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					PATHOLOGY OF SOFT TISSUE
4 Lecture Hours

OBJECTIVES
• Be able to identify certain syndromes including: LiFraumeni, Sturge-Weber, Klippel-Trenaunay, Gardner, Carney (complex), Tuberous sclerosis, Osler-WeberRendu, Sturge-Weber, Turner, Stewart-Treves, Beckwith Wiedemann, and Denys Drash by clinical presentation, gross appearance, microscopic findings, IHC & special stains, cytogenetic abnormality, and/or FISH finding (distinctive fusion gene product). • Understand the inheritance, clinical presentations, cytogenetic findings and key microscopic findings in Neurofibromatosis type 1 (NF 1) and NF 2.

OBJECTIVES
• Be able to identify the following lesions or tumors based upon age at presentation, clinical findings, location, gross appearance, characteristic histology, key IHC & special stains, ultrastructural (electron microscopic) findings, cytogenetic abnormality, and FISH/fusion gene product: nodular fasciitis, proliferative fasciitis, myositis ossificans, spindle cell lipoma, angiolipoma, lipoblastoma, hibernoma, angiomyolipoma, liposarcoma (well differentiated sclerosing, myxoid, round cell), fibrous histiocytoma, fibromatosis, dermatofibrosarcoma protuberans, giant cell fibroblastoma, infantile fibrosarcoma, rhabdomyoma, rhabdomyosarcoma (embryonal, botryoid, alveolar), leiomyosarcoma, alveolar soft part sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, clear cell sarcoma, extrarenal rhabdoid tumor, gastrointestinal stromal tumor, solitary fibrous tumor, solitary fibrous tumor, synovial sarcoma, neurofibroma, schwannoma, malignant peripheral nerve sheath tumor, cystic hygroma, pyogenic granuloma, Kaposi sarcoma, angiosarcoma, neuroblastoma, and Wilms’ tumor.

SOFT TISSUE (ST) PATHOLOGY: LECTURE 1
• • • • • • • • • • Key syndromes: Li-Fraumeni, Carney complex, Gardner syndrome Cell types, general histology, architectural patterns Ultrastructural/electron microscopic findings Overview of cytogenetic/molecular findings Immunohistochemical stains overview Grading, staging, prognosis, and treatment in ST sarcomas Pseudosarcomatous lesions: nodular fasciitis, proliferative fasciitis, myositis ossificans Fibrous histiocytoma Fibromatosis Dermatofibrosarcoma protuberans (DFSP) and DFSP with fibrosarcomatous transformation (DFSP-FS) Giant cell fibroblastoma Infantile fibrosarcoma Malignant fibrous histiocytoma

• • •

SOFT TISSUE: GENERAL
• Soft tissue – nonepithelial extraskeletal structures exclusive of supportive tissue of organs and lymphoid/hematopoietic tissue • Consists of fibrous tissue, adipose tissue, skeletal muscle, smooth muscle, blood and lymphatic vasculature, peripheral nervous system • Usually mesodermal in origin • Malignancy of soft tissue: sarcoma • Benign soft tissue tumors are far more common than sarcomas

SOFT TISSUE (ST) TUMORS
• Proliferation of mesenchymal cells that occur in extraskeletal & nonepithelial tissue • Classified by tissue recapitulated(smooth or skeletal muscle, fat, fibrous, vessels, nerves) • Benign: malignant; 100:1 • 8,100 ST sarcomas diagnosed/year • 0.8% of invasive malignancies; 2% deaths

SARCOMAS: GENERAL
• Annual incidence of ST sarcoma: 30/million vs benign ST tumors 3000/million population • Congenital soft tissue tumors rarely behave malignantly, even with aggressive cytologic features • Nodal involvement uncommon, and a poor prognostic variable similar metastatic disease often to lungs • Local recurrences show increased number of genetic changes, including loss of 9p, gains of 5p and 20q

SOFT TISSUE TUMORS
• • • • • • One/third of benign tumors: lipomas One/third fibrohistiocytic and fibrous tumors 10%: vascular tumors 5%: nerve sheath tumors Lipomas: rare in hand, lower leg & foot; very uncommon in children Multiple angiolipomas: sometimes painful, most common in young men • Angioleiomyomas: often painful, common in lower leg of middleaged women • 50% of vascular tumors: in patients <20 years • Benign soft tissue tumors: 99% superficial, 95% <5 cm in diameter

• 5-10% of adult sarcomas, higher percentage in children • Distinctive lesions are nasopharyngeal angiofibroma and sinonasal hemangiopericytoma • Tumors with predilection for head and neck include benign fibroblastic lesions, atypical fibroxanthoma, nerve sheath tumors, cutaneous angiosarcoma, capillary hemangioma, pediatric rhabdomyosarcoma, solitary fibrous tumor • Obtaining adequate margins is difficult • Ddx: melanoma, spindle cell carcinoma (more common than sarcoma)

SOFT TISSUE LESIONS: HEAD AND NECK

• Arise from primitive multipotential mesenchymal cells that differentiate during neoplastic transformation • Not related to trauma, although trauma may reveal tumor • May rarely follow chemical or heat burn, phenoxyherbicide, chlorophenols, dioxins • Most arise de novo (sporadic) • Malignant degeneration does occur in neurofibromas especially large lesions in NF1 • May arise after radiation therapy (MFH, soft tissue osteosarcomas, fibrosarcomas, MPNST, angiosarcomas, synovial sarcomas), usually 10 years after treatment, poor prognosis • MFH and angiosarcoma may develop 2-50 years after introduction of foreign bodies (bullet, shrapnel, surgical implant) • Sarcomas after orthopedic prosthesis/hardward: osteosarcoma and MFH rarely occur after mean 11 years (2.5-33 yr), usually in bone, high grade, frequent metastases

