Pathology of tumors of retina - sathyashree k v.pptx

Pathology of tumors of retina

1. PATHOLOGY OF TUMORS OF RETINA & NEUROECTODERM OF EYE Presenter: Dr. Sathyashree K V Moderator: Dr. B R Yelikar 1

2. Headings Embryology of neuroectoderm and eye Anatomy of eye Histology of retina, iris & ciliary body Neuroectodermal tumours of eye -Retinoblastoma -Nevi & melanoma - Mesectodermal leiomyoma - Medulloepithelioma -PNET/ Ewings sarcoma of retina Other intraocular tumors References 2

3. Embryology Ectoderm receives BMP(Bone morphogenetic protein) inhibiting signals like noggin & differentiate into neuroectoderm. Noggin is released from notochord, regulates BMP during development & involved in the development of nervous tissue, muscles and bone. 3

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5. Neural Tube D erivatives Cranial part- brain Caudal part- spinal cord Cavity- central canal of spinal cord & ventricles of brain Retina, optic nerve, iris & ciliary body 5

6. Neural Crest Derivatives Neurons of spinal posterior nerve root ganglia Neurons of sensory ganglia of V,VII,VIII,IX & X cr.n . Neurons of sympathetic ganglia Schwann cells Chromaffin cells of adrenal medulla Pigment cells ( melanoblasts ) Leptomeninges Odontoblasts (dentine forming cells) Parafollicular cells Skeletal & connective components of pharyngeal arches 6

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8. EMBRYOLOGY OF EYE Central Nervous System develops from Neural groove On either side of lateral portion of this structure, a thickening called optic plate appears After it meets the surface ectoderm, the primary optic vesicle (optic cup) develops The inner layer of the cup forms the main structure of retina The outer layer remains as a single layer of pigment epithelium 8

9. Embroyology … contd 6 weeks- Differentiation of retinal pigment epithelium 3 rd month- Differentiation of precursors of rods and cones 4 th month- formation of major arterial circle 7 th month- Rods differentiate Retinal vessels start reaching nasal periphery 9 th month- Retinal vessels reach temporal periphery After birth- Retina develops further 9

10. NORMAL ANATOMY 10

11. Histology of retina 11

12. Histology of iris Anterior limiting layer Stroma Constrictor muscle Dilator muscle( myopeithelium ) Anterior pigment epithelium Posterior pigment epithelium 12

13. Histology of ciliary body 13

14. NEUROECTODERMAL TUMORS OF EYE 14

15. Case 1 2year old child is brought by their parents to hospital with complaints of whitish glow in the right eye. Diagnosis? 15

16. RETINOBLASTOMA Most common primary malignant intraocular neoplasm of infants & children Congenital 40% familial (Autosomal dominant) – Mostly bilateral & multifocal 60% sporadic – Mostly unilateral & unifocal Derived from primitive neuroectodermal cells exhibiting retinal differentiation Age: 16months – 2 years 16

17. Pathogenesis: Caused by mutation(loss/inactivation) of RB gene, located on chromosome 13q14 Gene mutations in both alleles are necessary to produce inactivation of RB protein (negative regulator of cell growth) Knudson’s ‘two-hit hypothesis’ -In familial cases; germ cell mutation occurs in one allele and somatic mutation in second allele -In sporadic cases; both mutations are sporadic 17

18. Clinical presentation Leukokoria (white glow in pupil) Strabismus Red eye Excessive tears Buphthalmos Corneal clouding Discoloration of iris Loss of fundal reflection 18

19. Pathology: Exophytic pattern – tumor grow from retina towards RPE & choroid Endophytic pattern – Tumor grows into vitreous cavity Trilateral retinoblastoma: pineoblastoma + bilateral retinoblastoma 19

20. Microscopy Retinoblasts ( have large basophilic nucleus and scant cytoplasm) Cellular necrosis Intralesional calcification Flexner Wintersteiner rosettes Homer Wright rosettes Fleurettes 20

