PART 1: SPINDLE CELL LESIONS.pptx

Spindle cell lesions of oral cavity

1. SPINDLE CELL TUMOURS Part 1 SHERIN JAMES

2. CONTENTS Introduction Types of spindle cells and its origin General considerations Pathogenesis Pretreatment evaluation Classification Description of lesion specific Treatment/Prognosis Conclusion

3. INTRODUCTION

4. FIBROBLASTS MYOFIBROBLASTS SMOOTH MUSCLE SCHWANN CELL OSTEOCYTE MYOEPITHELIAL CELL SPINDLE CELLS IN NORMAL TISSUES

5. GENERAL CONSIDERATIONS For most of the spindle cell tumors of head and neck/oral cavity etiology is unknown Various identified causes are: Exposure to ionizing radiation Inherited or acquired immunologic defects Environmental factors like - trauma Chemical carcinogens Oncogenic virus (Ex: HHV8- Kaposi’s sarcoma, EBV-smooth muscle tumor in immunodeficiency syndrome patients) Genetic factor (Ex: Neurofibromatosis 1 and 2)

6. PRETREATMENT EVALUATION Clinical Examination Most lesions in the oral cavity arises as painless mass, this will generally cause delay in diagnosis Suspected cases require Biopsy. Prior to biopsy depending on peripheral or intra-osseous lesion: Radiographic evaluation CT Scan CBCT in case of oral lesion MRI – gives better demonstration of soft tissue tumor Helps in clinical staging and helps to locate nerve of origin and vessel involved in case of neural/vascular tumors. Inaccessible area FNAC advised, or incisional biopsy

7. CLASSIFICATION

8. A simple working type classification proposed for the spindle cell neoplasms of the oral cavity Thorakkal Shamim : A simple working type classification proposed for spindle cell neoplasma of oral cavity; journal of cytology, 2013; vol- 30; issue- 1; 85 1

9. 1. Fibrous tissue origin a ) Benign: Fibroma , Nodular fasciitis, Proliferative fasciitis and myositis , solitary fibrous tumor b)Intermediate: Fibromatoses , Infantile fibromatoses , Desmoid tumor c) Malignant: Fibrosarcoma , Congenital or Infantile fibrosarcoma 2. Fibrous histiocyte origin a) Benign: Fibrous histiocytoma b) Intermediate: Dermatofibrosarcoma , Plexiform fibrous histiocytic tumor c) Malignant: Malignant fibrous histiocytoma 3. Myofibroblast origin a)Benign: Myofibroma , b) intermediate: Inflammatory myofibroblastic tumor b)Malignant: Low grade myofibrosarcoma 4. Muscle tissue origin Benign: Leiomyoma . Cellular rhabdomyoma b) Malignant i . Leiomyosarcoma , 5. Lipomatous origin a) Benign: Spindle cell lipoma b)Malignant: Dedifferentiated liposarcoma 6. Epithelial origin a) benign: spindle cell nevus Malignant: Mal. Melanoma, Spindle cell carcinoma 10. Vascular origin a) Benign: Angiofibroma b) Intermediate: Spindle cell hemangioma , Hemangiopericytoma c) Malignant: Angiosarcoma , Kaposi sarcoma 8. Neural origin a ) Benign: Traumatic neuroma , Neurofibroma , Schwannoma , PEN b) Malignant: Malignant peripheral nerve sheath tumor 7. Osseous origin Fibroblastic variant of osteosarcoma,Desmoplastic fibroma 9. Salivary gland Myoepithelioma , Myoepithelial carcinoma 11. Odontogenic origin Odontogenic fibroma, Odontogenic myxoma 12. Miscellaneous Synovial sarcoma, diffuse mesothelioma , fibromyxoma 4/17/2018 10

10. Classified based on APPEARANCES AND THE ARCHITECTURAL PATTERN. A. MONOMORPHIC SPINDLE CELL LESIONS : uniform spindle cells which may be arranged in fascicles, a storiform pattern or a ‘herringbone’ pattern , or are sometimes associated with a dense collagenous stroma. The most common are spindle cell squamous carcinoma and melanoma. B. PLEOMORPHIC SPINDLE CELL LESIONS: Spindle cells showing wide variation in size and shape , often with marked nuclear pleomorphism and tumour giant cells . These malignancies can occur both in mucosal sites and as lymph node metastases in the neck and parotid glands. 2 Catriona E Anderson, Awatif Al- Nafussi ; Spindle cell lesions of the head and neck: an overview and diagnostic approach . Diagnostic histopathology, 2009; 15:5 265 -272

11. C. BIPHASIC SPINDLE CELL LESIONS: Two distinct components, spindle cell areas and epithelioid areas . Epithelioid areas may be sparse and several levels should be examined in biopsies of spindle cell lesions in an attempt to identify these elements. D. MYXOID SPINDLE CELL LESIONS : S pindle cell component may be conspicuous or less easily identified, but it is set in a loose, myxoid stroma . Some tumours in this category may also have a prominent inflammatory infiltrate.