PATHOGENESIS: SARCOMAS

•

ST TUMORS: INHERITED BASIS OR FAMILIAL DISTRIBUTION Cutaneous leiomyoma: occ familial suggesting
autosomal dominant (AD) Familial gastrointestinal stromal tumor: germlike mutation of c-kit Glomus: occ familial following autosomal dominant Osler-Weber-Rendu disease (hereditary hemorrhagic telangiectasia): autosomal dominant (AD) Blue rubber nevus syndrome (cavernous hemangiomas of skin and GIT): autosomal dominant

• • • •

•

ST TUMORS: INHERITED BASIS OR FAMILIAL DISTRIBUTION Palmar, plantar, penile fibromatosis: occ in sev
generations and in twins Mesenteric fibromatosis: freq assoc with familial polyposis coli and Gardner syndrome Lipoma: about 5% familial Multiple lipomas: inc familial incidence Angiolipoma: about 5% familial Angiomyolipoma: tuberous sclerosis complex in about one-third of pt Xanthoma tuberosum and tendinous xanthoma: familial hyperlipidemia

•
• • • •

•

• • Neurofibromatosis 2: AD; NF2 gene on chrom 22 • Bilateral (inherited) retinoblastoma: germline deletion of Rb1 locus on chromosome 13; assoc with secondary sarcomas • Neuroblastoma: rare familial cases • Paraganglioma: occ familial suggesting AD • Tumoral calcinosis: inc familial incidence; about 40% of siblings • Li-Fraumeni syndrome: germline deletion of p53 locus resulting in familial rhabdomyosarcoma, early onset breast carcinoma, and other neoplasms

ST TUMORS: INHERITED BASIS OR FAMILIAL DISTRIBUTION Neurofibromatosis 1: AD; NF1 gene on chrom 17

• • Caused by germline mutations in the TP53 tumor • TP53 on 17p13, codes for 53-kilodalton nuclear protein transcription factor important in regulatory control over cell cycle and in DNA repair processes with potential to induce apoptosis in cells with extensive DNA damage • Most LFS-associated defects involve missense point mutations in region of exons 5-8 (“hot spot”) leading to functionally defective protein • 50% LFS pts have developed malignant tumors by age 30 • >30%: soft tissue and bone sarcomas (OS, CS), also breast cancer, brain tumors, adrenal cortical carcinoma • Diagnosed by having a parent, first or second degree relative with a diagnosis of sarcoma <45 years

LI-FRAUMENI SYNDROME (LFS) Rare autosomal dominant disease

• Carney syndrome (complex): melanotic schwannoma, myxoma; also multiple lentigenes, endocrine overactivity; 2p16 • Gardner syndrome: desmoid (fibromatosis); also osteomas (jaw), multiple tubular adenomas (colon) (FAP) • Kasabach-Merritt: kaposiform hemangioendothelioma • Klippel-Trenaunay: hemangiomas • Maffucci: spindle cell hemangioendothelioma; also multiple enchondromas, 15% risk of chondrosarcoma • McCune-Albright: myxomas; also café au lait macules, polyostotic fibrous dysplasia, sexual precocity • Multiple endocrine neoplasia 1: multiple lipomas • Neurofibromatosis type 1: neurofibromas, MPNST • Osler-Weber-Rendu: telangiectasias • Sturge-Weber: port-wine spot (stain) of face • Turner: cystic hygroma; also amenorrhea, streak gonads

SOFT TISSUE LESIONS ASSOCIATED WITH SYNDROMES

CARNEY COMPLEX: MELANOTIC SCHWANNOMA

CARNEY COMPLEX: CARDIAC MYXOMA, OFTEN MULTIPLE

CARNEY COMPLEX: MULTIPLE LENTIGENES

GARDNER SYNDROME: >100 COLONIC TUBULAR ADENOMAS

GARDNER SYNDROME: TORUS MANDIBULARIS (L); TORUS PALATINUS (R) OSTEOMAS

GARDNER SYNDROME: ABDOMINAL DESMOID - FIBROMATOSIS

CELL TYPES
• Pleomorphic: MFH, leiomyosarcoma, liposarcoma, rhabdomyosarcoma • Spindle cell: leiomyosarcoma, fibrosarcoma, MPNST, synovial sarcoma • Small round cell: rhabdomyosarcoma, Ewing/PNET, desmoplastic small round cell tumor • Round cell: round cell liposarcoma • Epithelioid: leiomyosarcoma, epithelioid sarcoma, MPNST, synovial sarcoma

HISTOLOGY OF CELLS IN SOFT TISSUE(ST) TUMORS
Spindle cell Rodshaped Long axis 2X short axis Small 1-2X size of round cell lymph, hi N:C Epithelioid Polyhedral, much cyto, central nucleus Fibrous, FH, sm mus, Schwann RMS, EW/PNET Smooth mus, Schwann cell, Synovial sarc

• Spindle cell fascicles intersecting at right angles: smooth muscle: LMS • Storiform (short fascicles radiating from central point): fibrohistiocytic: BFH, DFSP, MFH • Palisading: Schwann cells (Verocay bodies) • Herringbone: fibrosarcoma • Biphasic: synovial sarcoma

ARCHITECTURAL PATTERNS

• Desmoid, fibrosarcoma, MFH: fibroblast-like cells with scattered bundles of actin filaments • Smooth muscle tumors, glomus tumor: cytoplasmic bundles of actin filaments, attachment plaques, basal lamina • Rhabdomyosarcoma: Ribosome myosin complexes, collections of thin and thick filaments, sarcomeres and Z-bands • Angiosarcoma: Weibel-Palade bodies • Schwannoma: spindle cells, complex interdigitating cell processes, prominent basal laminas • Perineurial cell tumors: Spindle cell with long cytoplasmic processes, prominent intermediate filaments, frequent pinocytotic vesicles, basal laminas