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23. Recommendations for reporting histological features for retinoblastoma 23 HISTOLOGIC CHARACTERISTICS COMMENTS Optic nerve invasion Unfavorable outcome Extraocular extension Poor prognosis Choroidal & scleral invasion <3mm diameter: Minimal choroidal invasion >3mm diameter: Massive choroidal invasion & extends to sclera Anterior chamber seeding Aggressive clinical course Growth pattern Exophytic / Endophytic / Diffuse Differentiation Rosettes ( Flexner Wintersteiner rosettes, Homer Wright rosettes, Fleurettes ) Optional features: DNA deposition in blood vessels Iris neovascularisation Does not influence outcome

24. Baseline systemic evaluation in Retinoblastoma History & physical examination CBC MRI/CT brain (in bilateral cases to look for ectopic intracranial retinoblastoma) CSF analysis Bone marrow aspiration/biopsy 24

25. Clinical mimickers: PHPV(Persistent hyperplastic primary vitreous) Toxocara endophthalmitis Massive gliosis of retina 25

26. Treatment Chemotherapy Radiotherapy: EBRT Plaque radiotherapy Photocoagulation & laser therapy Cryotherapy Enucleation Observation 26

27. UVEAL NEVUS Benign tumor arises from melanocytic cells derived from neural crest cells Most common primary intraocular tumor Approximately 20% of persons >50yrs have atleast one choroidal nevus Equal in men & women Common in light pigmented races 27

28. Site: Choroid ( Most common) Iris Ciliary body Optic disc Mostly nevi are asymptomatic Macular choroidal nevus - visual loss in the affected eye. 28

29. Iris nevus: -Is a localised melanotic stromal lesion of the iris -Involve any portion of the iris from pupillary margin to the iris root -Is 3mm or less in diameter & 0.5mm or less in thickness -Cause pupillary peaking, focal ectropion iridis or both - Surface plaque: tightly packed benign spindle cells present over the iris nevus. 29

30. Choroidal nevus: - Appears as a small gray to brown choroidal tumour with a bland surface appearance -Well circumscribed - 5mm or less in diameter & 1mm or less in thickness -Composed of spindle shaped melanocytes lacking nucleoli -Exhibit characteristic surface alterations such as drusen and retinal pigment epithelial pigment clumping 30

31. Melanocytoma of optic disc: -Benign condition -Is a brown to black tumour involving the optic disc -Surface of the lesion appears striated because of insinuation of darkly pigmented cells of the tumor between axons in the nerve fibre layer -Produces prominent visual field defects, if it compresses optic disc 31

32. - Lesion is composed of magnocellular nevus cells ( uniformly large, pigmented round to polygonal or spindled cells with small, round, uniform nucleus containing central small nucleoli) - Spindled melanocytes signify a locally aggressive course with local infiltration . 32

33. Melanocytoma of ciliary body: - Enlarge & compresses the lens – sectoral cataract -Increases intraocular pressure by infiltrating the angle, rotating the ciliary body to close the angle or spontaneous necrosis / liberation of melanin into aqueous humour- Melanocytomalytic glaucoma. 33

34. Melanocytoma of choroid 34

35. Congenital melanosis oculi : -Diffuse congenital nevus affecting iris, ciliary body and choroid. -Precursor of melanoma Nevus cells are differenciated from melanoma cells by the absence of nucleoli in melanocytes. 35

36. Case 2 55year old male came with history of visible spot / discoloration in iris of left eye 36

37. MELANOMA OF EYE Most common primary intraocular neoplasm in adults. Malignant neoplasm of neuroectodermal melanocytes of choroid, ciliary body or iris Mutation of GNAQ & GNA11(encodes G –protein coupled receptor) Cytogenetic abnormalities: - Monosomy 3 -Duplication of chromosome 8q -Partial deletion of chromosome 9p -Complementary gain of material on chromosome 6p & loss of material on 6q 37

