Pitfalls in diagnosis of soft tissue tumors of childhood

Pitfalls in diagnosis of soft tissue tumors of childhoodPresenter: Dr. Sonic V.SModerator: Dr. Sumita TripathyDept Of Pathology, MKCG Medical College, Berhampur, Odisha.

• Soft tissue is defined as nonepithelial extraskeletal tissue of the body exclusive of the reticuloendothelial system, glia, and supporting tissue of parenchymal organs.

• Represented by voluntary muscles, fat and fibrous tissue, along with vessels serving the tissues.

• By convention peripheral nervous system is also included because tumors arise from them also present as soft tissue masses and pose similar problems in differential diagnosis and therapy.

Introduction

Soft tissue tumors are a heterogeneous group Classified by line of differentiation, the adult tissue they

form Benign tumors: mostly resemble normal tissue Malignant tumors: aggressive and invasive or destructive

growth Incidence varies in adults and children

WHO classification of STT 2013 Classified based on histologic category Each category have benign and malignant tumors Some have a borderline (low malignant potential) group

Adipocytic Vascular

Fibroblastic/Myofibroblastic Chondroosseous

So-called fibrohistiocytic Gastrointestinal stromal

Smooth muscle Nerve sheath

PericyticTumors of uncertain differentiation

Skeletal muscleUndifferentiated/unclassified sarcoma

Childhood Soft Tissue Sarcomas

Constitute 5-8% of all childhood tumors. Pose significant diagnostic challenges due to:

histological diversity Overlap in morphologic features

Some overlap with adult tumors, but unique. Outcome increased dramatically over the last two decades. Attention now directed to reduce the toxic effects of therapy

as it hampers growth and quality of life. In the realization of clinical implications of misdiagnosis, we will

be discussing the potential pitfalls encountered in pediatric soft tissue pathology.

International classification of childhood cancers 2005 – Soft tissue and

extraosseous sarcomas

(a) Rhabdomyosarcomas

(b) Fibrosarcomas, peripheral nerve sheath tumors, and other fibrous neoplasms

(b.1) Fibroblastic and myofibroblastic tumors

(b.2) Nerve sheath tumors

(b.3) Other fibromatous neoplasms

(c) Kaposi sarcoma

(d) Other specified soft tissue sarcomas

(d.1) Ewing tumor and Askin tumor of soft tissue

(d.2) pPNET of soft tissue

(d.3) Extrarenal rhabdoid tumor

(d.4) Liposarcomas

(d.5) Fibrohistiocytic tumors

(d.6) Leiomyosarcomas

(d.7) Synovial sarcomas

(d.8) Blood vessel tumors

(d.9) Osseous and chondromatous neoplasms of soft tissue

(d.10) Alveolar soft parts sarcoma

(d.11) Miscellaneous soft tissue sarcomas

(e) Unspecified soft tissue sarcomas

Embryonal

Rhabdomyosarcomas

Alveolar

PleomorphicBotryoid

Embryonal NOS

Anaplastic

Spindle cell

Embryonal

Classification of sarcomas According to major therapeutic significance, Pediatric soft tissue sarcomas are classified as:

Rhabdomyosarcomas (RMS) Non-rhabdomyosarcomatous soft tissue sarcoma

(NRSTS) Undifferentiated soft tissue sarcoma (USTS)*

*USTS indicates a high grade mesenchymal tumor which fails to demonstrate a specific line of differentiation by pathological and molecular investigations.

Problems arising before reporting

Problems occur mainly with interpretation of small or crushed biopsies or poorly fixed tissue.

Well prepared sections remain the gold standard for diagnosis. Priority for triaging is fixation in 10% neutral buffered formalin. There is overlap in histology and immunohistoprofile of many

tumors. So cytologic or molecular confirmation is valuable in such

cases. These studies are particularly helpful when presentation

occurs at unusual age group or location, when unusual morphologic variants or aberrant immunoreactivity encountered.

With recent advance in technology, Fluorescence in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR) can be done in paraffin embedded tissue.

Tumor cells can also be retrieved from fixed tissue by laser capture microdissection and subsequently analyzed by RT-PCR for signature translocations.

