Spindle cell lesions of head & neck

spindle cells lesions of oral cavity in particular

1. SPINDLE CELL LESIONS

2. CONTENTS Introduction Spindle cells in normal tissues. Spindle cell lesions of head & neck . Conclusion References

3. Introduction Spindle cell Any of various cells that are shaped like spindles, being more or  less round in the middle with two ends that are pointed. A generic term for an elongated and/or fusiform cell, regardless of origin. Mosby's Medical Dictionary, 9th edition. © 2009, Elsevier

4. Spindle cells in normal tissues FIBROBLASTS MYOFIBROBLASTS SMOOTH MUSCLE SCHWANN CELL MYOEPITHELIAL CELL OSTEOCYTE

5. S pindle cell lesions of Head & Neck

6. Spindle cell neoplasms are defined as neoplasms that consist of spindle-shaped cells in the histopathology. The head and neck is an embryologically and anatomically complex area, with a number of important structures and organs lying in close proximity to one another. The histological diagnosis of spindle cell lesions can be challenging in any site, but in this region is particularly so, due to the variety of structures from which they can arise. Account for less than 1% of all tumors in the oral regions.

7. Spindle cell tumor is not a specific diagnosis or a specific type of cancer. Spindle cell tumor is a descriptive diagnosis based on the presence of elongated/spindle cells under the microscope.

8. Origin Of Spindle Cells??? Epithelial Origin Fibroblastic & Myofibroblastic Origin Muscle Origin Nerve Tissue Origin Adipocytic Origin Vascular Origin Bone Origin Odontogenic origin

9. Epithelial origin Spindle Cell Carcinoma Melanocytic nevus Mucosal Melanoma Fibroblastic & myofibroblastic origin Nodular fasciitis Benign Fibrous Histiocytoma Fibromatosis Desmoplastic Fibroma Fibrosarcoma Pleomorphic sarcoma/ MFH Myofibroma Inflammatory Myofibroblastic Tumour Myofibrosarcoma Muscle origin Leiomyoma Leiomyosarcoma Rhabdomyoma Rhabdomyosarcoma Smooth muscle origin Skeletal muscle origin Neural origin Palisaded encapsulated neuroma Neurilemmoma Neurofibroma MPNST Adipocytic origin Spindle cell Lipoma Spindle cell Liposarcoma Vascular Origin Spindle cell hemangioma Solitary fibrous tumour Angiosarcoma Kaposis ’ Sarcoma Bone Origin Fibroblastic Osteosarcoma Synovial sarcoma Odontogenic origin Odontogenic Fibroma Odontogenic Myxoma Salivary gland origin Myoepithelioma Myoepithelial carcinoma

10. Epithelial Tumours Spindle Cell Carcinoma Melanocytic nevus Malignant Mucosal Melanoma

11. Spindle cell carcinoma Variant of squamous cell carcinoma characterized by dysplastic surface squamous epithelium in conjunction with an invasive spindle cell component which simulate a true sarcoma but are epithelial in nature. (WHO;2005) 3% of all squamous carcinomas in the head and neck region Etiology: still under debate. Other names: Carcinosarcoma, sarcomatoid carcinoma Pseudosarcoma Pleomorphic carcinoma Metaplastic carcinoma Polypoid SCC, Lane tumor

12. Pathogenesis ‘‘Collision’’ tumors where there are two separate neoplastic clones combined in the same lesion. Spindle cells: anaplastic type of carcinoma cell. Squamous cell carcinoma ‘‘drives’’ the proliferation of a pseudosarcomatous stromal response . EM & IHC analysis: spindle cells are of epithelial origin , with the ability to produce mesenchymal intermediate filaments. Dysfunctional cadherin-catenin complex : tumor cells shift from a squamous to a spindled type. Most of the cases: recurrences after radiotherapy for well differentiated SCC: DEDFIFFERENTAITION

13. Clinical features Common sites: upper aero-digestive tract : larynx, oral cavity & esophagus. Oral cavity : lower lip, lateral posterior tongue & alveolar ridges. Typically appears as a pedunculated, polypoid mass ; occasionally as sessile, nodular, fungating mass or as an ulcer. Pain &paresthesia prominent features. Tumor grows rapidly, tends to metastasize early; diagnosed in a late stages. Mean age : 57 years; no sex predilection

14. Histopathologic features ( a ) Spindled and pleomorphic tumor cells ‘‘ dropping off’’ from squamous cell carcinoma in situ; arrow indicates a tumor giant cell ; ( b ) cellular spindle cell component of a spindle cell carcinoma with fascicles of relatively regular cells with fusiform nuclei.

15. Squamous differentiation

16. Biphasic tumors. Conventional SCC admixed with spindled/pleomorphic tumour cells . Squamous cell component can range from varying grades of dysplasia to carcinoma-in-situ or frank SCC with varying grades of differentiation. Spindle cells show a variety of architectural patterns : fascicles , a storiform pattern, a ‘herringbone’ pattern similar to fibrosarcoma , associated with dense collagen as seen in fibromatosis or with a nodular- fascitis like appearance . Direct transition between the two cell types can be seen. Spindled component – may be bland and regular or markedly pleomorphic , mitotic figures, multinucleated tumour giant cells. Metastatic lesions - only spindle cells, only squamous cells or combination. Bone, cartilage or muscle differentiation may be seen.

