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Summary Table

Category	Detail
Risk Factors	Family history, fair skin/light eyes/red-blonde hair (Fitzpatrick type I), history of sunburn, numerous or dysplastic nevi, chronic sun exposure, tanning bed use, immunosuppression (post-transplant, hematologic disease), atypical nevus syndrome
Etiology	Malignant transformation of melanocytes originating from neural crest cells; can arise in skin as well as extracutaneous sites (GI tract, brain) where neural crest cells migrate
Patient Presentation	Changing mole (color, size, shape), new pigmented lesion with irregular borders, bleeding/crusting/itching nodule; often found incidentally during routine skin examination
Classic Physical Exam	ABCDE criteria: Asymmetry, Border irregularity, Color variation, Diameter >6 mm, Evolution; pigmented lesion with multiple colors (brown, black, blue-gray, red, white); satellite lesions or in-transit metastases; palpable regional lymphadenopathy
Key Diagnostic Results	Dermoscopy showing atypical pigment network, blue-white veil, irregular streaks, regression structures; histopathology with atypical melanocyte nests at dermo-epidermal junction, pagetoid spread, loss of maturation; IHC markers S100, Sox10, HMB-45, Melan-A; Breslow thickness and ulceration status for staging
Management	Wide local excision with margins based on Breslow thickness (in situ: 0.5-1 cm, up to 1 mm: 1 cm, 1-2 mm: 1-2 cm, >2 mm: 2 cm); SLNB for Breslow >=1 mm; adjuvant pembrolizumab 200 mg IV q3w or 400 mg IV q6w for stage III; systemic therapy with checkpoint inhibitors or BRAF/MEK inhibitors for advanced disease
Keywords	"Changing mole," "irregular borders with multiple colors," "Breslow thickness," "ABCDE criteria," "blue-white veil on dermoscopy," "sentinel lymph node biopsy," "BRAF V600 mutation"

1. Pathophysiology

Melanoma maligna arises from the malignant transformation of melanocytes, which are pigment-producing cells derived from the neural crest. Because their embryologic origin is neural crest, melanocytes are not limited to skin. They migrate during development to the GI tract, meninges, and other mucosal surfaces, which explains why melanoma can occur in extracutaneous locations such as the oral cavity, nasal sinuses, anorectal region, and genitourinary tract.

The pathogenesis involves a combination of genetic susceptibility and UV-induced DNA damage. Intermittent intense sun exposure (the pattern that causes blistering sunburns) is more strongly associated with superficial spreading melanoma and nodular melanoma, while chronic cumulative sun exposure drives lentigo maligna melanoma. UV radiation induces mutations in key oncogenes, most notably BRAF (found in up to 56% of melanomas, particularly SSM and NM), NRAS, and c-KIT (more common in acral and mucosal subtypes). BRAF V600 mutations activate the MAPK signaling pathway, promoting uncontrolled cell proliferation and survival.

The number of melanocytic nevi (both common and dysplastic) shows a stronger correlation with melanoma risk than their size, reflecting overall melanocyte burden and genetic instability. Immunosuppressed patients (transplant recipients, hematologic malignancies) have a disproportionately elevated risk because intact immune surveillance is critical for eliminating transformed melanocytes.

Histologically, melanoma progresses through two phases. The radial growth phase represents horizontal spread within the epidermis and superficial dermis; the tumor is thin and carries a favorable prognosis. The vertical growth phase marks invasion into deeper dermis and subcutis, granting the tumor metastatic potential. This progression directly correlates with Breslow thickness, the single most important histologic prognostic factor.

