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Approach to cytopathology diagnosis of soft tissue tmors.pptx

Mar. 25, 2023
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Approach to cytopathology diagnosis of soft tissue tmors.pptx

  1. APPROACH TO CYTOPATHOLOGY DIAGNOSIS OF SOFT TISSUE TUMORS MERHAWI A. MD, RII HADAS W. MD, PATHOLOGIST 1
  2. OUTLINE  Objective  Introduction  General approach 2
  3. 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 3
  4. 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
  5. 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
  6. ANCILLARY STUDIES  Immunohistochemistry, cytogenetics, and molecular genetics significantly useful  Electron microscopy – rare  Flow cytometry is useful when lymphoma is in the differential diagnosis. 6
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  9. 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 9
  10. 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 - 10
  11. 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
  12. 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
  13.  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. 13
  14. LIPOMA ANGIOLIPOMA 14
  15. LIPOMA CHONDROID LIPOMA 15
  16. MYELOLIPOMA 16
  17. 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
  18. 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 18
  19. PLEOMORPHIC LIPOMA 19
  20. SPINDLE LIPOMA 20
  21. 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
  22. ALT/WDL  22
  23. 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 23
  24. PLEOMORPHIC LIPOSARCOMA 24
  25. 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 25
  26. 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 26
  27. 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 27
  28. 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 28
  29. 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 29
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  31. 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 31
  32.  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
  33. 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 33
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  35. 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 35
  36. 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 36
  37. 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 37
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  39. • 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
  40. 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 40
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  42. 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
  43. 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
  44. 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
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  46. 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
  47. 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 47
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  49. 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
  50. 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
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  52.  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
  53. 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 53
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  55. 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
  56. 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 56
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  58. 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
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  60. 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
  61. 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
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  63. 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
  64. ADULT FIBROSARCOMA  Best regarded as a diagnosis of exclusion.  Cannot reliably diagnosed by FNA 64
  65. 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
  66. 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
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  68. 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
  69. 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
  70. 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
  71. 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
  72. 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
  73. 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
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  75. 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
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  77. 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. 78
  79. 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
  80. 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. 81
  82. 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. 83
  84. 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. 85
  86. DIFFERENTIAL DIAGNOSIS OF ALVEOLAR RHABDOMYOSARCOMA  Ewing sarcoma  Neuroblastoma  Poorly differentiated synovial sarcoma  Precursor lymphoblastic lymphoma/leukemia  Extrarenal malignant rhabdoid tumor 86
  87. 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. 88
  89. 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. 90
  91. 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
  92. 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. 93
  94. 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. 95
  96. 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
  97. 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
  98. 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. 99
  100. 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. 101
  102. 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
  103. 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
  104. 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
  105. 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. 106
  107. 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
  108. 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
  109. 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
  110. 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. 111
  112. 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. 113
  114. 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

Editor's Notes

  1. The DDX is wide – it might include carcinoma, melanoma and lymphoma – narrows the ddx Recurrence of sarcoma DX
  2. Three main reasons for a false diagnosis are sampling error, A technically limited specimen, and misinterpretation
  3. Romanowsky – cytoplasmic details and matrix material Papnicolaou – nuclear details, optimizes results rom aspirates performed without the benefit of rapid evaluation, and can be used for adjunct studies, but cells can appear smaller, rounder, and falsely epithelioid, and useful background information (e.g., vascular patterns, chondromyxoid material) is sometimes lost.
  4. Immunohistochemistry is useful in narrowing a differential diagnosis, poorly differentiated neoplasm or soft tissue tumor that exhibits specific ultrastructural features, such as the Weibel-Palade bodies of vascular tumors. Karyotyping, FISH, and RT-PCR can provide results which are reproducible, relatively specific genetic/molecular abnormalities
  5. along with a descriptive interpretation, is useful
  6. Ewing sarcoma, synovial sarcoma, and angiosarcoma are high-grade malignancies, well-differentiated liposarcoma and dermatofibrosarcoma protuberans are low grade. General category Histologic subtype, or description with differential diagnosis Grade Mitoses (including atypical forms) Necrosis Ancillary study results Notes and recommendations
  7. Accounts for around half of soft tissue tumors but spare the hands and feet; DDX – Subcutaneous adipose tissue Pleomorphic lipoma Atypical lipomatous tumor/well-differentiated liposarcoma
  8. 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 older 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.