This is particularly important when frozen tissue is not available as in cases of small biopsies or outside referral cases.

Pitfalls in diagnosis Pitfalls in diagnosis of STS can be divided into five main

categories. They include:

Misclassification of specific sarcomas

Benign lesions misdiagnosed as sarcomas

Sarcoma misdiagnosed as benign lesions

Misgrading of sarcomas

Non soft tissue tumors misdiagnosed as soft tissue sarcomas

Potential pitfalls Specific pitfalls

Misclassification of specific sarcomasRMS versus non RMSAlveolar versus Embryonal RMSSynovial sarcoma versus other adult type NRSTS

Benign lesions misdiagnosed as sarcoma

Fetal RhabdomyomaPlexiform cellular schwannomaPseudosarcomatous myofibroblastic tumorsInfantile myofibroma/myofibromatosis

Sarcomas misdiagnosed as benign lesionsEmbryonal RMSLow grade fibromyxoid sarcomaMyofibrosarcoma

Misgrading of sarcomaIMT as embryonal RMSInfantile fibrosarcoma as malignant spindle cell tumorAngiomatoid fibrous histiocytoma as RMS, EFT or MFH


Deep juvenile xanthogranulomaNon Hodgkin lymphomaGranulocytic sarcoma






Rhabdomyosarcomas

Most common pediatric STS (approximately 50%) 3.5% of all malignancies under age of 15 2% of all malignancies in 15-19 age group 90 % of all RMS in individuals < 25 years; 60-70% in <10 years Peak age 2- 5 years Male preponderance (1.4:1)

Embryonal RMS Most common

60-70% of all childhood RMS Usually children ages 3-10 years Head and neck and GUT, nasal and

oral cavities, orbit, middle ear, prostate, paratesticular region

Intermediate prognosis Variants include:-

Embryonal NOS Spindle cell Botryoid Anaplastic

Grossly• well circumscribed,

multinodular• Gray white glistening,

gelatinous cut surface

Cells are primitive stellate or fusiform to well differentiated forms.

Extensive rhabdomyoblastic differentiation round, strap or tadpole shaped

eosinophilic cells in a myxoid stroma.

Cytoplasmic striations present (20 to 30% cases).

Hypercellular areas, typically concentrated around blood vessels with alternate mucoid matrix rich hypocellular areas.

Spindle cell embryonal RMS

50% of more of tumor cells should be spindled for this diagnosis

Low grade, fascicular or storiform pattern

Uniform, relatively differentiated elongated spindle cells

Blunted central nuclei and tapered ends, pale indistinct cytoplasm

Scattered rhabdomyoblasts present Spindled or polygonal Brightly eosinophilic cytoplasm Pleomorphic nuclei

Cross-striations seen occasionally Low mitotic activity

Botryoid embryonal RMS

Hypercellular zone beneath epithelium (Nicholson's cambium layer)

Cells are undifferentiated, round or spindled Minimal cytoplasm Frequent mitotic figures

Less cellular in deeper layers differentiating and

undifferentiated cells resembling embryonal NOS

Superior prognosis

Alveolar RMS

20% of all rhabdomyosarcomas More common in early to mid-

teens but all ages affected Neonatal cases have poor

prognosis, are associated with skin and brain metastases

Rapid growing, often high stage at presentation.

Associated with t(2;13) and t(1;13)

Round cells with frequent mitoses Hyperchromatic nuclei, coarse

chromatin, distinct nuclear membrane.

Classic variant consists of Anastomosing fibrous septa Aggregates of discohesive cells.

Solid variant – little fibrous septa Reticulin stain is useful as it

encircles the variably sized solid aggregates of tumor cells.

Single focus of alveolar morphology is sufficient

Immunoprofile Express Myogenin/myf4, MyoD1/myf3 The extent and intensity of staining

can be used to differentiate between the two main types of RMS.

Alveolar RMS display an extensive (>50%) nuclear staining for myogenin

Embryonal RMS show a focal pattern of staining

Other non specific markers include desmin, CD99, ALK, CD56, smA, cytokeratin, S100 and neurofilament protein.

