Melanoma

History

• Described as early as Hippocrates
• Described as 'cancer noire' in the writings of René Laennec

Epidemiology

• Causes the majority of skin cancer-related deaths
• Australia has the highest incidence in the world

Risk factors

• UV exposure
  • Intermittent and intense - especially blistering sunburn
  • Chronic sun exposure is not as much of a risk
  • Especially UVA radiation (penetrates deeper than UVB, and is commonly used in tanning beds)
• Skin type - lighter skin is higher risk (Fitzpatrick types I and II)
  • Fair complexion
  • Blonde or red hair
  • Blue eyes
  • Sunburn easily
  • Tendency to freckle
  • Inability to tan
• Personal or family hx melanoma
• Xeroderma pigmentosum
• Multiple clinically atypical moles/dysplastic nevi/melanocytic nevi/giant congenital nevi
• Immunosuppression

Pathophysiology

Precursor lesions

• • 60% de novo, 40% from a pre-existing lesion
  • Melanoma-in-situ
    • Does not invade through the basement membrane
    • Significant likelihood of progression to invasive melanoma
  • Can arise from dysplastic naevi, congenital naevi, and Spitz naevi
    • Dysplastic naevi
      • 6-15mm macular pigmented skin lesion with indistinct margins and variable colour
      • Difficult to actually distinguish between a naevus with and with dysplasia though (clinically), so require close monitoring regardless
      • Will be described as having mild, moderate or severe dysplasia on histology
        • Mild - closely observe
        • Moderate or severe - excise with negative margins (not WLE)
    • Congenital naevi
      • Risk of melanoma proportional to the size and number of naevi
      • Giant (>20cm) although very rare, should generally be excised
      • Others represent lower risk and don't need to be closely observed unless they change in appearance
    • Spitzoid melanocytic lesions
      • Represents a spectrum from Spitz naevus (benign) to melanoma with spitzoid features
      • Spitz naevus - rapidly-growing, pink or brown, benign skin lesion with little or no risk for further progression to melanoma. Most common in children. When seen in adults, higher risk for melanoma with spitzoid features.
      • Spitz naevus can be completely excised with negative margins, but may need WLE if there is thought to be risk of melanoma

Histological subtypes

• • Lentigo maligna (Hutchinson melanotic freckle)
    • Can transform into lentigo maligna melanoma
    • Most common on sun-exposed skin of older patients
    • Flat, dark, variably pigmented lesion; irregular borders; slow development
    • Can become quite large prior to diagnosis
    • Better prognosis than other subtypes, but can be hard to excise due to location
    • Histologic extent can be well beyond the clinical borders - best to ensure negative margins prior to complex flap reconstruction
  • Superficial spreading
    • Most common
    • Not necessarily associated with sun-exposed skin
    • Most commonly seen on trunk and proximal extremities
    • Flat pigmented lesion growing radially; asymmetric; irregular borders
    • Will develop a vertical growth phase if untreated
    • Can ulcerate
  • Acral lentiginous
    • Classified by anatomic site of origin - arises in subungual areas beneath fingernails and toenails, and on palms and soles
    • Most common type in non-white patients
    • Often mistaken for subungual haematomas (however does not change in position underneath the nail, whereas haematomas move distally with nail growth)
    • Biopsy either by removing the nail or doing a punch biopsy through the nail itself
  • Nodular
    • Raised papular lesions
    • Can occur anywhere on the body
    • Tend to develop a vertical growth pattern early in their course
    • Poorer prognosis due to thicker tumour at diagnosis
  • Desmoplastic
    • Combination of melanoma cells with prominent stromal fibrosis
    • Often amelanotic
    • Classified as either pure or mixed, depending on the degree of desmoplasis present
    • Greater propensity for local recurrence, and often exhibit neurotropism
    • Pure desmoplastic - low risk of lymph node metastasis - often forego SLNB
    • Mixed - similar rate compared to subtypes

Depth assessment

• • Clark level - extent of invasion into the anatomic levels of the skin
  • Breslow thickness - distance from the top of the granular layer to the lowest tumour cell - more accurately predicts prognosis
    • Thin <1mm
    • Intermediate 1-4mm
    • Thick >4mm
  • Ulceration is defined histologically as the absence of an intact epithelium over the melanoma; portends worse prognosis

