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Congenital nevus Melonocytic nevus Birth marks

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Melonocytic nevus

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MELANOCYTIC NEVUS PIGMENTED NEVUS MOLE Dr. OM JHA
INTRODUCTION Congenital or acquired melanocytic neoplasms. Common acquired moles: well-demarcated, uniformly tan-brown papules ( 6mm). Have several variants: Congenital nevus Blue nevus Spindle & Epithelioid cell nevus (Spitz nevus) Halo nevus Dysplastic nevus
PATHOGENESIS: Many nevi: acquired mutations in BRAF or NRAS, genes involved in RAS signaling. Lead to a limited period of proliferation --> Followed by permanent growth arrest (most cases) --> due to: Accumulation of p16/INK4a (inhibitor of CDKs).
MORPHOLOGY Arise from basal melanocytes. Nevus cells: rounded cells exhibiting uniform nuclei and inconspicious nuclei Nevi mature through characteristic stages: Junctional nevi: nests of nevus cells at DE junction --> earliest lesion. Compound nevi: develop as nests or cords of melanocytes that extend into the underlying dermis. Dermal nevi: epidermal component is lost.
JUNCTIONAL NEVUS
COMPOUND NEVUS: GROSS:- RAISED & DOME SHAPED LESION. HISTO:- BOTH JUNCTIONAL AND DERMAL COMPONENTS
INTRA-DERMAL NEVUS: Gross:- Raised domed shaped. Histo:- Only dermal component.
Contd... As nevus cells enter the dermis:- Undergo maturation: Larger, pigmented cells --> smaller non-pigmented cells --> Spindle shaped cells --> resemble neural tissue (Neurotization). In comparision, Melanoma exhibit little to no maturation.
TYPE A CELLS NUCLEUS: ROUND TO OVAL ,SMALLER THAN KERATINOCYTES , FINELY DISPERSED CHROMATIN, INCONSPICUOUS NUCLEOLI. CYTOPLASM: PROMINENT AND CONTAINS COARSE GRANULES TYPE B CELLS NUCLEUS: SMALL AND ROUND. CYTOPLASM: SCANT. PRESENT IN DERMIS. TYPE C CELLS SPINDLE SHAPED. BASE OF NEVUS (DERMIS).
DYSPLASTIC NEVUS Larger (> 5mm) than most acquired nevi. Flat macule to slightly raised papules with veriegated pigmentation and irregular borders. Both in sun-exposed and protected skin. Can number in hunderds: Dysplastic nevus syndrome. 50% develop Melanoma by 60 years of age. Most lesions clinically stable and sporadic isolated lesions have low risk of malignant transformation.
PATHOGENESIS AD disorder often a/w mutations in proteins a/w cell cycling. CDKN2A --> p16/INK4, CDK4. Acquired NRAS & BRAF mutations also common. Not all germline mutation in CDKN2A / CDK4 --> Dysplastic nevi. Not all Dysplastic nevi --> have mutations in these genes. Means: other modifiers genes also involved (eg. TERT over-expression).
MORPHOLOGY Histologically, most are compound nevi exhibiting architectural and cytological atypia. Enlarged and fused nests of nevus cells. Lentigenous melanocytic hyprtplasia. Linear papillary dermal fibrosis. Pigmant incontinence: release of melanin from dead melanocytes in dermis.
DYSPLASTIC NEVUS: GROSS:- Flat Macules to Target like Lesions with Darker Raised Centre & Irregular Flat Periphery. HISTO:- Dermal fibrosis, Inflammation, and Proliferation of melanocytes at D-E Jnx, with Bridging of Rete Ridges.
DYSPLASTIC NEVUS: HISTO:- Dermal fibrosis, Inflammation, and Proliferation of melanocytes at D-E Jnx, with Bridging of Rete Ridges.
MELANOMA Malignant melanocytic tumor. Most common site: Skin. Can also occur in: Oral & anogenital mucosal surfaces, esophagus, meninges and eyes. Incidence of cutaneous malignant melanoma increasing.