17. Sometimes present as extensively ulcerated masses with tumor cells widely spaced apart in a loose, pale or myxoid background. There are frequently abundant small vessels with plump endothelial cells and numerous inflammatory cells , particularly neutrophils. Closely mimic exuberant granulation tissue

18. Immunohistochemistry AE1/AE3 Cytokeratin, K1, K18 Vimentin Carcinoembryonic antigen p63 SMA -30% MSA -15 %, desmin less than 2% S-100- 5%

19. AE1/AE3

20. Vimentin Vimentin

21. p63

22. Melanocytic nevus Malformation of the skin & mucosa that are congenital or developmental. Arise from the surface epithelium or from any of the connective tissue tissues. Common recognized nevus – ACQUIRED MELANOCYTIC NEVUS . Represents a benign, localized proliferation of cells from the neural crest called NEVUS CELLS. Neural crest origin. Ability to produce melanin. First cousins of melanocytes.

23. Clinical features Begin to develop on skin during childhood Before 35 years of age. Women > men; whites> blacks. Site : above the waist; H &N region. Clinical stages : JUNCTIONAL NEVUS – sharply demarcated , brown or black macule (< 6 mm) COMPOUND NEVUS – when nevus cells proliferate to produce a slightly elevated, smooth surfaced, soft papule. Degree of pigmentation becomes less; appear brown or tan. INTRADERMAL NEVUS – nevus gradually loses its pigmentation, surface- papillomatous , hairs are seen growing from the center. Many of them involute & disappear. Intra –oral nevi : uncommon; palate, mucobuccal fold, gingiva

24. Histopathology Characteristic feature – benign, Unencapsulated proliferation of small, ovoid cells.(nevus cells); lack the dendritic processes. Small, uniform nuclei, eosinophilic cytoplasm, indistinct cell borders; produce melanin Tend to get organized into small, round aggregates ( theques ) JUNCTIONAL NEVUS : theques of nevus cells found only on the basal layer of the epithelium; junction of the epithelium – connective tissue interface. COMPOUND NEVUS : Nevus cells proliferate to drop off into the underlying connective tissue; present along the junctional area & within the underlying connective tissue. INTRADERMAL/ INTRAMUCOSAL NEVUS: nests of nevus cells are no longer found in the epithelium, but are found only within the underlying connective tissue.

25. Histopathology Superficial cells ( TYPE I: EPITHELIOD ) – appear larger & epitheliod ; abundant cytoplasm, frequent intra-cellular melanin & tendency to cluster into theques . Middle portion ( TYPE II: LYMPHOCYTIC- LIKE ) - less cytoplasm, seldom pigmented, appear like lymphocytes. Deeper cells ( TYPE III : SPINDLE SHAPED ) - appear elongated; spindle shaped, like schwann cells or fibroblasts.

26. Mucosal malignant melanoma Malignant neoplasm of neural crest derived melanocytic cells. Uncommon, accounting for less than 1% of head and neck melanomas. Most commonly occurs in the nasal cavity and paranasal sinuses , but may also arise in the oral cavity, larynx and pharynx . Macroscopically , mucosal melanomas are often polypoid and pigmented tumours .

27. Histologically, ulceration is often present , although intact surface epithelium is usually identifiable in some areas and pagetoid spread of melanoma cells may be seen . Like cutaneous melanomas, the malignant cells can show a variety of appearances. Usually epithelioid or ovoid cells with large nuclei, prominent nucleoli &nuclear pseudo-inclusions, cytoplasm will be uniformly eosinophilic or clear. Occasionally, the cells become spindle or desmoplastic in areas.. Desmoplastic melanoma - prominent hyalinized stroma, are amelanotic and often show perineural invasion.

28. Immunohistochemistry S-100 HMB-45 MART-1 Melan A

29. MART-1 MELAN- A

30. Fibroblastic & myofibroblastic origin Nodular fasciitis Benign Fibrous Histiocytoma Fibromatosis Desmoplastic Fibroma Fibrosarcoma Pleomorphic sarcoma/ MFH Myofibroma Inflammatory Myofibroblastic Tumour Myofibrosarcoma

31. Nodular fasciitis (Pseudosarcomatous fasciitis) 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. Etiology : unknown; trauma ?? Because of the location of the lesions over bony prominence (angle of the mandible & Zygoma ). Although considered a reactive condition, recent molecular studies suggests that the cells are clonal, thus confirms that it is a benign neoplasm.

32. Clinical features: Trunk &extremities – most commonly involved. 10 % - soft tissues of the head and neck region, usually presenting as a rapidly enlarging mass. Rare cases : parotid gland. Occur in 3- 5 th decade of life. Intra –oral sites: buccal mucosa, tongue and alveolar mucosa Occur mostly in areas which serve as sites of origin and insertion of muscles of mastication.

33. The lesion will be well-delineated but not encapsulated proliferation of spindle cells inside the lamina propria Histopathologic features

34. A nodular growth contains plump fibroblasts with vesicular nuclei in a haphazard t o storiform arrangement.

35. Myxoid areas are often found, multinucleated giant cells are occasionally Found originating from the adjacent muscle or fusion of macrophages.