  9. Angiolipoma Mature adipose tissue with anastomosing capillaries
  10. Chondroid lipoma. (a–f) Clusters and small fragments of mature adipocytes with admixture of lipoblasts, small chondroid cells, and abundant myxochondroid background matrix (MGG and H&E). Note the lipoblast-like cells in (a–d)
  11. Myelolipoma. (a) Cellular smear showing trilineage hematopoietic elements with a megakaryocyte in the center. Hemosiderin-laden macrophages (arrow) and calcifications are common in large lesions (DQ stain). (b) Adipose tissue, frequently admixed with hematopoietic elements and/or lymphocytes, gives a false impression of hypercellularity, mimicking liposarcoma
  12. Hibernoma. (a–c) Clusters, sheets of round to oval and polygonal cells with abundant microvacuolated or granular cytoplasm, and centrally placed small uniform nuclei, sometimes mimicking a lipoblast (b) (MGG; H&E). (d) Overall hibernoma architecture is preserved in cell block material (H&E)
  13. spindle cells in short fascicles
  14. Pleomorphic lipoma (A) Mature adipose tissue; scattered large, dark multinucleated cells (H&E, IP); (B) Same case as A; large multinucleated cell (floret cell) (H&E, HP oil). Pleomorphic lipoma. (a) In scanning power fragments of mature fat, variable number of floret cells and spindle cells (H&E). (b–d) Floret cells and occasionally prominent myxoid background matrix (MGG)
  15. Spindle-cell lipoma. (a, b) Mixture of loosely cohesive clusters and dispersed bland spindle cells, mature adipose tissue, and fragments of brightly eosinophilic collagen–hyaline fibers (H&E). (c, d) Myxoid background and mast cells are common (MGG)
  16. Liposarcoma - most common soft tissue sarcoma of adults. well differentiated and dedifferentiated myxoid, and pleomorphic.
  17. Atypical lipomatous tumor/well-differentiated liposarcoma. (a–d) Mixture of ordinary lipoma-like fragments and atypical stromal cells and floret cells with enlarged, irregular hyperchromatic nuclei (H&E; MGG). (c) Occasional myxoid background in smears. (e) Dedifferentiated liposarcoma with non-lipogenic pleomorphic/spindle cells (Pap stain). Immunoreactivity with MDM2 (f) and CDK4, indicative of MDM2/CDK amplification, is characteristic for ALT/ well-differentiated liposarcoma and dedifferentiated liposarcoma
  18. multivacuolated, highly atypical lipoblasts. Extensive sampling to identify unequivocal atypical lipoblasts is necessary to separate pleomorphic liposarcoma from a pleomorphic sarcoma of another lineage.
  19. Fig. 14.26 Pleomorphic liposarcoma. (a–c) Smears are similar to non-lipogenic high-grade sarcomas but with admixed atypical lipoblasts (MGG). (d) Markedly atypical, bizarre, and giant multinucleated tumor cells (H&E)
  20. Cellular myxoma - morphologic variant that has increased cellularity and a vascular component, lacks the nuclear atypia and hyperchromasia of low-grade myxofibrosarcoma. Juxtaarticular myxoma - round knee GNAS 1 mutation –ve
  21. low-grade fibromyxoid sarcoma, which has alternating areas of myxoid and collagenous stroma. Adequate sampling is needed.
  22. Perineurial cells are positive for EMA, claudin-1, and CD34 (in two-thirds of cases) and negative for S-100 elongated spindle cells with bland nuclei in the myxoid background.
