APPROACH TO CYTOPATHOLOGY DIAGNOSIS OF
SOFT TISSUE TUMORS
MERHAWI A. MD, RII
HADAS W. MD, PATHOLOGIST
1

OUTLINE
 Objective
 Introduction
 General approach
2

INTRODUCTION
 Soft tissue refers to non-epithelial tissue excluding the skeleton, joints, central nervous system, hematopoietic
and lymphoid tissues.
 FNAC screening tool for soft tissue masses.
 Technical ease
 Less invasive; less morbidity
 Allows for immediate assessment of specimen adequacy, allocation of tissue for special studies, and initiation of
treatment in emergency scenarios.
 Provides suitable material for ancillary studies
 No contamination of tissue planes
 Doesn’t change the architecture
 Cost effective - fastest, least expensive, and least invasive diagnostic procedure
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INTRODUCTION
 87%–100% diagnosed benign or malignant, with
 an average sensitivity and specificity for malignancy of approximately 95%.
 Differentiation b/n lymphoma, carcinoma, and sarcoma has specificity of 54% to 98%(sarcoma)
 Positive predictive value of 91% - 99%
 false-positive rate is relatively low (≤5%)
 False-negative rates vary a little more (2%–15%)
Any suspicious Lesion should be further evaluated by biopsy
4

SPECIMEN COLLECTION AND PREPARATION
 Evaluation should be done using both pap and geimsa
 Cell block preparations
 Architecture
 IHC
 Molecular studies
 Unstained slides and cytospin
 suitable for ancillary testing, including FISH and molecular studies.
 core biopsy – primary soft tissue lesions
5

ANCILLARY STUDIES
 Immunohistochemistry, cytogenetics, and molecular genetics significantly useful
 Electron microscopy – rare
 Flow cytometry is useful when lymphoma is in the differential diagnosis.
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REPORTING TERMINOLOGY
 For clarity of communication general category headings
 Non diagnostic
 Benign
 Atypical
 Suspicious
 Positive
 When the findings are not conclusive for a specific entity?
 A descriptive interpretation with a differential diagnosis is appropriate
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REPORTING TERMINOLOGY
 Benign Vs Malignant
 Pleomorphism, high cellularity, nuclear hyperchromasia and nuclear membrane irregularity
 Grading – done based on Cellularity, pleomorphism, mitoses, and necrosis.
 High grade moderate to marked nuclear atypia, intermediate to high cellularity with prominent nuclear overlap,
definite necrosis, and frequent mitoses, often with atypical forms
 Mitoses and necrosis is an objective finding worthy of separate mention in the report.
 Low grade - Mild nuclear atypia, minimal or absent necrosis, low cellularity with minimal nuclear overlap, and rare
or absent mitoses (<3/10HPF)
 Definitional grading -
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Soft tissue tumors
Adipocytic and Lipogenic
Neoplasms
Myxoid Neoplasms
Fibrohistiocytoid Neoplasms
Spindle Cell Neoplasms
Epithelioid Neoplasms
Pleomorphic Neoplasms
Dedifferentiated Sarcomas
• Neoplasms with lipogenic differentiation occur over a broad age range,
• but malignant tumors occur almost exclusively in adults.
• ATL/WDL needs adequate(representative) sampling.
11

LIPOMA
 Most common soft tissue tumor
 Slowly growing, subcutaneous or intramuscular
tumors
 Occurs over a wide anatomic distribution
 Soft, mobile, and painless lump rarely exceed 10cm
 Retroperitoneal lipoma – exceedingly rare
 Cytomorphology of lipoma
 Small tissue fragments
 Large, univacuolated adipocytes of uniform size
 Small, bland nuclei without atypia 12

 Variants
 Fibrolipoma is a lipoma with increased interstitial, connective tissue that is often hyalinized.
 Myxolipoma contains alcian blue-positive and hyaluronidase-sensitive myxoid stroma. There are no lipoblasts and no
plexiform capillaries. Myxoid material plus fat excludes a diagnosis of myxoma.
 Chondrolipoma is a lipoma with metachromatic chondromyxoid stromal material.
 Osteolipoma is a lipoma with osteoid components.
 Angiomyolipoma is a lipoma with vascular and smooth muscle components. Women are affected more than men, and
half have tuberous sclerosis; it is more common in the kidney but also occurs elsewhere. usually symptomatic, including
abdominal pain, hematuria, and fever.
 Myelolipoma is a lipoma with hematopoietic elements. It is most common in the adrenal gland; patients are usually
than 40, and the diagnostic feature is the presence of megakaryocytes and immature blood cells.
 Angiolipomas are subcutaneous lipomatous tumors. They are often multiple and tender at palpation. Most angiolipomas
are smaller than 2cm. An angiolipoma should be suspected when the tumor is small and tender at palpation, in
conjunction with the FNA findings of numerous branching capillary vessels within the fat tissue fragments.
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LIPOMA
ANGIOLIPOMA
14

LIPOMA
CHONDROID LIPOMA
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MYELOLIPOMA
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HIBERNOMA
 Rare benign tumor of brown fat
 Predominantly in adults aged 20 to 50 years
– thigh
 Often subcutaneous
 Cytology
 Large tissue fragments containing many
delicate capillaries
 Numerous brown fat cells with multiple small
cytoplasmic vacuoles
 Variable cytoplasm (granular, microvesicular,
or macrovesicular)
 Small, bland nuclei 17

