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LEC 01 - Melanocytic Lesions
Terms in this set (54)
1. Flat, unelevated change in color.
2. Examples: freckles, measles, petechaia...
1. A solid mass greater than 1 cm in diameter.
2. Limited to the surface of the skin (epidermis).
1. A thickened outer layer of skin that is dry and whitish colored.
1. Elevated, dome-shaped lesion.
2. Papule: <5mm
3. Nodule: >5mm
1. Also known as a blister.
2. This is a thin-walled sac filled with a fluid, usually clear and small.
Wheal (hives) and Edema
1. Small, round, raised area on the skin that may be accompanied by itching.
--> Raised due to interstitial fluid.
2. Usually seen in allergic reactions.
1. Elevation of skin containing pus.
2. Sometimes known as a papule that contains pus (filled with neutrophils and debris).
1. Fluid-filled vesicles larger than 1 cm in diameter.
1. Redness of the skin due to capillary dilation.
1. Prolonged, intense scratching eventually thickens the skin and produces tightly packed sets of papules.
2. Looks like surface of moss (or lichen).
1. Stratum Corneum
2. Stratum Lucidum (only acral skin)
3. Stratum Granulosum
4. Stratum Spinosum
5. Stratum Basale
Layers of Epidermis
Stratum Spinosum (Prickly Layer)
--> Produce keratin and cytokines
2. Langerhans cells:
--> Antigen presenting cells (APC)
--> Produce melanin
2. Basal keratinocytes
1. Hair follicles
2. Sebaceous gland
3. Eccrine gland (at SBQ/Dermis Junction)
4. Blood vessels
7. Dermal dendrocytes: antigen presentation, wound healing
8. Fat /subcutaneous tissue
Components of this Layer?
1. Hyperplasia of the Stratum CORNEUM.
2. Thickening of the skin caused by a mass of keratinocytes.
1. Keratinization pattern characterized by RETENTION OF NUCLEI in the stratum corneum.
2. This is normal on mucous membranes.
1. Diffuse epidermal hyperplasia.
1. Abnormal keratinization generally in the stratum SPINOSUM.
1. The loss of intercellular connections (desmosomes) between keratinocytes.
1. Epidermal accumulation of edematous fluid in intercellular spaces.
2. The spinous processes (desmosomes) are still intact.
1. Complete LOSS of the epidermis.
From the NEURAL CREST.
Melanocytes - Origin
1. Basal layer of epidermis (by 8wk gestation).
2. Hair matrix
3. Inner ear
4. Uveal tract
Melanocytes - Migration Pattern
1. Produce melanin that gets transferred to neighboring keratinocyte via dendritic processes.
--> cell body is in the BASAL layer of the epidermis.
2. 1 melanocyte supplies melanin to ~30 keratinocytes.
1. MART-1 (specific)
2. S-100 (sensitive)
--> Langerhans cells, too.
Stains for Melanocytes
1. Loss of melanocytes due to
auto-antibodies to melanocytes.
2. Occurs in all races, but most
visible in darkly pigmented individuals.
3. Depigmented macules and patches on hands, wrists, axillae, perioral, periorbital, anogenital.
1. Defect in melanin SYNTHESIS (tyrosinase deficiency) but number of melanocytes is normal.
2. Congenital/ inherited
1. Small, tan-red or light brown macule.
2. Appear in early childhood after sun exposure; fade and reappear with sun exposure.
3. Histology: Increased MELANIN in basal keratinocytes.
4. Normal number of melanocytes
1. 5 - 10 mm dark brown patch on skin or mucous membranes.
2. Fixed; do NOT darken when exposed to sun.
3. Histology = Minimal increase in number of melanocytes with NO nesting.
4. Increased pigment at tips of elongated rete ridges ("dirty socks")
1. Congenital or acquired melanocytic neoplasm= "mole."
2. Composed of melanocytes that have lost their dendritic processes.
3. Types (junctional, compound, dermal) refer to location of the melanocytes...
4. Tan to brown, uniformly pigmented.
5. Usually <5mm.
6. Macular (flat) or papular (raised).
Nevocellular Melanocytic Nevus
1. Junctional nevus
2. Compound nevus
3. Dermal nevus
4. Neurotized dermal nevus
Maturation Sequence of Non-Dysplastic Nevi
1. Presence of nevus cell NESTS in the basilar region of the epithelium, primarily at the tips of the epithelial rete pegs.
2. These are macular only & occurs in children and adolescents.
1. Proliferation of nevus cells at tips of rete ridges.
2. Nests and cords of dermal cells demonstrate nevocellular maturation.
Moving from the epidermis to the dermis...
1. Decrease in size of cells
2. Decrease in size of nests
3. Decrease in amount of melanin production
1. Sharply defined papule or nodule-skin colored, round dome shaped.
2. Usually occurs after the 2nd-3rd decade.
1. Congenital melanocytic nevus
--> Giant congenital nevi (>20 cm) have increased risk of melanoma transformation.
2. Blue nevus
--> Clinical mimic of melanoma b/c of color.