12. 1. NEURAL TUMOR – Neurofibroma – Schwannoma – Traumatic neuroma – Palisaded encapsulated neuroma – Malignant peripheral nerve sheath tumor 2. MYOFIBROBLASTIC TUMORS – Myofibroma – Inflammatory myofibroblastic tumor – Low-grade myofibroblastic sarcoma 3. SMOOTH MUSCLE TUMORS – Angiomyoma /vascular leiomyoma Jordan RC, Regezi JA. Oral spindle cell neoplasms: a review of 307 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 2003;95:717-24. 3

13. 4. FIBROBLASTIC TUMORS – Solitary fibrous tumor – Nodular fasciitis – Fibromatosis – Desmoplastic fibroma – Fibrosarcoma 5. VASCULAR TUMORS – Vascular malformation – Kaposi’s sarcoma 6. CARCINOMAS – Spindle cell SCC – Sarcoma NOS/Atypical spindle cell neoplasm – Benign fibrous histiocytoma Jordan RC, Regezi JA. Oral spindle cell neoplasms: a review of 307 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 2003;95:717-24.

14. TODAY!!! Fibroblastic Fibrohistiocytic Myofibroblastic Adipose tissue Epithelial

15. FIBROBLASTS

16. ORIGIN OF FIBROBLAST CELL 18

17. MYOFIBROBLASTS  Myofibroblasts are short, bipolar or tripolar, spindle shaped or stellate cells with long cytoplasmic extensions, containing sparse to moderate amounts of acidophilic cytoplasm with indistinct cell margins, and ovoid, often indented, pale nuclei containing a small nucleolus.  They have contractile elements and synthesize collagen, fibronectin, and laminin.  Widely used marker- α -SMA,  Endoscalin, p311, integrin, osteopontin, periostin seems specific for certain conditions.

18. ORIGIN OF MYOFIBROBLASTS 20

19. Lesion wise description

20. FIBROBLASTIC 1

21. FIBROBLASTIC  Fibroma  Giant cell fibroma  Fibromatosis  Solitary fibrous tumor  Nodular fasciitis  Fibrosarcoma

22. FIBROMA Synonyms: • Reactive hyperplasia of the fibrous connective tissue, in response to local irritation or trauma.

23. DEMOGRAPHICS & CLINICAL FEATURES:

24. HISTOPATHOLOGY: Pedunculated fibroma CT gradually blends Collagen bundles – streaming pattern

25. Hyperkeratosis due to irritation Dense, hyalinized collagen in sclerotic fibroma

26. Collagen bundles in whirling pattern with numerous blood capillaries – less inflammatory cell

27. TREATMENT: • Conservative surgical excision • Recurrence is rare

28. GIANT CELL FIBROMA • Not associated with any chronic irritation. • It represents approximately 2% to 5%of all oral fibrous DEMOGRAPHICS: • 10 – 30 years • No gender predilection (Female ) • Most commonly it occurs on the mandibular gingiva , followed by tongue, and palate.

29. CLINICAL FEATURES: • It appears as an asymptomatic, sessile, or a pedunculated nodule Usually less than 1 cm in size Bosselated or a papillary surface.

30. HISTOPATHOLOGY: Corrugated, atrophic SSE Thin elongated rete ridges Vascular fibrous CT (loosely arranged) Numerous large STELLATE FIBROBLASTS with several Nuclei, in superficial CT

31. Mono or multinucleated Fibroblasts Stellate/spindle shaped fibroblasts within the superficial connective tissue

32. H& E 10x and 40x

33. DIFFERENTIAL DIAGNOSIS: • Retrocuspid papilla (Site specific) Papilloma • Irritational fibroma TREATMENT : • Conservative surgical excision • Recurrence is rare

34. FIBROMATOSES Fibromatoses comprise a broad group of benign fibrous tissue proliferations of similar microscopic appearance whose biologic behavior and histopathologic pattern is intermediate between that of benign fibrous lesions and fibrosarcoma. In the soft tissues of the head and neck- frequently called Juvenile aggressive fibromatoses or extraabdominal desmoids.

35. These non-encapsulated lesions are locally aggressive in behavior with a tendency for recurrence . They do not metastasize but presents with local infiltration into the vital structures

36. CLINICAL FEATURES Enzinger and Weiss subdivide the fibromatoses into two broad categories: Superficial (fascial) fibromatoses and Deep (musculo - aponeurotic) fibromatoses 40

37. Sporadic (Familial multicentric) 41

38. Adjacent to the mandible, where underlying bone may be eroded or destroyed by invasion. Can spread through fascial planes and invade surrounding structures, causing pain, dysphagia, respiratory distress, proptosis and epistaxis. When airway or major vessels are involved, there may be life-threatening consequences 42

39. A firm, painless mass - rapid or insidious growth. Most common in para-mandibular soft tissue. Facial disfigurement

40. PATHOGENESIS Remains unexplained. Some endocrinal disturbances , because these tumors are characterized by high levels of estrogens and pituitary gonadotropins. Steroid hormones have an important role in the regulation or fibroblastic activity and proliferation. Cases have occurred in surgical scars , in irradiated areas , in burn scars , in regions of healed fractures , and in areas of previous trauma , and one case occurred after a silicone implant . Occasional cases with familial history have been reported.