SPINDLE CELL/PLEOMORPHIC LIPOMA
 Benign lipoma variants that represent a morphologic continuum.
 Solitary, painless, well-circumscribed, and slowly growing
 Subcutis or dermis of the upper back, shoulder neck, or anterior head and neck regions of middle-aged
to older men.
 Cytology
 Fragments of mature adipose tissue
 Often myxoid background
 Occasional multivacuolated lipoblast-like cells
 Bland and uniform spindle cells in short fascicles with Ropy collagen fibers and Mast cells
 “Floret” cells with smudged chromatin
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PLEOMORPHIC LIPOMA
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SPINDLE LIPOMA
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ATYPICAL LIPOMATOUS TUMOR/WELL DIFFERENTIATED
LIPOSARCOMA
 ALT – superficial lesions of the limbs and trunk that do not recur if adequately excised.
 WDL - deep-seated lesions (e.g., retroperitoneum, spermatic cord, and mediastinum)
 Complete resection is difficult – recurrence and local aggressiveness are possible
 Cytomorphology
 Clusters of variably sized Lipogenic cells with lipid vacuoles
 Atypical stromal cell nuclei
 Lipoblasts may be present
 Occasional floret cells with hyperchromatic nuclei
 Nonlipogenic pleomorphic or spindle-cell tissue fragments suggestive of dedifferentiation
21

ALT/WDL

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PLEOMORPHIC LIPOSARCOMA
 Rare malignancy,(5% of liposarcomas).
 Commonly involves extremities of elderly adults and has a poor prognosis.
 Cytology
 Moderately to highly cellular smear
 Dispersed cells and three-dimensional clusters
 Pleomorphic polygonal to spindle shaped cells with marked nuclear atypia
 Variable number of atypical lipoblasts
 Mitoses and necrosis
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PLEOMORPHIC LIPOSARCOMA
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Soft tissue
tumors
Adipocytic and
Lipogenic Neoplasms
Myxoid Neoplasms
Fibrohistiocytoid
Neoplasms
Spindle Cell Neoplasms
Spindle Cell Neoplasms
Epithelioid Neoplasms
Pleomorphic Neoplasms
Dedifferentiated
Sarcomas
• Soft tissue lesion with abundant homogeneous matrix share similar morphologic feature
• Amorphous, finely granular film that stains pale blue green with the Papanicolaou stain and a striking
blue-violet with Romanowsky stains.
• DDx include Nodular fasciitis, benign myxoid tumors, and myxoid sarcomas.
• Most benign lesions are superficially located whereas sarcomas are deep-seated
• Cellularity
• Molecular analysis and immunohistochemistry is helpful in resolving the differential diagnosis
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INTRAMUSCULAR MYXOMA
 Benign, painless, slowly growing, well-circumscribed but
unencapsulated neoplasm
 40 – 70 years old adults
 Usually involves thigh, shoulder and upper arm muscles.
 Have GNAS1 mutations
 Cytomorphology
 Sparsely cellular, consisting in large part of abundant, myxoid
matrix
 Absent or very scant vascular component
 Uniform cells with a bland nucleus
 Long, fibrillary cytoplasmic processes
 Multinucleated atrophic muscle fibers
 Macrophages with vacuolated cytoplasm
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INTRAMUSCULAR MYXOMA
DIFFERENTIAL DIAGNOSIS
 Ganglion cyst – absence of ophages; the spindle-shaped, stellate, or polygonal myxoma cells
 Nodular fasciitis - haphazard cellular arrangement of polymorphic myofibroblasts and ganglion-like
cells,
 Soft tissue perineurioma with prominent myxoid stroma - more slender perineural cells, EMA and cludin
1 +ve
 Low-grade myxofibrosarcoma
 Low-grade fibromyxoid sarcoma - prominent vascular component + nuclear atypia.
 Myxoid liposarcoma – adipose cells
 Extraskeletal myxoid chondrosarcoma - brightly magenta and fibrillarstroma, lacelike arrangement of
tumor cells is more uniform than
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SOFT TISSUE PERINEUROMA
 Benign peripheral nerve sheath neoplasm
composed of perineurial cells
 Subcutaneous tissue of the limbs
 Middle-aged adults.
 Cytomorphoogy
 Variable cellularity
 Myxoid or collagenous stroma
 Absent or very scant vascular component
 Slender cells with a bland nucleus and bipolar, thin,
 Long cytoplasmic processes
Differential diagnosis
• DFSP
• Cellular myxoma
• low-grade fibromyxoid sarcoma
• Neurofibroma
• Schwannoma – S-100
• low-grade sarcomas - more cytologic
atypia
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MYXOFIBROSARCOMA
 One of the most common sarcomas.
 Extremities of elderly patients
 Usually dermal or subcutaneous,
 Recuurence common(60%)
 Cytomorphology
 Variable amounts of myxoid matrix
 Short segments of curved, collagenized vessels
 Mildly atypical spindle and stellate cells (low-grade tumors)
 Marked nuclear pleomorphism, multinucleation, and necrosis (high-grade tumors)
 Pseudolipoblasts
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LOW-GRADE FIBROMYXOID SARCOMA
 Affects mainly Younger adults(3rd to 5th decades).
 Arises in the deep soft tissue of the thigh or trunk.
 Deceptively bland morphology.
 Up to 45% of cases eventually metastasize after a long indolent course.
 Cytomprphology
 Abundant myxoid matrix
 Uniform fibroblast-like oval to spindle cells with mild nuclear atypia
 No significant vascularity or nuclear pleomorphism
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 Cellular myxoma – less cellular and poorly vascularized.
 Soft tissue perineurioma - longer cytoplasmic processes
 Low-grade myxofibrosarcoma – clinical
 Low-grade malignant peripheral nerve sheath tumor
 Extraskeletal myxoid chondrosarcoma – MUC 4 -ve
 Solitary fibrous tumor CD 34 +ve
 Desmoid fibromatosis
More notable nuclear
atypia.
32

