# Melanoma: Risk Factors, Staging, and Early Detection

## Epidemiology

Melanoma accounts for approximately 5 percent of skin cancers but is responsible for the majority of skin cancer deaths. Its incidence has risen steadily, with the lifetime risk now approximately 1 in 38 for Caucasians. The median age at diagnosis is 65 years, yet melanoma remains one of the most common cancers in young adults aged 20 to 39. Males are affected more often than females at a ratio of roughly 1.5 to 1, with the trunk being the most common site in men and the lower extremities in women. In darker-skinned individuals, acral lentiginous melanoma is the most common subtype.

## Risk Factors

The most significant environmental risk factor is **UV exposure**, particularly intermittent intense exposure causing blistering sunburns, which confers greater risk than chronic cumulative exposure. Phenotypic risk factors include fair skin, light hair and eyes, a freckling tendency, and Fitzpatrick skin types I and II. The number of melanocytic nevi is relevant as well: having more than 50 common nevi or clinically atypical (dysplastic) nevi substantially raises risk. A personal history of melanoma confers a 12-fold increased risk of a second primary, and familial melanoma syndromes are well recognized. Key genetic susceptibility factors include **CDKN2A** mutations (encoding p16INK4a), **CDK4** mutations, **MC1R** variants, and **BAP1** tumor predisposition syndrome. Immunosuppressed individuals, particularly organ transplant recipients on chronic immunosuppressive therapy, face elevated risk. Giant congenital melanocytic nevi exceeding 20 cm in projected adult size carry risk of melanoma development and neurocutaneous melanosis.

## Clinical Subtypes

| Subtype | Frequency | Growth Pattern | Key Features |
|---|---|---|---|
| Superficial spreading | ~70% | Prolonged radial | Irregular borders, color variegation; trunk and extremities |
| Nodular | 15-30% | Primarily vertical | Often amelanotic; lacks ABCDE features; worst prognosis; use "EFG" criteria |
| Lentigo maligna | 5-15% | Radial (years-decades) | Chronically sun-damaged skin; face/forearms of elderly; extensive subclinical extension |
| Acral lentiginous | 5-10% | Radial then vertical | Palms, soles, nail unit; most common in skin of color; KIT mutations > BRAF |
| Desmoplastic | ~1-4% | Vertical | Amelanotic firm nodule; head/neck; perineural invasion; S100+, HMB-45- |

### Superficial Spreading Melanoma (70%)

Superficial spreading melanoma is the most common subtype. It characteristically displays a prolonged radial growth phase lasting months to years, presenting with irregular borders and striking color variegation including brown, black, pink, white, and blue. It can occur on any body site but is most common on the trunk and extremities.

### Nodular Melanoma (15-30%)

Nodular melanoma arises de novo or within an existing lesion and is defined by a primarily vertical growth phase. It is often amelanotic or uniformly dark and frequently lacks the classic ABCDE features, making it the most commonly missed subtype. The **"EFG" criteria** -- Elevated, Firm, and Growing for more than one month -- are more useful for identifying these lesions. Nodular melanoma carries the worst prognosis due to its rapid vertical growth and frequent delayed diagnosis.

### Lentigo Maligna Melanoma (5-15%)

This subtype arises on chronically sun-damaged skin, typically on the face and forearms of elderly patients. It is preceded by lentigo maligna (melanoma in situ), which may persist for years or decades before invasion develops. Clinically, it appears as an ill-defined, asymmetric tan-brown macule with dark foci indicating the onset of dermal invasion. Surgical margins are challenging because of extensive subclinical extension within the surrounding field of sun-damaged skin.

### Acral Lentiginous Melanoma (5-10%)

Acral lentiginous melanoma occurs on the palms, soles, and nail unit and is the most common melanoma subtype in Black, Asian, and Hispanic patients. It is not UV-related, and **KIT** mutations are more common than BRAF mutations in this subtype. Subungual melanoma presents as longitudinal melanonychia with the **Hutchinson sign** (periungual pigmentation extending onto the proximal nail fold). Acral melanoma is often diagnosed late because of low clinical suspicion in these locations.