38. Choroidal & ciliary body tumors(>7mm diameter & >2mm thick) are larger than iris tumours Mostly unilateral Male>Women Most commonly metastasise to liver Positive for S 100, HMB 45,Vimentin, CAM5.2,p53 & Bcl2 38

39. Types of melanoma cells Spindle A cells: cohesive cells, slender, bland with indistinct cell borders, small fusiform nuclei and no nucleoli, scant cytoplasm with few small intracytoplasmic melanin granules; appear benign 39

40. Spindle B cells: cohesive cells are larger and more pleomorphic than spindle A with more cytoplasm, large oval nuclei and prominent nucleoli, prominent mitotic activity 40

41. Epithelioid cells: cells are larger and more irregular than spindle B with abundant cytoplasm and well demarcated cell borders; may be markedly enlarged or multinucleated; large nuclei and very prominent nucleoli; usually less cohesive than spindle A or B 41

42. Spindle cell melanoma Composed of mixture of spindle A&B cells or exclusively spindle B cells. Have most favourable survival prognosis Iris melanomas 42

43. Mixed cell melanoma Composed of both spindle B cells and epithelioid cells Have intermediate survival prognosis Most of the uveal melanomas Choroidal melanomas- spindle B cells 43

44. Epithelioid cell melanoma 44 Composed of epithelioid cells Have least favourable survival prognosis Choroidal & ciliary body melanomas

45. Recommendations for reporting histological features 45 HISTOLOGIC CHARACTERISTICS COMMENTS Location Choroidal tumors have favourable prognosis than ciliary body tumors Extra ocular extension Sclera / conjunctival extension Growth pattern Localised Ring melanoma - aggressive Flat & diffuse - aggressive Size Look for dimensions of maximal scleral contact instead of vertical measurements Cell type Spindle A Spindle B Epithelioid - aggressive Proliferation Mitotic figures or Ki 67 Tumor infiltrating lymphocytes Tumors with >100lymphocytes/20hpf show poorer prognosis than those with <100lymphocytes/20hpf Vasculogenic mimicry pattern Closed loops of PAS positive material encircles the tumor cells or atleast in three back to back loops . These are positive for laminin & fibronectin . Rich in evtracellular matrix proteins, generated by invasive melanoma cells.

46. Clinical mimickers of uveal melanoma: Choroidal haemorrhage Cavernous hemangioma Metastasis to choroid 46

47. Treatment: Iridectomy Iridocyclectomy Enucleation 47

48. MESECTODERMAL LEIOMYOMA Occurs in ciliary body and choroid Smooth muscle of ciliary body is derived from the neuroectoderm Patients presents with blurring of vision, on ophthalmic examination appears as a choroidal mass suggesting amelanotic melanoma 48

49. On immunohistochemistry; these tumors expresses sex steroid hormone receptors, both progesterone and androgen. This is supportive evidence that sex steroid hormones may have a role in the pathogenesis of this tumour and suggest that it may be amenable to hormonal manipulation therapy, in a manner similar to conventional uterine leiomyomas . 49

50. EMBRYONAL MEDULLOEPITHELIOMA Rare Affects infants & young children D erived from immature medullary epithelial cells of embryonic optic cup Arises from non pigmented epithelium of ciliary body, also from iris, retina or optic disc Range from benign proliferations to malignant neoplasms with unequivocal invasive capacity 50

51. Microscopy: Cells closely resembles neural medullary epithelium Well differentiated cases have prominent rosettes and cystic spaces filled with hyaluronic acid Teratoid type: contains heterotopic elements like hyaline cartilage, striated muscle Nonteratoid type 51

52. PNET/EWINGS SARCOMA OF RETINA Ewing sarcoma is the second most common malignancy of bone in children and adolescents . Although EWS is a skeletal tumor, rarely extraskeletal lesions can occur in the chest wall ( Askin tumor), retroperitoneum , pelvis, thyroid, eye and brain . Ewing sarcoma/primitive neuroectodermal tumor (EWS/PNET) is a primitive round cell tumor with varying degrees of neuroectodermal differentiation. Site: peripheral retina/ciliary body from the area of the ora serrata 52