MYXOID LIPOSARCOMA
Occurs in slightly younger individuals
Deep soft tissue of the lower limbs, especially the thigh.
could be classified as high and low grade
 Cytomorphology
 Low grade
 Prominent myxoid matrix.
 Characteristic branching vascular pattern,
uniform round or ovoid tumor cells, and
 Uni or multi vacuolated small lipoblasts.
 No mitoses
 Few dispersed tumor cells
 Rich yield of clusters and clumps of round or
ovoid tumor cells embedded in matrix.
 Tumor cells with a high nuclear/cytoplasmic
(N/C) ratio and round nuclei with vesicular
chromatin.
 Less conspicuous myxoid matrix and capillaries
compared to low grade.
 Few to none lipoblasts
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MYXOFIBROSARCOMA-LIKE DEDIFFERENTIATED
LIPOSARCOMA
 Nonlipogenic spindle cell or pleomorphic sarcoma with
distinict areas of ALT/WDL.
 Dedifferentiation is not limited to liposarcomas
 Undifferentiated pleomorphic sarcoma or
myxofibrosarcoma.
 Grade – range from low to high
 Myxofibrosarcoma encountered in the retroperitoneum -
dedifferentiated liposarcoma tops the DDX
 Cytomorholgy
 Abundant granular myxoid matrix
 Thick-walled branching vessels
 Spindle cells with mild to moderate nuclear atypia and
sometimes, vacuolated cytoplasm
 Occasional multinucleated tumor cells
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MYXOINFLAMMATORY FIBROBLASTIC SARCOMA
 Locally aggressive fibroblastic neoplasm of the distal
extremities in middle-aged adults.
 Low grade sarcoma with frequent local recurrence risk
 Most arise in the subcutaneous tissue of the feet and
hands.
 Translocation t(1;10) involving TGFBR3 and MGEA5
 CYTOMORPHOLOGY
 Myxoid matrix
 Mixed population of bland spindle cells and mononuclear
epithelioid cells
 Large atypical Reed-Sternberg-like cells with macronucleoli
 Mixed inflammatory cells with hemosiderin and macrophages
 Pseudolipoblasts
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EXTRASKELETAL MYXOID CHONDROSARCOMA
 Slowly growing malignant tumor of adults.
 Involves deep soft tissues of the proximal limbs, especially thigh and popliteal fossa.
 Cytomorphology
 Chondromyxoid background
 Dispersed cells, branching cords, strands, and cell balls
 Spindly shaped, fusiform or round cells with ovoid or rounded nuclei
 Bland nuclear chromatin and small nucleoli
 Chondroblast-like lacunar structures
 Lack of significant vascularity
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• Soft tissue lesion with spindle cell feature having smooth muscle, nerve sheath, myofibroblastic, or other
mesenchymal origin.
• Specific entity or line of differentiation, definitive classification depends on IHC studies using a panel of
antibodies
• DDx include Spindle cell carcinoma and melanoma
• Most benign lesions are superficially located whereas sarcomas are deep-seated
• Cellularity
• Molecular analysis and immunohistochemistry is helpful in resolving the differential diagnosis
Spindle Cell Neoplasms
Soft tissue tumors
Adipocytic and Lipogenic
Neoplasms
Myxoid Neoplasms
Fibrohistiocytoid Neoplasms
Spindle Cell Neoplasms
Epithelioid Neoplasms
Pleomorphic Neoplasms
Dedifferentiated Sarcomas 39

LEIOMYOSARCOMA
 Accounts for 10–15% of all primary soft tissue sarcomas
 Most often occure in the retroperitoneum and limbs
 Intraabdominal (40% to 45%), Subcutaneous/deep soft tissue, vascular leiomyosarcomas
 Superficial LMS – show indolent clinical course where as deep seated have aggressive Bhr with high risk of mets.
 Immunoreactive for smooth muscle actin (SMA), desmin, and caldesmon and –ve for S-100
 Partly reactive for CK and EMA
 Cytomorphology
 Hypercellular smears (hypocellular in tumors with hyalinized)
 Three major cellular patterns in low power: mixed fascicular/pleomorphic(most common), predominantly fascicular, and
predominantly pleomorphic
 Spindle-shaped cells
 “Cigar-shaped” nuclei, some with indentation
 Naked nuclei
 Abundant homogeneous, finely granular cytoplasm(
 Mitoses are common
 High-grade LMS, marked cellular atypia, pleomorphism, necrosis, and multinucleated giant cells
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41

SCHWANNOMA
 Benign tumors of nerve sheath origin that
 Primarily affect adults.
 Usually involve the limbs, head and neck,
retroperitoneum, and posterior mediastinum.
 Painful on aspiration
 Cytopathology
 Large, cohesive fragments
 Wavy, “fishhook” nuclei
 Pointed nuclear ends
 Nuclear palisading
 Filamentous cytoplasm 42

SCHWANNOMA
 Cellular and ancient schwannoma variants may mimic malignancy –
 S-100 and SOX10 is characteristic of schwannoma
 Spindle cell lipoma – mature adipocytes + CD 34+ve
 MPNST, low grade focal S-100 and S-100 expression
 Leiomyosarcoma, low grade
 Solitary fibrous tumor - ropy collagen fibers, bland spindle cells, and oval rather than wavy nucle, CD34
and STAT6+ve
 Neurofibroma – variably S- 100 expression
 Desmoid fibromatosis - less cellular smears and more abundant collagenous stroma
43

MALIGNANT PERIPHERAL NERVE SHEATH TUMOR
 Sarcoma arising from a peripheral nerve or as a malignant transformation of neurofibromas
 Commonly affects - large- and medium-sized nerves of the upper arm, buttock, brachial plexus, and
paraspinal nerves.
 Cytomorphologic features are non-specific
 Cells having elongated with fusiform, often comma-shaped, wavy, or buckled nuclei
 Small fascicles
 Discrete cells
 Pointed ends
 Fibrillar collagenous matrix
 Necrosis and apoptosis can be present. 44

45

DDX OF MPNST
 Schwannoma (especially with “ancient” change) -
 Synovial sarcoma - less morphologic variability and nuclear pleomorphism
 Leiomyosarcoma - blunted/truncated ends nuclei with dense cytoplasm
 Spindle cell carcinoma
 Spindle cell melanoma
 Malignant solitary fibrous tumor
 Dedifferentiated liposarcoma (retroperitoneum)
46