PATHOGENESIS: DRIVER MUTATIONS AFFECTS 3 PATHWAYS Mutations that disrupt cell cycle control genes. CDKN2A GENE MUTATION IN 40% CASES OF AD MELANOMA & 10% SPORADIC CASES NET EFFECT IS INCREASED MELANOCYTE PROLIFERATION. Mutations that activate pro- growth signaling pathways. ABBERANT INCREASE IN RAS AND PI3K/AKT SIGNALLING. ACTIVATING MUTATIONS IN BRAF. ACTIVATING MUTATIONS OF NRAS. NON-SUN EXPOSED AREAS SHOW MUTATIONS UPSTREAM OF RAS IN RTK. NET EFFECT IS INCREASED MELANOCYTE PROLIFERATION & SURVIVAL. Mutations that activate telomerase. MUTATIONS IN PROMOTER TERT GENE ACTIVATES TELOMERASE IN NEARLY 70% OF TUMORS ACT AS ANTIDOTE TO SENESCENCE
Contd... Growth factors activate signaling circuits involving RTK, RAS, and two key downstream pathways that include BRAF and PI3K. Proteins indicated by asterisks are mutated in melanoma. Components of these pathways that are being targeted by drugs are indicated.
WARNING SIGNS OF MELANOMA
GROSS FINDINGS UNLIKE BENIGN NEVI THEY SHOW STRIKING VARIATIONS IN SHADES OF BLACK BROWN RED DARK BLUE AND GRAY. ZONES OF WHITE OR FLESH COLOURED HYPOPIGMENTATION ALSO APPEARS SOMETIMES DUE TO FOCAL REGRESSION OF TUMOR. BORDERS ARE IRREGULAR AND NOTCHED UNLIKE SMOOTH ROUND AND UNIFORM BORDERS OF MELANOCYTIC NEVUS
MORPHOLOGY Composed of: Large cells. With expanded, irregular nuclei. Containing peripherally clumped chromatin. Have prominent eosinophilic nucleoli. Progress from radial to vertical growth pattern.
RADIAL GROWTH Horizontal spread within the epidermis and superficial dermis. Tumor cells typically lack the capacity to metastasize. Lesions include: Lentigo maligna: indolent lesion on the face that may not progress for decades. Superficial spreading: mc form, usually involve sun-exposed skin. Acral and Mucosal lentiginious melanoma: unrelated to sun exposure.
RADIAL GROWTH PHASE: SHOWING IRREGULAR NESTED AND SINGLE CELL GROWTH OF MELANOMA CELLS WITHIN THE EPIDERMIS.
LENTIGO MALIGNA SUN EXPOSED AREA OF ELDERLY WHITE MC IN CHEEKS. FLAT SLOW GROWING. Histo: PROLIFERATION OF ATYPICAL MELANOCYTES IN BASAL LAYER, DISTRIBUTED INDIVIDUALLY AS WELL AS IN NESTS. WHEN CONFINED TO EPIDERMIS: LENTIGO MALIGNA (FORM OF MIS). WHEN A DERMAL COMPONENT IS PRESENT: LENTIGO MALIGNA MELANOMA.
SUPERFICIAL SPREADING MELANOMA: Pagetoid appearance of melanocytes in superficially spreading malignant melanoma.
ACRAL LENTIGINOUS MELANOMA
VERTICAL GROWTH Occurs unpredictably. Characterized by dermal invasion of expanding clonal mass of cells. Lack cellular maturation. Often have capacity to metastasize. Probability of distal spread corelates with depth of invasion (Breslow thickness).
Congenital nevus Melonocytic nevus Birth marks
PROGNOSTIC FACTORS Breslow thickness (thinner is better). Number of mitosis (<1/mm2 ). Evidence of regression (absent). Ulceration (absent). Presence of tumor-infiltrating L陸 (many). Gender (female). Location (extremity). Sentinal LN mets (absent).