41. GROSS APPEARANCE Firm, glistening mass resembling scar tissue Margins are usually poorly circumscribed 45

42. HISTOPATHOLOGY  Non- encapsulated, poorly circumscribed, infiltrative lesion with a fascicular growth pattern, usually striated musculature  Cellular proliferation of spindle shaped cells that are arranged in streaming fascicles & associated with variable amount of collagen.  No atypia, mitotic figures.  Slit like vascular spaces seen

43. Low, paucicellular fibrous proliferation in long fascicles, numerous slit-like vessels Fibroblasts, spindled, dense, wavy nuclei and minimal cytoplasm

44. Some cases show moderate numbers of lesional cells in a background stroma of abundant mature collagen , and others show minimal stroma with large numbers of active mesenchymal cells. Occasionally normal-appearing mitotic figures may be found, but they should not exceed 4 mitoses per high-power field. Vesicular nuclei with minute nucleoli, indistinct cytoplasm, interstitial collagen

45. Streaming fascicles of spindled cells highly cellular with variable amount of collagen Hyperchromatic and pleomorphic nuclei are seldom seen

46. Cellular interlacing bundles Elongated fibroblasts

47. Little or no Pleomorphism Little or no mitotic activity No inflammation. Slit-like vascular spaces

48. H&E, 4x,10, 40x 53

49. IMMUNOHISTOCHEMISTRY  The spindle cells express vimentin, SMA and MSA  Some show desmin expression, β- catenin (adenomatous polyposis coli (APC) gene) positivity β- catenin

50. Reactive to smooth muscle actin (SMA), Vimentin SMA

51. DIFFERENTIAL DIAGNOSIS Fibrosarcoma – one or more than one mitotic figure PHF Nodular fasciitis- Negative for β - catenin Leiomyoma - bright pink cytoplasm of smooth muscle, desmin+ 56

52. TREATMENT: • A locally aggressive tumor. • Wide excision, including a generous margin of the adjacent normal tissues. • Recurrence rate of for oral and paraoral fibromatoses – 23%. • No metastases.

53. NODULAR FASCIITIS (Pseudosarcomatous Fasciitis/ Infiltrative Fasciitis, Subcutaneous Pseudosarcomatous Fibromatosis)  A benign and reactive fibroblastic growth extending as a solitary nodule from the superficial fascia into the sub-cutaneous fat and subjacent muscle.  It is closely related to “ proliferative myositis ” which occurs in muscle.

54. Definition: A pseudosarcomatous, self-limiting, reactive process composed of fibroblasts and myofibroblasts Common benign mesenchymal lesion often misdiagnosed as a sarcoma Etiology : unknown; trauma ?? Recent molecular studies suggests that the cells are clonal , thus confirms that it is a benign neoplasm.

55. DEMOGRAPHICS: • Age: Fourth and fifth decades of life • Sex: Equal gender distribution • Site: Buccal mucosa, labial mucosa, tongue, Angle & inferior border of the mandible, zygomatic arch, anterior mandible Trunk & extremities – most commonly involved.

56. CLINICAL FEATURES: Occur mostly in areas which serve as sites of origin and insertion of muscles of mastication. 10 % - soft tissues of the head and neck region, usually presenting as a rapidly enlarging mass. (skin of face & parotid sheath).

57. • Rapidly growing (1 to 2 months), sometimes painful nodule • Exophytic lesion some times may be ulcerated Dan Dayan et al, Clinico -pathologic correlations of myofibroblastic tumors of the oral cavity: nodular fasciitis; J Oral Pathol Med (2005) 34: 426–35

58. GROSS APPEARANCE Depends on amount of myxoid or fibrous stroma, cellularity Well circumscribed, non-encapsulated lesion Cut surface is soft and gelatinous- if myxoid Rarely hemorrhagic areas are seen.

59. HP Zonation effect with hypocellular central region and hypercellular periphery Composed of uniform, plump, immature, spindled to stellate fibroblasts or myofibroblasts without atypia, with a feathery, "tissue-culture" like growth pattern due to abundant ground substance Mucoid / myxoid pools (microcysts ), a very useful diagnostic finding Cellular areas may have storiform or fascicular patterns (S or C shaped )

60. Subcutaneous tumor is partially circumscribed nodule infiltrating focally along fascial planes

61. Focal infiltration into fat, with evenly distributed g ranulation tissue-like vessels throughout the lesion

62. Gently curving C and S shaped fascicles of myofibroblastic cells exhibit a characteristic "torn Kleenex" pattern

63. Focal storiform pattern is suggestive of fibrous histiocytoma

64. Mitotic figures, but no abnormal forms

65. A nodular growth contains plump fibroblasts with vesicular nuclei in a haphazard to storiform arrangement.

66. Spindle cells in myxoid background

67. DD: Benign fibrous histiocytoma : in dermis, storiform pattern, infiltrative borders with collagen trapping, sometimes prominent xanthoma cells and often Touton giant cells, no myxoid microcysts Fibromatosis : infiltrates surrounding soft tissue, spindled cells are parallel and separated by abundant collagen and arranged in broad sweeping fascicles, no loose tissue culture appearance or myxoid microcysts Sarcoma : nuclear atypia is prominent, necrosis, larger size usually

68. • Spindle cell shows both myofibroblastic and histiocytic immunoprofile – SMA – MSA – Vimentin – CD68 Dan Dayan et al, Clinico-pathologic correlations of myofibroblastic tumors of the oral cavity: nodular fasciitis; J Oral Pathol Med (2005) 34: 426–35 SMA

69. Smooth muscle actin, vimentin that shows strong and diffuse cytoplasmic positivity

70. TREATMENT • Local excision is the treatment of choice

71. SOLITARY FIBROUS TUMOR (SFT) The diagnosis of Hemangiopericytoma (HPC) was first described by Arthur Purdy Stout and Margaret Murray in 1942  derived from pericytes Solitary fibrous tumor (SFT) was originally described as a primary tumor arising in the pleura, presumably as a tumor of submesothelial fibroblasts Now recognized as ends of the spectrum within a single biologic entity.