Familial syndromes

• • Variously called dysplastic naevus syndrome, familial atypical multiple mole-melanoma syndrome, and B-K mole syndrome
  • Patients with melanoma in one or more first or second degree relatives and large numbers of melanocytic naevi (often >100)
  • Can also be prone to pancreatic cancer

Pathogenesis

• • Genotypic
    • The highest mutational burden of any malignancy studied in humans
    • Mutations generally exert effects via MAPK signalling pathway, which modulates gene expression in the nucleus. Alterations can result in unchecked cellular growth.
      • BRAF and RAS are gain-of-function mutations, while NF1 is loss of inhibition
    • Other affected pathway is the PI3/AKT pathway, which can potentially be altered in all four genomic subtypes
  • Cellular
    • Proliferates in the basal layer of the skin
    • Radial growth phase: expands radially in the epidermis and superficial dermal layer
    • Vertical growth phase: invasion into deeper layers of the skin, and the skin lesion may become palpable. May ultimately develop metastatic potential by invasion of blood vessels and lymphatic channels.

Genotypic subtypes

• • Mutant BRAF (50%)
    • Tend to be younger patients
    • V600 mutation in BRAF gene, which activates the mitogen-activated protein kinase (MAPK) pathway, resulting in oncogenesis
  • Mutant RAS (30%)
  • Mutant NF1 (15%)
    • Typically older patients
  • Triple-wild-type (5%)

Pathology report

• • Macroscopic
    • Dimensions
    • Description
    • Orientation
    • Lesion dimensions
    • Other lesions?
  • Essential:
    • Diagnosis
    • Breslow thickness
    • Ulceration
    • Mitoses per mm squared
    • Microscopic satellites
    • Vascular invasion
    • Surgical margins - invasive, in-situ, deep
  • Other:
    • Clark level
    • Growth phase (radial or vertical)
    • Regression - present or absent
    • Tumour-infiltrating lymphocytes - present (brisk or non-brisk) or absent
    • Histologic/morphologic type
    • Desmoplastic melanoma
    • Neurotropism (infiltration along nerve sheaths, associated with higher local recurrence, common in desmoplastic melanoma)

Clinical evaluation

• Most common presentation is an irregular pigmented skin lesion that has grown or changed over time
• ABCDE criteria
  • Asymmetry
  • Border irregularity
  • Colour variegation
  • Diameter >6mm
  • Evolution
• Other concerning signs:
  • New pigmented lesion >40yo
  • Pigmented lesion out of character with patient's mole pattern
  • Lesion that becomes itchy or bleeds with minor injury
• Regional disease
  • Only 10% present with regional disease and 5% with metastatic
  • Check for in-transit disease
  • Ask about masses, neurologic symptoms, headaches, anorexia, weight loss, bone pain, respiratory symptoms
• Amelanotic melanoma
  • Raised pink or flesh-coloured skin lesion
  • Need a low threshold for biopsy - very hard to identify
  • Three R's: red, raised, recent change

Biopsy

• Suspicious pigmented lesions should be excised with a technique that allows full thickness pathologic assessment
  • 1-2mm margins are ok in difficult areas
  • Punch biopsies or incisional biopsies are only ok with very small lesions or for broader lesions where it is necessary to establish a diagnosis before excision
    • Biopsy from darkest, most raised or otherwise most suspicious aspect
    • Use at least 4mm punch biopsy
  • Traditionally, avoid shave biopsies
    • However frequently used by dermatologists

Staging

• Prior to pathological lymph node assessment:
  • T1a cN0: WLE without SLNB and no staging imaging
  • T4b cN0: CT CAP prior to WLE + SLNB
  • cN1: USS +/- FNA
    • If confirmed regional melanoma, PET/CT and MRI brain
    • If negative FNA, stage nodes with SLNB according to guidelines below
  • In-transit/satellite metastases: PET/CT and MRI brain
• After pathological assessment of lymph nodes:
  • IIB or IIIA: CT CAP
  • IIC or IIIB: CT CAP and PET. MRIB for symptoms.
  • IIIC or IIID; CT CAP, PET and MRIB
  • IV: CT CAP, PET, MRIB, LDH
• Calculators such as www.melanomaprognosis.org and www.melanomacalculator.com can provide additional prognostic information

