Melanoma pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Pathophysiology

Nodular melanoma on the leg of an elderly woman.

Generally, an individual's risk for developing melanoma depends on two groups of factors: intrinsic and environmental. "Intrinsic" factors are generally an individual's family history and inherited genotype, while the most relevant environmental factor is sun exposure.

Epidemiologic studies suggest that exposure to ultraviolet radiation (UVA and UVB) is one of the major contributors to the development of melanoma. UV radiation causes damage to the DNA of cells, typically thymine dimerization, which when unrepaired can create mutations in the cell's genes. When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in oncogenes or tumor suppressor genes, the rate of mitosis in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor. Occasional extreme sun exposure (resulting in "sunburn") is causally related to melanoma. Those with more chronic long term exposure (outdoor workers) may develop protective mechanisms. Melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure) and is more common in indoor workers than outdoor workers (in a British study). Other factors are mutations in or total loss of tumor suppressor genes. Use of sunbeds (with deeply penetrating UVA rays) has been linked to the development of skin cancers, including melanoma.

Genetics

Familial melanoma is genetically heterogeneous, and loci for familial melanoma have been identified on the chromosome arms 1p, 9p and 12q. Multiple genetic events have been related to the pathogenesis of melanoma. The multiple tumor suppressor 1 (CDKN2A/MTS1) gene encodes p16INK4a - a low-molecular weight protein inhibitor of cyclin-dependent protein kinases (CDKs) - which has been localised to the p21 region of human chromosome 9.

Today, melanomas are diagnosed only after they become visible on the skin. In the future, however, physicians will hopefully be able detect melanomas based on a patient’s genotype, not just his or her phenotype. Recent genetic advances promise to help doctors to identify people with high-risk genotypes and to determine which of a person’s lesions have the greatest chance of becoming cancerous.

A number of rare mutations, which often run in families, are known to greatly increase one’s susceptibility to melanoma. One class of mutations affects the gene CDKN2A. An alternative reading frame mutation in this gene leads to the destabilization of p53, a transcription factor involved in apoptosis and in fifty percent of human cancers. Another mutation in the same gene results in a non-functional inhibitor of CDK4, a [cyclin-dependent kinase] that promotes cell division. Mutations that cause the skin condition Xeroderma Pigmentosum (XP) also seriously predispose one to melanoma. Scattered throughout the genome, these mutations reduce a cell’s ability to repair DNA. Both CDKN2A and XP mutations are highly penetrant.

Other mutations confer lower risk but are more prevalent in the population. People with mutations in the MC1R gene, for example, are two to four times more likely to develop melanoma than those with two wild-type copies of the gene. MC1R mutations are very common; in fact, all people with red hair have a mutated copy of the gene. Two-gene models of melanoma risk have already been created, and in the future, researchers hope to create genome-scale models that will allow them to predict a patient’s risk of developing melanoma based on his or her genotype.

Pathology

Histopathological Analysis

The microscopic hallmarks of nodular melanoma are:

• Dome-shaped at low power
• Epidermis thin or normal
• Dermal nodule of melanocytes with a 'pushing' growth pattern
• No "radial growth phase"

The microscopic hallmarks of acral lentiginous melanoma are:

• Atypical melanocytes in junctional nests
• dermal invasion
• Desmoplasia
• Hyperplastic epidermis

Superficial spreading melanoma

• Presence of intraepidermal lateral spread (most characteristic feature)
• Appearance of epithelioid cells with occasional spindle cells

Nodular Melanoma

• Sharp border differentiating malignant vs. normal tissue due to absence of intraepidermal lateral spread (most characteristic feature)
• Appearance of epithelioid cells with occasional spindle cells
• Melanocytes may have absent/minimal pigmentation

Acral Lentiginous Melanoma

• Epidermal acanthosis and hyperkeratosis (mmost characteristic feature)
• Malignant melanocytes spread along the basal layer
• Cells arranged in lentiginous and dycohesive pattern along the dermoepidermal junction
• May be any of round, epithelioid, spindle, or oval cells
• May have perineural or endoneural invasion

Lentigo Maligna Melanoma=

• Epidermal atrophy and flattening (most charactersitic feature)
• Large, pleomorphic cells
• Malignant melanocytes spread along the basal layer
• Cells arranged in lentiginous and dycohesive pattern along the dermoepidermal junction
• May be any of round, epithelioid, spindle, or oval cells
• Evidence of actinic damage of the dermal matrix
• May have perineural or endoneural invasion

Desmoplastic melanoma

• 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 subtypes (co-existing tumors, especially lentiginous melanoma)

Nevoid melanoma

• 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 melanoma

• Appearance of melanocytic proliferation along with features of Spitz tumors (small diametes, 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

• 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

• Asymmetric nodular/multinodular appearance
• Aggregates of melaninized, atpical spindle cells

Future thought

One important pathway in melanin synthesis involves the transcription factor MITF. The MITF gene is highly conserved and is found in people, mice, birds, and even fish. MITF production is regulated via a fairly straightforward pathway. UV radiation causes increased expression of transcription factor p53 in keratinocytes, and p53 causes these cells to produce melanoctye stimulating hormone (MSH), which binds to MC1R receptors on melanocytes. Ligand-binding at MC1R receptors activates adenyl cyclases, which produce cAMP, which activates CREB, which promotes MITF expression. The targets of MITF include p16 (a CDK inhibitor) and Bcl2, a gene essential to melanocyte survival. It is often difficult to design drugs that interfere with transcription factors, but perhaps new drugs will be discovered that can impede some reaction in the pathway upstream of MITF.

Studies of chromatin structure also promise to shed light on transcriptional regulation in melanoma cells. It has long been assumed that nucleosomes are positioned randomly on DNA, but murine studies of genes involved in melanin production now suggest that nucleosomes are stereotypically positioned on DNA. When a gene is undergoing transcription, its transcription start site is almost always nucleosome-free. When the gene is silent, however, nucleosomes often block the transcriptional start site, suggesting the nucleosome position may play a role in gene regulation.

Finally, given the fact that tanning helps protect skin cells from UV-induced damage, new melanoma prevention strategies could involve attempts to induce tanning in individuals who would otherwise get sunburns. Redheads, for example, do not tan because they have MC1R mutations. In mice, it has been shown that the melanin-production pathway can be rescued downstream of MC1R. Perhaps such a strategy will eventually be used to protect humans from melanoma.