72. The recent discovery of the reproducible NAB2-STAT6 gene fusion, resulting from a t(12q13) translocation in tumors previously classified as both soft tissue SFT and HPC has largely ended the controversy .. The histologic features of HPC, using the Enzinger and Smith 1976 definition , include randomly distributed (“patternless”) ovoid to short spindle cells prominent thin-walled vasculature in a branching (“stag horn”) pattern. The tumor cells lack overt differentiation and show uniformly high cellularity. Mitotic activity is usually low (1-4 mf / 10 hpf ) while necrosis and pleomorphism are absent.

73. CLINICAL FEATURES Middle-aged adults (median age 50 years) Wide anatomic distribution; essentially arises from any soft tissue or visceral location Rarely causes paraneoplastic hypoglycemia due to insulin-like growth factor production Slow growing painless mass, usually benign; histologically malignant tumors may be grossly infiltrative .

74. GROSS APPEARENCE

75. HISTOPATHOLOGY Patternless architecture of hypo- and hypercellular areas separated by thick, hyalinized collagen with cracking artifact and stag horn vessels Perivascular sclerosis Bland and uniform oval to spindle cells dispersed along thin parallel collagen bands, cells have minimal cytoplasm, small elongated nuclei and indistinct nucleoli Some have myxoid change, mast cells, adipose tissue or multinucleated giant cells Minimal pleomorphism

76. Moderately cellular fibroblastic appearance

77. Scant cytoplasm and uniform spindled nuclei, note the thin bands of intercellular collagen Storiform growth

78. Typically circumscribed neoplasms ( A) bland ovoid or spindled fibroblastic cells in “patternless” distributions within variably collagenous stroma (A-F) that frequently shows areas of dense hyalinization (C) as well as interspersed large branching or “ staghorn ”-shaped thin-walled hemangiopericytic vessels(D Note the marked intertumoral variation in cellularity, with hypercellular stroma-poor areas that alternate with more sparsely cellular collagenous areas (E). The cells are typically uniform with basophilic nuclei that are hyperchromatic or vesicular and scanty amphophilic cytoplasm with indistinct cell borders (E, F).

79. POSITIVE STAINS CD34 (90 - 95%),  CD99 (70%), 1/3 positive for  bcl2 ,  EMA and  actin

80. DIFFERENTIAL DIAGNOSIS Benign neural tumors : S100+ Smooth muscle tumors : fascicles of cells with more abundant eosinophilic cytoplasm, blunted nuclei, desmin+, actin+ Synovial sarcoma (monophasic) : Ovoid cels , no thick collagen bands; keratin+, t(X;18)

81. FIBROSARCOMA “A malignant spindle cell tumor composed of Fibroblasts arranged in a herringbone/ interlacing fascicular pattern, with varying amounts of collagen in the background with no expression of other connective tissue markers”

82. Fibrosarcoma accounts for approximately 15% of all soft tissue sarcomas, of which only 1% occur in the head and neck region. Men commonly affected 4 th decade Usually lower extremities (femur and tibia) Also reported to arise from pre- existing lesions: fibrous dysplasia, chronic osteomyelitis, bone infarct, Paget's disease & previously irradiated areas. Large painless mass, often of shorter duration, ulceration can be seen Soft tissue and bone lesion

83. CLINICAL FEATURES An infantile/congenital form (in children < 10 years) of fibrosarcoma exists, defined in the World Health Organization classification However, most are discovered at birth or within first year of life. Unlike fibrosarcoma in adults, it has an excellent prognosis, even in the face of metastatic disease at presentation, when treated with a combination of neoadjuvant and adjuvant chemotherapy and resection . 96

84. • DEMOGRAPHICS: • Age: 30 – 50 yrs (wide age range), younger • Sex: no sex predilection • Site: Buccal mucosa, tongue – 1/4th of the oral lesions

85. GROSS FINDINGS  Typically, the lesions are solitary, multilobulated, fleshy masses 5–10 cm in diameter when first detected.  About two-thirds of these tumors are located in skeletal muscle, <10% are confined to the subcutis. A multinodular white mass with areas of hemorrhage and necrosis.

