Melanocytic Skin Lesions Flashcards
Melanocytes and Melanin
- Neural crest-derived cells
- Stratum basale of epidermis
- Middle layer of the eye –> The uvea
- Inner ear
- Vaginal epithelium
- Meninges
- Bones
- Heart
- Melanin synthesized –> contained in melanosomes –> transported to nearby keratinocytes vie dendrites –> pigmentation
- Protects against UV radiation
- May have role in the immune system
Types of Naevus cell
Type A: Epithelioid Cell
* In superficial dermis
* Amphophilic cytoplasm with granular melanin
* Nuclei –> uniform chromatin, slightly clumped texture
Type B: Lymphocytes
* Deeper in dermis
* Diminished content of cytoplasm
* Arranged in linear cord
Type C: Spindled Cell
* Cells separated by fine connective tissue
* Look simliar to fibroblasts, or schwann cells
Benign melanocytic tumour
Epidermal Melanocytic Lesions
* Freckles
* Solar Lentigenes
* Melanocytic Macules of Albright
* Becker Melanosis
* Cafe-au-lait
Dermal Melanocytic Lesions
* Blue Nevus
* Mongolian Spot
* Nevi of Ota and Ito
Lentigo Simplex
- Most common form of lentigo
- AKA simple lentigo and juvenile lentigo
- Single or multiple (lentigines)
- May be present at birth, more commonly in early childhood
- NOT induced by sun exposure
- Multiple lentigine occur with associated abnormalities
Syndromes:
* Peutz-Jeghers syndrome
* Xeroderma pigmentosum
* LAMB syndrome
* LEOPARD syndrome
* Carney’s complex
Solar Lentigo
- Lentigines are pigmented macules that occur primarily on sun exposed sites in older adults
- Sun exposed areas of the skin, including the face, scalp, forearms and dorsa of hands
- Chronic exposure to UV radiation leads to enhancement of melanin production and alteration of cellular proliferation
Macro:
* Flat
* Uniformly brown
* Can be quite large
Micro:
* Acanthosis composed of elongated, bulbous rete ridges, although this feature is not always observed in lesions on the face
* Lentigines on the face may show flattened epidermis with basal melanosis and typically more severe elastosis
* Hyperpigmented basal layer that is often denser at tips of rete ridges, giving a dirty socks appearance
* Typically atrophic epidermis between the rete ridges
* Solar elastosis
Junctional Naevus
- Usually non-sun exposed areas
- Earliest stage of intraepidermal melanocytic proliferation
- Melanomas may arise from junctional nevi
Micro:
* Rounded nests of melanocytic cells
* On epidermal side of dermoepidermal junction
* Originating from tips of rete ridges
* Cells are oval or cuboidal in shape
* Clear cytoplasm
* Variable pigmentation
Compound Naevus
- Benign, common
- Features of both junctional and intradermal nevi
- Elevated or dome shaped
- Less pigmented than junctional naevi
Micro:
* Naevus cells are present in the epidermis and papillary dermis
* Nests are uniform in size without any evidence of confluence
Dermal/Intradermal Naevus
- Most common adult naevus
- All melanocytes are within the dermis
- Represents final stage in progression –> Junctional, Compound, Dermal
- Seen mainly after adolescence
Micro:
* Symmetrical
* Circumscribed tumour with nests of melanocytes
* No nuclear atypia
* Pseudoinclusions noted
Blue nevus
- Blue to black macule, papule or nodule on the head, distal extremities or buttock
- Small (< 1 cm)
- Bluish black color due to the deep location and abundant melanin –> tyndall effect
- It can be amelanotic
- Dermal proliferation of melanocytes
- Mostly acquired but it can rarely be congenital
- Predilection to extremities (dorsa of hands and feet), buttock, scalp and face
- Extracutaneous can occur –> conjunctiva oral mucosa, lymph nodes, vagina, prostate