CLINICAL FEATURES Warning signs: ABCDE (if rapid). Cutaneous melanoma: most Asx, pain, pruritis. Majority: >10mm at Dx, usually a/w olor variegations. Most consistent sign: recent change in size, shape or color. Borders: often irregular &/or notched, with zones of hypopigmentation (d/t focal regression)
Congenital nevus Melonocytic nevus Birth marks
Congenital nevus Melonocytic nevus Birth marks
SQUAMOUS CELL CARCINOMA (SCC)

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Congenital nevus Melonocytic nevus Birth marks

  • 2. INTRODUCTION Congenital or acquired melanocytic neoplasms. Common acquired moles: well-demarcated, uniformly tan-brown papules ( 6mm). Have several variants: Congenital nevus Blue nevus Spindle & Epithelioid cell nevus (Spitz nevus) Halo nevus Dysplastic nevus
  • 3. PATHOGENESIS: Many nevi: acquired mutations in BRAF or NRAS, genes involved in RAS signaling. Lead to a limited period of proliferation --> Followed by permanent growth arrest (most cases) --> due to: Accumulation of p16/INK4a (inhibitor of CDKs).
  • 4. MORPHOLOGY Arise from basal melanocytes. Nevus cells: rounded cells exhibiting uniform nuclei and inconspicious nuclei Nevi mature through characteristic stages: Junctional nevi: nests of nevus cells at DE junction --> earliest lesion. Compound nevi: develop as nests or cords of melanocytes that extend into the underlying dermis. Dermal nevi: epidermal component is lost.
  • 6. COMPOUND NEVUS: GROSS:- RAISED & DOME SHAPED LESION. HISTO:- BOTH JUNCTIONAL AND DERMAL COMPONENTS
  • 7. INTRA-DERMAL NEVUS: Gross:- Raised domed shaped. Histo:- Only dermal component.
  • 8. Contd... As nevus cells enter the dermis:- Undergo maturation: Larger, pigmented cells --> smaller non-pigmented cells --> Spindle shaped cells --> resemble neural tissue (Neurotization). In comparision, Melanoma exhibit little to no maturation.
  • 9. TYPE A CELLS NUCLEUS: ROUND TO OVAL ,SMALLER THAN KERATINOCYTES , FINELY DISPERSED CHROMATIN, INCONSPICUOUS NUCLEOLI. CYTOPLASM: PROMINENT AND CONTAINS COARSE GRANULES TYPE B CELLS NUCLEUS: SMALL AND ROUND. CYTOPLASM: SCANT. PRESENT IN DERMIS. TYPE C CELLS SPINDLE SHAPED. BASE OF NEVUS (DERMIS).
  • 10. DYSPLASTIC NEVUS Larger (> 5mm) than most acquired nevi. Flat macule to slightly raised papules with veriegated pigmentation and irregular borders. Both in sun-exposed and protected skin. Can number in hunderds: Dysplastic nevus syndrome. 50% develop Melanoma by 60 years of age. Most lesions clinically stable and sporadic isolated lesions have low risk of malignant transformation.
  • 11. PATHOGENESIS AD disorder often a/w mutations in proteins a/w cell cycling. CDKN2A --> p16/INK4, CDK4. Acquired NRAS & BRAF mutations also common. Not all germline mutation in CDKN2A / CDK4 --> Dysplastic nevi. Not all Dysplastic nevi --> have mutations in these genes. Means: other modifiers genes also involved (eg. TERT over-expression).
  • 12. MORPHOLOGY Histologically, most are compound nevi exhibiting architectural and cytological atypia. Enlarged and fused nests of nevus cells. Lentigenous melanocytic hyprtplasia. Linear papillary dermal fibrosis. Pigmant incontinence: release of melanin from dead melanocytes in dermis.
  • 13. DYSPLASTIC NEVUS: GROSS:- Flat Macules to Target like Lesions with Darker Raised Centre & Irregular Flat Periphery. HISTO:- Dermal fibrosis, Inflammation, and Proliferation of melanocytes at D-E Jnx, with Bridging of Rete Ridges.
  • 14. DYSPLASTIC NEVUS: HISTO:- Dermal fibrosis, Inflammation, and Proliferation of melanocytes at D-E Jnx, with Bridging of Rete Ridges.
  • 15. MELANOMA Malignant melanocytic tumor. Most common site: Skin. Can also occur in: Oral & anogenital mucosal surfaces, esophagus, meninges and eyes. Incidence of cutaneous malignant melanoma increasing.