FREQUENT DISTINCTIVE EM FINDINGS IN ST TUMORS

Z- BAND

WEIBEL-PALADE BODY

• • Paraganglioma: dense core neurosecretory granules of variable size and morphology, typically abundant • Neuroendocrine carcinoma: membrane bound dense core granules of 100-400 nm diameter, typically abundant • Rhabdoid tumor: perinuclear spherical collections of cytoplasmic intermediate filaments displacing cytoplasmic organelles • Alveolar soft part sarcoma: cytoplasmic rhomboid crystals with 70 angstroms periodicity • Mesothelioma, differentiated: long, slender microvilli that are typically 15 times longer than their width • Dendritic reticulum cell sarcoma: desmosomes

FREQUENT DISTINCTIVE EM FINDINGS and premelanosomes IN ST TUMORS Melanoma: melanosomes

PREMELANOSOMES AND MELANOSOMES

NEUROSECRETORY GRANULE (ARROW)

DESMOSOME

• Reverse transcriptase (RT) – Polymerase chain reaction (PCR) • Testing of paraffin-embedded tissue for tumor fusion transcripts • Followed by DNA sequence analysis • Useful for malignant small blue round cell tumors, spindle cell tumors, and many sarcomas

MOLECULAR/CYTOGENETI CS

• Alveolar Rhabdomyosarcoma: t(2;13)(q35;q14) – PAX3FKHR fusion gene • Chondrosarcoma, myxoid, extraskeletal: t(9;22)(q22;q12) – CHN-EWS • Clear cell sarcoma: t(12;22)(q13;q12) – AFT1-EWS fusion gene • Congenital fibrosarcoma/mesoblastic nephroma: t(12;15)(p13;q25) – ETV6-NTRK3 • Dermatofibrosarcoma Protuberans/Giant Cell Fibroblastoma: t(17;22)(q21-22;q13) – collagen type 1 alpha 1 and platelet derived growth factor B chain gene; also supranumerary ring chromosomes derived from t(17;22)

MOLECULAR/CYTOGENETI CS

• Desmoplastic small round cell tumor: t(11;22)(p13;q12) – WT1-EWS • Ewing/Primitive Neuroectodermal Tumor, extraskeletal: t(11;22)(q24;q12) – EWS-FLI1 • Liposarcoma, myxoid/round cell: t(12;16)(q13;p11) – CHOP-TLS/FUS • Liposarcoma, well differentiated: marker ring and giant chromosomes derived from 12q13-15 • Synovial sarcoma: t(X;18)(p11.23;q11) – SYT-SSX1 and t(X;18)(p11.21;q11) – SYT-SSX2

MOLECULAR/CYTOGENETI CS

SOFT TISSUE TUMORS
• 46% LE esp thigh, 14% UE, 8% head and neck, 19% trunk, and 13% retroperitoneum • Sex: 1.4M:1F • Generally increased risk with age • 15% in children; 4th most common malig after brain tumors, heme, and Wilms’ tumor • RMS children, synovial sarcoma young adult, LPS and MFH in mid to late adult life

SELECTED AGE RANGES IN ST PATHOLOGY
Fibrosarc 0-10 0-25 Childhood RhabdoMS Childhood & adolescence Young adults Young adults Older adults Older adults

Synovial sarc 20-40 Clear cell Angiosarc MFH 20-40 50-80 40-80

•

BASIC ANTIGEN GROUPS (IHC) FOR SARCOMA IMMUNODIAGNOSIS Synovial sarcoma, epithelioid sarcoma: pan-

cytokeratin (CK) • Nerve sheath group: CD57, S-100, nerve growth factor (NGF) receptor • Muscle group: desmin, muscle actins, desmin, myogenic regulatory proteins (MYOD1), myogenin • Endothelial/vascular group: von Willebrand factor (vWF), CD34, CD31

• • CD34 (KS, some fibroblastic tumors) • von Willebrand factor: AS, hemangioendothelioma (especially epithelioid) • Ulex europaeus/BNH9: AS, many carcinomas • VEGFR-3: KS, many AS, hemangiomas • Podoplanin: KS, many AS • Thrombomodulin (CD141): Variable in AS, pos also in mesothelioma, Squamous CA

GUIDELINES FOR IHC IN ST TUMORS – ENDOTHELIAL MARKERS CD31: Angiosarcoma (AS), Kaposi Sarcoma (KS)

• • • • •

GUIDELINES FOR IHC MARKERS IN ST TUMORS – Actin: Common muscle: smooth and CELL MUSCLE skeletal muscle tumors, myofibroblastic tumors
Actin: Smooth muscle: smooth muscle and myofibroblastic tumors Actin: Sarcomeric: skeletal muscle and rhabdomyosarcoma Desmin: smooth and skeletal muscle tumors HCD (heavy caldesmon): smooth muscle and its tumors, myoepithelia, GI stromal tumors (GISTs) Calponin: smooth muscle, myofibroblasts, myoepithelia, often synovial sarcoma MyoD1, myogenin: rhabdomyosarcoma, reactive skeletal muscle Myoglobin: rhabdomyosarcoma (differentiated) Myosins: isoforms of smooth and skeletal muscle tumors

• • • •

•

• • •

GUIDELINES FOR IHC IN ST TUMORS – NEURAL AND NEUROENDOCRINE MARKERS Synaptophysin: neuroblastoma, paraganglioma, neuroendocrine CA Chromogranin: paraganglioma, neuroendocrine CA (esp low-grade) NSE: general neuroendocrine marker, low specificity NF proteins, alpha-Internexin: neuroblastoma, paraganglioma, Merkel cell carcinoma (CA)

• S100 protein: melanocytic, schwannian, chondroid, Langerhans cell • Nerve growth factor receptor p75: dermatofibrosarcoma protuberans, many other sarcomas, nerve sheath tumors • CD56 (NCAM): neuroendocrine CA, rhabdomyosarcoma, many other sarcomas • CD57: nerve sheath tumors, also synovial sarcoma, leiomyosarcoma, relatively nonspecific

