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
Acral melanoma
- Melanoma relating to or affecting the non-hair bearing / glabrous or volar skin of the soles, palms and digits as well as the nail apparatus
- Weight bearing areas are most likely affected; heel more common than palm
- Most common type of melanoma in patients of Asian, Hispanic and African descent
Micro:
* Prominent acanthosis of epidermis with elongated rete ridges can be seen
* Spindle morphology
* Pagetoid spread
* Atypical nuclei
* Increased N:C ratio
* Proliferation of melanocytes downward along eccrine ducts
Molecular:
* Often triple negative –> BRAF, NRAS, KIT
* Generally develop from genetic amplifications de novo
Histologically, early acral lentiginous melanomas are characterised by a lentiginous array of atypical melanocytes, which later form large junctional nests. Two features that can help distinguish these lesions from benign acral naevi include:
(1) predominance of single-cell pattern in the melanomas
(2) lichenoid inflammation in the melanomas
Regarding the molecular pathogenesis different sources place an emphasis on different mutations. The WHO Classification of Skin Tumours lists KIT mutations as a key driver mutation. Indeed, this has clinical significance because these mutations are actionable, with some cases responding to KIT inhibitors (e.g., imatinib). However, primary literature surveys suggest that the five most common mutations in order from most common to least common are as follows:
(1) BRAF
(2) NRAS
(3) NF1
(4) GNAQ
(5) KIT
Features reported histologically
TM SMART GUN
* Thickness (Breslow)
* Margins
* Subtype
* Mitotic index
* Angiotropism
* Regression
* Tumour infiltrating lymphocytes
* Growth phase
* Ulceration
* Neurotropism
* Satellites
Breslow Thickness
- Important prognostic factor
- Increasing thickness –> increasing metastatic risk, decreased survival
- Measured from top of granular layer to deepest extent of invasion
- Deep extension along periappendageal sheaths should be discounted
- Microsatellites must not be included in the measurement of thickness
Growth Phase
Radial/Horizontal Growth Phase:
* Malignant cells grow radially in the epidermis and superficial dermis
* Lymphocytic host response usually present at the base
* Mitotic rate is low
Vertical Growth Phase:
* Malignant cells grow in the deep dermis
* No maturation
* High mitotic rate
* Worse prognosis –> increased metastatic potential
Ulceration
- Major prognostic factor
- Upstages each stage from a to b
Definition
* Full thickness epidermal defect
* Evidence of host reactive changes –> fibrin deposition and neutrophils
* Thinning, effacement or reactive hyperplasia of surrounding epidermis in the absence of a recent trauma or surgical procedure
Satellite/Microsatellite/In-transit Mets
Satellite melanoma:
Cancer cells that have spread to an area within 2 centimeters of the primary tumor.
Microsatellite melanoma:
Tiny amounts of cancer cells that are found next to the primary tumor (within 2 cm), but can only be seen under a microscope.
**In-transit metastases: **
These are found more than 2 centimeters away from the primary tumor, but before reaching the nearby lymph nodes.
The presence of these entities are associated with:
* Increased locoregional recurrence
* A decreased disease free survival rate
* Decreased overall survival
Tumour Infiltrating Lymphocytes
- Specific host response
- Early sign of attempted regression
- Must infiltrate the tumour and either disrupt or apposed the tumour cells
AFIP survival model –> 3 levels
Absent
* No lymphocytes within the tumour
* Adverse survival factor
Non-Brisk
* Patchy/Discontinuous lymphocytes in peripheral tumour cells or middle of the tumour
Brisk
* Continuous infiltration around the periphery or within the tumour
* Favourable prognostic factor
Regression
Features
* Variable destruction of melanoma cells with either a partial or nearly complete absence of tumour cells within the dermis
* Variable lymphohistiocytic infiltrate
* Fibrosis
* Increase in dermal blood vessels
* Melanin-laden melanophages
If regression is present to a greater depth than breslow, the regression is not included in the thickness measurement