  23. principally during the sixth to eighth decades Could be high, intermediate or low grade Higher grade tendency to metastasis to lung, bone and LN
  24. Loosely cohesive cell clusters of moderately to markedly pleomorphic spindle end epithelioid cells and dispersed atypical single cells in a myxoid background. Note fragments of curved vessels (MGG; H&E). (e) Low-grade myxofibrosarcoma is sometimes indistinguishable from benign cellular myxoid neoplasms, such as cellular intramuscular myxoma (H&E). Pseudolipoblasts are common
  25. Cytogenetic testing is helpful - FUS-CREB3L2 fusion secondary to the translocation t(7;16)(q34;p11)
  26. Clinically - superficial soft tissues of elderly patients
  27. primarily those in their fourth and fifth decades
  28. round-to-oval, hyperchromatic nucleus with evenly distributed chromatin and an indistinct nucleolus. Molecular analysis and clinical details are important for the correct diagnosis. MDM2 and CDK4 by immunohistochemistry or amplification of MDM2
  29. Proximal sites can be affected. but infrequent distant metastases.
  30. median age at diagnosis of 50 years. no evidence of cartilaginous differentiation - tumor of unknown differentiation(WHO)
  31. (a–c) Dispersed cells, branching cords, strands, and cell balls of spindly shaped, fusiform, or round cells with ovoid or rounded nuclei in the myxoid back-ground matrix (H&E; MGG). (d) The typical histologic appearance of branching cords and strands of bland spindle cells is best appreciated in cell-block sections (H&E; cell block; Shandon kit)
  32. occur in older women in the retroperitoneum, mesentery, or omentum. extremities, particularly the thigh, with a slight male predominance Adjacent to muscular-walled blood vessels, particularly the inferior vena cava and large veins of the lower limbs in older adults.
  33. Small clusters and dissociated tumor cells with elongated, cigar-shaped, occasionally truncated or “in tandem” position nuclei Cohesive fascicles of atypical spindle cells (MGG; H&E). (c) Similar pattern is obvious in the cell-block section. (d) Strong desmin positivity supports diagnosis Leiomyoma Schwannoma – wavy, fishhook nuclei with fibrillary cytoplasmic process & S-100 MPNST- GIST vascular component Solitary fibrous tumor Desmoid fibromatosis
  34. Pleomorphic and multinucleated tumor cells – high grade Polygonal or rounded cells may predominate – epitheloid
  35. loosely fascicles of slightly or moderately atypical spindle cells with fusiform, wavy, or comma-like nuclei and occasional cytoplasmic processes in the fibrillary background matrix may be difficult to distinguish from benign nerve sheath tumors (MGG; H&E). (d) Corresponding cell block section with slightly pleomorphic spindle cells but atypical mitosis (cell block;) Pleomorphic epithelioid and spindle cells with hyperchromatic nuclei in loosely clusters and dispersed tumor cells. Without nowledge of clinical history and ancillary immunostains, correct diagnosis of MPNST is difficult to render based on cytomorphology alone (MGG; H&E). (d) Loss of H3K27me3 expression is seen in high-grade MPNST
  36. IHC -
  37. 10 – 35 years old Monophasic or biphasic, poor
  38. Tissue fragments mixed with dispersed uniform spindle cells in almost equal proportions. Note nuclear hyperchromasia and mitosis (H&E). (d) Cell block section with hyperchromatic spindle cells in a collagenous stroma Biphasic subtype showing small acinar-like and alveolar structures (MGG). (c, d) Poorly differentiated synovial sarcoma resembling Ewing sarcoma (H&E). (e, f) immunoreactivity for CD99 and focal positivity for keratin confirms diagnosis (cell block; CD99; Ck 19)
  39. SFT – IHC - STAT6 and CD34 and negative for EMA.
  40. common sites of involvement include deep soft tissue of the lower extremities, head and neck region, mediastinum, and retroperitoneum. 5% to 10% behave in a malignant fashion.
  41. A mixture of dispersed cells and fascicle-like clusters of uniform population of bland spindle cells with inconspicuous nucleoli (MGG; H&E). (c) Clusters of spindle cells mixed with mature fat in the fat-forming variant (MGG). (d) Classic architecture of SFT with HPC-like vessels better appreciated in the cell block sections (H&E). (e) Nuclear STAT6 staining is a useful diagnostic marker for solitary fibrous tumor (cell block)
  42. All mesenchymal mimics are negative for STAT6.
  43. Abdominal, extraabdominal, or intraabdominal mass. oval to elongated nucleus with bipolar ends
  44. Desmoid fibromatosis. (a–d) The mixture of cohesive or loosely cohesive clusters and dispersed uniform or slightly atypical spindle cells and fragments of paucicellular collagenous stroma (MGG; H&E). (e, f) Bland spindle cells in long fascicles, a useful clue suggestive of fibromatosis (H&E; MGG). Superficial fibromatosis. (g) Dispersed uniform or slightly enlarged fibroblasts with cytoplasmic processes and admixture of naked spindle-shaped bland nuclei (MGG).Juvenile hyaline fibromatosis. (h) Fragments of amorphous, paucicellular, eosinophilic hyaline material containing uniform fibroblasts and small capillaries (H&E)
  45. 50% of cases turn out to be non-diagnostic – paucicellular highly collageneous – use larger needles.
