Melanocytic tumors

Melanocytes = melanin-producing cells located in the basal layer of the epidermis.

1. Lentigo Simplex

• Small pigmented spot on the skin.
• Benign hyperplasia of melanocytes.
• Features: symmetric, well-demarcated, evenly pigmented, small (1–3 mm).
• Unlike freckle: does not darken with sun exposure.

2. Melanocytic Nevi (Mole)

A) Congenital Nevus

• Present at birth, can be multiple.
• 1.5–20 cm → ↑ risk of malignancy (giant > 20 cm → highest risk).
• Dark, verrucous, occasionally hairy.

B) Acquired Nevus

• Develops during childhood; regresses with age.
• Sites: skin, mucosa, conjunctiva.
• Features: symmetric, sharp border, evenly pigmented, small (≤ 5 mm).

Three types by location

Type	Location of melanocytes
Junctional nevus	Nests at dermo-epidermal junction only (early)
Compound nevus	Both epidermis + dermis
Intradermal nevus	Only in dermis (late; mature)

Maturation

• Nevi grow from DE junction down into dermis.
• Superficial nevi: larger + less mature → produce melanin.
• Deeper nevi: smaller + more mature → no melanin pigment.
• Maturation = good sign of benign process.
• Melanomas show NO maturation.
• Deeper nevi = lower risk of melanoma (opposite of melanoma).

Genetics

• Most benign nevi: BRAF mutation (V600E), less commonly RAS.

C) Dysplastic Nevi (Atypical Mole)

• Atypical melanocytic nevus different from common nevi.
• Enlarged, mixture of colors (pink–dark brown), flat with smooth/scaly surface, irregular edges.

Pathogenesis

• Sporadic or familial (familial atypical multiple mole-melanoma syndrome — FAMMM).
• Familial dysplastic nevus syndrome → nearly 100 % risk of melanoma.
• Number of dysplastic nevi correlates with melanoma risk.
• Most melanomas do NOT arise from preexisting nevi (de novo).
• BRAF + RAS mutations.

Clinical

• Larger than 5 mm, variable pigmentation, irregular borders.
• Sun-exposed (back) + non-exposed (breasts, abdomen) areas.

3. Malignant Melanoma

Malignant tumor of melanocytes.

Predisposing Factors

• Sun exposure (UV DNA damage) — intense intermittent exposure at early age (sunburn).
• Preexisting nevi (especially dysplastic).
• Hereditary predisposition (CDKN2A, fair skin, family Hx).

Major Subtypes

1. Superficial spreading melanoma (SSM) — most common (~70 %):
   • Horizontal/radial growth as a flat lesion.
2. Lentigo maligna / lentigo maligna melanoma (LM / LMM):
   • Elderly; severely sun-exposed skin (face); may become raised.
3. Acral lentiginous (AL):
   • Palms, soles, subungual of dark-skinned people.
   • NOT related to UV light.
4. Nodular melanoma (NM):
   • Abrupt vertical growth; worst prognosis (no radial phase).

Growth Patterns

1. Radial growth

• Horizontal growth within epidermis + superficial dermis as a flat lesion.
• No metastasis, no angiogenesis.

2. Vertical growth

• Vertical growth deep into dermis as expanding mass lacking maturation.
• Presents as nodules in previous flat lesions.
• Metastasis possible: deeper = more chance of mets (opposite to nevi).
• Other indicators: mitotic rate, overlying ulceration, lymphatic density.

Genetics

• Sporadic or hereditary.
• Mutations: CDKN2A (p16), BRAF (V600E #1), NRAS, PTEN, KIT.

Morphology

• Flat lesions (radial) → nodules (vertical).
• Cells larger than nevi cells.
• Prominent “cherry-red” eosinophilic nucleoli.
• Irregular borders, multiple colors, inflammatory cells.
• IHC: S-100⁺, HMB-45⁺, Melan-A⁺, SOX10⁺.

ABCDE of Detection

• A — Asymmetry.
• B — Border (irregular).
• C — Color (not uniform).
• D — Diameter (> 6 mm).
• E — Evolving (changes in size, shape, color, elevation, itching, pain).

Clinical Features

• Usually asymptomatic.
• Signs: enlargement/itching/pain of preexisting lesion, new pigmented lesions in adulthood, irregular borders or color change.
• Late-stage neoplasm → mets to brain, liver, lung, GI in late stages.
• Tx: superficial → surgical excision; BRAF-mutant → vemurafenib, dabrafenib; immunotherapy (anti-PD-1, anti-CTLA-4).

Staging

• Breslow thickness (depth from granular layer to deepest tumor cell) — most important prognostic factor.

Stage	Breslow thickness	5-year survival
In situ	In situ	90–100 %
I	< 1 mm	80–90 %
II	1–2 mm	70–80 %
III	2.1–4 mm	60–70 %
IV	> 4 mm	~50 %

• Clark levels (anatomic depth):
  • I: in situ (epidermis).
  • II: papillary dermis.
  • III: papillary–reticular junction.
  • IV: reticular dermis.
  • V: subcutaneous fat.

💡 High-yield: Nevi mature with depth (good sign); deeper = more benign. Dysplastic nevus = > 5 mm, irregular borders, variable color, sun-exposed + unexposed sites; familial form → ~100 % melanoma risk. Melanoma: UV (intense intermittent sunburn); subtypes: SSM (#1), lentigo maligna (elderly, face), acral lentiginous (palms/soles, dark-skinned, non-UV), nodular (vertical only, worst). Two growth phases: radial (no mets) → vertical (metastasizes); lack of maturation; cherry-red nucleoli. Mutations: BRAF V600E, CDKN2A, NRAS, PTEN. ABCDE. Breslow thickness = #1 prognostic factor. Tx: vemurafenib (BRAF) + immunotherapy (anti-PD-1/CTLA-4). IHC: S-100, HMB-45, Melan-A.