86. HISTOPATHOLOGY  Highly cellular fibroblastic proliferation in herringbone pattern (cells in columns of short parallel lines with all the lines in one column sloping one way and lines in adjacent columns sloping the other way).  fusiform or spindle-shaped cells that vary little in size and shape, have scanty cytoplasm with indistinct cell borders, tapering elongated dark nuclei with increased granular chromatin, variable nucleoli and are separated by interwoven collagen fibers arranged in a parallel fashion.  Mitotic figures are frequent.  Collagen may be sparse. Patterns: Keloid-like (thick hyalinized collagen fibers), loose fascicular, focally myxoid

87. HISTOLOGICAL GRADING OF FIBROSARCOMA Based on • Cellularity • Differentiation • Mitotic activity • Necrosis

88. Histologic grading of fibrosarcomas is based on the cellularity and differentiation, mitotic activity, and necrosis  Low-grade (well differentiated) fibrosarcomas are characterized by a uniform, orderly appearance of the spindle cells associated with abundant collagen

89. Atypical uniform cells in herringbone pattern

90. Malignant, with coarse chromatin but minimal pleomorphism

91. LOW GRADE Minimal pleomorphism and low mitotic index, but is more cellular than fibromatosis INTERMEDIATE GRADE: intermediate features

92.  HIGH GRADE: high grade atypia and high mitotic index

93. HIGH GRADE FIBROSARCOMA Closely packed and less well oriented cells Round tumor cells with high grade nuclear features

94. Herring bone pattern Bipolar spindle cells scanty cytoplasm

95. Low grade fibrosarcoma resembling fibromatosis Variation in shape and size Mitotic activity moderate Mild pleomorphism

96. H&E Vimentin+

97. POSITIVE STAINS Reticulin  stain demonstrates fibers surrounding each cell Phosphotungstic acid-hematoxylin  demonstrates abundant cytoplasmic fibrils Also  vimentin ,  type 1 collagen ,  p53 High Ki67 May be  CD34+  if arises from DFSP or solitary fibrous tumor

98. Immunohistochemistry/Cytogenetics and Molecular Genetics Vimentin- positive Weak positive for smooth muscle actin- due to focal myofibroblastic differentiation Little is know about molecular or cytogenetic alterations in adult fibrosarcoma, but multiple complex chromosomal rearrangement as be reported in infantile fibrosarcoma ( chromosomal change involving- t(2;19).

99. Marked vimentin positivity

100. Differential diagnosis Nodular fasciitis Cellular benign fibrous histiocytoma Fibromatoses Malignant peripheral nerve sheath tumor Malignant fibrous histiocytoma Monophasic fibrous synovial sarcoma Diagnosis of Exclusion!!

101. TREATMENT Wide local excision Radical neck dissection

102. HISTOLOGICAL VARIANTS OF FIBROSARCOMA Adult type fibrosarcoma Myxo fibrosarcoma Sclerosing epitheliod type Hyalinising spindle cell type Infantile fibrosarcoma 120

103. MYXOID TYPE OF FIBROSARCOMA Spindle or stellate shaped cells deposited in a myxoid matrix composed of predominantly of hyaluronic acid. The cells have slightly eosinophilic cytoplasm and indistinct cell borders; the nuclei are hyperchromatic, are mildly pleomorphic, and have only rare mitotic figures. DD 1: Nodular fasciitis 2: Myxoma 3: Nerve sheath Myxoma 4: Spindle cell lipoma 5. Myxoid liposarcoma 6. Extraskeletal myxoid chondrosarcoma

104. FIBROMYXOID TYPE OF FIBROSARCOMA Composed of bland spindle-shaped cells with small hyperchromatic oval nuclei, finely clumped chromatin, and one to several small nucleoli. The cells have indistinct pale eosinophilic cytoplasm and show only mild nuclear pleomorphism with little mitotic activity. The cells are deposited in a fibrous and myxoid stroma that tends to vary in different areas of the tumor

105. SCLEROSING EPITHELIOID TYPE OF FIBROSARCOMA  The neoplastic cells are predominantly epithelioid in appearance and are arranged in a variety of patterns, including nests, cords, strands, and occasionally acini or alveoli.  The cells have oval to round angulated nuclei with finely stippled or vesicular chromatin, small basophilic nucleoli, and scanty cleared-out or faintly eosinophilic cytoplasm

106. TREATMENT: Radical excision, radiation if residual tumor or positive margins Possibly chemotherapy, if high grade

107. FIBROHISTOCYTIC TUMORS 2

108. BENIGN FIBROUS HISTIOCYTOMA Neoplastic lesion composed of mixture of fibroblastic and histiocytic cells accompanied by varying number of inflammatory cells, foam cells, MNG’s Cell of origin : Histiocyte. 127 Dermatofibroma Sclerosing Hemangioma Fibroxanthoma Nodular sub-epidermal fibrosis

109. Solitary - slow growing - firm nodule Typically seen in middle aged and older adults (5 th decade). Common site: skin of the extremities : DERMATOFIBROMA Oral cavity: rare, if present: Buccal mucosa & vestibule.