Myogenin and MyoD1 expression helps in differentiating RMS from a variety of tumors like: MPNST Nodular fasciitis Inflammatory myofibroblastic tumor Benign and malignant smooth muscle and neural tumors

Problems with immunomarkers Focal positivity for myogenin can be seen in

Blastemal component of Wilm’s tumor Synovial sarcoma Infantile fibrosarcoma Non neoplastic entrapped or regenerating skeletal muscle

fibres especially at the infiltrative edges of a round or spindle cell tumor

Mimics of embryonal RMS and its variants

Embryonal RMS can be confused with Benign and malignant myxoid

tumors How to differentiate?

Immunohistochemistry is useful in such situations.

Myogenin expression, focal in case of embryonal RMS

MyoD1 expression

Spindle cell variant can be confused with Benign fibrous histiocytoma Neurofibroma Leiomyosarcoma Inflammatory myofibroblastic

tumor (IMT)

How to differentiate? Positive myogenin

expression helps to rule out BFH and NF.

Negative h-caldesmon rules out leiomyosarcoma.

IMT overdiagnosed as RMS due to its infiltrative growth pattern, high mitotic count, moderate atypia and vascular bulging Mixture of growth patterns Absence of atypical mitotic figures Myogenin expression absent.

Botryoid variant is mimicked by Fetal rhabdomyoma

How to resolve the issue? Fetal rhabdomyoma is a benign

tumor Absence of cellular pleomorphism Absence of cambium layer in

submucosal tumors Very low mitotic count

Alveolar RMS Diagnosis is difficult when

there is a small biopsy, as the alveolar component may not be appreciable.

Such cases necessitate cytogenetic and molecular studies. t(2;13) and t(1;13)

IHC helps in differentiating from other small round cell tumors. Myogenin Desmin

Anaplastic RMS Poor prognosis Large hyperchromatic

nuclei with multipolar mitotic figures

More common in embryonal RMS

Sclerosing RMS Recent inclusion by WHO Now considered with spindle cell

RMS as a separate entity Rare, usual location is head and

neck Abundant stroma

Obscures the small blue tumor cells

Micro alveolar architecture. Can be confused with

Angiosarcoma Carcinoma

Myogenin and myoD1 positivity helps in differentiation

Pediatric Non rhabdomyosarcomatous STS

Ewing sarcoma family of tumors

Desmoplastic round cell tumors

Malignant rhabdoid tumor

Ewing sarcoma family of tumors

This group include Extra osseous Ewing tumor and its variants Peripheral primitive neuroectodermal tumors (pPNET)

Second most common pediatric soft tissue tumors (20%)

Usual sites - chest wall, paraspinal tissues and abdominal wall.

Children more than 10years. Chromosomal abnormality include t(11;22) and

t(21,22).

Microscopic features depend on degree of neural differentiation.

Ewing sarcoma - undifferentiated end

pPNET - varying degree of neural differentiation.

Predominantly lobular or trabecular growth pattern with predominant ramifying capillary

network. Stroma is very little.

Undifferentiated lesions Cells with scanty, pale cytoplasm Round to ovoid open nuclei with fine

chromatin Variable nucleoli.

Differentiated end Cells with eosinophilic cytoplasm Coarse chromatin Frequent nucleoli. Presence of rosettes, usually Homer Wright

type.

Diagnostic challenges

All the tumors of this family show positive immunoreactivity for CD99 FLI-1*

But not specific Should be used along with a panel of

other markers to exclude tumors which mimic same histology like Haematolymphoid Neuroblastic Myogenic tumors

* Friend Leukemia Integration 1

Mimickers of EFT Lymphoblastic lymphoma

Shows positivity for CD99 and FLI-1

Sometimes can be negative for CD45 (LCA)

A combination of haematolymphoid markers are used in such cases

TdT, CD43, CD34, CD10 and CD79a.

Neuroblastomas Usually negative for CD99 Neuroblastic marker NB84 is

positive in 20% of EFT. It is also important to note that

EFT can be positive for CD117, CK, CD31 and desmin.

How to resolve cases which pose difficulty in routine and IHC studies?

Cytogenetic or molecular genetic confirmation required

t(11;22) and t(21,22) - EWS-FLI

This is useful especially in visceral location of the tumor.