36. Spindle shaped cells have large oval nuclei and discrete pleomorphism

37. Unencapsulated with an infiltrative margin. The component spindle cells are plump, often pleomorphic and arranged in a ‘ tissue culture’ pattern , often with accompanying hemorrhage and scattered lymphocytes. Mitotic figures are usually present but abnormal forms will not be seen . HISTOLOGIC DD : FIBROMATOSIS : more infiltrative & show a fascicular growth pattern also produces more collagen, less cellular & mitotic figures. FIBROUS HISTOCYTOMA : More cellular with a storiform pattern, but may not be as well- circumscribed as Nodular fasciitis. FIBROSARCOMA : infiltrative and shows a herring-bone pattern, cellular atypia ( nuclear pleomorphism & hyperchromatism, abundant mitoses .

38. Immunohistochemistry The spindle cells often show both a myofibroblastic and histiocytic immunoprofile . SMA, MSA, vimentin and CD68 ( KP1) – positivity , Desmin – Negative SMA

39. Benign Fibrous Histiocytoma Diverse group of tumors that exhibit both fibroblastic and histiocytic differentiation. Cell of origin : still uncertain (may arise from tissue histiocyte, which then assumes fibroblastic properties ) Other names : Dermatofibroma Sclerosing Hemangioma Fibroxanthoma Nodular sub-epidermal fibrosis

40. Clinical features Common site: skin of the extremities : DERMATOFIBROMA Oral cavity: rare, if present: Buccal mucosa & vestibule Frequently affects the older adults. Appears as painless nodular masses (few mm to cms) that may be ulcerated. Deeper tumors tend to be larger

41. 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.

42. Immunohistochemistry POSITIVE Vimentin CD 68 SMA / CD 34: diffuse NEGATIVE S100 CD117 Desmin Leu7 (CD 57) Neurofilament Vimentin

43. Fibromatosis Broad group of fibrous proliferations that have a biologic behavior & histopathologic pattern that is intermediate between those of benign fibrous lesions & Fibrosarcoma. Show infiltrative, destructive and recurrent growth but no tendency to metastasize. Types Superficial Deep ( desmoid) Palmar/plantar Oral cavity Sporadic Familial adenomatous polyposis (FAP) associated Multicentric (familial ) Abdominal Extra -Abdominal Intra - Abdominal H &N region

44. Clinical features Presents as firm, painless mass which exhibit rapid growth. Most frequently occurs in children or young adults : JUVENILE FIBROMATOSIS Common site : para-mandibular soft tissue region. Tumor grow to a considerable size, resulting in facial disfigurement. Destruction of bone seen on radiographs.

45. 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

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

47. Desmoplastic Fibroma Benign, locally aggressive tumor of fibroblastic origin. Osseous counter- part of the soft tissue Fibromatosis. Few cases reported to be associated with tuberous sclerosis. Patients younger than 30 years of age; no sex predilection. Sites : mandible (body- ramus) affected more than maxilla. Slowly progressive, causing swelling of the jaws. Multilocular or unilocular radiolucency. Margins –well defined or ill- defined; bone expansion; thinned out cortex Clinical features Radiographic features

48. Histopathology Consists of interlacing bundles & whorled aggregates of densely collagenous tissue that contains uniform spindled and elongated fibroblasts Some areas shows hypercellularity with plump fibroblast nuclei & less collagen. No cytologic atypia or mitotic figures. Bone spicules may be present at the interface between the tumor and the adjacent normal bone; but not an integral part of the lesion.

49. Interlacing bundles & whorled aggregates of densely collagenous tissue that contains uniform spindled and elongated fibroblasts

50. Radiographic Differential diagnosis Odontogenic cysts Odontogenic tumors Malignancy arising from bone. Fibrosarcoma Odontogenic fibroma (presence of odontogenic rests) Histopathologic DD

51. IHC The spindle cells express vimentin and SMA but are negative for CD34. Oestrogen receptor positivity may be present and some show desmin expression.

52. Fibrosarcoma Malignant tumor of fibroblasts. Once - most common soft tissue sarcoma. Most common in the extremities ( femur & tibia ); 10% occur in the H& N region. Two main types : primary & secondary. Also reported to arise from pre- existing lesions: fibrous dysplasia, chronic osteomyelitis, bone infarct, Paget's disease & previously irradiated areas.

53. Clinical features Rare soft tissue and bone malignancy of H&N (nasal cavity, paranasal sinus, nasopharynx ) When occurs in bone, they may arise from periosteum , endosteum or PDL. More common in men than in women; fourth decade, also common in children and young adults (infantile form; good prognosis) Present as slow- growing masses that may reach considerable size before they produce pain; secondary ulceration seen as it enlarges.

54. Classification ADULT – TYPE FIBROSARCOMA Myxoid type ( myxofibrosarcoma , low grade myxoid MFH) Fibromyxoid type ( low grade fibromyxoid type/ fibromyxoid type with giant rosettes. Sclerosing epitheliod type II. JUVENILE/INFANTILE TYPE FIBROSARCOMA.

55. Histopathology Uniform fasciculated growth Pattern fusiform or spindle-shaped cells that vary little in size and shape, have scanty cytoplasm with indistinct cell borders, and are separated by interwoven collagen fibers arranged in a parallel fashion. Mitotic activity varies & Multinucleated giant cells – rarely seen.

56. 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

57. In some cases the cells are oriented in curving or interlacing fascicles, forming a classic herringbone pattern. In others, the cells are separated by thick, wire-like collagen fibers. Secondary features are common. Low-grade fibrosarcomas may show focal chondro -osseous differentiation.