53. A translocation involving the EWS gene on chromosome 22q12 and FLI1 gene on chromosome 11q24 Overexpression of the FLI1 protein resulting from the translocation is observed in 71% to 100% of EWS/ PNETs. Prognostic and biologic immunohistochemical markers for EWS/PNET include p53 and p16 mutation. Overexpression of p53 by immunohistochemistry has been associated with a poor outcome. 53

54. Microscopy: Tumor is composed of sheets of small, round cells with hyperchormatic nuclei, scanty cytoplasm and indistinct cell borders. In some cases there can be more larger , irregular cells with irregular nuclear contours, pseudorosettes , nesting pattern, and spindle cells. Necrosis may be present with preserved perivascular clusters of tumor cells. Mitotic figures: 1 per 40 high-power fields 54

55. 55 Immunohistochemical stain: positive for neuron-specific enolase , vimentin , synaptophysin , cluster of differentiation 99 (CD99), Friend leukemia integration 1 and CD56. Negative for S 100.

56. D/D: Retinoblastoma Medulloepithelioma Diagnosis confirmed by PCR Polymerase chain reaction of the tumor shows Ewing sarcoma/Friend leukemia integration gene fusion product. 56

57. OTHER INTRAOCULAR TUMOURS 57

58. CHOROIDAL HEMANGIOMA Benign vascular tumour of the choroid Congenital Detected in 2 nd -4 th decade Idiopathic Two clinical forms Circumscribed form: isolated & nonsyndromic Diffuse form: Usually a part of Sturge –Weber syndrome of encephalofacial hemangiomatosis 58

59. Circumscribed form Diffuse form Reddish orange, round to oval tumor Fundus of the affected side has more saturated red appearance than the uninvolved fundus 59

60. Circumscribed form Detected when they produce visual symptoms by accumulation of serous subretinal fluid and degeneration of macula Located in posterior half of fundus, within two disc diameters from the optic disc and fovea Diffuse form Detected before onset of symptoms during examination of patients having facial nevus flammeus Choroid is thickened diffusely Optic disc cupping It becomes progressively thinner peripherally and gradually blends into the normal peripheral choroid Retinal vascular tortuosity 60

61. Circumscribed form Microscopy: Usually consists of cavernous vascular channels lined by mature endothelial cells supported by thin fibrous septa End abruptly at their margins & cause compression of adjacent normal choroid Diffuse form Microscopy: Consists of both cavernous & some capillary vascular channels End indistinctly in the periphery & do not have abrupt margins 61

62. Associated changes RPE overlying the tumor shows fibrous metaplasia Ossification of transformed pigment epithelium Neurosensory retina overlying the tumor becomes thickened and cystic Dilated episcleral & intrascleral vessels, synechial closure of anterior angle, optic disc cupping-in diffuse form Serous nonrhegmatogenous RD 62

63. HEMANGIOMA OF RETINA Two types: Cavernous hemangioma Capillary hemangioma 63

64. Capillary haemangioma of retina: -Benign vascular tumor of optic disc or retina - Unifocal and unilateral –isolated cases -Multifocal and bilateral – syndromic cases associated with VHLS 64

65. Symptoms: Blurring of vision or loss of visual field In some cases, arteries and veins are segmented with fusiform dilatation Intraretinal & subretinal exudation is common leading to exudative RD 65 Appears as reddish spherical lesion fed & drained by dilated tortuous vessels

66. Microscopy: Consists of small capillary like vessels lined by endothelial cells and stroma is made of vacuolated fibrous astrocytes Complication: tractional or exudative RD 66