FISH is useful in such instances to detect translocation.

Desmoplastic round cell tumor

Highly aggressive clinical entity primarily of young adults.

Rare in children. Displays striking diversity in location. Wide histological spectrum with several

morphological variants Polyphenotypic immunoreactivity.

Sharply demarcated nests of varying size

Small round or oval cells embedded in a hypervascular desmoplastic stroma.

Large tumor cell nests often central necrosis.

Neoplastic cells are undifferentiated scant amount of eosinophilic

cytoplasm small hyperchromatic nuclei inconspicuous nucleoli

Nuclei are relatively uniform in most cases

Some show increased nuclear atypia, and

Rare tumors show markedly atypical cells.

IHC profile of DRCT Immunostaining for carboxy-terminus of WT1 is

most sensitive Cytokeratins EMA Desmin Vimentin NSE Synaptophysin S100

Cytogenetic and molecular genetics t(11;22) EWS-WT1

Diagnostic challenges EFT Alveolar rhabdomyosarcoma Neuroblastoma Lymphoma Small cell carcinoma

Immunostaining with desmin is characteristic – perinuclear globular pattern of immunoreactivity.

Malignant rhabdoid tumour Aggressive neoplasm of infancy and

childhood Propensity for wide-spread metastases. Usual sites - kidney, CNS, extrarenal soft

tissue Congenital disseminated form. Abnormalities of 22q11 and

mutations and homozygous deletions of INI1(hSNF5) gene characteristic

Presence of rhabdoid cell is the hallmark of MRT.

Rhabdoid cells are large polygonal cells eccentric vesicular nuclei prominent nucleoli. abundant cytoplasm containing

juxtanuclear eosinophilic PAS-positive hyaline inclusions or globules.

These inclusions are paranuclear intracellular aggregates of intermediate filaments ultrastructurally.

Arranged in patternless sheets and cords.

Wide variety of cytologic and architectural features small, round cells and a myxoid

collagenous stroma.

Immunophenotype of MRT: Vimentin Cytokeratin EMA SMA Lack of reactivity to INI1/BAF1

antibody(Normal cells and rhabdoid cells which lack INI1(hSNF5) deletion express nuclear reactivity to INI1/BAF1* antibody)

*Integrase interactor 1/Barrier to autointegration factor1)

Diagnostic challenges: Rhabdomyosarcoma DRCT EFT Epithelioid sarcoma Synovial sarcoma

Diagnosis can be made by lack of immunoreactivity to INI1/BAF1 antibody, as other markers are expressed by other tumors also.

Adult type NRSTS in children

This is a heterogenous group which include entities that are usually seen in adults. They are: Synovial sarcoma MPNST Liposarcoma Epithelioid sarcoma Constitute 70% of

adult type NRSTS Leiomyosarcoma Adult type fibrosarcoma

GIST constitutes 2% of all soft tissue sarcomas.

Synovial sarcoma Third most common sarcoma in

childhood Second decade of life and also

newborns Extremities common site Visceral sites and mediastinum

also Gross – well circumscribed

round/multilobular maybe cystic occasional calcification

Biphasic Monophasic Poorly differentiated

Biphasic : Large round/oval epithelial cellshaving pale cytoplasm and vesicular nuclei Arranged in solid cords, nests or

glands Surrounded by well oriented plump

uniform spindle cells – indistinct cytoplasm and oval dark staining nuclei

Areas of hyalinization, myxoid change and calcification maybe present

Monophasic type: Mostly spindle cells

Plump fascicles with hyalinization

Accompanied by mast cells

Occasional osseous or cartilaginous metaplasia

No particular pattern as in other fibrous tumors

Monophasic epithelial type is rare

Poorly differentiated Large cell or epithelioid

pattern having variably sized round nuclei and prominent nucleoli

Small cell pattern with nuclear features similar to other SRCTs

High grade spindle cell pattern with high grade nuclear features and high mitotic count with necrosis

Highly vascular tumors

Mimickers of synovial sarcoma

Biphasic type MPNST as both the tumors show

glandular elements. How to differentiate? The glands of MPNST show intestinal

type epithelium Presence of goblet cells and microvilli Synovial sarcoma lack these features IHC – SS is positive for CK and EMA

Monophasic type MPNST Fibrosarcoma

How to diagnose SS? Thorough search for epithelial component Foci of calcification Above favors SS Positivity for CK and EMA is confirmatory

Poorly differentiated Small round cell tumors MPNST Embryonal RMS in case of myxoid

variant Infantile hemangipericytoma

How to differentiate? Routine histology and IHC not helpful Cytogenetic study for t(X;18) in SS

TLE 1 has emerged as a useful marker for differentiating difficult cases of synovial sarcoma.