58. Consists of closely packed, less well-oriented tumor cells that are small, ovoid or rounded, and associated with less collagen. The fascicular or herringbone growth pattern is less distinct, nuclei - more pleomorphic, mitotic figures- more numerous, areas of necrosis and/or hemorrhage. High-grade fibrosarcoma ( poorly differentiated )

59. Differential diagnosis Benign processes : nodular fasciitis to cellular benign fibrous histiocytoma and fibromatosis . Malignant neoplasms : malignant peripheral nerve sheath tumor, malignant fibrous histiocytoma , and monophasic fibrous synovial sarcoma .

60. Immunohistochemical findings Vimentin positivity In some fibrosarcomas , scattered cells stain for smooth muscle or muscle-specific actin, reflecting focal myofibroblastic differentiation. The lack of cytokeratin immunoreactivity - distinction from monophasic fibrous synovial sarcoma . Negative immunostaining for S-100 - distinguishes from spindle cell or desmoplastic malignant melanomas.

61. 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

62. 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

63. 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.

64. Undifferentiated Pleomorphic sarcoma Once called as Malignant Fibrous Histiocytoma with both fibroblastic & histiocytic features. (introduced in 1963) Most common soft tissue neoplasm in late adult life. Most lesions were later reclassified into other categories- liposarcoma , leiomyosarcoma , rhabdomyosarcoma , myxofibrosarcoma , melanoma, anaplastic carcinoma. 5 histological variants : storiform- pleomorphic myxoid giant cell (malignant giant cell tumor of soft parts) inflammatory ( xanthosarcoma , malignant xanthogranulomas) angiomatoid : seen in childhood

65. Clinical features Tumor of old age groups. Men > females Seen more in extremities & retroperitoneum , rare in H&N regions. Presents as an expanding mass that may or may not be painful or ulcerated. Nasal & para nasal sinus tumors : obstructive symptoms. Irregular nodular lesion, Unencapsulated, attached to surrounding tissues. Myxoid variant: soft in consistency Angiomatoid variant : superficially placed than other variants. Radiographic features: radiolucency with poorly defined margins.

66. 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.

67. 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

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

69. 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

70. 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. CD68 stain of an inflammatory MFH with staining of benign xanthoma cells

71. Myofibroblastic Origin MYOFIBROMA INFLAMMATORY MYOFIBROBLASTIC TUMOR MYOFIBROSARCOMA

72. Myofibroblast… A myofibroblast is a cell that is in between a fibroblast and a smooth muscle cell in phenotype Developmental origin Partial smooth muscle differentiation of a fibroblastic cell Loss of contractile phenotype of a smooth muscle cell Direct myofibroblastic differentiation of a progenitor cell resident in a stromal tissue Epithelial to mesenchymal transdifferentiation (EMT) of an epithelial cell 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 .

73. MYOFIBROMA/ MYOFIBROMATOSIS Myofibroma/ myofibomatosis are benign tumours of myofibroblasts which are solitary or multicentric , respectively. These tumours show a predilection for the head and neck, with a particular propensity for arising in and around the oral cavity More commonly described in childhood

74. Clinical features Rare neoplasms with predilection for H& N region. Most frequently in the first 4 decades of life (mean age:22 yrs ) Site : mandible, tongue & buccal mucosa. Presents as painless mass that show rapid enlargement. Radiographs: radiolucent defects that are poorly defined, sometimes well- defined & multilocular. Multicentric myofibromatosis : affects neonates & infants who have tumors of the skin, sub-cutaneous tissue, muscle, bone & viscera. Number of tumors may vary from several to more than 100.

75. 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.

76. Immunohistochemistry SMA POSITIVE Positive for SMA, MSA and negativity for DESMIN which rules out Leiomyoma & Leiomyosarcoma DESMIN NEGATIVE

77. INFLAMMATORY MYOFIBROBLASTIC TUMOR Intermediate type of neoplasm consisting of variable numbers of inflammatory cells and myofibroblastic spindle cells. Rare outside the lung, liver and orbit. Liston et al. in 1981 was the first to report IMTs of oral cavity in three children. Seen in the sinonasal tract, larynx, oral cavity and salivary glands. Other names : Inflammatory pseudotumor (IPT ) plasma cell granuloma, Benign myofibroblastoma Inflammatory fibrosarcoma Histocytoma X anthomatous granuloma Spindle cell pseudotumor

78. 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 tumour cells

79. Spindle shaped cells with fasciculated architecture, hypocellular fibrous areas with numerous plasma cells, and concurrent Fascitis -like foci

80. Immunohistochemistry SMA MSA POSITIVE DESMIN ANAPLASTIC LYMPHOMA KINASE-1 (ALK-1) - 35 TO 60 % POSITIVE SMA

81. LOW GRADE MYOFIBROSARCOMA Malignant tumour of Myofibroblasts. Indolent neoplasms but can recur and metastasize after a long period . Clinical features Usually affects adults and is uncommon in children. Intra oral tumors- usually slows growing & asymptomatic. Oral cavity-the tonsil, mandible, maxilla

82. Usually affects deep soft tissue sites and is more often poorly circumscribed with fascicles and individual cells infiltrating between muscle fibers , although focal circumscription is not unusual . The lack of significant atypia confuses with benign diagnosis such as nodular fascitis , proliferative myositis, and Fibromatosis.

83. Histopathology

84. 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 , extending between individual skeletal muscle fibers. A mild degree of nuclear pleomorphism, anisonucleosis , and hyperchromatism will be seen. 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.