  46. Including the salivary gland collagenous stroma are more common in long-standing lesions. Nuclei are uniform and lack significant atypia Cytoplasm is generally abundant, Higher mitotic figure could be seen Proliferative fasciitis and myositis
  47. Cellular smears with numerous myofibroblasts embedded in a myxoid matrix Dispersed, polymorphic myofibroblasts are characteristic Mitoses are not unusual
  48. Small percentage – scalp(head and neck region) fibroblastic like and stealate cells display minimally pleomorphic, with bland, oval nuclei. chromatin is fine and homogeneous, and nuclear smooth and round Small, distinct nucleoli are usually present
  49. (a, b) Compact, often three-dimensional clusters of spindle cells with poorly defined cytoplasmic borders (MGG; H&E). (c, d) Cell block sections show a storiform pattern and positive CD34 staining by immunohistochemistry (cell block; Shandon kit; H&E; CD34+).
  50. most common on the extremities
  51. Epithelioid cytomorphology, myxoid stroma, and a neutrophil-rich inflammatory infiltrate, - epithelioid inflammatory myofibroblastic Sarcoma highly cellular smears with a prominent inflammatory cell population Isolated spindle-shaped tumor cells are admixed with loose clusters and dense aggregates. slightly eccentrically placed, plump nuclei with finely granular chromatin and conspicuous small nucleoli. Fine cytoplasmic vacuolization and cytoplasmic tails or extensions are typical Anaplastic lymphoma receptor tyrosine kinase (ALK)
  52. Spindle cells with plump nuclei, prominent nucleoli, and frequent cytoplasmic tails are arranged in loose clusters (Papanicolaou stain). (B) Up to half of all cases show cytoplasmic ALK expression, secondary to an ALK gene rearrangement.
  53. Most DDx distinguished from IMT by immunohistochemistry
  54. Most of the cases diagnosed before the era of immunohistochemistry and electron microscopy turned to be MPNST and monophasic synovial sarcoma
  55. Localized and Diffuse Types - share similar cellular compositions and cytomorphology but differ in their growth pattern, clinical features, and biologic behavior. Tumors have moderate to high cellularity. The predominant cells—mononuclear histiocytoid cells with folded nuclei and foamy cytoplasm, Larger epithelioid cells with eccentric nuclei—are dispersed as isolated cells and arranged in irregular clusters minimal nuclear variation. ovoid, with smooth contours, finely granular chromatin, inconspicuous nucleoli, frequent grooves, and occasional intranuclear inclusions
  56. (a–c) Dispersed and small clusters of mononuclear cells with round to oval nuclei and mild to moderate cellular and nuclear pleomorphism with admixture of osteoclast-like giant cells, xanthomatous histiocytes, and siderophages (H&E; MGG). (d) Similar morphology in cell block sections Mononuclear histiocytoid cells are arranged in clusters. There is prominent intracytoplasmic hemosiderin, imparting a speckled, ladybug-like appearance to the cells (Papanicolaou stain).
  57. Immunohistochemistry is very ueful - mononuclear cells and the giant cells are both positive for the histiocytic markers CD163 and PU.1, and subset may show desmin staining
  58. Histologically, tumors show a multinodular growth pattern, with fibrous septae separating tumor nodules comprised of ovoid and round mononuclear cells, osteoclast-like giant cells, and hemosiderin-laden macrophages within a richly vascularized stroma. Mononuclear histiocytoid cells, often with vacuolated cytoplasm may look plasmacytoid, unipolar, or bipolar. They are accompanied by large and often bizarrely shaped multinucleated giant cells
  59. Immunohistochemistry is very ueful - mononuclear cells and the giant cells are both positive for the histiocytic markers CD163 and PU.1, and subset may show desmin staining
  60. rarely in other sites such as the lung and bone. Histologically it is characterized by nodules and sheets of histiocytoid cells arranged in ill-defined fascicles or whorls; cystic spaces with hemorrhage; and a peripheral, thick fibrous pseudocapsule containing a lymphoplasmacytic infiltrate Ball-like clusters of histiocytoid cells are commonly associated with capillaries lined by spindle-shaped endothelial cells.