Micro:
* Dermal proliferation of pigmented dendritic bipolar spindle melanocytes
* Fibroblastic and collagenous stroma
* Admixed scattered heavily pigmented melanophages
* Melanocytes aggregate around blood vessels, nerves or cutaneous appendages
* May present in the superficial dermis or extend into subcutis
* No maturation
* No cytologic atypia, no mitotic figures
Molecular:
Mostly acquired but it can rarely be congenital:
* LAMB (lentigines, atrial myxomas and blue nevi)
* NAME (nevi, atrial myxoma, myxoid neurofibromas and ephelides)
* Epithelioid blue nevus, a rare variant, may be associated with Carney complex (a multiple neoplasia syndrome)
* GNAQ and GNA11 mutations
* No BRAF, NRAS or NF1 mutations
Cellular blue nevus
- Pigmented biphasic tumor with a component of classic blue nevus and distinct cellular areas of spindled to oval melanocytes with clear or finely pigmented cytoplasm
- Slowly growing, grayish blue-black nodules
- Large (> 1 cm); can be up to 10 cm
- May be clinically and histologically confused with melanoma
- Buttock and sacrococcygeal more common
- Also scalp, face, trunk and extremities with predilection to dorsal foot
Micro:
* Oval to plump spindle cells intermingled with dendritic melanocytic cells; usually not heavily pigmented
* Variable numbers of melanophages
* Margin may be pushing and infiltrates adjacent nerve trunks
* Mitotic activity is usually absent and should be low (< 1/mm²)
* No atypical findings (including cell crowding, nuclear atypia, hyperchromasia, necrosis or expansile growth)
Molecular:
* GNAQ and GNA11 mutations
* No chromosomal aberrations
Spitz nevus
- Benign melanocytic tumors
- Composed of large spindled and epithelioid melanocytes
- Primarily affect children and young adults
- Can resemble hemangioma or pyogenic granuloma
Macro:
* Well circumscribed, dome shaped
* Pink or pigmented papule
* Size is several millimeters (usually < 1 cm)
Micro:
* Well circumscribed, symmetrical and show an overall wedge shaped silhouette
* Large junctional and dermal melanocytic nests formed by spindled or epitheliod cells
* Melanocytes are large, spindled or epithelioid, contain abundant pale or ground glass cytoplasm and finely dispersed pigment (if present)
* Mild nuclear pleomorphism may occur, mitoses are rare or absent
* Junctional nests often show separation artifacts (clefting) to the surrounding epidermis and are oriented perpendicularly to the epidermis –> raining down appearance
* Mild pagetoid scatter of single melanocytes may be a feature but is usually confined to the lower half of the epidermis and found only in the center of the lesion
* PAS+, eosinophilic, hyaline globules, so called Kamino bodies, located at the dermoepidermal junction
* Perivascular lymphocytic infiltrates are variably present
Molecular:
* No BRAF or NRAS mutations
* Genomic rearrangements of ALK (ALK fusions), ROS1 and NTRK1 kinases can occur
* HRAS mutation occurs, especially in desmoplastic Spitz nevi
Reed nevus
- Heavily pigmented nevus, often recent onset, widely considered a Spitz nevus variant
- Clinically and histologically simulates melanoma
- Young adults, commonly women
- Median age 25
- Proximal extremities or trunk
Macro:
* < 1 cm, solitary, deeply pigmented and well circumscribed maculopapule
* Clinically resembles melanoma
Micro:
* Symmetric with cytologic maturation
* Nests and fascicles of spindled melanocytes along dermoepidermal junction and within dermal papillae
* May be junctional or compound
* Expansive, not infiltrative growth pattern
* Extends no deeper than reticular dermis