### Desmoplastic Melanoma

Desmoplastic melanoma typically presents as an amelanotic, firm dermal nodule on the head and neck of elderly patients. It has a high rate of perineural invasion but a comparatively low rate of lymph node metastasis. Histologically, spindle cells are embedded in a desmoplastic stroma, and the tumor is characteristically S100-positive and SOX10-positive but HMB-45-negative and Melan-A-negative.

<image>Clinical photograph comparing the four major melanoma subtypes: superficial spreading, nodular, lentigo maligna, and acral lentiginous melanoma</image>

## Clinical Detection

### ABCDE Criteria

The ABCDE criteria provide a systematic framework for evaluating pigmented lesions. **A**symmetry refers to one half not matching the other. **B**order irregularity describes scalloped, ragged, or poorly defined edges. **C**olor variation encompasses multiple shades of tan, brown, and black, sometimes with red, white, or blue. **D**iameter greater than 6 mm is suggestive, although melanomas can be smaller. **E**volving captures any change in size, shape, or color, as well as new symptoms such as bleeding or itching.

### Ugly Duckling Sign

The ugly duckling sign identifies a nevus that looks different from the patient's other nevi, functioning as an "outlier lesion." This concept may be more sensitive than ABCDE for detecting melanoma, particularly the nodular subtype that often lacks classic features.

### Glasgow 7-Point Checklist

This checklist assigns two points each for major features (change in size, irregular shape, irregular color) and one point each for minor features (diameter greater than 7 mm, inflammation, oozing or crusting, change in sensation). A score of 3 or more warrants referral for further evaluation.

## Biopsy Technique

**Excisional biopsy with narrow margins of 1 to 3 mm** is the gold standard for suspected melanoma, as it allows full assessment of Breslow thickness, ulceration, and mitotic rate. When excision is impractical due to lesion size or cosmetically sensitive location, a **punch biopsy** of the most clinically concerning area is acceptable, though partial biopsy may underestimate the true Breslow thickness. **Shave biopsy should be avoided** when melanoma is in the clinical differential because transection of the base prevents accurate microstaging. Importantly, **incisional biopsy does not adversely affect prognosis**, as there is no evidence of tumor seeding from biopsy.

<image>Dermoscopic image of a superficial spreading melanoma showing atypical pigment network, irregular dots and globules, blue-white veil, and regression structures</image>

## Histopathology and Microstaging

### Breslow Thickness

Breslow thickness, measured from the top of the granular layer (or the base of ulceration) to the deepest invasive melanoma cell, is the **most important prognostic factor** for localized melanoma. The AJCC 8th edition T-staging classifies tumors as follows: T1 is 1.0 mm or less (subdivided into T1a for less than 0.8 mm without ulceration and T1b for less than 0.8 mm with ulceration or 0.8 to 1.0 mm), T2 is greater than 1.0 to 2.0 mm, T3 is greater than 2.0 to 4.0 mm, and T4 is greater than 4.0 mm.

### Clark Levels (Anatomic Depth)

Clark levels describe anatomic depth of invasion: Level I (epidermis only, in situ), Level II (papillary dermis), Level III (filling papillary dermis), Level IV (reticular dermis), and Level V (subcutaneous fat). Clark levels carry less prognostic value than Breslow thickness and are no longer used in the AJCC 8th edition staging system.

### Additional Histologic Features

**Ulceration** is an independent adverse prognostic factor that upstages a tumor within each T category. **Mitotic rate**, while no longer formally part of AJCC 8th edition staging (it was included in the 7th edition), remains prognostically relevant. **Tumor-infiltrating lymphocytes** (TILs) are associated with better prognosis when brisk. **Regression**, characterized by fibrosis replacing melanoma cells, has controversial prognostic significance. **Microsatellites**, defined as discrete tumor nests larger than 0.05 mm separated from the main tumor by normal tissue, are staged as N1c.

## AJCC 8th Edition Staging (2018)

### Stage I-II (Localized Disease)

Stage IA (T1a N0 M0) carries a 5-year survival of approximately 99 percent. Stage IB encompasses T1b or T2a with no nodal or distant involvement. Stage IIA includes T2b or T3a tumors, Stage IIB includes T3b or T4a tumors, and Stage IIC (T4b N0 M0) has a 5-year survival of approximately 82 percent.