2. Classification and Clinical Manifestation

Subtypes of Cutaneous Melanoma

Subtype	Proportion	Typical Patient/Location	Clinical Features	Growth Pattern	Key Genetic Feature
Superficial Spreading Melanoma (SSM)	~70%	Lower extremities (women), upper back (men); intermittent sun-exposed areas	Flat lesion with irregular borders, uneven pigmentation, multiple colors (brown, black, blue-gray, red, white); often arises from pre-existing nevus	Slow radial phase (months to years); often mistaken for atypical nevus or seborrheic keratosis	High BRAF mutation rate (up to 56%)
Nodular Melanoma (NM)	15-30%	Trunk	Elevated, dome-shaped nodule; blue-black or blue-red, homogeneous color; 5% are amelanotic	Rapid vertical growth (weeks to months); lacks a clear radial phase	High BRAF mutation rate
Lentigo Maligna Melanoma (LMM)	10-15%	Chronically sun-damaged skin of face (cheeks, nose), neck, scalp, ears; elderly patients	Flat, slowly enlarging brown macule with irregular color variation (brown and tan shades); begins as lentigo maligna (melanoma in situ) before becoming invasive	Very prolonged radial phase	c-KIT aberrations (28%) more common than BRAF (6%); rarely associated with nevi
Acral Lentiginous Melanoma (ALM)	2-8% of melanoma in light-skinned; 29-72% in dark-skinned populations	Palms, soles, subungual areas; mean age ~65 years	Brown-to-black patch with irregular borders on acral skin; subungual variant presents as longitudinal melanonychia (brown-black nail streak) at great toe or thumb	Variable	BRAF (21%), c-KIT (13%), c-KIT copy number changes up to 36%
Desmoplastic Melanoma (DM)	Uncommon	Head and neck in patients aged 60-70; chronically sun-exposed skin	Firm, sclerotic, or indurated lesion; ~50% amelanotic; ~50% associated with lentigo maligna	Tends toward perineural invasion; high local recurrence but low nodal metastasis	NF1 mutations (>90%); lacks BRAF/NRAS mutations; high UV-mutation burden
Mucosal Melanoma	1.3%	Conjunctiva, nasal/sinus cavity, oral cavity, genital/anorectal, urethral mucosa	Pigmented patches or bleeding masses on mucosal surfaces; often detected late	Variable	NRAS/KRAS mutations (5-30%); activates MAPK pathway

Less Common Subtypes

Subtype	Key Features
Nevoid Melanoma	Papule or light-brown nodule >1 cm; young adults; mimics benign nevus
Spitzoid Melanoma	Resembles Spitz nevus but larger (>1 cm), thick invasive component (>2 mm), high mitotic activity, atypical cells; harbors HRAS mutations and BAP1 inactivation rather than BRAF/NRAS
Rare types	Metaplastic, balloon cell, signet-ring cell, myxoid, rhabdoid, animal-type melanoma, malignant blue nevus

The test-writer perspective here: SSM is the most common subtype overall, but in a vignette describing a dark-skinned patient with a pigmented lesion on the sole of the foot, the answer is ALM. A rapidly growing blue-black nodule on the trunk without a preceding flat phase points to NM. A slowly expanding flat brown patch on the face of an elderly patient with chronic sun damage is LMM. Do not confuse the subungual variant of ALM with subungual hematoma: a hematoma migrates distally with nail growth, while melanoma does not.

3. Diagnostic Workup

Investigation	Role	Key Findings
Dermoscopy (best initial test for clinical evaluation)	Non-invasive magnified evaluation of pigmented lesions	Atypical pigment network, negative network, atypical dots/globules, irregular streaks, regression structures, blue-white veil, shiny white lines, atypical blotch, polymorphous vessels; presence of at least one feature raises suspicion
Excisional biopsy with histopathology (gold standard/confirmatory)	Provides definitive diagnosis, Breslow thickness, ulceration status, mitotic rate	Atypical melanocyte nests at dermo-epidermal junction, pagetoid spread of melanocytes above basal layer, loss of maturation with depth, confluent nests in dermis, predominance of single atypical melanocytes
Immunohistochemistry (IHC)	Confirms melanocytic lineage in poorly differentiated or amelanotic tumors	S100, Sox10 (sensitive); HMB-45, Melan-A, MiTF (more melanocyte-oriented); DM typically expresses only S100 and Sox10; Ki-67 helps assess proliferation in nevoid melanoma
Serum markers (S100B, LDH)	Monitoring disease course, not for primary diagnosis	S100B and LDH for prognosis and monitoring; LDH recommended for patients with distant metastasis (part of AJCC staging)
Imaging	Staging and metastatic workup	CXR, USG/CT abdomen, bone scan, CT head (if indicated), CT thorax/abdomen/pelvis, PET/CT whole-body for advanced stages
Sentinel Lymph Node Biopsy (SLNB)	Determines microscopic nodal spread	Recommended for Breslow >=1 mm; can be considered for thinner melanomas with additional risk factors (ulceration, high mitotic rate)

The clinical workup begins with visual inspection using the ABCDE criteria, which is the screening framework for any pigmented lesion. If a lesion raises concern, dermoscopy is the best initial test because it improves diagnostic accuracy without requiring tissue. The presence of at least one dermoscopic feature (blue-white veil, atypical pigment network, irregular streaks, regression structures) should prompt biopsy.

The gold standard is excisional biopsy with narrow margins (1-3 mm) for histopathologic analysis. The pathology report must include Breslow thickness (measured in millimeters from the granular layer to the deepest invasive melanocyte) and ulceration status, as both are essential for AJCC TNM staging. Shave biopsies that transect the base are unacceptable because they make accurate Breslow measurement impossible.

When a suspicious lesion is examined after biopsy, the surrounding area must be inspected for satellite lesions and in-transit metastases. All other skin surfaces including scalp, interdigital spaces, genitalia, and subungual areas should be checked for additional primary tumors. All regional lymph node basins must be palpated.

