Soft Tissue Pathology

KULIAH PPDS BEDAH-2006Nurjati Siregar

OBJECTIVESTo know classification of soft tissue tumorTo know the biological behaviour of soft tissue tumor (benign vs malignant)To know characteristic features of benign and malignant soft tissue tumors (size, location, age, gender)To know the limitation of biopsy (FNA, core, incision) in diagnosisTo know how to fill pathology request form

Soft TissueFibrous tissueAdipose tissueSynovial tissueSkeletal muscleBlood vesselsPeripheral nerves

Soft tissue tumorMajority are benignHigh cure rate after surgical excisionMalignant < 1%> 50 STS histological typesUnique clinical, prognostic and therapeutic featuresClose interaction pathologist-surgeon-radiologist-oncologist --- 5 y survival rate: 65-75% of STS in limbs

EPIDEMIOLOGYBenign > 100 X malignant/sarcomaBenign: 3000 in 1.000.000Malignant: 30 in 1.000.000Benign STT33% lipomas, 33% fibrohistiocytic tumor10% vascular tumor5% nerve sheet

Relation between type of tumor-symptom-location-age-gender.Lipoma: painless, rare in hand, very uncommon in children

Soft tissue sarcomas (STS) (1)Occurs anywhere: 75% in extremities (most common in thigh)10% in trunk wall and retroperitoneumMale predominance (slightly)More common in elderly (median age 65 y)

In extremity and trunk-wall: 1/3 superficial, diameter 5 cm2/3 deep seated with diameter 9 cmRetroperitoneal:Much larger10% have detectable metastasis (lung)33% because of metast in lungSoft tissue sarcomas (STS) (2)

75% classified as MFH-like sarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma and MPNST75% of those are in grade 2 and 3Children: embryonal rhabdomyosarcomaYoung adult: synovial sarcomaElderly: pleomorphic HG sarcoma, liposarcoma and leiomyosarcomaSoft tissue sarcomas (STS)(3)

ETIOLOGYUnknownGeneticEnvironmental factorsIrradiation Viral infectionsImmune deficiency Chemical carcinogenesis: phenoxyacetic herbicides, chlorophenols, dioxin

Tumors and Tumor-Like Conditions of Fibrous TissueBenignNodular FasciitisPalmar fibromatosisAbdominal fibromatosis (desmoid tumor) MalignantFibrosarcoma

Tumor differentiationScore 1.Sarcoma closely resembling normal adult mesenchymal tissue (e.g. low grade leiomyosarcoma)Score 2.Sarcoma for which histological typing is certain (e.g. myxoid liposarcoma)Score 3.Embryonal and undifferentiated sarcomas of doubtful type, synovial sarcoma, osteosarcomas, PNET

Mitotic countScore 1: 0-9 mitoses/10 HPFScore 2: 10-19 mitoses/ 10 HPFScore 3: 20 mitoses/ 10HPF.Tumor necrosisScore 0: no necrosisScore 1: < 50% tumor necrosisScore 2: 50% tumor necrosis

Histological gradeGrade 1: total score 2,3Grade 2: total score 4,5Grade 3: total score 6,7,8

FNLCC (French Federation Nationale des Centres de Lutte Contre le CancerNCI (United States National Cancer Institute)

GradingShould be used only for untreated primary STSShould be performed on representative and well processed material.Not a substitute for a histologic diagnosis and does not differentiate benign and malignant lesionNot applicable to all STS (e.g MPNST, angiosarcoma, extraskeletal myxoid chondrosarcoma, alveolar soft part sarcoma, clear cell sarcoma and epithelioid sarcoma)

StagingBased on both histological and clinical information (UICC) and AJCCAppears to be clinically useful and of prognostic valueTNM incorporates histological grade, tumor size and depth, regional lymph node involvement and distant metastasis.