  61. expresses EMA, desmin, CD68, and CD99 in about 50% cases and lacks reactivity for keratin, S-100, CD34, and follicular dendritic cell markers (CD21, CD35).
  62. But they can occur anywhere along the sympathetic chain. Most cells are uniformly small and undifferentiated in appearance. Larger and have a moderate amount of cytoplasm – differentiating cells In better differentiated lesions, Schwannian-type spindle cells are present. binucleated and multinucleated ganglion-like cells have a more coarsely granular chromatin, prominent nucleoli, and a moderate amount of cytoplasm. round to oval, with only slight irregularities finely granular (“salt-and-pepper”) chromatin, and small nucleoli.
  63. (a, b) Small clusters of molded neuroblasts, some with kidney- or V-shaped nuclei. No neuropil (MGG); mitotic figures (c) and delicate cytoplasmic processes (d) can be easily found in smears (MGG and HTX) Rosettes in neuroblastoma
  64. Accounts for 10% to 20% of cases. Rare before age 5 and after age 30, 80% of cases arise in patients younger than 20 years old. Pseudorosettes are a fairly specific but rare finding. ES cells are approximately two to three times the size of a small lymphocyte and have a high nuclear-to-cytoplasmic ratio. Nuclear molding is prominent. No multinucleated or ganglion-type cells are present.
  65. Tumor cells show small- to medium-sized irregular nuclei with tiny nucleoli and mitoses (H&E). (d–f) Tigroid background of the smears and two cell types: large light cells with vacuolated and clear cytoplasm mixed with small dark cells are evident in air-dried smears (MGG) (c, d) Smears with rosettes (H&E; Pap stain). (e) Cell block showing well-preserved morphology with presence of rosettes and (f) distinct membranous CD99 positivity
  66. The DDX includes all small round cell neoplasms, Immunohistochemistry is paramount in addressing the DDx
  67. but can involve the pelvis, retroperitoneum, scrotum, and pleura.
  68. (a) Loosely cohesive small clusters of ovoid undifferentiated cells with slightly irregular nuclear contours, finely granular chromatin, and scant cytoplasm (Pap stain). (b) Tight cluster of malignant cell with scant and poorly preserved cytoplasm, irregular hyperchromatic nuclei, and molding (MGG). (c) Small nests of tumor cells with associated desmoplastic stroma are characteristic (cell block; H&E). Demonstration of polyphenotypic differentiation with positive immunoreactivity for cytokeratins, EMA, desmin (d), and neuroendocrine markers is diagnostically helpful. Note the perinuclear dot-like staining pattern for desmin (cell block)
  69. distinction between embryonal and alveolar, has significant prognostic implications, Cytomorphology is usually insufficient for this distinction, ancillary diagnostic methods, especially cytogenetic/molecular studies, are the standard of care
  70. (a–d) Hypercellular smears with loosely cohesive clusters and dispersed single cells of various morphologies (triangular, rounded, tadpole- or strap-shaped) (H&E; MGG). Mitoses and multinucleation are Common Embryonal RMS cells show myogenic differentiation manifested by positive immunoreactivity for desmin and muscle-specific actin, and multifocal expression of the protein products of the specific myogenic nuclear transcription factors myo-D1 and myogenin
  71. Alveolar RMS cells are rounder, with larger and more irregular nuclei. Immunoreactive for desmin, muscle-specific actin, myo-D1, and myogenin(diffuse nuclear expression – charactersticks). Most ARMS have either PAX3-FOXO1 or PAX7-FOXO1 gene fusion, which can be detected by FISH
  72. (a, b) Loosely cohesive clusters and dispersed, single, small- and medium-sized cells with hyperchromatic nuclei and prominent nucleoli (H&E). (c, d) Rhabdomyoblastic morphology (H&E; MGG). (e, f) Diffuse and strong desmin and myogenin positivities support with diagnosis (cell block; desmin; myogenin)
  73. granular cell tumor, epithelioid sarcoma, and alveolar soft part sarcoma.
