• Clinical science

Melanoma

Abstract

Melanoma, a highly malignant tumor arising from melanocytes, is the most common life-threatening dermatological disease. Risk factors include UV radiation exposure, particularly in light-skinned individuals that are easily sunburned, increasing age, family history, and immunosuppression. The superficial spreading melanoma is the most common subtype. Other subtypes, such as nodular melanoma, have a significantly worse prognosis because they tend to metastasize more rapidly. Invasive melanoma is particular in its propensity to metastasize to unusual locations that are not commonly affected by other malignancies. Immediate full-thickness surgical excision of the primary tumor is usually the best initial diagnostic test and may be therapeutic for localized disease. Chemotherapy, biologics, and/or radiation therapy is recommended for recurrent or widespread disease. Tumor thickness is the most important prognostic factor.

Epidemiology

Most common life-threatening dermatological disease

References:[1]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

References:[2][3][4]

Classification

TNM Classification for Malignant Melanoma

TNM Spread Correlating AJCC staging of malignant melanoma
Carcinoma in situ 0
T1

Thickness: ≤ 1 mm

T1a: Without ulceration and mitosis < 1/mm2 IA
T1b: With ulceration or mitosis ≥ 1/mm2 IB
T2

Thickness: 1.01–2 mm

T2a: Without ulceration
T2b: With ulceration IIA
T3

Thickness: 2.01–4 mm

T3a: Without ulceration
T3b: With ulceration IIB
T4

Thickness: > 4 mm

T4a: Without ulceration
T4b: With ulceration IIC
N1

Single regional lymph node

N1a: Microscopic spread

N1b: Macroscopic spread
N2

2–3 regional lymph nodes

N2a: Microscopic spread
N2b: Macroscopic spread
N2c: no lymph node involvement, but satellite or in-transit metastases
N3

IIIC

M1 Distant metastasis

M1b: Lung metastasis, normal LDH

IV

References:[5]

Clinical features

  • Pruritic, persistently bleeding skin lesion
  • Dermoscopy should be used to examine lesions for ABCDE criteria:
    • A = Asymmetry
    • B = Border (irregular border with indistinct margins)
    • C = Color (new changes in pigmentation or variations in pigmentation within the same lesion)
    • D = Diameter > 6 mm
    • E = Evolving (new lesion or a lesion that changes in size, shape, or color over time)

Types of melanoma

Frequency and characteristic features Predilection sites Clinical appearance Growth

Superficial spreading melanoma

  • ∼ 60%
  • Back or chest (common in men)
  • Extremities (common in women)
  • Flat irregular tumor; sometimes with nodular segments
  • Variable pigmentation
  • Relatively prolonged horizontal growth .

Nodular melanoma

  • ∼ 20%
  • Reddish-brown-black, smooth nodules
  • Verrucous surface or ulceration with bleeding
  • Fast growth in depth

Lentigo maligna melanoma

  • Sun-exposed skin areas (esp. face)
  • Large and irregularly shaped patch
  • Irregular pigmentation
  • Relatively slow horizontal growth

Acral lentiginous melanoma

  • ∼ 5%
  • More common in dark-skinned and Asian populations
  • Palms, soles, nailbed, mucous membranes
  • Irregularly shaped, brown-black pigmented macule
  • Ulceration may occur
  • Hutchinson's sign in subungual type: dark linear patch, widens with time, arising from the nail
  • Slow horizontal growth

Superficial spreading melanoma (∼ 60%)

  • Predilection sites: back, chest, extremities
  • Clinical presentation
    • Usually irregularly shaped, flat tumor; sometimes with nodular segments
    • Variable pigmentation
  • Growth: relatively slow horizontal growth
  • Histology: atypical melanocytes in a "buckshot" (pagetoid) scatter within the epidermis

Nodular melanoma (∼ 20%)

  • Predilection sites: back, chest, extremities
  • Clinical presentation:
    • Reddish-brown black, smooth nodules
    • Verrucous surface or ulceration with bleeding may occur
  • Growth: Fast growth into lower tissue → subtype with worst prognosis!

Lentigo maligna melanoma (∼ 10%)

  • Predilection sites: areas of skin that are exposed to sunlight
  • Clinical presentation: large, irregularly shaped patch with irregular pigmentation
  • Growth:
    • Often arises from lentigo maligna in the elderly
    • Relatively slow horizontal growth → screening helps in early detection

Acral lentiginous melanoma (∼ 5%)

  • Epidemiology: more common in African-American and Asian populations
  • Predilection sites:
  • Clinical presentation:
    • Irregularly shaped, brown-black pigmented macule
    • Ulceration may occur over time
    • In nail involvement: dark linear patch that widens over time = Hutchinson's sign
  • Prognosis: Generally good because of relatively slow horizontal growth pattern. Late diagnosis often occurs, however, due to poorly visible predilection sites (e.g., sole of the foot)