SYNOVIAL SARCOMA
 Malignant tumor that account for 10% of all sarcomas occurs at any age but mainly in young adults
 Wide anatomic distribution
 Most are deep seated and arise in the lower limbs, especially the thigh, might occur in the trunk and a wide variety of visceral
organs.
 Immunoreactive for CK and EMA, CD99 (O13)(2/3), S-100(30%) TLE1(highly sensitive but)
 Cytomorphology
 High cellularity
 Cell clusters alternating with dispersed cells
 Cell clusters with shaggy edges and thin, branching capillaries
 Extreme uniformity of cells
 Bland, oval nucleus
 Scant, delicate, tapering cytoplasm
 Occasional epithelial elements
 Mitoses
 Mast cells
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48

DDX OF SYNOVIAL SARCOMA
 Leiomyosarcoma – blunted nucleus and dense cytoplasms
 Malignant peripheral nerve sheath tumor - coma like, curved and pointed nucleus, and pleomorphism
 Solitary fibrous tumor – has fewer dispersed cells, more complex cellular clusters, ropy collagen fibers &
blood
 Ewing sarcoma – immunohistochemistry and analysis by SS18 FISH
 Ectopic hamartomatous thymoma - bland spindle cells, squamoid epithelial islands, and mature adipose
tissue,
 Metastatic carcinoma - atypia
 Carcinosarcoma
49

SOLITARY FIBROUS TUMOR
 Formerly called hemangiopericytomas.
 Benign fibroblastic neoplasm that involves mainly
the pleura, practically occurs at any location in the
body.
 Affects adults and presents as a slowly growing
mass.
 Characterized by an NAB2STAT6 fusion, -
 IHC - STAT6 expression helpful.
 Cytomorphology
 Variable cell yield and bloody background
 A meshwork of irregular fascicles and individual cells
 Bland spindle cells with a fusiform nucleus
 Scant elongated cytoplasmic processes
 Ropy collagen
 Naked nuclei
50

51

 MPNST, low grade - nuclear pleomorphism and atypia.
 Monophasic synovial sarcoma - uniformity of cell population and cellular arrangements is prominent.
 Desmoid fibromatosis - hypocellular smears, with more abundant collagenous stroma.
 Sarcomatoid mesothelioma
 Spindle cell thymoma
 Benign or malignant lipomatous tumor (for fat-forming variant)
Positive for keratins and negative for CD34.
52

DESMOID (DEEP) FIBROMATOSIS
 Broad spectrum of locally aggressive fibroblastic neoplasms.
 Infiltrative growth pattern and can recur but never metastasize.
 Could be initial manifestation of FAP
 IHC – Nuclear β catenin expression(75%)
 CYTOMORPHOLOGY
 Variable, often low cellularity
 Bland spindle-shaped cells, isolated or in slender fascicles
 Fragments of dense collagenous stroma
 Oval to elongated nuclei, frequently with crush artifact
 Multinucleated degenerated skeletal muscle cells (if infiltrative or intramuscular)
 Rare mitotic activity
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DDX OF DESMOID FIBROMATOSIS
 Nodular fasciitis -
 Low-grade fibromyxoid sarcoma
 Scar tissue
 Nerve sheath tumor
 Smooth muscle tumor
 Solitary fibrous tumor
 Gastrointestinal stromal tumor
Cellular and pleomorphic smears with a haphazard cellular
arrangement and ganglion likelike cells.
has alternating myxoid and fibrous areas and is positive for
MUC4.
less cellularity and greater cohesion.
longer and wavier nuclei
blunted nuclei
more complex, irregular tissue fragments
and a
more prominent vascular component.
55

NODULAR FASCIITIS
 Relatively common, self-limiting, fibroblastic and myofibroblastic pseudosarcomatous
proliferation
 Typically occurs in subcutaneous tissue.
 Affects all age groups but most common in young adults.
 Most common sites are the upper extremities, trunk, and head and neck
 Rapid growth over a relatively short period of time, usually no more than 2 months
 usually measures 2 to 3 cm in greatest dimension rarely exceed 5cm
 Tender and some times ulcerate
 Trauma history reported in some patients
 recurrent gene rearrangements involving the USP6 locus
CYTOMORPHOLOGY OF NODULAR FASCIITIS
• Myxoid background (early phase)
• Clusters and numerous dispersed polymorphic (e.g., spindle-shaped, stellate)
myofibroblasts
• No significant hyperchromasia
• Uninucleated or binucleated ganglion-like cells with eccentric nuclei and prominent
nucleoli
• Inflammatory cells
• Myofibroblasts are positive for SMA and panmuscle actin, but negative for desmin and
S-100,
The differential diagnosis includes a variety of sarcomas – clinical information
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57

DERMATOFIBROSARCOMA PROTUBERANS
 Slowly growing fibroblastic tumor of the dermis and subcutis
 Young adults,
 Stays for 5 years (even decades) before diagnosis
 Occurs mainly on the trunk, proximal extremities, and groin,
 Progression to fibrosarcoma occurs in 10% to 15% of cases.
 CYTOMORPHOLOGY
 Dense, storiform cell clusters in a collagenous stroma
 Dispersed or loose clusters of spindle cells in a myxoid stroma(myxoid variant)
 Mildly atypical spindle cells with minimal pleomorphism
 Occasional entrapped adipose tissue 58

59

DDX OF DESMOID FIBROMATOSIS
 Benign fibrous histiocytoma
 Nodular fasciitis
 Scar tissue
 Soft tissue perineurioma
 Neurofibroma
 Low-grade fibromyxoid sarcom
Anatomic location and rate of growth
Haphazard cellular arrangement, spindle-shaped and
ganglion-like cells, less rounded nuclei, and more prominent
nucleoli, often with an inflammatory infiltrate.
Less cellularity and greater cohesion.
Excluded by the lack of neural
nuclear features and the absence of immunoreactivity
for
S-100 and EMA
Deep-seated, negative for CD34, and
positive for MUC4.
60