Malignant peripheral nerve sheath tumor (MPNST)

15% of adult type sarcomas in children

Usually infrequent in childhood High grade tumors with poor

prognosis Second decade Occurs in children with NF1 Extremities, trunk, H&N Gross:

Large fusiform mass >5cm Tan white fleshy Areas of hemorrhage and

necrosis

Spindle cells in fascicular pattern Branching hemangiopericytoma like

vascular pattern Alternate hypo and hypercellular

areas Whorling or rarely palisading pattern Geographic areas of necrosis Hyperchromatic nuclei and pale

cytoplasm Cells concentrate around blood

vessels MPNST in children shows

prominent neuro-epithelial foci and primitive cells

Epithelioid MPNST Plump epithelioid cells Abundant eosinophilic cytoplasm Abundant extracellular myxoid

matrix Lobulated growth

• Malignant Triton tumor• Skeletal muscle

differentiation• Glandular MPNST

• Glandular differentiation with or without mucin production

Mimics of MPNST

Synovial sarcoma Distinguished using neural marker Nestin

Plexiform cellular schwannoma Commonly in first decade Present as congenital tumors No association with NF1 Uniform S100 positivity and lack of p53

expression Electron microscopy well differentiated

Schwann cells Leiomyosarcoma Embryonal RMS

Leiomyosarcoma Leiomyosarcoma in pediatric age group rare Showed focally typical features of smooth muscle

differentiation In the form of fascicles of eosinophilic spindle

cells With cigar-shaped nuclei. Unusual whorled growth pattern maybe seen

Low grade lesions usually Differential diagnosis include

Infantile myofibromatosis Leiomyoma Monophasic synovial sarcoma Spindle cell rhabdomyosarcoma.

Liposarcoma (LPS) Rare soft-tissue sarcoma of childhood Presents in the second decade Female predilection (2F:1M) Preference for the lower extremity

Myxoid LPS accounts for 80% to 90% of cases

Usually myxoid-round cell types Spindle cell and pleomorphic variants Differential diagnosis include:

Lipoblastoma Rhabdomyosarcoma Lipoma

Cytogenetics: t(12;16) (q13;p11) FUS-CHOP fusion EWSR1-CHOP rearrangement






Benign tumors misdiagnosed as sarcoma Fetal rhabdomyoma Plexiform schwannoma Pseudosarcomatous fibroblastic/myofibroblastic

lesions Nodular fasciitis Proliferative fasciitis

Infantile myofibroma/myofibromatosis

Fetal rhabdomyoma

Rare tumor Mean age in children 2years 25% cases are congenital Head and neck region

Esp post auricular region Intranasal or intraoral

Gross: Circumscribed soft mass with glistening

c/s

Irregular bundles of immature skeletal muscle fibres

Myxoid background Spindle cells with central oblong

nuclei and eosinophilic cytoplasm Mitosis can be relatively frequent Has to be distinguished from

Embryonal RMS – botryoid variant Absence of cellular pleomorphism Absence of cambium layer Absence of nuclear atypia Absence of atypical mitoses or

necrosis

Plexiform schwannoma

Involve multiple nerve fascicles or nerve plexus

Usually seen in childhood or at birth

Arise from skin and subcutaneous tissue

Grossly: encapsulated and multinodular

Plexiform architecture Lobules of tumor cells

separated by fibrous septa Biphasic pattern may not be

prominent Often cellular with

hyperchromatic nuclei and mitotic activity

No necrosis, no myxoid change Has to be differentiated from

MPNST Uniform positivity for S100 Lack of P53 positivity

Pseudosarcomatous fibroblastic/myofibroblastic lesions 12% of STTs in childhood Group of benign tumors Due to rapid growth clinical suspicion of malignancy Pathologically