GUIDELINES FOR IHC IN ST TUMORS – S100 PROTEIN AND OTHER MULTISPECIFIC NEURAL MARKERS

GUIDELINES FOR IHC IN ST TUMORS – MELANOMA MARKERS OTHER THAN S100 PROTEIN

• HMB45: melanoma, clear cell sarcoma, angiomyolipoma • Tyrosinase: nevi, melanoma • Melan A: nevi, melanoma, angiomyolipoma • Micro-ophthalmia transcription factor: melanoma, osteoclastic giant cells • CD63: melanoma, some carcinomas, alveolar soft part sarcoma

• Lysozyme: histiocytes, myelomonocytic cells • AAT (alpha-1-antitrypsin): histiocytes, many tumors of any lineage • AACT (alpha-1-antichymotrypsin): histiocytes, many tumors of any lineage • Factor XIIIa: histiocytes, especially dendritic ones • CD68: histiocytes, any lysosome-rich cells of any derivation, melanoma, paraganglioma, schwannoma, granular cell tumor • CD163: histiocytes, seems highly specific but experience limited

GUIDELINES FOR IHC STAINS IN ST TUMORS - HISTIOCYTIC

•

EPITHELIAL AND MESOTHELIAL CELL Keratins: carcinomas (CAs), SS, epithelioid sarcoma, MARKERS

•
• •

• • •

chordoma EMA: epithelial tumors, perineurial tumors, SS, epithelioid sarc B72.3: many adenoCAs, epithelioid angiosarcoma BerEp4: many adenocarcinomas, biphasic synovial sarcoma Calretinin: mesothelioma, some carcinomas (focal), often SS CEA: many adenoCAs, biphasic synovial sarcoma Desmoplakins: epithelial tumors, meningioma, Ewing sarcoma

•

EPITHELIAL AND MESOTHELIAL CELL HBME-1: mesothelioma, some adenoCAs, SS, MARKERS

•
• • • •

chordoma, chondrosarcoma Mesothelin: mesothelioma, ovarian serous CA, biphasic SS MOC31: most adenoCAs, rare mesotheliomas TTF-1: CAs of thyroid & pulmonary (adeno, small cell) Villin: GI and renal CAs, some carcinoids WT protein: small round cell desmoplastic tumor, mesothelioma, ovarian serous CA

IHC – SPECIFIC TUMOR TYPES
• ALK: large cell anaplastic lymphoma (systemic type), inflammatory myofibroblastic tumor, Schwann cell tumors, AS • BCL-2: many, synovial sarcoma • CD10: endometrial stromal sarcoma, renal cell CA • CD99: Ewing sarcoma/PNET, SS, lymphoblastic lymphoma • CD117: GIST, mast cell neoplasms, AS, Ewing sarcoma, neuroblastoma, seminoma/dysgerminoma, some melanomas and clear cell sarcomas, adenoid cystic CA, myeloid sarcoma

IHC – SPECIFIC TUMOR TYPES
• ER/PR: CA of breast, endometrium, some ovarian, most uterine & retroperitoneal leiomyomas(women),aggressive angiomyxoma • GFAP: glial tumors, schwannomas, myoepithelial tumors • Inhibin: granulosa cell tumor, adrenal cortical carcinoma • Osteocalcin: osteosarcoma, osteoid material • Vimentin: widespread in mesenchymal tumors, some poorly differenitated carcinomas, melanoma, renal cell CA

CD117 POSITIVE “NON-GISTS”
• Small cell carcinoma • Many ovarian carcinomas, some colon carcinomas • Malignant melanoma – uniform strong CD117 positivity typical of a GIST: 20-45% • Clear cell sarcomas • Angiosarcoma (50%) • Ewing sarcoma/PNET • Angiomyolipoma (PEComa) (myomelanocytic tumor) • Myeloid leukemia • Mast cell tumors, mastocytoma, urticaria pigmentosa • Non-neoplastic processes: Reactive myofibroblast (fibromatosis)

CD34 POSITIVE TUMORS
• • • • • • • • Dermatofibrosarcoma protuberans Solitary fibrous tumor Hemangiopericytoma Kaposi sarcoma GISTs (70%) Angiosarcoma (50%) Epithelioid sarcoma (50%) Neurofibroma (a CD34+ component)

MAJOR PROGNOSTIC FACTORS
• • • • • • • Size Depth of invasion Histologic type Margins Grade Clinical stage Other ploidy, proliferation oncogenes: important but not independent variables

• Differentiation: how much neoplastic cells resemble cell of origin – 1 = similar, 2 = moderate, 3 = markedly pleomorphic and not resembling cell of origin • Mitotic activity: 1 = 1-9/10 HPF, 2 = 10-19/10 HPF, 3 = greater than or equal to 20/10 HPF • Tumor necrosis: 0 = none, 1 = less than 50% of tumor, 2 = more than 50% of tumor • Add three numbers: Grade 1 = 2-3, Grade 2 = 4-5, Grade 3 = 6-8

GRADING: COINDRE, FRENCH FEDERATION: 3-TIERED

• • • • •

HISTOLOGIC GRADE – FRENCH FEDERATION OF CANCER CENTERS Sum of the preceding 3 scores Grade 1: 2 or 3 Grade 2: 4 or 5 Grade 3: 6, 7, or 8 This grading system calculates the overall grade based on total points from tumor differentiation, mitotic rate, and tumor necrosis

SUMMARY OF CURRENT TNM OR AJCC STAGING SYSTEM FOR SOFT TISSUE SARCOMAS

• • • • • • •

IA: Low grade; T1a or T1b; N0; M0 IB: Low grade; T2a or T2b; N0; M0 IIA: High grade; T1a or T1b; N0; M0 IIB: High grade; T2a; N0; M0 III: High grade; T2b; N0; M0 IV: Any grade; T1 or T2; N1; M0 IV: Any grade; T1 or T2; N0 or N1; M1