* Nevus cells typically contain abundant melanin pigment, may be associated with melanophages
* Nuclei are monotonous, resemble normal keratinocytes and may have small nucleoli
* Often has architectural or cytologic atypia
* No / rare mitotic figures
Molecular:
* FISH targeting 6p25 (RREB1), 11q13 (CCND1), 6q23 (MYB) and centromere 6 may differentiate from melanoma
Halo nevus
- Nevus surrounded by zone of hypopigmented skin
- Back, followed by head / neck are most common sites
- Single or multiple
- Usually due to regression caused by cell mediated immunity, or less commonly humoral immunity or granulomatous inflammation
- No fibrosis, in contrast to melanoma
- Seen in 18% of Turner syndrome patients
- May persist for decades
- Residual melanocytes with heavy infiltration by lymphocytes and histiocytes that destroy pigment containing cells
Deep penetrating naevus
- Cellular melanocytic neoplasm with extension into deep dermis or subcutis
- Mostly indolent; some may exhibit atypical histologic features
- Rare metastatic potential in lesions with atypical features
- Wedge shaped appearance on microscopy
- Cellular with deep extension into dermis and subcutis
- Typically with abundant pigment
Micro:
* Melanocytic neoplasm
* Exhibits a wedge shaped or plexiform growth pattern with melanin pigmentation
* Usually well circumscribed and symmetrical
Extends into deep dermis or subcutis with no clear maturation with depth
* Can have encircling of blood vessels, adnexal structures, nerves
* Cellular, nested or fascicular with abundant pigment
* May be entirely intradermal, have an inconspicuous junctional component or uncommonly exhibit prominent junctional nests
* Grenz zone may be present
* May be combined with other nevi
* C shaped melanocytes surrounding epithelioid nests can be seen
* Occasional dermal mitotic figures (nonatypical, < 1 - 2/mm2)
Molecular:
* Wnt / beta catenin pathway activation
* Can demonstrate mitogen activated protein kinase (MAPK) mutations (i.e., BRAF, MAP2K1 / MEK1, HRAS)
Dysplastic nevus
- Pigmented lesions that share clinical and histological features of both common nevi and melanoma
- Dysplastic nevi are characterized by histological, rather than clinical, criteria
Micro:
Architectural changes:
* >5 mm
* Dysplastic nevus should not be diagnosed solely based on architectural atypia; cytologic atypia should also be present
* Shouldering: the epidermal component extends at least 3 rete ridges beyond the lateral margin of the dermal component in compound nevi
* Bridging: connection of the adjacent nests along elongated rete ridges
* Lentiginous hyperplasia
* Irregular nesting: nests show irregular sizes and shapes and are not confined to the tips of rete ridges
Cytological changes:
* Increased nuclear size and hyperchromatic nuclei
* Irregular nuclear membrane
* Prominent nucleoli
* Pleomorphism
* Multivacuolated melanocytes in the dermal component
* Cytologic atypia classified into mild, moderate or severe or simplified to low or high grade
Stromal changes:
* Lamellar fibroplasia
* Meyerson phenomenon: a subacute spongiotic dermatitis
* Possible epidermal changes: acanthosis, focal parakeratosis, effacement of rete ridges, attenuation of the epidermis; however, the latter 2 features are typically absent in dysplastic nevus and are more characteristic of melanoma
* Epidermolytic hyperkeratosis may be present but not specific
Molecular:
* BRAF (most commonly V600E)
* p53 and p16 mutation
* In familial cases, mutations in the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, which encodes tumour suppressors such as p16/INK4A, are particularly significant.
