid SCL/PL Myxoid SCL/PL Myxoid SCL/PL Myxoid SCL/PL Case 7 40-year-old male with inner left arm lesion above elbow, present for a long time and increasing in size
25 Diagnosis?
26 2007: CNT 2011: CNT Cellular neurothekeoma 2011: ESMC 2017: ESMC
27 Diagnosis? Clinical: ESMC Extraskeletal myxoid chondrosarcoma (ESMC) Rare, 2.5% of all soft tissue sarcomas Painless mass of deep soft tissues of proximal extremities and trunk, but may be seen anywhere M>F, 4-7 th decades 50% rate of metastasis But long term survival characteristic Surgical excision 159 ESMC: Pathologic Features Uniform oval and spindled cells embedded in myxoid ground substance arranged in cords strands nest and sheets, with cells touching end to end Fibrous bands dividing tumor lobules Hypovascular Focal S100+ EWSR1-NR4A3 & RBP56-NR4A3 fusions
28 ESMC: Differential Cellular neurothekeoma NKIC3, PGP9.5, MiTF, SMA + Soft tissue chondroma Lacks myxoid matrix and atypia Osseous chondrosarcoma with soft tissue extension Imaging evidence Myoepithelioma/mixed tumor of soft tissue Keratin positive Ossifying fibromyxoid tumor of soft parts Shell of bone, stronger S NKIC-3 Cellular neurothekeoma 28
29 Cellular Neurothekeoma: IHC ST Chondroma Positive: NKIC3 MiTF PGP9.5 NSE S100A6 Vimentin 40-60% SMA Negative: S100 CD34 EMA HMB45 MelanA CK 170 OFMT OFMT OFMT OFMT 29
30 OFMT OFMT Myxoid Soft Tissue Lesions Tumor Cellularity Atypia Architecture Vessels Myxoma Low None Even cell Few distribution LGFMS Low None-low Abrupt myxoid collagen zones; swirling Low-grade MFS Low-mod Low-mod Perivascular cellularity Prominent in myxoid zones Curvilinear; thick Key points: Myxoid soft tissue lesions Despite that numerous benign & malignant soft tissue lesions may have a myxoid matrix, they can be separated from each other by systematic evaluation of certain perameters in conjuction with the clinical features including age, site & rate of growth There is little need for ancillary techniques, however molecular testing for translocations is becoming standard of care as molecular confirmation of diagnosis is increasingly important for targeted therapy initiation & enrollment in clinical trials. Myxoid LS Low Low Even cell distribution Plexiform, fine ESMC Low-mod Low Cords, chains Random,thick 30
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