AJCC 8th edition melanoma TNM definitions

Primary tumor (T)
T category	Thickness	Ulceration status
TX: Primary tumor thickness cannot be assessed (eg, diagnosis by curettage)	Not applicable	Not applicable
T0: No evidence of primary tumor (eg, unknown primary or completely regressed melanoma)	Not applicable	Not applicable
Tis (melanoma in situ)	Not applicable	Not applicable
T1	≤1.0 mm	Unknown or unspecified
T1a	<0.8 mm	Without ulceration
T1b	<0.8 mm	With ulceration
	0.8 to 1 mm	With or without ulceration
T2	>1 to 2 mm	Unknown or unspecified
T2a	>1 to 2 mm	Without ulceration
T2b	>1 to 2 mm	With ulceration
T3	>2 to 4 mm	Unknown or unspecified
T3a	>2 to 4 mm	Without ulceration
T3b	>2 to 4 mm	With ulceration
T4	>4 mm	Unknown or unspecified
T4a	>4 mm	Without ulceration
T4b	>4 mm	With ulceration
Regional lymph nodes (N)
N category	Extent of regional lymph node and/or lymphatic metastasis
	Number of tumor-involved regional lymph nodes	Presence of in-transit, satellite, and/or microsatellite metastases
NX	Regional nodes not assessed (eg, SLN biopsy not performed, regional nodes previously removed for another reason). Exception: Pathological N category is not required for T1 melanomas, use cN.	No
N0	No regional metastases detected	No
N1	One tumor-involved node or in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes
N1a	One clinically occult (ie, detected by SLN biopsy)	No
N1b	One clinically detected	No
N1c	No regional lymph node disease	Yes'
N2	Two or three tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with one tumor-involved node
N2a	Two or three clinically occult (ie, detected by SLN biopsy)	No
N2b	Two or three, at least one of which was clinically detected	No
N2c	One clinically occult or clinically detected	Yes
N3	Four or more tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with two or more tumor-involved nodes, or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases
N3a	Four or more clinically occult (ie, detected by SLN biopsy)	No
N3b	Four or more, at least one of which was clinically detected, or presence of any number of matted nodes	No
N3c	Two or more clinically occult or clinically detected and/or presence of any number of matted nodes	Yes
Distant metastasis (M)
M category	M criteria
	Anatomic site	LDH level
M0	No evidence of distant metastasis	Not applicable
M1	Evidence of distant metastasis	See below
M1a	Distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph node	Not recorded or unspecified
M1a(0)		Not elevated
M1a(1)		Elevated
M1b	Distant metastasis to lung with or without M1a sites of disease	Not recorded or unspecified
M1b(0)		Not elevated
M1b(1)		Elevated
M1c	Distant metastasis to non-CNS visceral sites with or without M1a or M1b sites of disease	Not recorded or unspecified
M1c(0)		Not elevated
M1c(1)		Elevated
M1d	Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease	Not recorded or unspecified
M1d(0)		Normal
M1d(1)		Elevated

Suffixes for M category: (0) LDH not elevated, (1) LDH elevated. No suffix is used if LDH is not recorded or is unspecified.

Clinical (cTNM)
Clinical staging includes microstaging of the primary melanoma and clinical/radiologic/biopsy evaluation for metastases. By convention, clinical staging should be used after biopsy of the primary melanoma, with clinical assessment for regional and distant metastases. Note that pathological assessment of the primary melanoma is used for both clinical and pathological classification. Diagnostic biopsies to evaluate possible regional and/or distant metastasis also are included. Note there is only one stage group for clinical Stage III melanoma.
When T is...	And N is...	And M is...	Then the clinical stage group is...
Tis	N0	M0	0
T1a	N0	M0	IA
T1b	N0	M0	IB
T2a	N0	M0	IB
T2b	N0	M0	IIA
T3a	N0	M0	IIA
T3b	N0	M0	IIB
T4a	N0	M0	IIB
T4b	N0	M0	IIC
Any T, Tis	≥N1	M0	III
Any T	Any N	M1	IV
Pathological (pTNM)
Pathological staging includes microstaging of the primary melanoma, including any additional staging information from the wide-­excision (surgical) specimen that constitutes primary tumor surgical treatment and pathological information about the regional lymph nodes after SLN biopsy or therapeutic lymph node dissection for clinically evident regional lymph node disease.
When T is...	And N is...	And M is...	Then the pathological stage group is...
Tis	N0	M0	0
T1a	N0	M0	IA
T1b	N0	M0	IA
T2a	N0	M0	IB
T2b	N0	M0	IIA
T3a	N0	M0	IIA
T3b	N0	M0	IIB
T4a	N0	M0	IIB
T4b	N0	M0	IIC
T0	N1b, N1c	M0	IIIB
T0	N2b, N2c, N3b, or N3c	M0	IIIC
T1a/b-T2a	N1a or N2a	M0	IIIA
T1a/b-T2a	N1b/c or N2b	M0	IIIB
T2b/T3a	N1a-N2b	M0	IIIB
T1a-T3a	N2c or N3a/b/c	M0	IIIC
T3b/T4a	Any N ≥N1	M0	IIIC
T4b	N1a-N2c	M0	IIIC
T4b	N3a/b/c	M0	IIID
Any T, Tis	Any N	M1	IV