85. Immunohistochemistry SMA- POSITIVE Calponin - Diffusely Positive Desmin – Focal Positive h- caldesmon - Negative ALK – Negative

86. MUSCLE ORIGIN Leiomyoma Leiomyosarcoma Rhabdomyoma Rhabdomyosarcoma Smooth muscle origin Skeletal muscle origin

87. Leiomyoma Benign tumors of smooth muscle that most commonly occur in the uterus, GIT and skin. Uncommon in the oral cavity probably because of the general absence of smooth muscle except in the blood vessel walls and occasionally in the circumvallate papillae of the tongue. 3 types: Solid leiomyoma Vascular leiomyoma ( angiomyoma / angioleiomyoma ) Epitheliod leiomyoma

88. Clinical features Presents as slow growing, firm mucosal nodule; asymptomatic, sometimes painful, 1-2 cm in diameter. Symptoms : sore throat or tumor in the throat Can occur at any age. Solid leiomyoma normal colour Angio leiomyoma bluish hue Sites: tongue, lips, palate & cheek. Intra-osseous cases – unilocular radiolucencies

89. Histopathology Well circumscribed tumors that consists of interlacing bundles of spindle shaped smooth muscle cells. The nuclei are elongated, pale staining & blunt ended (cigar shaped) Angio -leiomyoma multiple tortuous blood vessels with thickened walls caused by hyperplasia of their smooth muscle coats. Interwining bundles of smooth muscle may be found between the vessels Special stains Masson trichrome : to differentiate between collagen & smooth muscle. Muscle: BRIGHT RED

90. IHC SMA MSA Desmin h- caldesmon Vimentin Actin Myosin Desmin

91. Leiomyosarcoma Malignant neoplasm of smooth muscle differentiation. Account for 5 - 10% of all soft tissue sarcoma. Common sites: uterine wall & GIT; Oral cavity – Rare. Develops either through malignant transformation of leiomyoma or de novo. Clinical features Middle aged & older adults. Site : jaw bones, cheek & floor of the mouth. Appears as an enlarging, lobulated mass that may or may not be painful; secondary ulceration.

92. Histopathology Fascicles of spindle shaped cells with abundant eosinophilic cytoplasm and blunt ended, cigar shaped nuclei. Some tumors : rounded epitheliod cells with eosinophilic / Clear cytoplasm. Degree of pleomorphism varies. More than 5 or more mitosis per 10 high power field : MALIGNANT. PAS: POSITIVE (GLYCOGEN) & MASSON TRICHROME: CELL CYTOPLASM – BRIGHT RED IHC SMA SMMS Desmin MSA (HHF 35)

93. Skeletal muscle origin tumors

94. Rhabdomyoma Benign neoplasm of skeletal muscle. Introduced by Zenker (1864). Rhabdomyoma - TYPES CARDIAC EXTRA- CARDIAC ADULT TYPE FETAL TYPE GENITAL TYPE RHABDOMYOMATOUS MESENCHYMAL HAMARTOMA

95. Clinical features – Adult Rhabdomyoma Middle aged & older adults; 70 % occurs in men. Sites : pharynx, oral cavity, larynx Oral cavity – floor of the mouth, soft palate, base of the tongue. The tumor appears as a nodule or mass that grows to many centimeters; sometimes multinodular in nature. Young children; male predilection Site : face &peri-auricular region, nasopharynx , but not in mouth. Clinical features – fetal Rhabdomyoma

96. Two related types: MYXOID TYPE AND INTERMEDIATE TYPE The myxoid type - primitive oval or spindle-shaped cells with indistinct cytoplasm, interspersed immature skeletal muscle fibers reminiscent of fetal myotubes seen during the seventh to tenth weeks of intrauterine life, and a richly myxoid matrix. Histopathology- Fetal Rhabdomyoma IHC Desmin MSA (HHF 35)

97. The intermediate type - characterized by the presence of numerous differentiated muscle fibers, less conspicuous or absent spindle-shaped mesenchymal cells, and little or no myxoid stroma. The predominant cells are broad, strap-shaped muscle cells with abundant eosinophilic cytoplasm, centrally located vesicular nuclei, and frequent cross-striations reminiscent of the cells seen in adult rhabdomyomas ; many of the cells contain glycogen and are often vacuolated Histopathology- Fetal Rhabdomyoma

98. Rhabdomyosarcoma Malignant neoplasm of skeletal muscle differentiation. More common in young children; 60% of soft tissue sarcomas in childhood. Only 2-5 % of soft tissue sarcomas in adults. 35 % of cases – H & N; Genitourinary tract – 2 nd most common site. Clinical features Occurs during the first decade of life. Embryonal type – most common in the first 10 years of life. (60%) Alveolar type – between 10-25 years.(20-30%) H& N Pleomorphic type - < 5 % cases extremities

99. NATIONAL CANCER INSTITUTE CLASSIFICATION OF RHABDOMYOSARCOMA (1992) Classification

100. Embryonal rhabdomyosarcoma , spindle cell type In 1992, Cavazzana et al. reported 21 ER composed predominantly (>80%) of elongated spindle cells. Rare variant; 3 % of all RMS Male predilection; paratesticular location (38%) followed by H & N(27%)

101. The tumor is composed almost exclusively of elongated fusiform cells with cigar-shaped nuclei and prominent nucleoli . The tumor cells have eosinophilic fibrillar cytoplasm with distinct cellular borders, closely resembling late-stage fetal myoblasts . Cytoplasmic cross-striations may be observed. The collagen-rich form is characterized by spindle cells separated by abundant collagen fibers arranged in a storiform or whorled growth pattern. The collagen-poor form is a more cellular proliferation of cells arranged in bundles or fascicles, reminiscent of leiomyosarcoma . Histopathology