110. HISTOPATHOLOGY  Fairly well-demarcated & often circumscribed at the periphery.  Cellular proliferation of spindle shaped fibroblast cells with plump, vesicular nuclei in storiform pattern (cart wheel or matlike ) with rounded histiocytic -like cells  Lipid containing xanthoma cells & Tuoton multinucleated giant cells with nuclei pushed to periphery.  A background of variably dense collagenous tissue & vascularity is seen.  Mixed inflammatory cells present

111. H&E 4x 10x 40x 10x 130

112. IMMUNOHISTOCHEMISTRY POSITIVE ▸Vimentin ▸CD 68 ▸SMA / CD 34: diffuse Vimentin

113. VARIANTS of fibrous histiocytoma Cellular fibrous histiocytoma Epitheloid fibrous histiocytoma Aneursymal fibrous histiocytoma Atypical fibrous histiocytoma 133

114. DIFFERENTIAL DIAGNOSIS Nodular fasciitis Neurofibroma Leiomyoma TREATMENT Wide surgical excision High rate of recurrence. 134

115. MALIGNANT FIBROUS HISTIOCYTOMA/ PLEOMORPHIC SARCOMA Malignant fibrous histiocytoma is a malignant neoplasm of fibroblasts with a propensity to differentiate into histiocytic and fibrohistiocytic cells. First described in 1964, by O'brien and Stout under the name malignant fibrous xanthoma Histopathological features were first described by Kempson and Kyriakos . 135

116. Clinical features Any age (50-70yrs) Firm submucosal mass expanding slowly or moderately fast Asymptomatic and may show ulceration Irregular nodular lesion measures less than 4cm 136

117. Depending on the dominant morphology, it is currently subclassified as: Pleomorphic storiform, Myxoid, Angiomatoid ( aneurysmal ), Inflammatory and Giant cell malignant fibrous histiocytoma Small group of undifferentiated sarcomas lacking differentiation markers of other sarcomas; DIAGNOSIS OF EXCLUSION.

118. HISTOPATHOLOGY Basic to all MFH - proliferation of pleomorphic spindle shaped cells showing fibroblastic morphology. Abnormal & frequent mitotic figures, necrosis & extensive cellular atypia. Storiform-pleomorphic type, with a predominantly storiform pattern

119. 139

120. The myxoid type is characterized by myxoid areas in association with cellular areas indistinguishable from ordinary MFH.

121. The giant cell type of MFH , also termed malignant giant cell tumor of soft parts is a multinodular tumor composed of a mixture of spindled, rounded, and osteoclast-type giant cells

122. CD68 stain of an inflammatory MFH with staining of benign xanthoma cells Inflammatory type of MFH - benign- and malignant-appearing xanthoma cells, the latter often assuming a gigantic size with bizarre nuclei. Typically, these neoplastic cells display phagocytosis of neutrophils. The inflammatory component is characteristically prominent and usually consists of a mixture of acute and chronic inflammatory cells with marked prominence on the former.

123. Immunohistochemistry/cytogenetic and molecular genetic of UNDIFFERENTIATED PLEOMORPHIC SARCOMA Immunohistochemistry is of little value in the diagnosis of malignant fibrous histiocytoma because no specific marker for these lesions exists. Factor XIII a or α-1- antichymotrypsin antibodies, CD68 are positive Loss of 4q31 and 18q22 were found but are independent predictors of metastasis. 143

124. TREATMENT: Radical surgical resection. 40% recur locally/ metastasize.

125. 145

126. MYOFIBROBLASTIC 3

127. MYOFIBROBLASTIC ORIGIN  Myofibroma  Inflammatory myofibroblastic tumor  Myofibrosarcoma

128. MYOFIBROMA & MYOFIBROMATOSIS The most common site of myofibroma is in the head and neck region followed by the trunk, extremities and viscera Infantile myofibromatosis (multicentric myofibromatois) occurs in infants and neonates.

129. CLINICAL FEATURES • Age: 1 st to 4 th decade (Infants – Myofibromatosis) • Sex: Common in males M-F ratio - 1.5:1 • Site: Most common Mandible >Tongue > BM > palate > gingiva > mandibular vestibule > retromolar area Marilena Vered et al, Clinico -pathologic correlations of myofibroblastic tumors of the oral cavity. II. Myofibroma and myofibromatosis of the oral soft tissues; J Oral Pathol Med (2007) 36: 304–14

130.  Rare neoplasms with predilection for H& N region.  Occurs as an exophytic mass  Presents as painless mass that show rapid enlargement.  Radiographs: radiolucent defects that are poorly defined, sometimes well defined & multilocular.

131. HISTOPATHOLOGY  Interlacing bundles of spindle cells with tapered or blunt ended nuclei and eosinophilic cytoplasm.  Nodular fascicles may alternate with more cellular zones- giving a biphasic appearance.  Centrally, the lesion is more vascular with hemangiopericytoma like appearance . imparting a biphasic appearance to the tumor .  Has monomorphic and biphasic spindle cells

132. Hemangiopericytoma like areas Interlacing bundles of spindle cells blunt-ended nuclei & eosinophilic cytoplasm

133. Scattered mitoses Cells are positive for SMA

134. 154

135. I MMUNOHISTOCHEMISTRY Positive for SMA, MSA Negativity for DESMIN which rules out Leiomyoma & Leiomyosarcoma SMA POSITIVE

136. MARKERS: • Positive for vimentin and actin

137. DIFFERENTIAL DIAGNOSIS Nodular fasciitis Neurofibroma Fibrous histiocytoma Hemangiopericytoma Leiomyoma Leiomyosarcoma 157 Marilena Vered et al, Clinico-pathologic correlations of myofibroblastic tumors of the oral cavity. II. Myofibroma and myofibromatosis of the oral soft tissues; J Oral Pathol Med (2007) 36: 304–14

138. TREATMENT: • Solitary tumors – surgical excision • Recurrent tumors – re-excision. • In some cases – spontaneous regression. • Those involving the viscera or vital organs in infants – more aggressive & may prove to be fatal.