Local excision:

• Melanoma in-situ should have 5-10mm margins
  • If non-lentigo maligna type, can have 5mm (although 10mm margins gives a better chance of achieving negative margins)
  • If lentigo maligna, may require wider
  • Down to subcutaneous tissue
• pT1 (<=1mm): 1cm
• PT2 (1.01mm - 2mm): 1-2cm (2cm recommended unless unfeasible)
• pT3 (2.01mm - 4mm): 2cm
• pT4 (>4mm): 2cm
• Should go down to, but not including, deep fascia
  • On sole of foot - down to plantar fascia, and will require coverage with skin graft or distant flap
  • Muscular fascia can be taken with thick primary tumours or limited subcutaneous tissue
• Subungual melanomas
  • Amputation of distal digit - generally at DIP joint in fingers
• Mohs micrographic surgery is not considered oncologically acceptable for melanoma in most cases

Re-excisions for margins

• Note that these recommendations refer to measured margin at OT, not the margins later measured in the lab. The specimen shrinks by about 20% in formalin. Extrapolating from UTD, it is reasonable to offer re-excision up to the recommended margins, once the 20% has been added back in, but this should be done on a case-by-case basis.
• Re-excise widely and down to fascia

Primary in transit disease

• Tumour deposits between dermis or subcutaneous tissue between the primary site (>2cm from primary) and nodal basin
• Means stage III disease: need systemic staging
• WLE may suffice for low-volume disease, otherwise needs systemic therapy
• Consider SLNB

Isolated limb infusion/perfusion

• Delivering a high dose of chemotherapy to the limb only
• Indications - locally advanced, multiple satellite or in-transit mets, invasion into non-resectable structures
• Isolated limb perfusion
  • Expose either the femoral or axillary artery and vein
  • Clamp those and connect to an extracorporeal circuit, which adds oxygen and maintains flow
  • Infuse a cytotoxic drug at high dose for 60-90 minutes
  • Flush out limb with saline and remove cannulas
  • 1% amputation rate
• Isolated limb infusion
  • Radiologically-placed percutaneous catheters into vessels
  • Low-flow circuit generates hypoxia and acidosis
  • High-dose chemotherapy for 30 minutes
  • Similar response rate to ILP but easier

Managing the nodal basin (therapeutic dissection, SLNB, and completion dissection)