  74. Mainly the hands and wrists Proximal type Vs Distal(conventional) Proximal type - affect the deep soft tissue of the pelvis and perineum and are more aggressive
  75. (a) Dispersed, round, or polygonal cells with an eccentrically placed nucleus and dense cytoplasm (Pap stain). (b, c) Smears from proximal type epithelioid sarcoma display similar morphology to conventional type (H&E; MGG). (d) Loss of nuclear expression of INI-1 is seen in both conventional and proximaltype epithelioid sarcomas
  76. clinical presentation of an extremity mass in a young patient is an important clue to the correct diagnosis S-100 favors metastatic melanoma, epithelioid MPNST, and myoepithelial carcinoma of soft tissue.
  77. AKA Malignant melanoma of soft parts Metastatic malignant melanoma is the most important differential diagnosis.
  78. Clear cell sarcoma (malignant melanoma of soft parts). (a-c) Polygonal or spindly shaped cells with moderately abundant, clear cytoplasm, and large, round, or ovoid nuclei (MGG; H&E). (d) Immunoreactivity for melanoma markers confirms diagnosis (cell block; HMB45)
  79. In children, the head and neck region is mainly affected. Background of disrupted cytoplasmic contents and capillary networks devoid of tumor cells is seen.
  80. Large, dyshesive tumor cells with round nuclei and abundant granular, fragile cytoplasm (MGG; H&E). (c, d) Presence of stripped nuclei with prominent, centrally situated nucleoli in a cytoplasmic granular background is a useful clue to the diagnosis (MGG; H&E) Large polygonal cells have abundant granular cytoplasm, large nuclei, vesicular chromatin, smooth nuclear contours, and a prominent central, round nucleolus
  81. All lack rhomboid crystals, and all have different immunoprofiles.
  82. The cells can form small, loose aggregates and rosette-like, pseudoacinar arrangements. Nuclear CAMTA1 expression by IHC is highly sensitive and specific for EHE.
  83. A poorly cohesive group of moderately pleomorphic, some binucleated, and occasional multinucleated cells showing round to oval nuclei with small nucleoli and abundant cytoplasm (MGG)
  84. Can be encountered in a variety of other sites, including the lower extremities, retroperitoneum, and abdominal cavity. Epithelioid angiosarcoma should be considered in the DDx of any poorly differentiated neoplasm with epithelioid cytomorphology, especially in the abdominal cavity.
  85. Bloody background with scattered epithelioid and spindle cells with occasional tumor cell fragments.
  86. Other common sites include the extremities, gastrointestinal tract, respiratory tree, thyroid, and breast. They also express NKI/C3, owing to their lysozyme-rich cytoplasm.
  87. bean-shaped or oval histiocytes with foamy cytoplasm, multinucleated giant cells, and other inflammatory cells. S100, CD68, calretinin, and inhibin +ve
  88. Poorly differentiated or dedifferentiated forms of entities that have a clear line of differentiation
  89. some are radiation associated. Pleomorphic neoplasm that is negative for differentiation markers – reported as pleomorphic malignant neoplasm, cannot classify further
  90. The bizarre tumor cells and necrotic background are nonspecific findings seen with any pleomorphic soft tissue neoplasm (Papanicolaou stain).
  91. Radiation-induced high-grade sarcoma should be considered when an undifferentiated high-grade pleomorphic sarcoma occurs at the site of prior radiation therapy. FNA represents only a portion of the neoplasm, excluding specific pleomorphic sarcomas, carcinoma, mesothelioma, melanoma, and lymphoma might not be possible - sampling error.
  92. Numerous dispersed rhabdoid cells have eccentrically located nuclei, prominent nucleoli, abundant cytoplasm, and a perinuclear cytoplasmic density (Romanowsky stain). Considering MPNST and dedifferentiated liposarcoma is critical before pleomorphic rhabdomyosarcoma
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