For staging workup in advanced melanoma (stage III-IV), imaging includes USG of regional lymph nodes, CT with contrast of the thorax/abdomen/pelvis (adding neck if clinically indicated), and/or PET/CT whole-body. BRAF mutation testing is recommended starting at stage III, as it determines eligibility for targeted therapy.

Serum markers S100B and LDH are used for disease monitoring rather than diagnosis. LDH is part of the AJCC M-category classification for stage IV disease.

4. Management and Treatment

Excision Margins Based on Breslow Thickness

Breslow Thickness	Recommended Surgical Margin
In situ	0.5 to 1 cm
Up to 1 mm	1 cm
>1 to 2 mm	1 to 2 cm
>2 mm	2 cm

Mohs micrographic surgery (MMS) can be considered for melanoma in situ or minimally invasive melanoma (T1a) in anatomically constrained areas such as the face, ears, or acral sites. For invasive melanoma, excision depth should extend to the fascia.

Management by Stage

Stage	Primary Management	Adjuvant/Systemic	Follow-up
0 in situ / IA (T1a)	Wide excision (1A)	None	Observation per education guidelines
IB (T1b)	Wide excision (1A); consider SLNB consultation (1B)	If SLNB positive, treat as stage III	Observation if SLNB negative
IB (T2a) / II (T2b-T4b)	Wide excision (1A); SLNB consultation (1B)	If SLNB negative: observation +/- radiation oncology consultation; if SLNB positive: treat as stage III	Per stage-based protocol
IIIA/IIIB/C/D (sentinel node positive)	Consider BRAF testing; routine regional nodal imaging q4-6 months OR CLND consultation	Adjuvant systemic therapy if available, OR observation	Imaging surveillance q4-6 months
III (clinically positive nodes)	Baseline imaging; BRAF testing; multidisciplinary consultation; FNA/core biopsy of nodes	Resectable: wide excision + TLND, then adjuvant systemic therapy or radiation. Unresectable: systemic therapy and/or palliative radiation	Per MDT recommendation
III (satellite/in-transit)	Baseline imaging; BRAF testing; multidisciplinary consultation	Resectable: wide excision, then adjuvant if NED. Unresectable: systemic therapy or local therapy (radiation, palliative excision, ablation)	Per MDT recommendation
IV (metastatic)	Biopsy metastatic lesion; BRAF testing; LDH; baseline imaging; multidisciplinary consultation	Oligometastasis: resection then systemic therapy if NED. Disseminated: systemic therapy, palliative/supportive care	Per MDT recommendation

Adjuvant Systemic Therapy (for resected stage III)

Agent	Dose and Schedule
Pembrolizumab	200 mg IV every 3 weeks, OR 400 mg IV every 6 weeks
Nivolumab	240 mg IV every 2 weeks, OR 480 mg IV every 4 weeks (not yet available in Indonesia)
Dabrafenib/trametinib (BRAF V600+)	(Not yet available in Indonesia)

Systemic Therapy for Unresectable/Metastatic Disease

Line	Options
First-line	Pembrolizumab 200 mg IV q3w or 400 mg IV q6w; OR nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV q3w x4 doses (not in Indonesia); OR nivolumab monotherapy (not in Indonesia)
First-line if BRAF V600+	Vemurafenib 720 mg or 960 mg PO BID / cobimetinib 60 mg, 80 mg, or 100 mg PO daily (various cycling schedules) (cobimetinib not in Indonesia); dabrafenib/trametinib (not in Indonesia); encorafenib/binimetinib (not in Indonesia)
Disease progression or intolerance	Check for KIT, NRAS mutations. Options: repeat prior therapy, dabrafenib/trametinib + pembrolizumab, imatinib (KIT+), binimetinib (NRAS+), cytotoxic chemotherapy (CVD, temozolamide, paclitaxel, carboplatin/paclitaxel), palliative/supportive care

Recurrent Disease

Recurrence Type	Approach
True scar recurrence	Biopsy, restage, re-excise, then manage per new histopathologic stage
Local satellite / in-transit	Biopsy, then treat as stage III (satellite/in-transit)
Nodal recurrence (no distant mets)	Treat as stage III (clinically positive nodes)
Distant recurrence	Treat as stage IV

Wide local excision is the backbone of melanoma management across all stages. The single most important number to know is the Breslow thickness, because it dictates both excision margins and whether SLNB is indicated. For the exam, if a question gives you a melanoma with Breslow 0.8 mm without ulceration (T1a), the answer is wide excision with 1 cm margins and observation. If Breslow is 1.2 mm, SLNB enters the picture.