3. Spindle and epithelioid cell nevus (Spitz)
--> Histologic mimic of melanoma b/c of cytology.
--> Occurs in CHILDREN.
4. Halo nevus
5. Dysplastic nevus (atypical)
Nevocellular Nevus - Variants
1. Median age at dx = 64
2. Males > Females
3. White>>> Hispanic or American Indian>>Black or Asian
Melanoma - Incidence
--> MOST common site.
2. Oral mucosa
3. Anogenital mucosa
Melanoma - Primary Sites
1. Past history of melanoma (900x)
2. Xeroderma pigmentosa (1000x)
3. Family history of melanoma (8x)
4. Brief, intermittent, intense UV exposure, especially during 10 -24 yr of age.
--> Chronic exposure increases risk of squamous cell carcinoma
5. Fair skin - regardless of sunburn history.
6. Severe sunburns in childhood
7. Dysplastic nevi (many)
8. Large congenital nevi
9. Use of UV sunbeds
10. Immune suppression
Melanoma - Risk Factors (Not Comprehensive)
1. Mutation of CDKN2A (p16) gene on chromosome 9p21 found in ~40% of families with melanoma.
2. This gene can also be silenced through methylation in sporadic melanomas.
Melanoma Genetics - Familial
1. BRAF mutation (activating)
--> V600E- target of BRAF inhibitor therapy (FDA approved for metastatic melanoma)
2. PTEN (10q23.3) mutation (loss of function) - also in Cowden's, endometrial carcinoma and many other malignancies.
3. C-KIT mutation (activating)
--> ACRAL and MUCOSAL melanomas.
Melanoma Genetics - Sporadic
A - asymmetry
B - border irregularity
C - color (>3 or a change)
D - diameter >6mm
E - evolution: ANY CHANGING NEVUS!
Melanoma - Clinical Mnemonic
There may be a very long latency from primary excision to presentation of metastasis - up to 10 years....
1. Lymph nodes
5. Any other site with hematogenous access.
Melanoma - Metastasis
1. Pagetoid cells (melanocytes in all layers of the epidermis)
2. Confluence (too many melanocytes too close together)
3. Cytologic Atypia
1. Lentigo maligna melanoma: arises on sun-damaged skin (head/neck)
2. Desmoplastic melanoma: subtle, easy to miss if not careful!
3. Nevoid: looks like nevus on low power!
4. Non-cutaneous sites
Melanoma - Variants
Sentinel lymph node status...
--> localized vs. regional disease.
Melanoma - Most Important Prognostic Indicator
1. Depth of invasion/ tumor thickness (x mm)
--> < 1.0 mm is generally considered "thin" melanoma
--> >0.8- 1.0 mm is indication for sentinel lymph node biopsy.
--> Survival inversely correlates with depth/thickness.
***Most important prognostic indicator if sentinel lymph node is negative (or unknown).
3. Tumor infiltrating lymphocytes
4. Lymphovascular invasion
Melanoma - Prognostic Histologic Features
1. Surgical excision for thin melanomas.
2. Surgical excision + sentinel lymph node biopsy for melanomas >0.8-1.0 mm (or <1.0 mm and ulcerated).
Melanoma - Treatment
1. BRAF or MEK inhibitor therapy (if activating mutation is detected in the melanoma).
2. Immune-modulating therapy (targeting CTLA-4, PD-1, PD-L1)
3. The above therapies have nearly completely replaced traditional chemotherapies, which were not effective.
Metastatic Melanoma - Treatment
1. Lymph nodes are clinically negative (not palpable).
2. Theory: Radioactive tracer (or blue dye) injected into primary tumor bed will track via lymphatics to regional lymph nodes.
--> First stop= "Sentinel" lymph node
3. If Sentinel lymph node is Negative for tumor, then low chance that disease has spread.
4. Used in breast cancer, cutaneous cancers...
Sentinel Lymph Node Biopsy
1. Vemurafenib and Dabrafenib (BRAF inhibitors) and Trametinib (MEK inhibitor) and others...
2. Specific against the V600E mutation.
3. About 50% of patients will respond
4. Response is rapid but resistance is nearly universal over time...
5. Often used in combination (BRAFi + MEKi)
BRAF and MEK inhibitors: Targeted Therapy in (Metastatic) Melanoma
1. Anti- CTLA4 antibody: ipilimumab
2. Anti-PD-1 antibodies: nivolumab and pembrolizumab, others...
Immune-Modulating Therapies - Immune Checkpoint Inhibitors
1. "Release the breaks" from immune system by blocking normal immune-inhibitory signals.
2. Generally slower response (over months) but more durable.
Immune-Modulating Therapies - Mechanism of Action
1. Checkpoint Inhibitors - one agent alone...
--> Response rates: 10-35%, but LONG LASTING!!
2. Combination tx (anti-CTLA4 + anti-PD-1)
--> Higher response (~50%) BUT higher toxicities...
3. Treatment with these agents limited by auto-immune related toxicities such as colitis, endocrine dysfunction, skin rash (b/c immune system has been overstimulated...
Treatment with Immune-Modulating Therapies
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