Increased cellularity Nuclear pleomorphism Mitotic activity Overlap with myogenic immunophenotype

Nodular fasciitis Self limiting fibrous neoplasm of

subcutaneous tissue Occurs in all ages Rare in children (cranial fasciitis

occurs in infants) Upper extremities, trunk, chest

wall, head and neck In children arise as rapidly

growing mass in orbital, periorbital, premaxillary areas

Grossly, <5cm, circumscribed, nonencapsulated nodule with a glistening mucoid appearance

Plump spindle shaped fibroblasts and myofibroblasts forming short fascicles

Less cellular area of mucoid-myxoid extracellular material (tissue culture pattern)

Mitotic figures are plentiful No nuclear hyperchromasia and

pleomorphism Border is focally infiltrative Presence of extravasated RBCs,

osteoclast like giant cells, lymphocytes

Overdiagnosis as malignancy: Unusual extracranial locations Erosion of bone Invasion of skeletal muscle,

nerves and lymph nodes Nuclear pleomorphism and mitosis

in cellular areas In children it can mimic

Embryonal RMS Synovial sarcoma DFSP Fibrosarcoma

• Can be differentiated by:• Small size (<4cm)• Absence of atypical mitotic

figures• Demonstration of myofibroblasts

• Vimentin• Muscle specific actin• SMA, Desmin

• Negative staining for• Myogenin• CK• EMA• CD34

Proliferative fasciitis Rare in childhood Subcutaneous lesions Sites include upper extremities,

head and neck, trunk Rapidly growing Poorly circumscribed

discoid/elongated mass grossly

Bland tissue culture like fibroblastic and myofibroblastic spindle cells

Variably myxoid and collagenous stroma

Presence of large basophilic ganglion like cells with vesicular nuclei and prominent nucleoli

Pediatric lesions are usually more cellular Frequent mitosis Acute inflammation and necrosis Less collagenous matrix

Childhood proliferative fasciitis can mimic Embryonal RMS Ganglioneuroblastoma

Differentiated by Demonstrating myofibroblastic

immunotype Negative staining for myogenin, NSE, GFAP

and neurofilament protein

Infantile myofibroma/myofibromatosis

20% of fibroblastic myofibroblastic lesions

Age <2 years, 60% at birth Solitary, multicentric and

generalized forms. Usually superficial lesions Grossly rubbery/firm

lesions C/s red or yellow soft centre

surrounded by white areas

Nodular or multinodular pattern Biphasic light and dark staining

areas Light areas show plump myoid

spindle cells with eosinophilic cytoplasm

Arranged in whorls or short fascicles with cigar shaped nuclei

Dark staining areas show round to polygonal cells with hyperchromatic nuclei

Arranged around vascular spaces

Features responsible for misdiagnosis as infantile fibrosarcoma Increased cellularity

Mitotic activity

Infiltration of myofibroblasts into adjacent tissues

Intravascular growth simulating vascular invasion

Multicentric occurrence mistaken as metastasis

Differentiation is usually difficult in routine sections and IHC

Genetic studies to exclude fibrosarcoma is indicated t(12;15)(p13;q25)






Sarcomas misdiagnosed as benign lesions Myxoid tumors Treacherous group accounting for misdiagnosis Clinical spectrum ranges from reactive, benign to high grade

sarcomas This include:

Embryonal RMS Myofibrosarcoma Low grade fibromyxoid sarcoma/hyalinising spindle cell tumor with

giant rosettes

Myofibrosarcoma

Rare in children Arise in bone and soft tissue Head and neck predilection Grossly:

Firm Pale fibrous cut surface Ill defined margins

Histology: Spindle to stellate shaped cells Intersecting fascicles, sheets

or storiform Collagenous/myxoid stroma Cells have pale eosinophilic

cytoplasm Fusiform nuclei Evenly dispersed chromatin Low mitosis Necrosis absent Infiltration to surrounding

tissues

Low cellularity Low mitotic activity can lead to a diagnosis of

benign lesion Absent necrosis

IHC can be helpful in such situations SMA Muscle specific actin Calponin

Low grade fibromyxoid sarcoma/hyalinising spindle cell tumor with giant rosettes

Morphologic spectrum of same entity

Majority in young adults 20% cases occur in <18years Deep soft tissue mass in adults Superficial form in children