TNM AJCC STAGING SYSTEM FOR ST SARCOMAS EXPLANATION OF ABBREVIATIONS • Grade = G: In a two-tier system, intermediate grade is merged with high grade • Primary Tumor = T: T1 = or < 5 cm T2 > 5 cm • Tumors of each T group are subclassified based on depth or anatomic location or both: a = Superficial tumors of the trunk and extremities not invading superficial fascia b = Deep tumors invading, permeating, or located below superficial fascia, or tumors in intra-abdominal, retroperitoneal, and intrathoracic location

• Accurate histologic classification may req IHC, EM, cytogenetics, molecular genetics • Grade: 1 to 3 based on differentiation: number of mitotic figures and extent of necrosis most important; also pleomorphism, cellularity, size, depth • Histologic type and subtype used to shortcut grade • High grade: alveolar rhabomyosarcoma, neuroblastoma, Ewing’s sarcoma/PNET family, and alveolar soft part sarcoma • Staging • Superficial better than deep location • Overall 5-yr survival for ST sarcoma in limbs: 65-75%

PROGNOSTIC FEATURES IN SOFT TISSUE TUMORS

5-YEAR DISEASE-FREE SURVIVAL GRADE 2-3 SURGERY RADIATION • • • • • • • <2.5 cm: 17 pt, 94% 2.6-4.9 cm: 48 pt, 77% 5.0-10.0 cm: 55 pt, 62% 10.1-15.0 cm: 24 pt, 51% 15.1-20.0 cm: 9 pt, 42% >20.0 cm: 6 pt, 17% Total, 159 pt, 65%

• Benign • Intermediate/Low malignant potential Predominantly fibroblastic and vascular - Benign but locally aggressive, for example, fibromatosis - Extremely rare metastatic potential, for example, angiomatoid (malignant) fibrous histiocytoma • Malignant

CATEGORIES: SOFT TISSUE TUMORS

THERAPY
• Enucleation acceptable for schwannomas; for other small tumors, must excise with rim of normal tissue • Wide local excision for infiltrative lesions (desmoid/fibromatosis, DFSP) • Sarcomas: minimum negative margin: 3 cm • Children/adults: radiation and chemotherapy may also be used • Surgical resection of pulmonary metastases often has value especially if solitary

PROGNOSIS/TREATMENT: ST TUMORS
• Benign neoplastic: may recur, treatment is complete excision • “Intermediate” category or low grade malignant potential (Grade 1/3): may recur or rarely metastasize, treatment is complete local, preferably wide excision, and careful patient follow-up • Intermediate or high grade sarcoma (Grade 2/3 or 3/3): may recur or metastasize, complete excision with adjuvant pre- and post-operative radiation, chemotherapy for large tumors (> 8 cm) or positive tumor margins and/or inability to completely resect

OVERVIEW OF SOFT TISSUE PHENOTYPES
• • • • • • • Fibroblastic Lipomatous Vascular Nerve sheath/Peripheral nerve Skeletal muscle Smooth muscle Uncertain phenotype

• Nodular fasciitis • Proliferative fasciitis • Fibrous histiocytoma (cellular)/ dermatofibroma/sclerosing hemangioma • Fibromatosis • Dermatofibrosarcoma protuberans (DFSP)/Fibrosarcoma • Malignant fibrous histiocytoma (MFH)

FIBROBLASTIC LESIONS/TUMORS

REACTIVE PSEUDOSARCOMATOUS NONNEOPLASTIC • Non-neoplastic proliferations • Develop in reaction to local trauma (physical or ischemic) or idiopathic • Clinically alarming due to sudden rapid growth • Histologically mimic sarcomas due to look primitive, hypercellularity, mitotic activity • Rep by nodular fasciitis,myositis ossificans

NODULAR FASCIITIS
• • • • • • Pseudosarcomatous fasciitis Reactive myofibroblastic proliferation Most common of reactive “pseudosarcomas” Relatively short several week history Solitary Rapidly growing, sometimes painful usually subcutaneous mass • History of trauma in almost all patients • Misdiagnosed rate: 57% • In AFIP series of 53 cases – 21% diagnosed as sarcoma

• Arise in subcutaneous, fascia, or skeletal muscle, rarely dermal • Gross: several cm, nodular, poorly circumscribed with illdefined margins • Very cellular proliferation of plump-immature fibroblasts arranged randomly:tissue culture • Spindle to stellate shaped fibroblasts with large nucleoli and many mitoses • Myxoid stroma with lymphocytes and extravasated RBCs • Granulation tissue type variant resembles biopsy scar

HISTOLOGY: NODULAR FASCIITIS

HISTOLOGY: NODULAR FASCIITIS
• May observe dense collagen in clumps • Myxoid degeneration, often centrally located – most important feature in diagnosis • Extravasated RBCs also common • Older nodular fasciitis – often associated with fibrosis/sclerosis

NODULAR FASCIITIS VARIANT
• • • • Cranial fasciitis Observed in < 2 year olds Associated with skull Erodes outer table of bone of skull

NODULAR FASCIITIS WELL CIRCUMSCRIBED

NODULAR FASCIITIS SPINDLE CELL PROLIFERATION

NODULAR FASCIITIS CENTRAL MYXOID TISSUE CULTURE-LIKE

CLINICAL FEATURES: NODULAR FASCIITIS
• Age: Children and young adults – most common in ages 15-40 years • Gender: Male (M) = Female (F) • Size: Mean 2.3 cm with range 0.6-10 cm • Location:
– Adults: volar forearm or any superficial location – Children: head and neck

PROGNOSIS: NODULAR FASCIITIS
• • • • Usually benign Self-limited Occasional spontaneous regression Rare local recurrence

