Pitfalls in diagnosis of soft tissue tumors of childhood

Pitfalls in diagnosis of soft tissue tumors of
childhood
Presenter: Dr. Sonic V.S
Moderator: Dr. Sumita Tripathy
Dept 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
Pericytic Tumors of uncertain differentiation
Skeletal muscle
Undifferentiated/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
Embryonal
Rhabdomyosarcomas Alveolar
Pleomorphic
Botryoid
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 sarcomas
RMS versus non RMS
Alveolar versus Embryonal RMS
Synovial sarcoma versus other adult type NRSTS
Benign lesions misdiagnosed as sarcoma
Fetal Rhabdomyoma
Plexiform cellular schwannoma
Pseudosarcomatous myofibroblastic tumors
Infantile myofibroma/myofibromatosis
Sarcomas misdiagnosed as benign lesions
Embryonal RMS
Low grade fibromyxoid sarcoma
Myofibrosarcoma
Misgrading of sarcoma
IMT as embryonal RMS
Infantile fibrosarcoma as malignant spindle cell tumor
Angiomatoid fibrous histiocytoma as RMS, EFT or MFH
Non soft tissue tumors misdiagnosed as soft tissue
sarcomas
Deep juvenile xanthogranuloma
Non Hodgkin lymphoma
Granulocytic sarcoma

Non soft tissue tumors misdiagnosed as soft tissue sarcomas

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

Pitfalls in diagnosis of soft tissue tumors of childhood

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)
 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:
 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 cells
having 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
 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
 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
 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
 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

Misgrading of sarcomas
 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:
 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

Non 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 tumors
CD45 NB84 CD99 Myogenin WT1 CK/EMA INI 1
Rhabdomyosarcom
a
- - - + - +, <10% +
EFT - + (20%) + - - +, <7% +
DRCT - + (50%) - - + + +
MRT - NK + - NK + -
NHL/ALL + - + - - + NK
Neuroblastoma - + - - - - NK
Blastemal
component of
Wilm’s tumor
- - - - + + +

Immunohistochemical reactivity for spindle cell sarcomas
– percentage positivity
Myogen
in
CK7 EMA S100 Nestin
RMS 95 <10 <1 <10 NK
SS 10 60 90 48 0
MPNST 0 0
13,
weak
55 78
FS 20 0 0 <5 NK

Genetic abnormalities in STS
Soft tissue tumor
Chromosomal
rearrangement
FISH
Chimeric fusion
transcript
RT-PCR
ARMS
t(2;13)(q35;q14)
t(1;13)(p36;q14)
Paraffin sections
PAX3 – FOXO1A
PAX7 – FOXO1A
RT-PCR
Q-PCR
EFT
t(11;22)(q24;q12)
t(21;22)(q22;q12)
Paraffin sections EWS-FLI RT-PCR
DRCT
t(11;22)(p13;q12)
t(21;22)(q22;q12)
Frozen sections EWS-WT1 RT-PCR
SS
t(X;18)(p11.23;q11)
t(X;18)(p11.21;q11)
Paraffin sections
SYT-SSX1
SYT-SSX2
RT-PCR
Q-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-PCR
Extrarenal 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.

Pitfalls in diagnosis of soft tissue tumors of childhood

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Pitfalls in diagnosis of soft tissue tumors of childhood