TherapyHistological diagnosis establishedMultidisciplinary team to to design most effective treatment planAdjuvant and neoadjuvant chemotherapyMultimodal protocols

5 years survival rate

Nodular FasciitisSelf-limiting pseudosarcomatous process composed of fibroblasts and myofibroblastsMost common lesion misdiagnosed as sarcomaRapidly growing, richly cellular with mitosesRelated to trauma?

Nodular FasciitisSigns/Symptoms:Rapidly growing solitary mass lesion over 1-2 weeks often at site of previous trauma50% of lesions are painfulNumbness or paresthesia if compression of peripheral nerveAge:Young adults (20-40 years)Sex:M = F

Nodular FasciitisAnatomic Distribution:May occur anywhere in the body, though predilection for upper extremities (volar surface of forearm), chest wall, back, head & neck and lower extremitiesHands and feet uncommonHead & neck most common in children and infants

Nodular FasciitisGross Findings:Well-circumscribed, non-encapsulatedMost lesions small (< 2.0 cm); lesions up to 10.5 cm have been describedDivided into subcutaneous, intramuscular and fascial subtypes

Nodular FasciitisMicroscopic Findings:Proliferating fibroblasts and myofibroblasts in short irregular bundlesReticulin stromal fibrosisMitotic activityCellular and myxoid areasLipid-filled macrophages and giant cells

Nodular FasciitisAncillary Testing:IHCActin positiveCytokeratin and S100 negativePrognosis/Treatment:Benign processSurgical excision curative

Palmar Fibromatosis (Dupuytrens Contracture)Benign fibrous tissue proliferationMore common in Northern Europeans; rare in BlacksGenetic component?Association with unrelated diseases and social behaviors:Types I and II DMEpilepsyAlcoholismHypercholesterolemiaCigarette smokingManual labor

Palmar FibromatosisSigns/Symptoms:Slow growing nodule of hand progression to cord-like band with contracture of 4th or 5th digitAge:Older adults (20% over 65 years); rare in childrenSex:M >>> FAnatomic Distribution:Palmar surface of hand (R > L)50% of cases bilateral

Plump immature fibroblasts with uniform appearance and no mitotic activity

Plump immature fibroblasts with uniform appearance and no mitotic activity

Palmar FibromatosisAncillary Testing:N/ATreatment:Surgical excisionRecurrence is high unless dermis and fascia are removed

Abdominal Fibromatosis (Abdominal Desmoid Tumor)Locally more aggressive than superficial fibromatosesHigh recurrence ratePrevious traumaCommon in patients with Gardners syndromeAutosomal dominantColonic polyposisFundic gland polypsSoft tissue and bone tumorsEstrogen?

Abdominal FibromatosisSigns/Symptoms:Deep-seated, poorly-circumscribed firm mass in abdominal wallLittle to no painAge:Young adults (20-30 years)Sex:F >>>>>>> MGravid or parous femalesAnatomic Distribution:Muscles and fascia of rectus abdominus and internal oblique

Abdominal FibromatosisGross Findings:Poorly-circumscribed tumorsOff-white and firm3-10 cm in diameterMicroscopic Findings:Proliferating spindle cells in bundles surrounded by collagenLimited mitoses

Abdominal FibromatosisAncillary Testing:N/A

Prognosis/Treatment:Surgical excisionRecurrence rate 15-30%Local radiation

FibrosarcomaMalignant mesenchymal tumorVariety of microscopic appearancesTumors arise from intramuscular and intermuscular fibrous tissue, fascia, aponeuroses or tendons

FibrosarcomaSigns/Symptoms:Solitary palpable mass (3.0 to 8.0 cm)Slow-growing1/3 of cases present with painAge:Adult-type30-55 yearsInfantile typeFirst 2 years of lifeCongenitalSex:M > F

FibrosarcomaAnatomic Distribution:Adult-typeDeep soft tissues of lower extremitiesUpper extremities; head & neckRare organ involvement (heart, lung, liver, CNS)Infantile-typeDistal extremitiesGross Findings:Solitary, lobulated, circumscribed and frequently encapsulatedMay invade adjacent structures

Cellular tumors comprised of fusiform spindle cells

Prominent mitotic activity; little pleomorphism; anaplastic tumor cells or giant cells are not seen