102. IHC Desmin, titin , troponin D, myoglobin, MyoD1 and myf-4 ( myogenin ) MyoD1 Myogenin

103. Neural Tumours Palisaded encapsulated neuroma Neurilemmoma Neurofibroma MPNST

104. Palisaded encapsulated neuroma Benign neural tumor with distinctive clinical & histopathological features. Represents one of the common superficial nerve tumors. Cause – uncertain ; trauma. Generally considered to be a reactive lesion rather than neoplasm. Clinical features Striking predilection for the face; 90% of the cases. Nose & cheek – most common sites; oral cavity – hard palate & maxillary labial mucosa 5- 7 th decade of life. Smooth surfaced, painless, dome shaped papule or nodule (< 1cm)

105. Histopathology Well – circumscribed & encapsulated tumor. Lobulated appearance. Tumor consists of moderately cellular interlacing fascicles of spindle cells that are consistent with Schwann cells. Nuclei – wavy & pointed; palisaded; no pleomorphism or mitotic activity. IHC S -100 POSITIVE

106. Neurilemoma Benign neoplasm that is derived from the proliferation of Schwann cells of the neurilemma or nerve sheath. 25- 48 % occur in H &N. Bilateral neurilemomas of the auditory- vestibular nerve- NEUROFIBROMATOSIS TYPE II Clinical features Slow growing, encapsulated tumor. As it grows, it pushed the nerve aside. Asymptomatic mass; pain & tender occur sometimes. Young & middle aged adults; few mm to several cms. Tongue – common site, centrally within the bone; bone expansion. Intra – osseous : posterior mandible; unilocular / multi- locular radiolucencies.

107. Histopathology Encapsulated tumor that shows two microscopic patterns in varying amounts: ANTONI A – streaming fascicles of spindle shaped Schwann cells. cells form a palisaded arrangement around central, acellular, eosinophilic areas: VERUCAY BODIES (reduplicated basement membrane & cytoplasmic processes) ANTONI B - less cellular & less organized spindle cells are randomly arranged within a loose myxomatous stroma. Degenerative changes can be seen in some older tumors : ANCIENT NEURILEMMOMAS. Changes - hemorrhage, hemosiderin deposits, inflammation, fibrosis & nuclear atypia S- 100

108. Ancient schwannoma Ancient schwannoma with cyst formation and interstitial hyalinization.

109. VARIANTS Neuroblastoma-like schwannoma composed of rounded Schwann cells forming rosettes (A). Other areas had a more conventional appearance (B).

110. VARIANTS Cellular schwannoma with long fascicles of Schwann cells without Antoni B areas or Verocay bodies

111. VARIANTS Plexiform schwannoma involving the dermis

112. VARIANTS Epithelioid schwannoma . Note the cohesive nests of bland epithelioid cells S- 100

113. Neurofibroma Most common type of peripheral nerve neoplasm. Arises from a mixture of cell types; schwann cells & perineural fibroblasts. Appear as solitary or multiple lesions as part of the syndrome: NEUROFIBROMATOSIS Clinical features Appears as slow growing, soft painless lesions that vary in size from small nodules to large masses. Site : skin; oral cavity – tongue & buccal mucosa; centrally within the bone. Well demarcated or poorly defined unilocular or multilocular radiolucency. THREE GROWTH PATTERNS : Localized, Diffuse, Or Plexiform NF 1 normal individuals

114. Histopathology Interlacing bundles of elongated cells with wavy, darkly-stained nuclei. The cells are intimately associated with wire-like strands of collagen that have been likened to “shredded carrots.” Small to moderate amounts of mucoid material separate the cells and collagen. The stroma of the tumor - mast cells, lymphocytes, and rarely xanthoma cells. Less frequently, the neurofibroma is highly cellular and consists of Schwann cells set in a uniform collagen matrix devoid of mucosubstances. S-100

115. Plexiform Neurofibroma Always develop during early childhood, often before the cutaneous neurofibromas have fully developed. Involve an entire extremity give rise to the condition known as elephantiasis neuromatosa , in which the extremity is enlarged. The overlying skin is loose, redundant, and hyperpigmented, and the underlying bone may be hypertrophied. Macroscopically , plexiform neurofibromas are large lesions that affect large segments of a nerve, distorting it and contorting it into a “bag of worms”

116. Histopathology The lesion consists of a tortuous mass of expanded nerve branches, which are seen cut in various planes of section. In the early stages the nerves may simply have an increase in the endoneurial matrix material, resulting in wide separation of the small nerve fascicles. With continued growth the cells spill out of the nerves into soft tissue, creating a diffuse variant of neurofibromatous tissue such that NF1 lesions can have both plexiform and diffuse areas . Unlike localized neurofibromas , they may display nuclear atypia . Because these lesions are at greatest risk to undergo malignant transformation

117. Malignant peripheral nerve sheath tumor Malignancy of peripheral nerve origin. 5 % of all soft tissue tumors. 50% occur in patients with NF1. Common sites : proximal portions of the extremities & trunk. Oral cavity : mandible, lips & buccal mucosa. 10 -15% - H & N. Young adults; NF -1 associated younger than the non associated. Enlarging mass showing rapid growth with associated pain.