IHC:
* SOX10, MART1 / MelanA, MITF
* HMB45: loss of staining with maturation in dysplastic nevus, lost in deeper layers
* Ki67 index –> <5%
* Microarray analysis of 4 markers (ING4, Cul1, BRG1 and Bim) may distinguish melanoma from dysplastic nevi
Lentigo maligna
- Lentigo maligna (LM) typically refers to the in situ form of this disease
- (Lentigo maligna melanoma (LMM) designates invasive disease)
- AKA Hutchinson melanotic freckle
- Excellent prognosis after excision if no invasive component
Micro:
* Proliferation of intraepidermal (single and nested) melanocytes overlying solar elastosis
* Melanocytes demonstrate crowded growth along the basal epidermis
* Associated epidermal alterations, including loss (effacement) of epidermal rete and associated irregular epidermal hyperplasia
* Pagetoid scatter (melanocytes above the basal layer)
* Involvement of adnexal epithelium
* Melanocytic cytology is variable, ranging from small cells with dark nuclei and scant cytoplasm to epithelioid pigmented melanocytes, to spindled melanocytes
* Lymphocytic infiltrate
* Invasive component, if present, consists of single or nested melanocytes in the dermis with similar cytologic features to those in the in situ component
Melanoma
- Malignant melanocytic tumour arising from melanocytes
- Majority of mortality from skin cancer
Risk Factors:
* Hereditary –> autosomal dominant trait, variable penetrance
* UV radiation
* Sunlight
* Fair skin
* Severe sunburns
Associated conditions:
* Dysplastic nevus syndrome (BK mole syndrome)
* MAP1 inactivated tumour syndrome
* Xeroderma pigmentosum
* Parkinson Disease
ABCDE of Melanoma
* Asymmetry
* Border
* Colour
* Diameter
* Evolving
Aetiology:
* De novo and in pre-existing naevus
* UV exposure is main factor
Categories:
* Cumulative sun damage (CSD) –> Pathways I - III
Low CSD
* Superficial spreading melanoma
* L CSD nodular melanoma
High CSD
* Lentigo maligna melanoma
* H CSD nodular melanoma
* Desmoplastic melanoma
Not consistently associated with cumulative sun damage –> Pathways IV - IX
* Spitz melanoma
* Acral melanoma
* Mucosal melanoma
* Melanoma arising in congential naevus
* Melanoma arising in blue naevus and uveal melanoma
Architectural Criteria
* Asymmetry
* Poor circumscription
* Consumpiton of the epidermis
* Epidermal nests of melanocytes –> confluence, varibility in size and shape, haphazard interval and array
* Pagetoid spread
* Dermal nests of melanocytes –> varibility in size and shape, confluence, lack of maturation in depth, variability in melanin distribution
* Melanocytes within lymphovascular spaces
Cytological Criteria
* Nuclear pleomorphism
* Nucleolar variability
* Mitosis –> even deep, sometimes atypical
* Apoptosis increased
Prognostic Factors
Favourable:
* Young age
* Female
* Low risk sites –> Extremities
* Early staged
* Brisk tumour infiltrating lymphocytes
Unfavourable:
* Elderly
* Male
* High risk sites –> Back, upper arm, head and neck, acral
* High breslow depth
* Positive sentinel LN biopsy
* High dermal mitotic rate
* Ulceration
* Absent/non-brisk tumour infiltrating lymphocytes
* Microsatellites
* Lymphatic invasion
* Local recurrence
* Increasing angiogenesis
IHC markers for Melanoma
Positive:
* S100 (Nuclear and cytoplasmic) –> most sensitive marker, used in SLNB
* SOX10 (Nuclear)
* MelanA/MART1 (Cytoplasmic)
* HMB45 (Cytoplasmic)
* Tyrosinase (Cytoplasmic)
* MiTF (Nuclear)
* PRAME (Nuclear)
* Ki67/MIB1 >10% (Benign melanocytic nevi <2%)
Negative:
* p16 (Nuclear loss in melanoma)
* Cytokeratin
* LCA marker (CD45)
Superficial spreading melanoma
- Superficial spreading melanoma (SSM) is the most common subtype of melanoma in the Western world
- Most common melanoma in whites
- Develops on sun exposed sites with low cumulative sun damage (low CSD)
- Most frequent melanoma subtype to arise with a nevus
- Has a radial growth phase
- Back in men
- Legs, calves in women
Micro:
* Radial growth phase with or without vertical growth phase
* Large epithelioid melanocytes
* Prominent junctional and intraepidermal component
* Irregular and enlarged nests of melanocytes along dermal - epidermal junction
* Junctional melanocyte confluence