67. Cavernous hemangioma of retina : - Is a benign retinal vascular hamartoma -Congenital - Nonsyndromic -Asymptomatic unless involves macula or causes intravitreal bleeding -Associated with cutaneous vascular lesions and minimal nonprogressive intracranial vascular lesions - No recognised malignant potential 67

68. Appears as a cluster of vascular saccules within the sensory retina in association with retinal vein of anomalous appearance, neither dilated nor tortuous Saccules range from microaneurysmal size to 0.1 mm in diameter Larger saccules have whitish glial proliferation on their surface(mistaken as intraretinal exudates) 68

69. Microscopy: Consists of thin walled intraretinal vascular saccules lined by normal endothelial cells. 69

70. ASTROCYTOMA OF RETINA Benign acquired neuroglial tumor arises from astrocytes of sensory retina Considered as a hamartoma Multifocal & bilateral Associated with tuberous sclerosis Can also occur in isolated form, where it is unifocal & unilateral Can arise from any part of retina 70

71. Appears as a white, superficial retinal mass Spectrum ranges from faint translucent intraretinal patches to more distinctly nodular, opaque white, inner retinal lesions to dense partially calcified mulberry-like tumors 71

72. Microscopy: -Consists of interlacing spindle shaped fibrous astrocytes with small bland elongated oval nucleus and indistinct wavy cytoplasmic borders. -Calcification in large lesions -In patients with tuberous sclerosis, giant astrocytes are seen 72 Basophilic calcium deposits Giant cells

73. Clinical D/D: Retinoblastoma Amelanotic choroidal melanoma 73

74. HYPERTROPHY OF RETINAL PIGMENT EPITHELIUM Uncommon benign fundus lesion Always congenital Three varieties: -Typical unifocal unilateral lesion(0.5%) -Typical multifocal unilateral lesion(1%):most common -Atypical multifocal bilateral lesion: associated with familial colonic adenomatous polyposis carcinoma syndrome( Chr 5q21-q22). Uncommon, occur in 1 in 100,000 persons 74

75. Appears as gray black, well defined, minimally elevated fundus lesion(2-5mm) Around the margin, develops narrow zone of depigmentation with aging 75

76. Microscopy: -Consists of well defined foci of taller than normal RPE cells, containing increased number of melanin granules -At depigmented areas, RPE cells are absent -Retinal photoreceptors overlying the lesion appears degenerated 76

77. CHOROID OSTEOMA Uncommon benign acquired bony tumor of choroid Unknown aetiology Earlier thought to be a choristoma Occurs 90% in women Occasional familial cases can occur (AD) No abnormalities in calcium & phosphorus metabolism Patients presents with painless progressive loss of vision over months to years or abrupt recent blurring of central vision 77

78. Appears as a yellowish to orange, well defined, juxtapapillary or circumpapillary choroidal tumor Surface is relatively flat or have uneven elevations & depressions Irregular margins Choroidal vessels ramify on the surface of tumour 78

79. Microscopy: -Consists of mature bone that replaces full thickness choroid in a pate adjacent to or around the optic disc -RPE & sensory retina overlying the lesion are disrupted 79

80. PRIMARY INTRAOCULAR LYMPHOMA Uncommon, but important lymphocytic neoplasia Arises diffusely or multicentrically within retina or uvea Subtypes: Primary vitreoretinal lymphoma Primary uveal lymphoma 80

81. Risk factors Old age Female Immunosuppression 81

82. Primary vitreoretinal lymphoma: - Associated with independent nonmetastatic foci of primary CNS lymphoma - Composed of malignant lymphoid cells that have cytological features of diffuse large cell lymphoma - Lymphoid cells have prominent nuclei & scant cytoplasm, occurs singly or in small clusters - Cells appears to be B cell derived 82

83. Primary uveal lymphoma: -Associated with visceral NHL -Characterised by diffuse or multifocal creamy yellow choroidal infiltrates -Composed of well differentiated small lymphoma cells -Cells may be either B cell or T cell derived 83