118. Histopathology Fascicles of atypical spindle shaped cells. More irregular in shape with wavy or comma shaped nuclei. In addition to streaming fascicles, less cellular myxoid areas are also present. Some tumors show skeletal muscle differentiation (malignant triton tumor), cartilage, bone or glandular structures.

119. Adipocytic origin Spindle cell Lipoma Spindle cell Liposarcoma

120. Spindle cell Lipoma Originally described as a distinct entity by Enzinger and Harvey in 1975. Usually arises in men; 45-60 years of age. 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

121. 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

122. 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. IHC- the spindle cells in spindle cell lipoma are consistently positive for CD34

123. Spindle Cell Liposarcoma 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.

124. Vascular tumors Spindle cell hemangioma Solitary Fibrous Tumour Angiosarcoma Kaposis’s Sarcoma

125. Spindle cell hemangioma First described in 1986 as “ spindle cell Hemangioendothelioma”; an acral vascular tumor characterized by cavernous blood vessels and spindled areas reminiscent of Kaposi sarcoma. Young adults ; subcutis of the distal extremities, particularly the hand. Occasionally associated with Maffucci syndrome, Klippel-Trénaunay syndrome. Most begin as a solitary nodule but have a remarkable tendency to give rise to multiple lesions in the same general area.

126. Histopathology The lesions are composed of thin-walled cavernous vessels lined by flattened endothelial cells and containing a mixture of erythrocytes and thrombi. Between the cavernous spaces are bland spindled areas reminiscent of Kaposi sarcoma.

127. Hemangiopericytoma - Solitary Fibrous Tumor First coined by Stout and Murray for tumors thought to originate from the pericytes , a modified dendritic-like smooth muscle cell encircling blood vessels. In 1976, by Enzinger and Smith emphasized the staghorn , partially hyalinized vessels surrounded by small rounded and fusiform cells. Hemangiopericytoma also coincided with the increasing popularity of the diagnosis of solitary fibrous tumor (SFT), a pleural-based lesion first described by Klemperer and Rabin. Had many overlapping features with classic hemangiopericytoma : CD34 immunoreactivity, paved the way for the popular belief that all hemangiopericytomas were, or should become, solitary fibrous tumors.

128. Clinical features Slow growing, mucosal, painless or deep soft tissue mass Buccal mucosa – 75%; adults & rare in children. Nasal cavity & paranasal sinuses with the symptoms of nasal obstruction & epistaxis.

129. Histopathology Well circumscribed lesions with variable microscopic appearance. The cellular end of this spectrum corresponds to “classic hemangiopericytoma ” and the hyalinized end to “classic solitary fibrous tumor.” Many cases have hybrid features. Classic hemangiopericytoma consists of tightly packed round to fusiform cells with indistinct cytoplasmic borders which are arranged around an elaborate vasculature. As a rule, the dilated, branching vessels divide and communicate with small or minute vessels which may be partly compressed and obscured by the surrounding cellular proliferation. Typically , the dividing sinusoidal vessels have a “ staghorn ” or “antler-like” configuration

130. In contrast, lesions having features of classic “solitary fibrous tumor” consist principally of spindle cells. The arrangement of the cells varies from area to area in the same tumor . In some zones the cells are arranged in short, ill-defined fascicles, whereas in others they are arranged randomly in what has been described as a “ patternless pattern .” Staghorn vessels, occasionally present, are not as striking as in classic hemangiopericytoma .

131. Immunohistochemistry Hemangiopericytoma like areas: CD34 SFT CD34 : 80-90% CD99: 70% bcl2 : 30% EMA : 30% ACTIN: 20% NEGATIVE Desmin Cytokeratin S-100 CD34

132. Angiosarcoma Rare malignancy of vascular endothelium which may arise from either blood or lymphatic vessel. More than 50% - occur in H&N (scalp & forehead) Oral lesions- rare Older adult patients Early lesions – bruise – delay in diagnosis; lesion continues to enlarge resulting in elevated, nodular or ulcerated surface.

133. Histopathology Vary from well-differentiated neoplasms with vascular channels lined by atypical endothelial cells with few mitoses to poorly differentiated neoplasms composed of solid sheets of epithelioid or spindle cells exhibiting brisk mitotic activity. Poorly defined vascular spaces, multilayered endothelial lining, and papillary projections into the vascular lumen may also be observed. Hemorrhage, necrosis , and lymphocytic infiltration are common features. One hallmark of poorly differentiated angiosarcoma - presence of fragmented erythrocytes in the intracytoplasmic vacuoles

134. Kaposi sarcoma Unusual vascular neoplasm that was described by Moritz Kaposi in 1872. Caused by HHV-8; more associated with HIV patients. Arises from endothelial cells; lymphatic origin. 4 CLINICAL PRESENTATION: Classic Endemic (African ) Iatrogenic immunosuppression associated AIDS related.