INFLAMMATORY MYOFIBROBLASTIC TUMOR
 Low-grade neoplasm of children and adolescents
 Usually associated with a clinical history of trauma, a surgical procedure, or infection.
 Has a local recurrence rate of 10% to 25%, and metastases occur in just under 5% of cases.
 Propensity to visceral organs comprising lung and liver, along with the abdominal cavity.
 Cytomorphology
 Fascicular proliferation of plump myofibroblasts with a prominent infiltrate of plasma cells and lymphocytes.
 Inflammatory cells
 Mildly pleomorphic spindle cells
 Large polygonal cells
 Elongated cytoplasmic tails
 Positive for SMA (80%), desmin (60%), and keratins(30%) ALK(50%)
61

62

DDX OF INFLAMMATORY MYOFIBROBLASTIC TUMOR
 Inflammatory pseudotumor
 Inflammatory leiomyosarcoma
 Desmoid fibromatosis
 Gastrointestinal stromal tumor
 Dedifferentiated liposarcoma
 Follicular dendritic cell sarcoma
 Angiomatoid fibrous histocytoma
Usually associated with a clinical history of trauma, a surgical procedure, or
infection.
SMA,desmin, and caldesmon
β-catenin
KIT and DOG1
MDM2 and CDK4
CD21 and CD35
EWSR1gene rearrangement by either FISH or RT-PCR
63

ADULT FIBROSARCOMA
 Best regarded as a diagnosis of exclusion.
 Cannot reliably diagnosed by FNA
64

Soft tissue tumors
Adipocytic and Lipogenic
Neoplasms
Myxoid Neoplasms
Fibrohistiocytoid Neoplasms
Spindle Cell Neoplasms
Epithelioid Neoplasms
Pleomorphic Neoplasms
Dedifferentiated Sarcomas
• Soft tissue lesion with histiocytoid and multinucleated giant cell morphology
• Only a few tumor types show true fibrohistiocytic differentiation mainly
• Tenosynovial giant cell tumor (localized and diffuse types) and
• Giant cell tumor of soft tissue.
65

TENOSYNOVIAL GIANT CELL TUMOR
 Localized type – AKA giant cell tumor of tendon sheath
 Slowly growing, circumscribed, and at least partially encapsulated nodule in close proximity to the
synovium of the tendon sheath of hand and feets
 occurs more commonly in females between the ages of 30 and 50 years
 Diffuse-type – previously known as pigmented villonodular synovitis
 Locally destructive lesion with an infiltrative growth pattern, occurring at intraarticular and
extraarticular sites
 tends to affect younger patients than its localized counterpart, and affected patients are prone to
recurrence.
 Predominantly affects the knee (75% of cases), followed by the hip (15%), ankle, elbow, and shoulder.
 Both have a COL6A3-CSF1 gene fusion in a small subset of tumor cells, mainly the larger epithelioid
cells.
CYTOMORPHOLOGY OF NODULAR
• Mononuclear histiocytoid cells of varying shapes (ovoid, polygonal, and spindle-
shaped)
• Foamy histiocytes
• Osteoclast-type giant cells
• Extracellular and intracytoplasmic hemosiderin (“ladybug cells”)
• Moderate anisocytosis and minimal anisokaryosis
• mitosis occasionally present, nuclear atypia and necrosis are rare
66

67

DDX OF TENOSYNOVIAL GIANT CELL TUMOR
 Gouty tophi –
 Chronic synovitis with synovial hyperplasia
 Metastatic melanoma
 Giant cell-rich sarcoma
Lack of mononuclear cells and the presence of birefringent needle shaped
crystals on polarizing microscopy
Has more inflammation and sometimes necrosis, but giant cells and
hemosiderin deposition are usually not prominent.
More pleomorphism, nuclear atypia, and necrosis.
68

GIANT CELL TUMOR OF SOFT TISSUE
 Usually arises as a superficial lesion in the limbs
of adults, although a wide patient age range
 May show local recurrence but seldom
metastasize.
 Genetically different from giant cell tumor of
bone, which has H3.3 mutations
 Cytomorphology
 Histiocytoid spindle-to-ovoid cells with bland nuclei
 Multinucleated osteoclast-like giant cells
 Have similar nuclei to the mononuclear cells,
 Loose clusters and dispersed cells
 Hemorrhagic background
69

DIFFERENTIAL DIAGNOSIS OF GIANT CELL TUMOR OF SOFT TISSUE
 Solid aneurysmal bone cyst
 Tenosynovial giant cell tumor
 Nodular fasciitis
 Giant cell-rich sarcoma
Morphologicaly similar but extraosseous solid aneurysmal bone cyst has UPS6
rearrangements.
Show more heterogeneous population of cells, including foamy histiocytes
and a morphologically varied mononuclear component that includes spindle,
ovoid, and polygonal shapes
may have osteoclast-like giant cells but typically has
myofibroblastic morphology and harbors USP6
fusions.
Show overt features of malignancy, including
pleomorphism and necrosis.
70

ANGIOMATOID FIBROUS HISTIOCYTOMA
 Distinctive mesenchymal neoplasm of uncertain lineage.
 Slowly growing tumor in the deep dermis and subcutis
of the extremities in
 children, adolescents, and young adults, commonly
affected butit may also occur in middle-aged patients
 Local recurrences occur in 2% to 10% and metastases in
less than 1% of patients.
 CYTOMORPHOLOGY
 At least moderately cellular
 Dispersed cells or clusters
 Whorled arrangement of tumor cells
 Ovoid to spindled histiocytoid cells
 Capillaries with spindled endothelial cells in cellular clusters
 Bloody background and hemosiderin granules
 Occasional lymphocytes and plasma cells
71

DIFFERENTIAL DIAGNOSIS OF ANGIOMATOID FIBROUS
HISTIOCYTOMA
 Benign fibrous histiocytoma
 Inflammatory myofibroblastic tumor
 Nodular fasciitis
 Follicular dendritic cell sarcoma
More variable cytomorphology and Touton-like multinucleated
cells.
The cells are myofibroblasts, which have plumper nuclei and more
distinctive cytoplasmic tails/extensions
Bloody background, hemosiderin, and capillary-rich
smears favor AFH over follicular dendritic cell
sarcoma.
FISH to detect an EWSR1 or FUS rearrangement is valuable in confirming
the diagnosis of AFH in the right setting
72