Special types

  • Amelanotic melanoma
    • Pink or skin-colored nodes → may be difficult to recognize
    • Histological diagnosis is necessary
  • Uveal melanoma

Metastatic disease

References:[3][6][7][8][9]

Diagnostics

  • A full-thickness excisional biopsy (best diagnostic test) is indicated in all suspicious lesions.
    • Pathology shows s100-protein positive, epithelioid cells with fine granules in cytoplasm
  • Staging tests (e.g., ultrasound or MRI) once diagnosis confirmed: to determine tumor thickness, spread to lymph nodes, or distant metastasis
AJCC staging criteria

≤ Ia

(tumor thickness < 1 mm)

Ib (tumor thickness ≥ 1 mm)–IIb (tumor thickness 2–4 mm)

IIc (tumor thickness > 4 mm with ulceration) - IIIc (with lymph node metastases)

IV

(Distant metastases)

Clinical examination
Ultrasound Lymph nodes
Abdomen
Laboratory tests Tumor marker S100B
Tumor marker LDH
Other imaging tests Full-body CT, MRI, or PET
MRI-head
Bone scintigraphy

Complete excisional biopsies are always preferred over incisional biopsies, as they allow tumor thickness to be properly estimated!
References:[10]

Differential diagnoses

Differential diagnosis of common skin cancers
Color Morphology Location Other characteristic features
Melanoma
  • Brown, black (variable pigmentation)
  • Irregular macule, nodule, or patch
  • Anywhere
  • Commonly on trunk or extremities
  • Slow growth (rapid growth possible)
Cutaneous squamous cell carcinoma
  • Red
  • Scaly, plaque-like, nodular, papillomatous, and/or verrucous lesion
  • Sun exposed areas (e.g., typically lower lip)
  • “Rough” texture
  • Slow growth
  • All eventually ulcerate (everted edges, friable, inflamed)
Basal cell carcinoma
  • Pink
  • Pearly, nodular lesion
  • Sun exposed areas (e.g., typically upper lip, eyelid, nose)
  • Superficial veins
  • Central dimpling
  • Slow growth

Benign lesions commonly resemble melanomas and should be biopsied to rule out cancer (see Benign skin lesions)!

The differential diagnoses listed here are not exhaustive.

Treatment

Surgical excision

Full-thickness incision with appropriate safety margins

  • 0.5 cm safety margin
    • Suspicious lesion without proven melanoma →
    • Melanoma in situ (T0) 0.5 cm safety margin
  • Other margins: according to Breslow's depth: thickness from the granular layer to the lowest detectable tumor cell
Breslow stage Historically (until 2001) Modified by AJCC (valid since 2001) Safety margin
I ≤ 0.75 mm ≤ 1.0 mm 1 cm
II 0.76–1.49 mm 1.01–2 mm 1–2 cm
III 1.50–2.49 mm 2.01–4 mm 2 cm
IV 2.50–3.49 mm ≥ 4 mm
V ≥ 3.5 mm not defined 2 cm
If tumor thickness > 1 mm (Breslow stage ≥ II): perform sentinel lymph node biopsy

The gold standard is immediate, complete excision of the tumor!

Medical therapy

AJCC staging of malignant melanoma TNM classification of malignant melanoma Management after surgical excision
Stage 0 - Ia T1 (< 1mm), N0, M0
(without ulcerations)
  • Frequent follow-up examinations
Stage Ib - IIc Up to T4 (> 4 mm), N0, M0
  • Sentinel lymph nodes should be identified (scintigraphy) and evaluated → elective lymphadenectomy if lymph nodes are affected
  • From stage IIb: optional adjuvant therapy with interferon α2
Stage IIIa - IIIc N1, regional skin metastases
(no distant metastases)
  • With satellite or in-transit metastaseshyperthermic perfusion with chemotherapeutic agents
  • In stage IIIb und IIIc: complete lymphadenectomy (optionally with adjuvant radiotherapy of lymphatic vessels)
  • Pharmacotherapy: adjuvant therapy with interferon α2
Stage IV M1

Palliative treatment options

Chemotherapy, biologic therapy (e.g., intravenous interferon therapy), and radiation therapy are recommended for recurrent or widespread disease!
References:[11][12]

Prognosis

  • Survival rate is highly unpredictable
AJCC staging TNM classification and Breslow thickness Estimated 5-year survival rate
Stage 0 - Ia T1 (< 1mm), no nodular involvement, no metastases
(without ulcerations)
> 90%
Stage Ib - IIc Up to T4 (> 4 mm), no nodular involvement, no metastases ≈ 70 %
Stage IIIa - IIIc N1, regional skin metastases
(no distant metastases)
≈ 20–40 %
Stage IV M1, distant metastases < 5 %
  • Negative prognostic factors
    • Epidemiological features: male sex
    • Clinical features: type , localization , and presence of ulcerations
    • Tumor thickness is the most important prognostic factor.

References:[13]