139. INFLAMMATORY MYOFIBROBLASTIC TUMOR (IMT) IMT is a rare neoplasm consisting of variable numbers of inflammatory cells and myofibroblastic spindle cells It was first observed in the lung and described by Brunn in 1939 Was so named by Umiker   et al.  in 1954 because of its clinical and radiological behavior that mimics a malignant process. Liston et al. in 1981 was the first to report IMTs of oral cavity in three children. 159

140. Described by various names   Inflammatory pseudotumor (IPT), Plasma cell granuloma , Benign myofibroblastoma , Inflammatory fibrosarcoma , Histiocytoma , Xanthomatous granuloma , and Spindle cell pseudotumor , describing its heterogeneous nature 160

141. CLINICAL FEATURES Age: 2 to 82 years, with a mean of 35 years. Sex: Female Site: The buccal mucosa > retromolar area region > premolar region > pterygoid and masseteric muscle > lingual alveolar mucosa of the edentulous molar region > tongue> maxilla > hard palate. In some cases localized to an extraction site.

142. Size ranged from 0.5 to 5cm , rapid growth rate is an alarming feature of oral IMT reportedly as short as 1 day, with a majority of lesions of 2 months duration or less Well circumscribed, solitary nodule or mass, 40% of the tumor were designated as firm or indurated and notably demonstrated ulceration, characterized with varying degrees of erythema . Pain was reported with concurrent clinical ulceration. Some patients experienced trismus

143. Most lesions are lobular, multinodular or bosselated . Hard or rubbery cut surface, appears white, grey or tan-yellow. Sometimes gritty sensation due to presence of calcification GROSS APPEARANCE 163

144. HISTOPATHOLOGY Three main patterns Monomorphic spindle cells arranged in fascicles Myxoid , nodular fasciitis like areas Hypocellular hyalinized areas A variable infiltrate of inflammatory cells associated with the tumor cells 164

145. Histopathology H&E

146. Spindle shaped cells with fasciculated architecture Hypocellular fibrous areas with numerous plasma cells Concurrent fascitis-like foci

147. IMMUNOHISTOCHEMISTRY  SMA  MSA POSITIVE  DESMIN  ANAPLASTIC LYMPHOMA KINASE-1 (ALK-1)

148. Cytogenetics and molecular genetics of myofibroblastic tumor Clonal rearrangement of ALK gene at 2q23. ALK gene codes for tyrosine kinase receptor that is a member of insulin growth factor receptor superfamily . ALK rearrangement – constitutive expression and activation of this gene with abnormal phosphorylation of cellular substrata 169

149. Differential diagnosis Inflammatory Leiomyosarcoma Inflamamtory fibrosarcoma Malignant fibrous histiocytoma 170

150. LOW GRADE MYOFIBROSARCOMA Malignant tumor of myofibroblast Indolent neoplasm that can recur and metastasize after long period of time 171

151. CLINICAL FEATURES Usually affects adults and is uncommon in children. Intra oral tumors- usually slows growing & asymptomatic. Oral cavity-the tonsil, mandible, maxilla Age: Affects young to middle aged adults. Sex: No sex predilection Site: 20-25% of cases arise in the head and neck region (especially the oral cavity and tongue). Painless growth, large mass.

152.  A population of spindle-shaped cells showing vesicular nuclei with fine stippled chromatin and a small nucleolus. The cytoplasm was pale and eosinophilic with indistinct margins.  The cells will be arranged in variably orientated short fascicles or vaguely storiform whorls , between individual skeletal muscle fibers.  A mild degree of nuclear pleomorphism, anisonucleosis, and hyperchromatism will be seen .

153.  A moderate amount of collagen was present in several foci, but a myxoid or hyalinized stroma can also be seen.  Occasional lymphocytes, plasma cells, and mast cells.  The lack of significant atypia confuses with benign diagnosis such as nodular fascitis, proliferative myositis, and Fibromatosis.

154. Histopathology of low grade myofibrosarcoma

155. Immunohistochemistry/Cytogenetics and Molecular genetics of low grade myofibrosarcoma  SMA- POSITIVE  Calponin- Diffusely Positive  Desmin – Focal Positive  h- caldesmon - Negative  ALK – Negative (eliminates IMFT and leiomyosarcoma) Comparative genomic hybridization shows gains of 1p11, 12p12.2 and 5p13.2. 176

156. DIFFERENTIAL DIAGNOSIS Nodular fasciitis Leiomyosarcoma Fibrosarcoma IMFT 177

157. ADIPOCYTIC ORIGIN 5

158. Spindle cell Lipoma Spindle cell Liposarcoma

159. Lipomatous Tumors • BENIGN TUMORS – Spindle cell lipoma/ Pleomorphic – Vascular ( angiolipoma ) – Lipoblastoma – Hibernoma – Chondroid type – Myolipoma – Myelolipoma – Angiomyolipoma • MALIGNANT TUMOR S Liposarcoma

160. SPINDLE CELL/PLEOMORPHIC LIPOMA • Enzinger and Harvey in 1975 • Both the lesions were grouped under “atypical lipomas ” • Definition: A spectrum of benign lesion composed of an admixture of mature adipocytes, spindle cells, and hyperchromatic multinucleated giant cells.