  • 16. PATHOGENESIS: DRIVER MUTATIONS AFFECTS 3 PATHWAYS Mutations that disrupt cell cycle control genes. CDKN2A GENE MUTATION IN 40% CASES OF AD MELANOMA & 10% SPORADIC CASES NET EFFECT IS INCREASED MELANOCYTE PROLIFERATION. Mutations that activate pro- growth signaling pathways. ABBERANT INCREASE IN RAS AND PI3K/AKT SIGNALLING. ACTIVATING MUTATIONS IN BRAF. ACTIVATING MUTATIONS OF NRAS. NON-SUN EXPOSED AREAS SHOW MUTATIONS UPSTREAM OF RAS IN RTK. NET EFFECT IS INCREASED MELANOCYTE PROLIFERATION & SURVIVAL. Mutations that activate telomerase. MUTATIONS IN PROMOTER TERT GENE ACTIVATES TELOMERASE IN NEARLY 70% OF TUMORS ACT AS ANTIDOTE TO SENESCENCE
  • 17. Contd... Growth factors activate signaling circuits involving RTK, RAS, and two key downstream pathways that include BRAF and PI3K. Proteins indicated by asterisks are mutated in melanoma. Components of these pathways that are being targeted by drugs are indicated.
  • 18. WARNING SIGNS OF MELANOMA
  • 19. GROSS FINDINGS UNLIKE BENIGN NEVI THEY SHOW STRIKING VARIATIONS IN SHADES OF BLACK BROWN RED DARK BLUE AND GRAY. ZONES OF WHITE OR FLESH COLOURED HYPOPIGMENTATION ALSO APPEARS SOMETIMES DUE TO FOCAL REGRESSION OF TUMOR. BORDERS ARE IRREGULAR AND NOTCHED UNLIKE SMOOTH ROUND AND UNIFORM BORDERS OF MELANOCYTIC NEVUS
  • 20. MORPHOLOGY Composed of: Large cells. With expanded, irregular nuclei. Containing peripherally clumped chromatin. Have prominent eosinophilic nucleoli. Progress from radial to vertical growth pattern.
  • 21. RADIAL GROWTH Horizontal spread within the epidermis and superficial dermis. Tumor cells typically lack the capacity to metastasize. Lesions include: Lentigo maligna: indolent lesion on the face that may not progress for decades. Superficial spreading: mc form, usually involve sun-exposed skin. Acral and Mucosal lentiginious melanoma: unrelated to sun exposure.
  • 22. RADIAL GROWTH PHASE: SHOWING IRREGULAR NESTED AND SINGLE CELL GROWTH OF MELANOMA CELLS WITHIN THE EPIDERMIS.
  • 23. LENTIGO MALIGNA SUN EXPOSED AREA OF ELDERLY WHITE MC IN CHEEKS. FLAT SLOW GROWING. Histo: PROLIFERATION OF ATYPICAL MELANOCYTES IN BASAL LAYER, DISTRIBUTED INDIVIDUALLY AS WELL AS IN NESTS. WHEN CONFINED TO EPIDERMIS: LENTIGO MALIGNA (FORM OF MIS). WHEN A DERMAL COMPONENT IS PRESENT: LENTIGO MALIGNA MELANOMA.
  • 24. SUPERFICIAL SPREADING MELANOMA: Pagetoid appearance of melanocytes in superficially spreading malignant melanoma.
  • 26. VERTICAL GROWTH Occurs unpredictably. Characterized by dermal invasion of expanding clonal mass of cells. Lack cellular maturation. Often have capacity to metastasize. Probability of distal spread corelates with depth of invasion (Breslow thickness).
  • 28. PROGNOSTIC FACTORS Breslow thickness (thinner is better). Number of mitosis (<1/mm2 ). Evidence of regression (absent). Ulceration (absent). Presence of tumor-infiltrating L陸 (many). Gender (female). Location (extremity). Sentinal LN mets (absent).
  • 29. CLINICAL FEATURES Warning signs: ABCDE (if rapid). Cutaneous melanoma: most Asx, pain, pruritis. Majority: >10mm at Dx, usually a/w olor variegations. Most consistent sign: recent change in size, shape or color. Borders: often irregular &/or notched, with zones of hypopigmentation (d/t focal regression)