Soft tissue
tumors
Adipocytic and
Lipogenic Neoplasms
Round cell Neoplasms
Fibrohistiocytoid
Neoplasms
Spindle Cell Neoplasms
Myxoid Neoplasms
Epithelioid Neoplasms
Pleomorphic Neoplasms
Dedifferentiated
Sarcomas
• Tumors of young patients and account for the majority of solid malignancies in the pediatric age group.
• Mostly high-grade malignancies
• FNA in conjunction with ancillary studies might be highly diagnostic.
• The sensitivity and specificity of FNA for the round cell neoplasms exceed 90%,
• Ancillary studies increases the accuracy.
• IHC is extremely helpful in resolving the DDX aand prompting confitmatory molecular testing
73

74

NEUROBLASTOMA
 Third-most common malignant tumor of childhood and the most common malignancy in the neonate.
 Most cases are diagnosed before the age of 5 years.
 Most cases arise in the adrenal gland or along the intraabdominal portion of the sympathetic chain.
 Cytomorphology
 Cellular smears with fibrillary matrix background
 Mostly noncohesive, small undifferentiated cells
 Rare neurogenic rosettes(Homer – Wright
 “Salt-and-pepper” chromatin
 Rare ganglion-like cells
 Invariably positive for neuron specific enolase and show occasional staining for neurofilament protein,
synaptophysin, and GFAP.
 Consistently positive for GATA3 and PHOX2B distinguishes neuroblastoma from it mimics.
 S-100 +ve schwanian differentiation.
75

76

EWING SARCOMA
 Primitive neoplasm showing varying degrees of neuroectodermal differentiation.
 Second-most common sarcoma of bone in children and young adults, after osteosarcoma.
 Shafts of the long bones, pelvic bones, ribs, and spine are most common sites affected.
 Rapidly enlarging, often painful mass of the deep soft tissues, with a predilection for the thigh, pelvis,
paravertebral region of the trunk, and foot.
 Characterized by an EWSR1-FLI1 (85%) or EWSR1-ERG (10%) gene fusion,
 Cytomorphology
 “Tigroid” background
 Hypercellular smears with dispersed isolated round cells
 “Light” cells and “dark” cells(mixture of viable and dying tumor cells.)
 Nuclear molding
 A thin rim of vacuolated cytoplasm
77

78

DIFFERENTIAL DIAGNOSIS OF EWING SARCOMA
 Alveolar rhabdomyosarcoma
 Poorly differentiated synovial sarcoma
 Desmoplastic small round cell tumor
 Precursor lymphoblastic leukemia/lymphoma
 Neuroblastoma
 Small cell osteosarcoma
 Mesenchymal chondrosarcoma
 “Molecular subsets” of undifferentiated round cell sarcomas
Usually has larger rhabdomyoblasts with more abundant, denser cytoplasm, and
multinucleated and spindle-shaped cells in addition to small round cells;
desmin and myogenin (myf-4) - +ve
TLE1, EMA, or keratins +ve along with cytogenetic analysis
Has smaller and more cohesive cells and exhibits a polyphenotypic
immunoprofile.
accompanied by lymphoglandular bodies and are
immunoreactive for lymphoid markers
Long, thin cytoplasmic processes, often connecting cells
More nuclear pleomorphism and hyperchromasia
EWSR1gene rearrangement by either FISH or RT-PCR
Molecular testing is needed. More variable (i.e., often negative or patchy) CD99
(O13) staining.
79

DESMOPLASTIC SMALL ROUND CELL TUMOR
 An aggressive malignant neoplasm of uncertain
histogenesis
 Has striking predilection for the serosal surfaces(Most
cases are intraabdominal).
 Affects mainly male adolescents and young adults b/n
the ages of 15 and 35 years.
 CYTOMORPHOLOGY
 Sheets and clusters of small to intermediate-sized cells
 Fragments of desmoplastic stroma
 Uniformly round, oval, or slightly angulated cells
 Nuclear molding.
 Vague, small acinar structures.
80

81

EMBRYONAL RHABDOMYOSARCOMA
 Rhabdomyosarcoma – four types.
 Embryonal, alveolar, pleomorphic, and spindle cell/sclerosing
 The embryonal and alveolar forms occur mainly in children,
 Pleomorphic RMSs occur almost exclusively in adults, and
 The spindle cell/sclerosing RMSs affect both children and adults.
 Most common sarcoma of childhood, and embryonal RMS accounts for the
majority in children (60%).
 Most common sites are the head and neck region (including the orbit and
meninges), the genitourinary tract, and the trunk.
82

83

ALVEOLAR RHABDOMYOSARCOMA
 A subtype with unfavorable prognosis
 Occurs most frequently in adolescents.
 Limbs, head and neck region, and trunk are the most common sites.
 Cytomorphology
 Highly cellular and infrequently have a “tigroid” background
 Most cells are undifferentiated, with larger cells than in embryonal rhabdomyosarcoma
 Uniformly round to polygonal cells
 Variable number of rhabdomyoblasts
 Multinucleated tumor giant cells with wreathlike nuclei
 Mitoses are common
84

85

DIFFERENTIAL DIAGNOSIS OF ALVEOLAR RHABDOMYOSARCOMA
 Ewing sarcoma
 Neuroblastoma
 Poorly differentiated synovial sarcoma
 Precursor lymphoblastic lymphoma/leukemia
 Extrarenal malignant rhabdoid tumor
86