### Stage III (Regional Disease)

Stage III includes any T classification with nodal involvement (clinical or pathologic) or in-transit/satellite metastases. It is substaged from IIIA through IIID based on the T stage, number of involved nodes, and presence of in-transit disease.

### Stage IV (Distant Metastasis)

Stage IV is categorized by metastatic site: M1a for distant skin, subcutaneous, or nodal metastases with normal LDH; M1b for lung metastases; M1c for non-CNS visceral metastases; and M1d for CNS metastases. Each category is further substaged by LDH level (0 for normal, 1 for elevated).

## Sentinel Lymph Node Biopsy (SLNB)

### Indications

SLNB is **recommended** for melanomas with Breslow thickness of 0.8 mm or greater, or any thickness with ulceration (T1b and above). It should be **considered** for T1a melanomas with other adverse features such as high mitotic rate, lymphovascular invasion, or young patient age. SLNB is **not indicated** for melanoma in situ or for thick melanomas with established distant metastatic disease.

### Technique and Interpretation

The procedure involves preoperative lymphoscintigraphy with technetium-99m followed by intraoperative identification using blue dye and/or a gamma probe. The sentinel node is evaluated with H&E staining and immunohistochemistry for S100, HMB-45, and Melan-A. SLN positivity is the strongest predictor of survival for intermediate-thickness melanomas. The landmark **MSLT-II trial** demonstrated that completion lymph node dissection after a positive SLNB does not improve melanoma-specific survival, establishing observation with ultrasound surveillance of the nodal basin as the current standard.

<image>Diagram illustrating the AJCC 8th edition melanoma staging system with corresponding T, N, and M classifications and 5-year survival rates</image>

## Total Body Skin Examination (TBSE)

A systematic head-to-toe examination under adequate lighting should include the scalp, interdigital spaces, soles, nails, and the genital and perianal regions. Dermatoscopy increases sensitivity for melanoma detection by 20 to 30 percent compared to naked-eye examination. Screening intervals should be tailored to risk: the general population benefits from opportunistic screening (the USPSTF currently finds insufficient evidence for or against population-level screening), while high-risk patients warrant examination every 3 to 6 months with consideration of total body photography and sequential digital dermoscopy. **Mole mapping** with standardized photography and serial comparison is particularly valuable for patients with many atypical nevi.

## Patient Self-Surveillance

Monthly self-skin examinations reduce melanoma mortality. "Partner-assisted" skin examination improves detection of truncal lesions. Patients should be educated on the ABCDE criteria and the ugly duckling sign, with emphasis that any new or changing pigmented lesion warrants professional evaluation.

<image>Clinical photograph demonstrating the ABCDE criteria of melanoma applied to a lesion showing asymmetry, border irregularity, color variation, large diameter, and evidence of evolution</image>

## Clinical Pearls

Nodular melanoma is the most commonly missed subtype because it often lacks the classic ABCDE features; the "EFG" criteria (Elevated, Firm, Growing for more than one month) should be applied to any rapidly growing nodule. Amelanotic melanoma accounts for approximately 5 percent of cases, and clinicians must maintain a high index of suspicion for any new, persistent, pink papule or nodule. Subungual melanoma should be considered in any case of longitudinal melanonychia, especially if the band exceeds 3 mm, is darkening, or involves the dominant hand or thumb. The Breslow thickness determines the recommended excision margins: in situ requires 0.5 to 1 cm, lesions 1 mm or less require 1 cm, lesions 1.01 to 2 mm require 1 to 2 cm, and lesions greater than 2 mm require 2 cm margins. Following the MSLT-II trial, completion lymph node dissection is no longer standard practice; nodal basin ultrasound surveillance has replaced routine dissection for positive sentinel lymph node biopsies.

## References
- AJCC Cancer Staging Manual, 8th Edition. Springer, 2017
- Swetter SM, et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol. 2019;80(1):208-250
- Faries MB, et al. Completion dissection or observation for sentinel-node metastasis in melanoma (MSLT-II). N Engl J Med. 2017;376(23):2211-2222
- Garbe C, et al. European consensus-based interdisciplinary guideline for melanoma. Eur J Cancer. 2022;170:236-255
- Bolognesi G, et al. Dermoscopy and melanoma. Dermatol Clin. 2023;41(1):69-83