FibrosarcomaAncillary Testing:IHCVimentin positiveCytokeratin and S100 negativeActin variablePrognosis/Treatment:Local recurrence rate 50%Metastasis via bloodstream to lung and bone5-year survivalAdult-type: 80% for grade 1; 21% for grade 4Infantile-type: > 80%Wide surgical excision, RT, chemo

Tumors and Tumor-Like Conditions of Fibrohistiocytic OriginBenign:Benign Fibrous Histiocytoma (Dermatofibroma) Intermediate:Dermatofibrosarcoma Protuberans (DFSP) Malignant:Malignant Fibrous Histiocytoma (MFH)

Benign Fibrous HistiocytomaSigns/Symptoms:Solitary slow-growing nodule of skinOften elevated or pedunculated1/3 of cases multipleAge:Young adults to mid-adulthood (20-45 years)Sex:M = FAnatomic Distribution:Most common on distal extremities

Small red-brown to blue nodules

Poorly-circumscribed, non-encapsulated, cellular proliferation in dermis; fibroblastic cells arranged in storiform pattern; numerous foreign body (Touton) giant cells; Mitoses rare to absent

Benign Fibrous HistiocytomaAncillary Testing:N/APrognosis/Treatment:Simple surgical excision< 5% recurrence

Dermatofibrosarcoma ProtuberansSigns/Symptoms:Slow-growing, non-painful tumorAntecedent trauma in 10-20% of casesAge:Younger than dermatofibromaSex:M > FAnatomic Distribution:Trunk, groin and proximal extremities (as opposed to dermatofibroma)

Solitary masses of subcutis and skin; average size 5.0 cm

May lead to ulceration of overlying skin with associated hemorrhage and cystic change

Cellular tumors of dermis and subcutis; slender fibroblasts in monotonous storiform pattern

Little pleomorphism with low to moderate mitotic activity

Dermatofibrosarcoma ProtuberansAncillary Testing:IHCCD34 positiveCytogeneticsSupernumerary ring structure formed by amplified sequences from chromosomes 17 and 22Fusion of COL1A1 and PDGF genesOverexpression of PDGF may lead to DFSPPrognosis/Treatment:Locally aggressive; recurs in 50% of casesRarely metastasizes (

Malignant Fibrous HistiocytomaMost common sarcoma of late adult lifeMay occur secondary to previous RTSigns/Symptoms:Painless, enlarging mass if on extremityRetroperitoneal tumors may present with obstruction and anorexiaFever and leukocytosisTumor production of IL-6, IL-8 and TNFAge:Late adulthood (50-70 years)Sex:M >> F (70% of MFH in men)

Malignant Fibrous HistiocytomaAnatomic Distribution:Lower extremities (thigh), followed by upper extremities and retroperitoneumGross Findings:Solitary, multilobulated fleshy masses5-10 cmTwo-thirds within skeletal muscleProminent areas of hemorrhage and necrosis

Varied microscopic appearance with pleomorphic tumor cells

Malignant Fibrous HistiocytomaAncillary Testing:> 80% show some cytogenetic abnormalityPrognosis/Treatment:Local recurrence rate between 19-31%Metastatic rate between 31-35%Most common site is lungUsually within 12-24 months of diagnosisTreatment by wide radical excisionRT and chemo

Tumors and Tumor-Like Conditions of Adipose TissueBenign:Lipoma Malignant:Liposarcoma

LipomaMost common mesenchymal neoplasmTumors may be single, multiple, superficial or deepSigns/Symptoms:Painless (except angiolipoma),soft, solitary, mobile massAge:Adults (40-60 years)Rare in 1st 2 decadesSex:M > F

LipomaAnatomic Distribution:Upper back, neck, shoulder and abdomen, proximal extremities, buttocks and upper thighSeldom in face,hands or feetGross Findings:Soft, well-circumscribed, thinly-encapsulated rounded massesFew millimeters to > 10 cmMicroscopic Findings:Mature adipose tissueMany histologic subtypes