Soft tissue
tumors
Adipocytic and
Lipogenic Neoplasms
Round cell Neoplasms
Fibrohistiocytoid
Neoplasms
Spindle Cell Neoplasms
Myxoid Neoplasms
Epithelioid Neoplasms
Pleomorphic Neoplasms
Dedifferentiated
Sarcomas
• Tumors composed of medium-sized or large, round or polygonal cells with ample cytoplasm.
• Metastatic carcinoma and melanoma are always in the differential diagnosis.
• Yield cellular smears with cohesive tumor cell aggregates, as well as numerous individually dispersed
neoplastic cells..
• Includes the epithelioid variants of many benign and malignant soft tissue neoplasms such as epithelioid
schwannoma and epithelioid angiosarcoma,
• IHC is helpful in establishing the Dx and excluding metastatic carcinoma, melanoma and large cell
lymphoma.
87

88

EPITHELOID SARCOMA
 Rare malignant mesenchymal neoplasm with an epithelioid cytomorphology and immunophenotype.
 Affects the distal extremities of young adults predominantly in males.
 Superficial tumors involving the dermis and subcutis, or tendo-aponeurotic.
 Slowly growing masses often of long duration.
 Pain and ulceration are frequent.
 have aberrations of the SMARCB1 (INI1) gene on 22q, which results in the nuclear loss of INI1 protein
expression
89

90

DIFFERENTIAL DIAGNOSIS OF EPITHELIOID SARCOMA
 Metastatic carcinoma and melanoma
 Epithelioid hemangioendothelioma
 Pseudomyogenic hemangioendothelioma
 Epithelioid angiosarcoma
 Epithelioid malignant peripheral nerve sheath tumor
 Myoepithelial carcinoma of soft tissue
 Extrarenal malignant rhabdoid tumor
Difficult to distinguish, clinical presentation of an extremity mass in a
young patient is an important clue to the correct diagnosis
Negative for vascular markers such as CD31 and ERG and +ve for
CAMTA1
FOSB +ve
S-100 +ve
younger patients, is CD34-negative, and has mutations in
SMARCB1 gene
Loss of nuclear INI1 expression, favors ES, epithelioid MPNST and extrarenal
malignant rhabdoid tumor
91

CLEAR CELL SARCOMA OF SOFT TISSUE
 Arises in the deep soft tissue of the extremities in young adults
 Often found in close proximity to aponeurotic structures and tendons.
 Cytomorphology
 Moderately cellular, containing mostly dispersed cells with occasional small clusters of loosely cohesive cells
 Polygonal or spindly shaped cells with abundant clear or pale cytoplasm and large round or ovoid nuclei and
prominent nucleoli.
 Intranuclear cytoplasmic pseudoinclusions, melanin, wreath like multinucleation, and tigroid background can also
present.
 Are diffusely and strongly positive for S-100 protein and HMB-45.
 Harbors the characteristic translocation t(12;22)(q13;q12) with EWSR1-ATF1 fusion,
92

93

ALVEOLAR SOFT PART SARCOMA
 Tumor of older adolescents and young adults, with a slight female predominance.
 Slowly growing, deep-seated, painless mass
 Most common in the lower extremities or limb girdle, especially the anterior thigh.
 Negative for keratins, EMA, chromogranin, and synaptophysin
 Unbalanced (X;17) translocation – results in an ASPSCR1-TFE3 fusion gene and nuclear overexpression of TFE3
protein. – charcterstick
 Cytomorphology
 Slight to moderate cellularity, with numerous naked nuclei.
 Largely noncohesive cells but sometimes aggregate in large Group
 Uniform Large, round to polygonal cells
 Prominent nucleolus
 Abundant granular and fragile cytoplasm
 Intracytoplasmic and extracellular PAS-positive rhomboid crystals are a helpful but rare 94

95

DIFFERENTIAL DIAGNOSIS OF ALVEOLAR SOFT PART SARCOMA
 Granular cell tumor
 Melanoma
 Rhabdomyoma
 Paraganglioma
 Renal cell carcinoma
 PEComa
 Strong nuclear staining with TFE3 and variable staining with desmin and S-100, and are negative for
keratins, EMA, chromogranin, and HMB-45.
96

EPITHELIOID HEMANGIOENDOTHELIOMA
 Rare malignant vascular neoplasm, affecting adults over the age of 20 years.
 Occurs in the extremities, head and neck region, trunk, mediastinum, bone, and visceral organs such as
lung & liver
 ~50% arise from a large or medium sized vein.
 Frequently multicentered.
 Cords of epithelioid endothelial cells embedded in a myxohyaline stroma.
 WWTR1-CAMTA1 gene fusion is identified in most cases.
97

DIFFERENTIAL DIAGNOSIS OF EPITHELIOID
HEMANGIOENDOTHELIOMA
 Metastatic carcinoma
 Melanoma
 Epithelioid sarcoma
 Epithelioid angiosarcoma
 Pseudomyogenic hemangioendothelioma
 Mesothelioma
 Epithelioid hemangioma
Ruled out by Lower degree of nuclear atypia and mitotic activity of
EHE
FOSB +ve
Positive for mesothelial cell markers (calretinin, WT-1)
More superficially located (and rarely sampled by FNA) and more
obviously vasoformative.
98

99

EPITHELIOID ANGIOSARCOMA
 Rare but highly aggressive malignant vascular tumor, has a marked predilection for males, usually adults
in mid- to late life.
 Rapidly growing tumor of deep soft tissues
 Cytomorphology
 Extensively bloody background
 Large, noncohesive epithelioid cells
 Moderate to marked nuclear pleomorphism
 Prominent nucleolus
 Occasional vasoformative structures: pseudoacini with central erythrocytes or intracytoplasmic lumina containing
erythrocytes
 Numerous mitoses
 Endothelial markers – endothelial markers CD31, CD34, ERG, and FLI1 +ve keratins in up to 50%.
100

101

GRANULAR CELL TUMOR
 Relatively common
 Slowly growing neoplasms with neuroectodermal differentiation.
 Benign with rare malignant counterpart.
 most commonly occure in the head and neck region, including the tongue of middle-aged adults.
 Cytomorphology
 Bare nuclei in a granular background
 Uniform cellular appearance
 Small nuclei
 Abundant granular cytoplasm
 Strong cytoplasmic staining for S-100 and SOX10, NKI/C3, positive for CD68, TFE3(lack TFE gene
rearrangement)
102