PROLIFERATIVE FASCIITIS
• • • • • • • Reactive myofibroblastic proliferation Occur in slightly older patients Often shoulder area Usually subcutaneous location Poorly circumscribed Less common than nodular fasciitis Rare history of trauma

HISTOLOGY: PROLIFERATIVE FASCIITIS
• Proliferating fibroblasts are large and round with a polygonal appearance • Often have a rim of eosinophilic cytoplasm • Have vesicular chromatin and prominent nucleoli • Proliferating cells resemble ganglion cells • Myofibroblastic ganglion-like cells in sheets found in childhood cases – desmin negative

PROLIFERATIVE FASCIITIS

PROLIFERATIVE FASCIITIS GANGLION-LIKE CELLS

CLINICAL FEATURES: PROLIFERATIVE FASCIITIS
• Age:
– Adults (40-70 years) – Rare in childhood

• Gender: F = M • Size: Median 2.5 cm (usually < 5 cm) • Location: Upper extremity > Lower extremity > Trunk > Head and Neck

MYOSITIS OSSIFICANS
• • • • Only one with metaplastic bone Found in athletic adolescents &young adults Follows episode of trauma in 50% Location: subcutaneous tissue & muscles proximal limbs • Early phase: lesion is swollen and painful • Wks later: circumscribed and firm • Late: painless, hard, well-demarcated mass

• Gross: 3-6 cm, well-delineated, center soft & glistening, and gritty firm periphery • Earliest: cellular resembles nodular fasciitis • Morphologic zonation begins within 3 wks: central fibroblast prolif, adjacent osteoblasts & woven bone, peripheral cancellous bone • Late: intertrabecular spaces filled with BM; mature lesion completely ossified

HISTOLOGY OF MYOSITIS OSSIFICANS

MYOSITIS OSSIFICANS ZONATION & ORGANIZATION

MYOSITIS OSSIFICANS MATURE BONE AT PERIPHERY

• X-ray: follow histologic progression with ST density initially; at 3 wk patchy flocculent radiodensities in periphery • Densities encroach on radiolucent center • Ddx with osteosarcoma (OS): cytologic atypia, no zonation, peripheral spread of OS most cellular • Usually curative: simple excision

CLINICAL: MYOSITIS OSSIFICANS

FIBROUS HISTIOCYTOMA
• Synonyms: dermatofibroma=sclerosing hemangioma; on extremities in mid-adult • Relatively common: dermis and subcutis • Painless, slow growing, firm, tan, small (up to 1 cm) mobile papule or nodule • Storiform (pin-wheel) pattern • Treatment: simple excision, may recur if incompletely excised; CD34-,CD68+(histio)

• Epidermal hyperplasia overlying the tumor • Infiltrative margins • Tendency of bland spindle cells(fibroblasts) to surround individual collagen bundles • Frequent storiform (pinwheel) pattern • Variant with vascular proliferation & hemosiderin depositis (sclerosing hemangioma) • Variable number of histiocytes (some foamy)

HISTOLOGY: FIBROUS HISTIOCYTOMA

HISTOLOGY: FIBROUS HISTIOCYTOMA
• Storiform to short fascicular growth pattern • Pushing border at deep margin • May have stellate lateral edges with collagen trapping – encirclement of collagen fibers by tumor • Production of collagen • Multinucleated giant cells • Perivascular lymphocytes

HISTOLOGY: FIBROUS HISTIOCYTOMA
• • • • Plasma cells at periphery 23% hemorrhage (cellular) Hemosiderin-laden macrophages 12% central necrosis, involving 20-50% of tumor (cellular) • Mitoses up to 10/10 HPF (cellular) • Heterogeneous population

FIBROUS HISTIOCYTOMA OVERLYING EPIDERMAL HYPERPLASIA

FIBROUS HISTIOCYTOMA (FH): STORIFORM (PINWHEEL) PATTERN

FH/SCLEROSING HEMANGIOMA HISTIOCYTIC (FOAM CELL) PROLIF

CLINICAL FEATURES: FIBROUS HISTIOCYTOMA
• • • • • • • Cutaneous or Cellular (5%) Solitary Slow growing Age: Young or middle aged adults Gender: Male predominance Size: < 1 cm up to 5 cm or more Location: Extremities most common

PROGNOSIS: FIBROUS HISTIOCYTOMA
• Cutaneous: 1% recurrence rate • Cellular if deep & subcutaneous: up to 26% local recurrence rate • Cellular placed in “intermediate” category even though benign • Local recurrence more likely after incomplete excision

FIBROMATOSIS
• • • • Fibroblastic proliferation Recapitulates scar Clonal origin May be multicentric especially if part of Gardner syndrome – nuchal fibromas, epidermal cysts, adenomatous polyps (FAP), osteomas (torus) jaw

TYPES: FIBROMATOSIS
• Superficial Fibromatoses: Dupuytrens contracture – palmar or plantar • Deep Fibromatosis (Desmoid), musculoaponeurotic:
– Extraabdominal – Abdominal: rectus abdominis, peripartum – Intraabdominal

• Palmar, plantar, and penile fibromatoses • Nodular or poorly defined fascicles of mature fibroblasts surrounded by dense collagen • IHC & EM: proliferating cell myofibroblast • Nonrandom karyotypic abnormalities: trisomy 3 and trisomy 8 unclear significance • True fibroma: rare: tendon sheath • Superficial type: more fibrous than deep

SUPERFICIAL FIBROMATOSIS

PALMAR FIBROMATOSIS: DUPUYTREN CONTRACTURE
• • • • Irregular nodular thickening palmar fascia Unilateral or bilateral (50%) Puckering & dimpling due to skin attachment Slowly progressive flexion contracture of fourth and fifth fingers • Plantar: similar except uncommon flexion contracture and infrequent bilateral involvement

• Palpable induration involving corpora cavernosa dorsolateral penis • May eventually cause abnormal curvature of the shaft • May lead to urethral constriction • May cause erectile dysfunction