* Dermal component is composed of similar appearing melanocytes that fail to mature and disperse with descent; dermal mitoses are noted
* Pagetoid scatter
* Presence of melanocytes above the basal layer
If invasive
* Failure of dermal melanocytes to mature (i.e., become smaller) and disperse (i.e., smaller nests, single unit melanocytes) with descent into the dermis
* With or without dermal mitotic figures
* With or without melanin pigmentation
* Lacks severe solar elastosis
Molecular:
BRAF most common
V600E most common amongst BRAF
NRAS
TERT
Biallelic inactivation of CDKN2A
PTEN, TP53 in advanced primary melanomas
Lentigo maligna melanoma
- Subtype of melanoma arising on chronically sun damaged skin
- Appearing as an irregular pigmented macule, corresponding to an intraepidermal proliferation of atypical melanocytes
- Presents as a flat, slow-growing, irregularly pigmented lesion on chronically sun damaged skin, which may develop a raised, papular or nodular focus, indicating tumorigenic growth
- Face, neck, ears, scalp (if not shielded by hair), forearms, dorsal hands
- Excellent prognosis after excision if no invasive component
Micro:
* Proliferation of intraepidermal (single and nested) melanocytes –> Contiguous growth
* Overlying solar elastosis
* Crowded growth along the basal epidermis
* Involvement of adnexal epithelium
* Melanocytic cytology is variable, ranging from small cells with dark nuclei and scant cytoplasm to epithelioid pigmented melanocytes, to spindled melanocytes
* Invasive component, if present, consists of single or nested melanocytes in the dermis with similar cytologic features to those in the in situ component
Molecular:
* Activating BRAF mutations are less common than in superficial spreading (nonchronic sun damage) melanomas
* Of cases with BRAF mutations, many are non-V600E (e.g., V600K)
Spindle Cell Melanoma
- Rare variant
- Desmoplastic melanoma is a variant of spindle cell melanoma
Micro:
* Abundance of spindle-shaped tumour cells (>90% of tumour)
* Uniform, wavy, slender nuclei
* Pleomorphism and atypia
* High mitotic index
* Greater cellular cohesion on cytology than with epithelioid types of melanoma
* Pagetoid spread
* Associated with lentigo maligna
Desmoplastic melanoma
- Rare desmoplastic / fibrosing variant of spindle cell melanoma with > 90% stroma / collagen
- Often amelanotic and mistaken for nonmelanocytic lesion, such as scar
- Prognosis variable, dependent on presence of conventional melanoma –> lentigo maligna type in 75% of cases
- Pure form: tumor predominantly / entirely desmoplastic (≥ 90%)
- Mixed form: significant component of conventional melanoma (> 10%)
Micro:
* Poorly circumscribed with deep infiltration
* Elongated spindle cell surrounded by collagen bundles
* Can resemble fibroblasts
* Scattered cells show hyperchromasia and bizarre nuclei
* Multinucleated cells often present
* Stromal component varies in different tumors
* Some tumors with scattered spindle cells and abundant collagen
* Others with high cellularity and little stroma (best classified as spindle cell melanoma)
* Small foci of lymphoid aggregates is a useful clue to the diagnosis on scanning
* Nerve infiltration found in about 50%
IHC:
S100 and SOX0 usually positive
HMB-45 and Melan-A usually negative
Nodular melanoma
- Nodular melanoma is a rapidly growing, aggressive form of malignant melanoma due to early vertical growth phase
- Nodular melanoma mutations overlap with other melanoma subtypes (both low and high cumulative sun damage)
- Tumor (Breslow) depth is the most important prognostic indicator
- Head, neck and back in men
- Legs in women
Micro:
* Atypical nests and sheets of mitotically active dermal melanocytes
* Limited overlying junctional component
* No radial growth phase
* With or without melanin pigment
Frequent features:
* Polypoid / exophytic profile
* Brisk tumor infiltrating plasma cells (TIPs)
* Tumor size > 10 mm
* Ulceration
* Epidermal collarettes
* High mitotic rate
* Necrosis
Molecular:
* BRAF mutations –> V600E most common
* Others V600K, K601E
* NRAS mutations
Others:
* TERT promoter mutations or amplifications
* Homozygous deletion or mutation in CDKN2A
* PTEN deletions or mutations
* TP53 mutations