No metastases Grossly:

Well circumscribed Fibrous, focally mucoid 1cm to >20cm

Low to moderate cellularity Bland spindle cells with

hyperchromatic oval nuclei Finely clumped chromatin One to several small nucleoli Cells are seen in fibrous and

myxoid stroma Low mitotic activity Whorled or random pattern Curvilinear blood vessels Collagen rosettes can be

found

Misinterpreted as benign due to: Low cellularity Infrequent mitoses Absent nuclear pleomorphism Well circumscribed borders

Mimics include: Nodular fasciitis – tissue culture

fibroblasts Myxoid neurofibroma Cellular myxoma

S100 negativity MUC4 positivity t(7;16) FUS/CREB3L2 chimeric

gene







Borderline neoplasms overdiagnosed as malignant lesions

Two of the fibroblastic/myofibroblastic lesions: Inflammatory myofibroblastic tumor Infantile fibrosarcoma

These two lesions are of intermediate biologic potential

Recur locally Rarely metastasize

Inflammatory myofibroblastic tumor

Borderline tumor Occurs in first two decades 90% occur in respiratory tract,

abdomen & genitourinary tract Associated with systemic symptoms

and polyclonal hyperglobulinemia Grossly:

2 to 20cm Lobular, multinodular/bosselated Hard/rubbery gray white cut surface

Predominantly bland spindle cells

In a myxoid or hyaline stroma Lymphoplasmacytic infiltrate Three patterns identified:

Nodular fasciitis Fibrous histiocytoma Scar like

Mitotic figures are variable, not atypical

Large ganglion like cells can be seen in first two

The fibrous histiocytoma like pattern can be misdiagnosed as high grade spindle cell sarcomas IHC is helpful in ruling out these lesions ALK positivity is seen in IMT, but not specific.

Other mimics include: Leiomyosarcoma GIST Both are rare in childhood H-caldesmon and CD117 negativity

Cytogenetics There is rearrangement of 2p23 and ALK gene in about

50%. FISH is useful.

Infantile/congenital fibrosarcoma

Rare tumor Presents in first year of life Superficial and deep soft tissue of

distal extremities, head&neck Rapidly enlarging mass Grossly:

Poorly circumscribed lobulated Pseudocapsule Fleshy tan c/s Cystic/mucoid areas with

hemorrhage/necrosis

Densely cellular

Intersecting fascicles of primitive, round, ovoid and spindle cells

Focal herringbone pattern

Nuclear pleomorphism is little

Mitotic activity is prominent

Tumors with abundant collagen resemble adult fibrosarcoma

Lymphocytic infiltration is common

Mimics Solid growth pattern with high mitosis:

Spindle cell sarcomas of childhood Infantile fibromatosis – difficult

Predominantly myxoid pattern: Myxoid mesenchymal tumor of infancy Multinodular Primitive tumor cells are embedded in uniform

myxoid stroma Branching blood vessels Focal interlacing fascicles Locally aggressive

IFS does not have specific immunotype t(12;15)(p13;q25) ETV6-NTRK3 fusion




Misgrading of sarcomasNon soft tissue tumors misdiagnosed

as soft tissue sarcomas

Non soft tissue tumors misdiagnosed as STS Atypical presentations of certain non soft

tissue tumors can be misinterpreted as soft tissue sarcomas

They include Histiocytic and haematolymphoid tumors

Usual culprits include: Deep juvenile xanthogranuloma Extranodal Non Hodgkin’s lymphoma Extramedullary myeloid tumors

