B110 Melanocytic tumors

Question 1

List the types of melanocytic tumors

Answer 1

Common Nevus

Dysplastic Nevus

Melanoma

Question 2

Common Melanocytic nevus types, morphology, and histology, and risk

Answer 2

Morphology:

• Well circumscribed.
• regular borders
• small < 5mm.
• tan/brown and uniformly colored.
• Show good maturation.

Common/melanocytic nevus progress through 3 developmental stages children, adolescents, and adults

Junctional nevus: Melanocytes in the epidermis, near the dermoepidermal junction. Seen in childhood, before puberty

Compound nevus: Growing through into the dermis. Seen until puberty.

Intrademal nevus: Have migrated all the way though, entirely in the dermis. In adults. Any nevus in adults that is not entirely intradermal is suspicious and may be a dysplastic nevus or melanoma.

Common nevi are not precursor lesions and do not pose a risk for development into melanoma.

Question 3

What is melanocyte maturation?

Answer 3

Superficial nevus cells are larger, grow in nests, are more mature, and produce pigment.

Deeper nevus cells are smaller, produce little to no pigment, and grow in cords.

(vertical stage of maturation, most poorly differentiated at the base, well differentiated superficially)

Normal nevi have good maturation, and melanomas have none.

Question 4

What is the common genetic mutation found in melanocytes of common, melanocytic nevi?

Answer 4

BRAF serine/threonine kinase activating mutations, and less commonly, RAS activating mutations. These mutations are mutally exclusive and only occur one or the other.

Question 5

What is the morphology, histology, and risk of dysplastic nevi?

Answer 5

These are atypical melanocytic nevi

• larger than 5 mm
• variable, irregular pigmentation called variegation
• irregular border
• slightly raised plaques with a pebbly, semi-flat surface
• may be extremely numerous, even in the hundreds
• tend to occur on body parts that are not sun exposed.

Histology:

• Nevus cells within the epidermis
• Epidermal nests may coalesce with adjacent nests, called bridging
• Nevus cells replace the basal cell layer, called lentiginous hyperplasia
• Cytologic atypia is seen, some hyperchromatic cells and nuclei
• Mild lymphocytic infiltrates
• Melanin release into the extracellular space and uptake by macrophages melanin incontinence
• Fibrosis surrounding the intra-epidermal nests of melanocytes.

Risks

• Dysplastic nevi transformation to melanoma is possible, but rare. Most melanomas arise de novo.
• They are better thought of as markers of the risk for separate spontaneous melanoma development,
• Not until there are more than 10 dysplastic nevi is an individual at increased risk for melanoma development.

Question 6

What is familial dysplastic nevus syndrome and its risks?

Answer 6

Inherited syndrome of many dysplastic nevi, with a lifetime risk of melanoma development essentially 100%

Question 8

Melanoma, morphology, histology

Answer 8

Morphology:

• striking variations in color
• irregular borders
• rapidly growing
• itching or painful
• new appearance of a mole in an adult

Assymetry, Border, Color, Diameter, Evolution

Histology:

Malignant melanocytes

• are considerably larger than normal melanocytes
• have large anaplastic nuclei
• chromatin clumping near the periphery
• Prominent nucleoli that may be cherry red nucleoili, strongly eosinophilic
• Stain with Masson silver melanin stain
• By EM, premelanosomes, melanin filled vesicles, may be visible if the melanin stains are negative.

Histology of the melanoma:

• First stage: intraepidermal horizontal growth.
  
  • malignant melanocytes form nests or individual cells at all levels of the epidermis.
  • They then grow radially, horizontally within the epidermis often for a very long time.
  • This stage of horizontal growth is not capable of metastasis and is easily curable by excision.
  • There is no angiogenesis
  • There is lymphocytic infiltration near the melanocyte nests
• Second stage: vertical growth
  
  • Melanocytes grow downward into the dermis.
  • Depth of dermal invasion is predictive for the likelihood of metastasis, and measured in mm is quantified as the Breslow thickness scale, measured from the top of the granular cell layer in the overlying epidermis.
  • The intradermal melanocytes lack maturation.
  • Angiogenesis occurs.

Question 9

Melanoma risk factors, common mutations

Answer 9

Main risk factor is episodes of severe sun damage,

much higher incidence in pale skinned people.

Mutations:

Germ line mutations in the CDKN2A gene cause familial melanoma

No well defined sporadic mutaitons

Question 10

Melanoma symptoms, clinical progression, prognosis

Answer 10

Melanoma usually exists as a confined skin lesion for a significant time, and is a “late stage neoplasm” not metastasizing until late in its course.

Less common sites for melanoma origination:

• oral mucosa
• anogenital mucosa
• esophagus
• meninges
• eye

It is clinically silent except for the skin or mucosal pigmentation, and in rare cases may cause itching.

Prognosis:

If it is epidermal confined, very good and is usually curable. 98% 5yrS

Metastasis risk is estimated by the Breslow thickness of vertical growth and by examining sentinel lymph nodes. Lymph node involvement 5yrS ~60%

When metastasis occurs it involves multiple sites, virtually anywhere that can be seeded hematogenously. 5yrS drops to 15%

Metastases may not appear for several years after primary tumor excision, and can involve a long dormancy period.

Metastasis indicates a very poor prognosis

CTLA-4 inhibitors, disinhibiting the cellular immune response have shown promise as therapies.