161. DEMOGRAPHICS: • Site: Tongue, cheek/buccal mucosa, floor of mouth, lip, hard palate, alveolar ridge, maxilla • Age: mean age of 55 yrs • Sex: males Subcutaneous tissue of the posterior neck, shoulder, and back; oral cavity- rare. Slow growing, typically solitary, circumscribed or encapsulated, painless, firm nodule, usually centered in the subcutaneous tissue

162. • CLINICAL FEATURES : – Slow growing – Solitary – Circumscribed – Painless – Firm nodule

163. GROSS APPEARANCE Resembles usual type of lipoma , except for grey white gelatinous foci, representing increased cellularity , some tumor show myxoid areas, other show predominantly lipomatous 184

164. HISTOPATHOLOGY  Vary widely in its appearance.  Some tumors are predominantly composed of mature adipose tissue with only scattered spindle cell or pleomorphic elements.  Other tumors are predominantly solid and lack any significant lipomatous component  The classic spindle cell lipoma consists of a relative equal mixture of mature fat and spindle cells.  The spindle cells are uniform with a single elongated nucleus and narrow, bipolar cytoplasmic processes .  The cells may be haphazardly distributed but tend to be arranged in short, parallel bundles.

165. HISTOPATHOLOGY 186

166. Cellular area Ropy collagen Well circumscription Mature adipocytes

167. Myxoid change Hyperchromatic multinucleated giant cells Bland spindle cells with elongated nucleus

168. Immunohistochemistry/ cytogenetics and molecular genetics of spindle cell lipoma Positive: strongly CD34 stains the nuclei of mature lipocytes . 55% to 75% of them show chromosomal aberrations. Harbor aberrations of 12q13-15. Gene HMGC located on 12q13-15 is affected 190

169. CD 34 positivity

170. DIFFERENTIAL DIAGNOSIS • Nodular fascitis • Neurofibroma • Solitary fibrous tumor • Hemangiopericytoma • Myxoid liposarcoma • Spindle cell liposarcoma TREATMENT • Completely benign lesion • Exceptionally recur • Dedifferentiation and metastasis - no

171. SPINDLE CELL LIPOSARCOMA Liposarcoma is a malignancy of fat cells Definition: Proliferation of mature adipocytes exhibiting marked variation in cell size with at least focal nuclear atypia Variants - Enzinger and Weiss - developmental stage of the lipoblasts , cellularity, pleomorphism – Well-differentiated – Myxoid – Round-cell – Pleomorphic – Spindle cell & Dedifferentiated 193

172. Age: 6 th to 7 th decade peak, men and women equally affected Symptoms depends on anatomic location. Slow growing mass- presents for months to even several years Unusual variant of liposarcoma- consisting of loosely arranged fibroblast like spindle cells

173. GROSS APPEARANCE Resembles normal fat, except for fibrous bands. 195

174.  A very rare and unusual form of liposarcoma consisting almost entirely of loosely arranged fibroblast-like spindle cells oriented along a single plane and surrounded by a delicate reticulin meshwork.  At low power, the lesion bears a superficial similarity to spindle cell lipoma, although it is far more cellular.

175. HISTOPATHOLOGY In mature cells the vacuole coalesce to form single vacuole that sits on the slender nuclei like a scoop of ice cream on a cone. 197

176. Scattered lipoblasts In various shapes and sizes Prominent spindle cells Resembling SCL

177. Nuclear Atypia Variable spindle cells devoid of lipoblasts

178. IMMUNOHISTOCHEMISTRY Express S-100 protein that may play a role in highlighting the presence of lipoblasts . Expression of MDM2 and CDk4 play a diagnostic role. 202

179. DIFFERENTIAL DIAGNOSIS Fibrosarcoma Pleomorphic liposarcoma 203

180. • Treatment • Wide surgical excision is the treatment of choice • Radiation therapy remains controversial

181. SUMMARY  Spindle cell lesions of head & neck are diverse & diagnostically challenging  High index of suspicion of spindle cell carcinoma for any malignant tumor with spindle cells  Clinical correlation is valuable.  Pathologists should take particular care before rendering final diagnosis.  Rule of thumb –in adults malignant spindle cell are more likely to represent ca or melanoma than a true sa

182. REFERENCE: Enzinger and weiss ; Soft tissue tumors. fifth edition Brad . W . Neville, Douglas D . Damm , Carl M . Allen. Oral and maxillofacial pathology. 2nd edition 2004 SHAFER, Text book of oral pathology. 6th edition 2006 Regezi , Sciubba , Jordon. Oral Pathology. Douglas .R. Gnepp ; Diagnostic surgical pathology of head and neck; 2 nd edition Cawson’s essentials of Oral pathology. 7 th edition. Contemporary oral & maxillofacial pathology. 2 nd edition. J Philip Sapp, Eversole . Textbook of oral pathology. Sanjay Saraf .

183. THANK YOU