135. Histopathology The Earliest ( patch) stage – a flat lesion characterized by a proliferation of miniature vessels surrounding larger ectatic vessels

136. Plaque stage produces slight elevation of the skin. The vascular proliferation usually involves most of the dermis and may extend to the subcutis . A discernible but relatively bland spindle cell component, initially centered around the proliferating vascular channels, appears at this stage . In time, the spindle cell foci coalesce and produce the classic Nodular lesions of Kaposi sarcoma. CD34 CD31 Factor VIII FLI-1

137. Intra-osseous tumours Fibroblastic Osteosarcoma Synovial Sarcoma

138. Fibroblastic osteosarcoma Osteosarcoma – malignancy of mesenchymal cells that have the ability to produce osteoid or immature bone. Variants : osteoblastic, chondroblastic , fibroblastic Minimal amount of osseous matrix with or without cartilage. Overall histological appearance is similar to fibrosarcoma or undifferentiated pleomorphic sarcoma (malignant fibrohistiocytic tumour)

139. Synovial Sarcoma Synovial sarcoma is a clinically and morphologically well-defined entity that, despite its name, is extremely uncommon in joint cavities and is encountered in areas with no apparent relation to synovial structures. It occurs primarily in the para-articular regions of the extremities, usually in close association with tendon sheaths, bursae , and joint capsules. Teenagers & young adults. Gradual enlarging mass associated with pain H &N region- paravertebral & parapharyngeal region. Oral cavity – tongue & cheek.

140. Histopathology Two major categories of synovial sarcoma: biphasic and monophasic types. biphasic type , with distinct epithelial and spindle cell components in varying proportions monophasic fibrous type rare monophasic epithelial type poorly differentiated (round cell) type. Cytokeratins EMA Bcl2 S100 CD99

141. Odontogenic origin Odontogenic fibroma Odontogenic Myxoma

142. Odontogenic Fibroma (OF) Tumors of odontogenic ectomesenchyme . Simple type: An expansile, non infiltrating connective tissue lesion resembling a dental follicle It is relatively acellular, the fibers being quite delicate, and there is a considerable amount of ground substance yielding a fibromyxoid quality. It may exhibit inactive-looking rests of odontogenic epithelium but they are seldom numerous. WHO type: cellular connective tissue. It often occurs in fibroblastic strands that are interwoven with less cellular areas in which numerous small blood vessels are present Foci of calcified collagenous matrix, resembling dysplastic cementum, osteoid atubular dysplastic dentin Islands or strands of inactive-looking odontogenic epithelium are an integral component

143. A myxoid tumour which is largely confined to the tooth-bearing areas of the jaws Posterior mandible Odontogenic myxomas are locally aggressive, non-encapsulated, non-metastasizing neoplasms that infiltrate bone marrow spaces. Cut sections characteristically reveal a white- gray color in the mucoid substance, which will stick to an instrument when touched.

144. Histolopathology Loose, abundant mucoid stroma that contains rounded, spindle-shaped, or angular cells Cellular and nuclear pleomorphism is rare, as is mitotic activity Usually tumor cells are evenly spaced with in a fine fibrillar mucinous matrix The stroma may be relatively avascular or may exhibit delicate capillaries Vimentin Occasional positivity to S-100 protein and muscle specific actin

145. Salivary gland origin Myoepithelioma Myoepithelial carcinoma

146. Myoepithelioma Myoepithelium -rich pleomorphic adenoma comprise a spectrum of benign myoepithelial tumor with overlapping histologic features and similar clinical behavior and arise almost exclusively in the normally or ectopically situated salivary glands. First used by Sheldon in 1943. Sites: parotid, palate < 1% of all major & minor salivary gland tumors.

147. Histopathology Composed exclusively of neoplastic myoepithelial cells. Predominantly spindle shaped cells or plasmacytoid. Epitheliod and clear cells are also present. Single cell type or combination of cell types predominates. Does not contain the chondromyxoid stroma of PA.

148. Myoepithelial carcinoma ELLIS GL (1991) defined it as a malignant epithelial neoplasm whose tumor cells demonstrate cytologic differentiation towards myoepithelial cells and lack ductal or acinar differentiation. Intermediate to high grade carcinoma Patient complaints of a painless mass.

149. Histopathologic features General morphologic features resemble tumor cells in myoepithelioma . Tumor cells are spindle shaped or plasmacytoid; they will be intermixed or one cell type predominates. Quite cellular ; suggestive sarcoma rather than carcinoma Stroma in other parts of the tumor may be conspicuous & myxoid. Distinguished from other benign tumors by their infiltrative & destructive growth; increased mitotic activity & pleomorphism IHC: CYTOKERATIN, S100, SMA, GFAP.

150. Diagnosis of Spindle cell Neoplasm

151. Spindle cell neoplasm on biopsy Malignant Epicentre on Radiology Intraosseous Mucosal Sarcomatoid carcionoma Melanoma Myoepithelial carcinoma Sarcomas Benign Leiomyoma , Schwannoma , Solitary Fibrous Tumour , Bening fibrous Histiocytoma , IMFT, Neurofibroma , Nodular fasciitis… Osteosarcoma Odontogenic tumours

152. Algorithm for mucosal malignant tumors If in situ component, dysplasia, squamoid traits If absent –IHC to be done Spindle Cell Carcinoma S100, HMB45, Melan A POSITIVE S100 POSITIVE, NEGATIVE HMB45, melan A SMA strongly and diffusely POSITIVE CK, EMA, AE1/AE3, HMWCK, p63 POSITIVE CD - 34 POSITIVE – Melanoma Leiomyosarcoma confirm with H- caldesmon , desmin Spindle Cell Carcinoma/ Myoepithelial carcinoma Vascular tumour FLI-1 –specific for Kaposis Sarcoma Neurogenic Sarcomas

153. 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 DAGNOSIS. RULE OF THUMB –IN ADULTS MALIGNANT SPINDLE CELL ARE MORE LIKELY TO REPRESENT CA OR MELANOMA THAN A TRUE SA

154. Thank you