DIFFERENTIAL DIAGNOSIS OF GRANULAR CELL TUMOR
 Fat necrosis
 Whipple disease
 Rhabdomyoma -
 Alveolar soft part sarcoma -
 Renal cell carcinoma -
-ve for S-100 prominent nucleoli, frequent Binucleation and multinucleation, and
pseudoacinar or pseudoalveolar arrangements, TFE3 FISH confirms
a TFE3 rearrangement.
have some cells with clear cytoplasm, and they are positive for
PAX8.
103

Soft tissue
tumors
Adipocytic and
Lipogenic Neoplasms
Round cell Neoplasms
Fibrohistiocytoid
Neoplasms
Spindle Cell Neoplasms
Myxoid Neoplasms
Epithelioid Neoplasms
Pleomorphic Neoplasms
Dedifferentiated
Sarcomas
• Poorly differentiated or dedifferentiated forms of entities that have a clear line of differentiation.
• Are aggressive and considered high grade for management purposes.
• Most pleomorphic sarcomas prove to show a definitive line of differentiation
• Undifferentiated pleomorphic sarcoma is a diagnosis of exclusion.
104

UNDIFFERENTIATED PLEOMORPHIC SARCOMA
 Considered part of the morphologic spectrum of all undifferentiated soft tissue sarcomas (USTSs)
 Include undifferentiated round cell, spindle cell, pleomorphic, epithelioid, or “not otherwise specified”
cytomorphology.
 account for 5% to 10% of sarcomas in adults over age 40
 Occur mostly in the extremities and trunk;
 Show no identifiable line of differentiation by morphologic, immunohistochemical, or genetic grounds.
 Diagnosis of exclusion and best deferred to surgical resection, unless presenting as a recurrence or
metastasis.
Cytomorphology
• Highly cellular smears
• Variable proportions of cellular clusters
and dispersed cells
• Marked cellular and nuclear
pleomorphism and anaplasia
• Giant cells with solitary or multiple
nuclei
• Numerous mitoses including atypical
forms
• Necrosis
105

106

DDX UNDIFFERENTIATED PLEOMORPHIC SARCOMA
 Sarcomatoid carcinoma
 Sarcomatoid mesothelioma
 Melanoma
 Anaplastic large cell lymphoma
 Pleomorphic sarcoma with a specific line of differentiation (e.g., rhabdomyosarcoma, liposarcoma)
 Dedifferentiated sarcoma
Both at least focal positivity for one or more keratins,
Mesothelioma is additionally positive for mesothelial cell markers
(calretinin, WT-1, and D2-40
Has melanin pigment in tumor cells and in adjacent macrophages
HMB 45, Melan a
Shows large, anaplastic, round cells with an embryo-like nucleus positive
for CD30 and in some cases for ALK as well.
Confirmed by demonstrating a clear line of differentiation
Morphologically or with ancillary techniques.
Clinical history and the presence of a differentiated area are essential for
the diagnosis of a specific dedifferentiated sarcoma
107

PLEOMORPHIC RHABDOMYOSARCOMA
 High-grade sarcoma showing large polygonal
cell cytomorphology and skeletal muscle
differentiation.
 Most commonly occurs in the lower extremities
of elderly patients.
 Cytomorphology
 Hypercellular smears with predominantly
dispersed cells
 Marked cellular and nuclear pleomorphism
 Large rhabdoid cells: eccentrically located nuclei,
prominent nucleoli, abundant cytoplasm with a
perinuclear density
 Frequent Binucleation and multinucleation
 Numerous mitoses including atypical forms
 Necrosis
108

DIFFERENTIAL DIAGNOSIS OF PLEOMORPHIC
RHABDOMYOSARCOMA
 Heterologous rhabdoid differentiation of other sarcomas
 Pleomorphic leiomyosarcoma
 Proximal-type epithelioid sarcoma
 Metastatic melanoma
 Metastatic carcinoma
Nuclear expression of myogenin (myf4) in additional to diffuse desmin
positivity is critical for establishing rhabdomyoblastic differentiation. 109

Soft tissue
tumors
Adipocytic and
Lipogenic Neoplasms
Round cell Neoplasms
Fibrohistiocytoid
Neoplasms
Spindle Cell Neoplasms
Myxoid Neoplasms
Epithelioid Neoplasms
Pleomorphic Neoplasms
Dedifferentiated
Sarcomas
• Rare.
• Well-differentiated liposarcoma, well-differentiated chondrosarcoma, and chordoma; undergo
dedifferentiation frequently
• Recent rapid growth of a previously stable mass is typical.
• Adjacent well-differentiated component – helpful to correct classify.
• Chondrosarcoma – 10% dedeifferentiation in => 10 years.
• Dedifferentiated liposarcoma is the most common of the three and accounts for up to 10% of
liposarcomas.
• It is usually retroperitoneal or intraabdominal
110

111

Soft tissue
tumors
Adipocytic and
Lipogenic Neoplasms
Round cell Neoplasms
Fibrohistiocytoid
Neoplasms
Spindle Cell Neoplasms
Myxoid Neoplasms
Epithelioid Neoplasms
Pleomorphic Neoplasms
Dedifferentiated
Sarcomas
112

113

APPROACH TO SOFT TISSUE LESIONS
 Is this a primary soft tissue tumour or others e.g. skin or bone lesion
 Is this benign or malignant ?
 What is the predominant cell pattern (pleomorphic, spindle cell, myxoid, small round cell, epithelioid
cell) ?
 Are there any specific diagnostic features ?
 If malignant, is it low or high grade ?
 Is it a primary sarcoma or metastasis (carcinoma, melanoma, lymphoma) ?
 Need to correlate with clinical history and radiology
 Perform immunostains and send sample for tumour cytogenetics
114