PENILE FIBROMATOSIS: PEYRONIE DISEASE

DEEP-SEATED FIBROMATOSIS (DESMOID)
• • • • Large, infiltrative mass recurs after excision Bland, mature fibroblasts don’t metastasize Most frequent: teens to thirties Extra-abdominal (abd) :M=F, musculature of shoulder, chest wall, back, and thigh • Ant abd wall: F during or after pregnancy • Intra-abd: mesentery, pelvic wall, can obst splenic artery, FAP (Gardner syndrome)

• Gross: unicentric, firm, gray-white, 1-15 cm, rubbery, tough, infiltrative margins • Central: dense collagen (oldest part) • Peripheral: uniform plump fibroblasts • Mitoses usually infrequent but may be increased, but no atypical mitotic figures • Common elongated vessels • Purposeful parallel arrangement of myofibroblasts • Trapped regenerating muscle cells resemble multinucleated giant cells

HISTOLOGY: DEEP FIBROMATOSIS (DESMOID)

GROSS: DESMOID: FIRM WHITE INFILTRATIVE BORDERS

HISTOLOGY: DESMOID: BLAND FIBROBLASTIC PROLIFERATION

• Age: Second and Third Decades • Gender: Equal M = F (except abdominal type in pregnant females) • Size: Up to 45 cm • Location
– Intraabdominal: small bowel mesentery, 13% have associated Gardner’s – Extraabdominal: shoulder, chest wall, back, extremities, more often trunkal

CLINICAL FEATURES: DEEP FIBROMATOSIS

CLINICAL: DESMOID TUMORS
• Painful, disfiguring, disabling • May be curable with adequate excision • Frequent local repeated recurrence when incompletely excised • Treatment: tamoxifen, chemotherapy, or radiation

• 40-60% local recurrence • Sporadic spontaneous regression (rare) • Recurrence rate increases with each recurrence (deep) • Radiation/Chemotherapy for select cases (deep) • Does not metastasize • May cause death of patient when wraps around vital organs or major arteries

PROGNOSIS: DEEP FIBROMATOSIS

• • • • • •

DERMATOFIBROSARCOMA PROTUBERANS (DFSP)

Low grade fibrohistiocytic tumor Well-differentiated primary sarcoma of skin Slow growing, locally aggressive Dermis, subcutaneous tissue Solitary Firm, solid, protuberant nodules within an indurated plaque on the trunk, may ulcerate • Frequent local recurrence due to deep extension/infiltration into subcutaneous fat • Childhood DFSP = Giant cell fibroblastoma, a benign lesion, shares genetic marker

GROSS: DFSP: PROMINENT NODULES WHICH MAY ULCERATE

HISTOLOGY: DFSP
• • • • • • Cellular with prominent storiform pattern Often uniform bland histology – monomorphous Overlying dermis thinned without epidermis involved No DFSP present in the papillary dermis; this zone clear of tumor is called Grenz zone Few or no histiocytes vs. many in FH Often extension from deep dermis into subcutaneous fat with common honeycomb infiltration pattern, Swiss cheese-like effect Pigmented DFSP (melanin pigment): called Bednar tumor: has no clinical significance Myxoid variant DFSP

• •

DFSP GRENZ ZONE: ZONE CLEAR OF TUMOR IN PAPILLARY DERMIS BELOW EPIDERMIS

DFSP GRENZ ZONE: CLEAR ZONE BELOW EPIDERMIS

DFSP STORIFORM OR PINWHEEL PATTERN

DFSP: DEEP INFILTRATION INTO SUBCUTANEOUS FAT WITH HONEYCOMB APPEARANCE

IHC AND GENETICS: DFSP
• IHC: strong diffuse CD34 positive staining, S100 protein negative • t(17;22)(q21-22;q13) – collagen type 1 alpha 1 and platelet derived growth factor B chain gene • Also supranumerary ring chromosomes derived from t(17;22) • Identical cytogenetic findings in childhood giant cell fibroblastoma

DFSP WITH FIBROSARCOMATOUS TRANSFORMATION (FS)
• • • • • Identified in the original specimen Deep to the DFSP component Loss of entrapped fat Increased cellularity Fascicular growth pattern – herringbone with intersecting fascicles at 45 degrees • Increased mitoses • IHC: Decrease or absence of CD34 staining

• Age

CLINICAL FEATURES: DFSP AND DFSP-FS

– DFSP: Early to mid adulthood, range 27-40 years – DFSP-FS: mean 45 years, range 15-66 years

• Gender: Male predominance • Size:
– DFSP: Mean 5 cm – DFSP-FS: Slightly larger

• Location: Trunk, proximal extremities

• DFSP: Locally aggressive

PROGNOSIS: DFSP AND DFSPFS
– Recurrence: 4.7-49% – Metastasis: 5.7% after repeated recurrences, to regional lymph nodes, lung

• DFSP-FS: Worse prognosis, in most series
– Recurrence: 42-89%, shorter intervals – Metastasis: 13.7-33%

• • Painless nodule in subcutaneous tissue or dermis • Characteristic feature: pseudovascular/pseudoangiectoid spaces lined by discontinuous row of multinucleated giant cells • Loosely arranged wavy spindle cells with some showing moderate nuclear pleomorphism with nuclear hyperchromasia • Vary in cellularity from those resembling DFSP to hypocellular with myxoid or hyaline stroma • May show deep infiltration into SQ like DFSP • Positive IHC: CD34, vimentin

GIANT CELL FIBROBLASTOMA adults Age: Mainly infants & children, infrequently in

GIANT CELL FIBROBLASTOMA

GIANT CELL FIBROBLASTOMA

GIANT CELL FIBROBLASTOMA

GIANT CELL FIBROBLASTOMA

• Unknown etiology • Histologically identical to classic fibrosarcoma of adults, but has a much more favorable prognosis • 13% of fibroblastic-myofibroblastic tumors in children & adolescents • 12% of ST malignancies in infants • 36% to 80% are congenital; 36% to 100% occur in 1st yr of life • Seldom found after 2 years of age