5. Differential Diagnosis and Distractors

For Superficial Spreading Melanoma

Differential	Why It Is Similar	Key Discriminator
Atypical (dysplastic) nevus	Irregular borders, variable pigmentation	Nevi tend to be symmetric, have a more uniform color pattern, and lack dermoscopic features like blue-white veil or regression structures; stable over time
Seborrheic keratosis	Can be darkly pigmented, irregular surface	"Stuck-on" appearance, well-demarcated borders, comedo-like openings and milia-like cysts on dermoscopy
Basal cell carcinoma (pigmented)	Dark pigmented nodule	Pearly/translucent border, arborizing telangiectasia on dermoscopy, lacks true melanocytic dermoscopic features

For Nodular Melanoma

Differential	Why It Is Similar	Key Discriminator
Blue nevus	Blue-black color, dome-shaped	Stable, symmetric, uniform blue color; no recent growth or change
Pigmented Spitz nevus	Dome-shaped, pigmented nodule	Typically in children/young adults, symmetric starburst pattern on dermoscopy
Pyogenic granuloma	Rapidly growing nodule, may bleed	Bright red, vascular, homogeneous color; lacks melanocytic features
Merkel cell carcinoma	Rapidly growing nodule on sun-exposed skin	Flesh-colored/red-violet, firm, typically in elderly/immunosuppressed

For Lentigo Maligna / LMM

Differential	Why It Is Similar	Key Discriminator
Solar lentigo	Flat brown macule on sun-damaged face	Uniform tan-brown, well-defined borders, no color variation or asymmetry
Pigmented actinic keratosis	Pigmented macule on chronically sun-exposed skin	Rough/scaly surface, dermoscopy shows annular-granular pattern rather than melanocytic features
Flat seborrheic keratosis	Flat brown patch on face	Sharp demarcation, fingerprint-like pattern on dermoscopy

For Acral Lentiginous Melanoma

Differential	Why It Is Similar	Key Discriminator
Plantar wart (verruca plantaris)	Lesion on the sole	Warts interrupt skin lines, have thrombosed capillaries ("black dots"), are flesh-colored/keratotic rather than pigmented
Subungual hematoma	Dark discoloration under nail	Hematoma migrates distally with nail growth; positive for hemosiderin, no Hutchinson sign
Longitudinal melanonychia	Dark nail streak	Benign melanonychia is uniform, narrow, and stable; melanoma shows widening, Hutchinson sign (pigment extending to nail fold), and irregular color
Onychomycosis	Nail discoloration and dystrophy	Yellowish-white rather than brown-black, KOH positive, no pigmented nail fold involvement

For Desmoplastic Melanoma

Differential	Why It Is Similar	Key Discriminator
Scar tissue	Firm, fibrous, skin-colored	History of prior trauma/surgery at that site; no progressive growth
Dermatofibroma	Firm dermal nodule	Dimple sign on lateral compression, stable, well-circumscribed
Desmoplastic nevus	Firm, skin-colored papule	Smaller, symmetric, stable over time; lacks perineural invasion on histology

6. Traps and High-Yield Pearls

The most common way students get melanoma questions wrong is by fixating on skin color as a reason to dismiss melanoma. ALM is the predominant melanoma subtype in dark-skinned populations, and it occurs on palms, soles, and subungual areas, which are sites students often forget to consider. A vignette describing a dark-skinned patient with a changing pigmented lesion on the sole is testing whether you know that melanoma does not spare individuals with darker Fitzpatrick types.

Another frequent trap is confusing Breslow thickness with Clark level. Breslow thickness (measured in millimeters) is the primary prognostic factor and determines excision margins. Clark level (anatomic depth of invasion through skin layers) is older and no longer used in the current AJCC staging system. If a question stem provides both, use Breslow.

Students also stumble on the nodular melanoma presentation. Because NM lacks a prolonged radial growth phase, it can present as a rapidly growing, symmetric, uniformly dark nodule that does not fit the classic ABCDE criteria (no asymmetry, no border irregularity, no color variation). The vignette will describe a fast-growing, dome-shaped blue-black nodule. The "E" in ABCDE (Evolution) becomes the critical criterion here.

For management questions, the trap is ordering SLNB for melanoma in situ or T1a without additional risk factors. SLNB is recommended at Breslow >=1 mm. For thinner melanomas, it is only considered when additional risk factors are present (ulceration, high mitotic rate, lymphovascular invasion).

Finally, do not forget that LDH is a staging marker, not a diagnostic marker. It is checked in stage IV disease to classify the M category and to assess prognosis. S100B and LDH are for disease monitoring, not for making the initial diagnosis. The confirmatory diagnosis is always histopathology from an adequate excisional biopsy.

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