AngiolipomaSpindle cell lipoma

LipomaAncillary Testing:50-80% have clonal cytogenetic abnormalities with most common alteration involving translocations of 12qPrognosis/Treatment:Simple surgical excisionRecurrence rate < 5%

LiposarcomaSigns/Symptoms:Extremity tumors develop as slow-growing massesRetroperitoneal tumors are associated with abdominal symptomsAge:Late adult life (60-70 years)Myxoid and round cell subtypes occur in 5th decadeSex:M = FAnatomic Distribution:Deep muscles of extremities or retroperitoneum

InflammatoryMyxoidRound Cell

LiposarcomaAncillary Testing:Well-differentiated liposarcomas often possess a giant ring chromosome (RCG) involving chromosome 12Myxoid liposarcomas are characterized by t(12;16)(q13;p11) resulting in fusion of CHOP gene with TLS gene. CHOP encodes a DNA transcription factor and TLS encodes an RNA binding proteinPrognosis/Treatment:Well-differentiated tumors of extremities recur around 50% of time though rarely cause deathPoorly differentiated tumors of retroperitoneum often recur, metastasize to lung and bone and have a 5-year survival of 20%Surgery with chemo and RT

Tumors and Tumor-Like Conditions of Skeletal MuscleMalignantRhabdomyosarcoma

RhabdomyosarcomaMost common soft tissue sarcoma of children under 15 years of ageSigns/Symptoms:Tumors in head & neck can present with cranial nerve signsTumors in GU tract present with dysuria, hematuria or incontinenceTumors in extremities present as painful, rapidly-growing massesAge:Predominantly infants and childrenSex:M > F

RhabdomyosarcomaAnatomic Distribution:Head and neck; GU tract and retroperitoneum; upper and lower extremitiesGross Findings:Botryoid embyonal tumors of urinary bladder and nasopharynx present as polypoid masses comprised of hemorrhagic gelatinous cystsTumors of extremities are usually solid and gray-whiteTumors rarely larger than 3-4 cm

Embryonal RhabdomyosarcomaAlveolar Rhabdomyosarcoma

Pleomorphic rhabdomyosarcoma

RhabdomyosarcomaAncillary Testing:IHCDesmin and Actin positiveCytogeneticsEmbryonal tumors consistently show LOH at 11p15.5Alveolar tumors are usually characterized by t(2;13)(q35;q14) resulting in generation of PAX3-FKHR chimeric gene which encodes a transcription factorPrognosis/TreatmentPrior to 1960, 5-year mortality 100%Now with surgery, chemo and RT, 5-year survival for botryoid embryonal rhabdo is 95%; classic embryonal rhabdo is 66%; alveolar rhabdo is 54%Metastasis in 20% of cases: lungs, bone, lymph nodes

Tumors and Tumor-Like Conditions of Blood VesselsBenign:Hemangioma Malignant:Angiosarcoma

HemangiomaMost common benign soft tissue tumor of infancy and childhoodSigns/Symptoms:Painless blue or red noduleAge:ChildhoodSex:F > MAnatomic Distribution:Predilection for head & neckInternal tumors of the liver

HemangiomaAncillary Testing:N/APrognosis/Treatment:Surgical excisionINF- for complex or multiple lesionsHemangiomas do NOT undergo malignant transformation

AngiosarcomaRareChronic lymphedema and previous RT predispose to angiosarcomaSigns/Symptoms:Ill-defined bruise with indurated borderEdema, ulceration and necrosisAge:ElderlySex:F > MAnatomic Distribution:Predilection for skin and superficial soft tissueRarely arise from major vessels

AngiosarcomaAncillary Testing:IHCCD34 and CD31 positiveCytogeneticsNo consistent abnormalityPrognosis/Treatment:POOR 5-year survival 10-20%Metastasis to lung, liver, spleen and lymph nodes

Tumors and Tumor-Like Conditions of Peripheral Nervous TissueBenign:Schwannoma (Neurilemoma)Neurofibroma Malignant:Malignant Peripheral Nerve Sheath Tumor (MPNST)