INFANTILE (CONGENITAL) FIBROSARCOMA

• Sites: superficial and deep ST of extremities, especially distally, accounting for 61% of cases, trunk (19%), neck (16%) • Presents as solitary, enlarging, nontender mass or swelling in ST with rapid growth, diameter exceeding 30 cm, with congenital cases grotesquely large in proportion to size of child • Overlying skin is tense, erythematous, ulcerated; imaging may reveal bony erosion

INFANTILE (CONGENITAL) FIBROSARCOMA

HISTOPATHOLOGY: INFANTILE FIBROSARCOMA (IFS)
• Gross: poorly circumscribed, lobulated mass infiltrating adjacent soft tissue with irregular & infiltrating margins • Cut surface: soft to firm, fleshy, gray-tan with variable myxoid or mucinous change, cystic degeneration, yellow-red discoloration • Densely cellular primitive ovoid or spindle cells composed of interlacing fascicles intersecting at 45 degree angle (herringbone pattern) or forming cords, sinuous bands or sheets

HISTOPATHOLOGY: INFANTILE FIBROSARCOMA (IFS)
• Frequent zonal necrosis and hemorrhage associated with dystrophic calcification • Prominent mitotic activity • Scattered chronic inflammatory cells and focal extramedullary hematopoiesis • IHC stains: vimentin positive (100%); otherwise heterogeneous for NSE (35%), alpha-SMA (33%), HHF35 actin (29%), MSA (30%)

INFANTILE FIBROSARCOMA: GROSS (L); OVOID CELLS SIMILAR TO HEMANGIOPERICYTOMA (R)

• Genetics: most contain t(12;15)(p13;q26) with ETV6/NTRK3 genomic fusion leading to oncogenic activation of NTRK3 (TRKC) receptor tyrosine kinase gene • Genetic profile similar to cellular congenital mesoblastic nephroma • Prognosis: IFS favorable outcome when compared with adult FS • Mortality rate: 4% to 25% • Recurrence rate of IFS: 5% to 50%

GENETIC AND PROGNOSTIC FACTORS: INFANTILE FS

• Metastasis rare in more recent series • Hemorrhage and involvement of vital structures by locally aggressive tumors may cause death • Spontaneous regression and nonrecurrence of incompletely excised IFS reported • Although surgery mainstay of therapy, chemotherapy has proven effective • Has natural history similar to that of fibromatoses

GENETIC AND PROGNOSTIC FACTORS: INFANTILE FS

FIBROSARCOMA (FS)
• Some experts only recognize as FS transformation of DFSP or observed in dedifferentiated liposarcoma or dedifferentiated chondrosarcoma • Rare: most common locations: retroperitoneum, thigh, knee, and distal extremities • Gross: soft, fish-flesh, unencapsulated, infiltrative with hemorrhage and necrosis • Histology:cellular spindle cells, herringbone pattern, +/pleomorphism, mitoses, necrosis • Aggressive tumors: 50% recur; 25% metastasize

HISTOLOGY: FIBROSARCOMA: HERRINGBONE PATTERN

MALIGNANT FIBROUS HISTIOCYTOMA (MFH)
• • • • AKA pleomorphic sarcoma Heterogeneous group aggressive ST tumors Cell of origin uncertain but not histiocyte Location: musculature of proximal limbs and retroperitoneum • Cutaneous variant: atypical fibroxanthoma • 30-50% metastasis except cutaneous form and angiomatoid form • Angiomatoid: indolent, teens & young adults

MALIGNANT FIBROUS HISTIOCYTOMA (MFH): SUBTYPES
• Storiform Pleomorphic: most common type, high grade • Myxofibrosarcoma (Myxoid MFH): grade 1 or 2/3, less cellular, less mitoses, less necrosis • Giant Cell Rich: Nodular, Benign osteoclastic type giant cells • Inflammatory: Only in retroperitoneum, sheets of neutrophils and/or xanthoma cells • Angiomatoid – separate from others now

STORIFORMPLEOMORPHIC MFH

STORIFORM-PLEOMORPHIC MFH MALIGNANT TUMOR GIANT CELL

STORIFORM-PLEOMORPHIC MFH: ATYPICAL MITOSIS

MYXOID MFH THICKER WALLED HAPHAZARD VESSELS VS. DELICATE PLEXIFORM IN MYXOID LPS

INFLAMMATORY MFH: SHEETS OF NEUTROPHILS AND HISTIOCYTES

PROGNOSIS FOR INTERMEDIATE AND HIGH GRADE MFH • Recurrence: 19-66%
• Metastasis: 31-50% to lung > bone > liver • Lower rates with current efficacious therapy – chemotherapy and radiation

• Age: Children and young adults – mean age 20 years, in AFIP series of 158 cases) • AFIP puts in intermediate category (low malignant potential) • Gender: Almost equal distribution • Size: Median 2.0 cm • Location:
– Extremities > Trunk > Head and Neck – 66% in areas of normal lymph nodes – epitrochlear, neck (cervical), inguinal

ANGIOMATOID (MALIGNANT) FIBROUS HISTIOCYTOMA

ANGIOMATOID MFH CHILDREN BETTER PROGNOSIS: NOW CONSIDERED BENIGN LESION

• IHC: 50% desmin positive • If round cell tumor morphology, IHC 75% CD99 positive • Prognosis: • Recurrence: 2%
– Metastasis: 1% to local lymph node, may rarely have metastasis to lung – Even with “metastasis” to lymph node, patients tend to do well

IHC AND PROGNOSIS: ANGIOMATOID (MALIGNANT) FIBROUS HISTIOCYTOMA


				
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