Melanoma pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Serge Korjian M.D.

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Overview

Malignant melanoma arises from the epidermal melanocytes, which are neural crest cells involved in the synthesis of melanin (a brown pigment with photoprotective properties). Development of melanoma is the result of multiple genetic mutations. The progression to melanoma usually involves the serine-threonine kinases of the MAPK/ERK pathway (mitogen-activated protein kinase) following mutation of either the N-RAS or BRAF oncogene. On gross pathology, the majority of melanomas appear as hyperkeratotic, black-brown, asymmetric nodules with irregular borders, but the morphology of the lesion mostly depends on the sub-type of melanoma. On microscopic histopathological analysis, each sub-type of melanoma has unique characteristic features.

Pathophysiology

Malignant melanoma arises from the epidermal melanocytes, which are neural crest cells involved in the synthesis of melanin (a brown pigment with photoprotective properties).

Genetics

• The development of melanoma begins with the disruption of nevus growth control.
• The progression to melanoma usually involves the serine-threonine kinases of the MAPK/ERK pathway (mitogen-activated protein kinase) following mutation of either the N-RAS or BRAF oncogene.
• It is thought that the progression to melanoma requires multiple genetic mutations, where activation of the oncogene alone does not lead to the development of melanoma, and additional mutations (multiple hits), such as loss-of-function mutation of P53 tumor suppressor gene (or less commonly P16/CDKN2A or PTEN in familial cases) is required for the development of melanoma.
• The development of melanoma may arise de novo or from pre-existing nevi. In both cases, mutations result in dysplasia and cytologic atypia that predispose to the malignant potential of the cells.
• As more genes are mutated and the tumor grows, changes include the overexpression of N-cadherin, αVβ3 integrin, MMP2, MSH, cAMP, and survivin, and the loss of E-cadherin and TRMP1 proteins.
• The following genes are involved in the pathogenesis of melanoma:

• Tumor-suppressor genes:

• P53
• P16/CDK2NA
• PTEN
• RB
• ARF

• Proto-oncogenes:

• N-RAS
• BRAF
• CCND1

Pathology

• Characteristic features on gross pathology and microscopic analysis are variable depending on the melanoma sub-type.
• The following table illustrates the findings on gross pathology and microscopic analysis of the sub-types of melanoma:

Melanoma Subtype	Features on Gross Pathology	Features on Histopathological Microscopic Analysis
Superficial spreading melanoma	Brown/black color, but may include reddish brown or white Hyperkeratotic, diffused borders with no distinct demarcation Irregular and elevated	Presence of intraepidermal lateral spread (most characteristic feature) Dermal invasion Desmoplasia Epidermal hyperplasia Appearance of epithelioid cells with occasional spindle cells
Nodular melanoma	Tan/reddish brown color Sharp borders Well-demarcated, dome-shaped papular/verrucous lesion	Sharp border differentiating malignant vs. normal tissue due to absence of intraepidermal lateral spread / no radial growth plate (most characteristic feature) Appearance of epithelioid cells with occasional spindle cells Melanocytes may have absent/minimal pigmentation
Acral lentiginous melanoma	Brown/black color, but may include reddish brown or white Hyperkeratotic, diffused borders with no distinct demarcation Irregular and elevated	Epidermal acanthosis and hyperkeratosis (most characteristic feature) Malignant melanocytes spread along the basal layer Cells arranged in lentiginous and dyscohesive pattern along the dermoepidermal junction May be any of round, epithelioid, spindle, or oval cells May have perineural or endoneural invasion
Lentigo maligna melanoma	Brown/black color, but may include reddish brown or white Hyperkeratotic, diffused borders with no distinct demarcation Irregular and elevated	Epidermal atrophy and flattening and prominent dermal invasion (most charactersitic feature) Large, pleomorphic cells Cells arranged in lentiginous and dyscohesive pattern along the dermoepidermal junction Preservation of retiform epidermis May be any of round, epithelioid, spindle, or oval cells Evidence of actinic damage of the dermal matrix May have perineural or endoneural invasion Positivity for CD133+ and CD34+
Non-cutaneous melanoma	Variable morphology depending on location of melanoma	Histopathologically similar to other sub-types of melanoma
Desmoplastic/Spindle cell melanoma	Skin colored and morphologically resembles scar tissue	Dermal, fibrotic nodule Ill-defined, variable spindle cells with irregular contours and stromal desmoplasia Highly infiltrative pattern Appearance of sclerotic collagen fibers Nuclear hyperchromasia Appearance of lymphoid aggregates Solar elastosis Involvement of endoneurium and perineurium (neurotropism) Possibly evidence of other melanoma sub-types (co-existing tumors, especially lentiginous melanoma)
Nevoid melanoma	Morphologically similar to a melanocytic nevus	Dermal mitosis Hypercellular and monomorphous-appearing dermal melanocytes that have a characteristic sheet-like appearance Evidence of cytologic atypia (nuclear enlargement, pleomorphism, irregular nuclear membrane, hyperchromasia) Irregular basal infiltration Evidence of angiotropism
Spitzoid melanocytic neoplasm	Morphologically similar to a Spitz nevus	Appearance of melanocytic proliferation along with features of Spitz tumors (small diameter, well-demarcated, symmetric lesion with no ulceration, epidermal effacement, dermal mitosis, or involvement of the subcutaneous fat) May have features that are not typically characteristic of Spitz tumors (ulceration, poor demarcation) Vertically oriented spindled melanocytes Clefts between junctional melanocytes
Angiotropic melanoma	No gross morphological features that distinguish angiotropic melanoma from other sub-types of melanoma	Melanoma cells in close proximity to abluminal surfaces of blood and/or lymphatic channels No invasion within the vascular lamina itself
Blue nevus-like melanoma	Morphologically similar to a blue nevus	Asymmetric nodular/multinodular appearance Aggregates of melaninized, atypical spindle cells
Composite melanoma	Features of more than one sub-type on gross pathology	Features of more than one sub-type on microscopic analysis May be characterized by one of the following: Collision tumor: Collision of melanoma and another nearby malignant tumor Colonization: Colonization of melanocytes in a tumor Combined: Two distinct tumors appear to have mixed features of the melanoma and the other tumor Biphenotypic: One tumor that simultaneously has features of melanoma and another epithelial malignancy