Deep Juvenile Xanthogranuloma Most common non-

Langerhan’s histiocytic disorder

Occurs in neonates and young children

Solitary or multiple skin lesions

Head and neck region usually Benign self limited lesion

Dense dermal infiltrate of lymphocytes

eosinophils and neutrophils, which may extend into subcutis

Touton giant cells (usually), Lipid laden macrophages and

histiocytes 0-2 mitotic figures per 10 HPF,

rarely numerous Epidermis thins out, rete ridges

become elongated

Diagnostic difficulty arise in deep JXG Esp in deep soft tissues and skeletal

muscles Poorly circumscribed Rapid growth Mistaken for sarcoma Composed of non lipidised mononuclear

histiocyte like cells Touton giant cells +/- Histiocytes show atypia and mitotic

activity This picture will confuse with sarcoma IHC is helpful in difficult cases

CD68 and FXIIIa is positive

Extranodal NHL in soft tissue

Very rare presentation Usually subcutaneous masses Association with HIV Lymph node involvement maybe

absent Can be misdiagnosed as small

round cell tumors IHC is mandated in such cases

Myeloid sarcoma in soft tissue

Rare presentation May precede or coincide with

AML Pose a potential pitfall in

diagnosis Can be mistaken for soft tissue

sarcoma esp small round cell tumor group

Immunotyping is advocated along with hematological evaluation

CD117, CD43, MPO, CD68 & CD34 are useful

IHC panel for Soft tissue sarcomas

IHC panel for small round cell tumorsCD45 NB84 CD99 Myogenin WT1 CK/EMA INI 1

Rhabdomyosarcoma - - - + - +,

<10% +

EFT - + (20%) + - - +, <7% +

DRCT - + (50%) - - + + +

MRT - NK + - NK + -NHL/ALL + - + - - + NKNeuroblastoma - + - - - - NKBlastemal component of Wilm’s tumor

- - - - + + +

Immunohistochemical reactivity for spindle cell sarcomas – percentage positivity

Myogenin CK7 EMA S100 Nestin

RMS 95 <10 <1 <10 NKSS 10 60 90 48 0MPNST 0 0 13,

weak 55 78FS 20 0 0 <5 NK

Genetic abnormalities in STSSoft tissue

tumorChromosomal rearrangemen

tFISH

Chimeric fusion

transcriptRT-PCR

ARMS t(2;13)(q35;q14)t(1;13)(p36;q14) Paraffin sections PAX3 – FOXO1A

PAX7 – FOXO1ART-PCRQ-PCR

EFTt(11;22)

(q24;q12)t(21;22)

(q22;q12)Paraffin sections EWS-FLI RT-PCR

DRCTt(11;22)

(p13;q12)t(21;22)

(q22;q12)Frozen sections EWS-WT1 RT-PCR

SSt(X;18)

(p11.23;q11)t(X;18)

(p11.21;q11)Paraffin sections SYT-SSX1

SYT-SSX2RT-PCRQ-PCR

IFS t(12;15)(p13;q25)

Frozen and paraffin ETV6-NTRK3 RT-PCR

IMT t(1;2)(q25;q23)t(2;19)(p23;q13) Paraffin sections TPM3-ALK

ALK-TPM2 RT-PCR

LGFMS t(7;16)(q34;p11) Paraffin sections FUS/CREB3L2 RT-PCRExtrarenal MRT Del(22q)(11.2) Paraffin sections hSNF/INI 1 del RT-PCR

Summary Soft tissue tumors in childhood pose great challenges in

accurate diagnosis Pitfalls in diagnosis include

Misclassification Benign tumors misdiagnosed as sarcomas Sarcomas interpreted as benign tumors Misgrading of sarcomas Non STS presenting as soft tissue tumors

Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood. Diagnosing the types and variants have therapeutic significance

Benign myofibroblastic tumors are the largest group involving misdiagnosis.

Extensive IHC may be necessary for accurate identification of round cell and spindle cell tumors, but none of the antibodies are specific.

Extrarenal soft tissue malignant rhabdoid tumor shows morphological and immunophenotypic variability. It can be diagnosed easily by the recent availability of commercial

antibody to the INI1/BAF gene product. Genetic studies provide valuable support to

pathological diagnosis Particularly for tumors having no specific histological

features. Critical in STTs presenting in unusual clinical settings or when

rare morphological variants or aberrant immunoreactivity is encountered.

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Pitfalls in diagnosis of soft tissue tumors of childhood

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