84. REFERENCES Kumar V, Abbas KA, Aster CJ. The Eye. Robbins and Contran : Pathologic Basis of Disease; 9 th Ed. Elsevier; 2015: p1319-43. Fletcher CDM. Tumors of eye and ocular adnexa. Diagnostic Histopathology of Tumors; 4 th Ed. Elsevier; 2013: Volume 2: p2086-2115. Rosai J and Ackerman’s Surgical pathology; 10th Ed. Elsevier; 2012: p95-128. Yanoff M, Duker JS. Intraocular tumors. Ophthalmology. 2 nd Ed. Mosby; 2004: p1043-96. Chaudhuri Z, Vanathi M. Intraocular tumors. Post Graduate Ophthalmology . 1 st Ed. Jaypee ; 2012:nVolume 2: p1436-49. 84

85. Abramson DH, Schefler AC. U pdate on Retinoblastoma . Retina, The Journal Of Retinal And Vitreous Diseases. 2004; 24(6): 828-48. Grossniklaus HE, Shehata B, Sorensen P, Bergstrom C, Hubbard GB. Primitive Neuroectodermal Tumor/Ewing Sarcoma of the Retina. Arch Pathol Lab Med. 2012; 136:829-831. Shields JA, Eagle RC, Shields CL, Marr BP. Aggressive retinal astrocytomas in four patients with tuberous sclerosis complex. Trans Am Ophthalmol Soc. 2004;102:139-148. Takagi T, Ueno Y, Matsuya N. Mesectodermal Leiomyoma of the Ciliary Body. An Ultrastructural Study. Arch Ophthalmol . 1985;103:1711-4. 85

86. THANK YOU 86

87. POST TEST Total 5 questions 2marks – 3questions – 1min 3marks- 1question- 2min 1marks-1question-0.5min 87

88. Mention neuroectodermal tumors of eye. (2M) What are rosettes? Mention their types? Mention the lesions in which they are seen? (2M) Mention the recommended histologic features for reporting a case of uveal melanoma . (3M) 4) Fixation time for eye specimen? (1M) 88

89. 5 ) Describe and diagnose? (2M) 89

90. Answers 1 ) -Retinoblastoma -Nevi & melanoma - Mesectodermal leiomyoma - Medulloepithelioma -PNET/ Ewings sarcoma of retina 90

91. 2) Rosettes are round groupings of cells found in nervous tumors. They consists of cells in a spoke –wheel or halo arrangement surrounding a central acellular region. Homer Wright rosettes: - Neurophil is present in central region. - Seen in Neuroblastoma , medulloblastoma & PNETs. Flexner Wintersteiner rosettes: - Central lumen contains cytoplasmic extensions of tumor cells. -Seen in retinoblastoma Ependymal rosettes: - Empty lumen - Seen in ependymoma Pseudorosettes : - Tumor cells are surrounded around blood vessel - Seen in ependymoma , medulloblastoma , PNET, Central neurocytoma , glioblastoma 91

92. 3) 92 HISTOLOGIC CHARACTERISTICS COMMENTS Location Choroidal tumors have favourable prognosis than ciliary body tumors Extra ocular extension Sclera / conjunctival extension Growth pattern Localised Ring melanoma - aggressive Flat & diffuse - aggressive Size Look for dimensions of maximal scleral contact instead of vertical measurements Cell type Spindle A Spindle B Epithelioid - aggressive Proliferation Mitotic figures or Ki 67 Tumor infiltrating lymphocytes Tumors with >100lymphocytes/20hpf show poorer prognosis than those with <100lymphocytes/20hpf Vasculogenic mimicry pattern Closed loops of PAS positive material encircles the tumor cells or atleast in three back to back loops . These are positive for laminin & fibronectin . Rich in evtracellular matrix proteins, generated by invasive melanoma cells.

93. 4) 24-48hrs 5) Retinoblastoma 93

94. THANK YOU 94