Schwannoma90% of tumors are sporadicSigns/Symptoms:Freely mobile, non-painful lesionAge:All ages; most common between 20-50 yearsSex:M = FAnatomic Distribution:Head & neck, flexor surfaces of upper and lower extremities

SchwannomaAncillary Testing:IHCS100 positivePrognosis/Treatment:Simple surgical excision

NeurofibromaGrowth pattern may be localized, diffuse or plexiformDiffuse and plexiform tumors occur in the setting of neurofibromatosis type I (NF1) aka, von Recklinghausens diseaseLocalized tumors are sporadic and not associated with NF1

Neurofibromatosis type 11 in every 2500 to 3000 live birthsAutosomal dominant with high penetrance50% of cases are new mutationsAssociated with deletions, insertions or mutations of the NF1 tumor suppressor gene on chromosome 17.NF1 encodes for neurofibrominCaf au lait spots; multiple neurofibromas involving skin, GI tract, larynx, blood vessels and heartCNS tumors (optic gliomas and astrocytomas)Asymptomatic pigmentation of iris (Lisch nodules)Skeletal abnormalities in 40% of cases)MALIGNANT TRANSFORMATION in a small percentage of cases (

NeurofibromaSigns/Symptoms:Slow-growing, painless nodulesAge:Young adults (20-30 years)Sex:M = FAnatomic Distribution:Dermis throughout the body (internally if NF1)

NeurofibromaAncillary Testing:IHCS100 positive (to a lesser extent than schwannoma)Prognosis/Treatment:Localized tumors removed by surgical excisionSurgery reserved only for large and painful lesions in patients with NF1

Malignant Peripheral Nerve Sheath Tumor25-50% of tumors found in patients with NF1Signs/Symptoms:Mass lesionAge:20-50 yearsSex:M = FAnatomic Distribution:Most arise in association with major nerve trunks (sciatic nerve, brachial and sacral plexi)Gross Findings:Eccentric masses (> 5 cm) with hemorrhage and necrosis

Malignant Peripheral Nerve Sheath TumorAncillary Testing:IHCS100 variable (weak if present)Prognosis/Treatment:Local recurrence rate between 40-60%5-year survival 50%Metastasis to bone, lung and pleuraSurgery, chemo and RT

Tumors of Primitive Neuroectodermal OriginMalignant:Extraskeletal Ewings Sarcoma / Primitive Neuroectodermal Tumor (PNET)

Ewings Sarcoma / PNETSigns/Symptoms:Rapidly growing deep-seated massesAge:Young adults (usually < 30 years)Sex:M > FAnatomic Distribution:PNETs usually arise in extremities, upper thigh, buttock and shoulderExtraskeletal Ewings sarcoma usually arises in paravertebral areas in association with vertebrae or ribs

Ewings Sarcoma / PNETAncillary Testing:Cytogenetics90-95% of tumors are characterized by t(11;22)(q24;q22) involving EWS on 22q and FLI1 on 11qPrognosis/Treatment:Highly aggressive (previously 24 month survival < 25%)Surgery, chemo and RT

Tumors of Uncertain TypeMalignant:Synovial Sarcoma

Synovial SarcomaMisnomer (occurs in para-articular areas though has no relation to synovium)Signs/Symptoms:Deep-seated, painful massAge:Adolescents and young adults (15-40 years)Sex:M > FAnatomic Distribution:Extremities (knee, hip and shoulder)Related to tendons, tendon sheaths and bursaeRarely reported in nasopharynx, bone and solid organs

MonophasicBiphasic

Synovial SarcomaAncillary Testing:IHCCytokeratin positive in biphasic tumorsCytogeneticsConsistent translocation t(X;18)(p11.2;q11.2) in 90% of tumors involving SYT gene on 18q and SSX gene on XpPrognosis/Treatment:Metastatic lesions in 50% of patients (lung)5-year survival 36-82%Surgery, chemo and RT