• If macroscopic nodal disease, confirm with FNA and stage with PET-CT and CT brain, CAP
• Therapeutic nodal dissection
  • Indication: clinically-apparent nodal metastases which are subsequently confirmed on FNA
  • Can be up-front or as salvage after SLNB/adjuvant therapy
  • Remove all the fibrofatty and lymphatic tissue in the involved regional nodal basin, according to standard anatomic boundaries
  • Locations
    • Axillary - levels I, II and III
    • Inguinal: superficial inguinal nodes, +/- pelvic nodes (internal iliac, external iliac and obturator nodes)
      • Indications for pelvic nodes: palpable deep nodal disease; imaging suggestive of pelvic nodal disease; metastasis to Cloquet node; gross involvement of multiple femoral nodes
    • Cervical nodes: functional neck dissection with sparing of IJV and spinal accessory nerve
• SLNB done when risk of having positive nodes is >5% and patients want it (may not be necessary with low life expectancy or comorbidities)
  • Indicated for melanoma >1mm thickness, and for high-risk patients with melanoma >0.75mm thick (ulceration/mitotic rate >= 1 mitosis/mm²). Can also be considered in younger patients (higher risk of nodal disease and low-risk GA and surgery) and thickness 0.8-1mm.
    • Helps with staging
    • Guide systemic management
    • Perform at time of primary wide excision
  • Controversial as to whether it is necessary in T4 disease, but Sabiston says should still do it
  • If SNB is positive, still probably doesn't need complete lymph node dissection. Can probably use close surveillance and ultrasound for 5 years, if they seem reliable.
    • USS every 4 months for first 2 years, then 6 months for years 3-5
    • Biopsy any suspicious nodes identified. If cross-sectional imaging excludes other metastatic disease, then they should have a therapeutic dissection at that point.
  • SLNB technique
    • Inject dye into the dermis at four points 0.5mm from the lesion (best to inject within margins of planned WLE)
    • Check for epitrochlear or popliteal nodes, in distal extremity lesions
    • All identified sentinel nodes should be removed
• Completion lymphadenectomy
  • The procedure to remove the remaining lymph nodes in a regional basin after a positive SLNB
  • Only offer when there is a high degree of concern for non-SLN metastases or inability to follow surveillance. The basis for this is two recent studies (DeCOG-SLT and MSLT-II) which showed not much difference between observation and dissection in terms of overall survival.
    • MSLT-I compared SLNB with observation of cN0 melanomas, and found that SLNB provided prognostic value and improved disease-free survival
    • MSLT-II randomised patients with positive SLNB to either immediate clearance or observation, and found no benefit to immediate clearance
  • Potential advantage: allows identification of non-sentinel metastases (important prognostically); may improve disease-free survival by removing micrometastatic disease (although only 15-20% of patients actually have this)
  • The maximum diameter of the largest tumour deposit in sentinel node is the best prognostic factor for micrometastatic disease

Neoadjuvant therapy

• Probably recommended for those with clinically identified locoregional disease

Adjuvant therapy

• Indications
  • Stage I or IIA: surveillance
  • Stage IIB and IIC (high-risk node negative): adjuvant immunotherapy, but surveillance or clinical trial are reasonable alternatives, especially for low-risk IIB disease
  • Stage IIIA (low-risk node positive):
    • Surveillance with non-ulcerated primary <=2mm thick, and SLNB with <1mm of tumour
    • Immunotherapy for all others
  • Stage IIIB, IIIC or IIID (high-risk node positive disease): immunotherapy, which probably should be as neoadjuvant therapy rather than adjuvant therapy based on the degree of response; but if no neoadjuvant was given, give adjuvant
  • Stage IV: adjuvant immunotherapy with nivolumab + ipilimumab, followed by maintenance nivolumab to complete one year of therapy
• Systemic options
  • Immunotherapy
    • Checkpoint immunotherapy - PD-1 (programmed call death 1) inhibitors - pembrolizumab, nivolumab
    • Cytotoxic T lymphocyte-associated antigen 4 - ipilimumab
    • Nivolumab + ipilimumab is the most common combination, and can be given for BRAF mutant or wild type melanoma
    • Associated with immune-related adverse effects - general immunological enhancement:
      • Systemic - fatigue, cytokine release syndrome
      • Dermatologic
      • Diarrhoea/colitis
      • Hepatoxocity
      • Pneumonitis
      • Endocrine - thyroiditis, hypophysis, , T1DM
      • Opportunistic infections
  • Targeted therapy
    • BRAF mutants can be targeted with dual BRAF + MEK inhibition - dabrafenib + trametinib or others, which has reduced resistance than BRAF inhibition alone
    • KIT mutants can be targeted with imatinib
  • Cytotoxic chemotherapy
    • Limited to patients that have progressed on other treatments
    • Only 20% respond, and that response is usually only 6 months
  • Radiotherapy
    • Historically thought be radiation-resistant
    • May be useful as palliative treatment and as an adjunct to systemic immunotherapy
    • Useful for brain metastases
• Approach
  • Usually start off with combination nivolumab and ipilimumab
  • BRAF mutants who are not eligible for immunotherapy should have dabrafenib + trametinib

Stage IV disease

• Surgery in stage IV
  • Can be appropriate for palliation of symptoms
  • E.g. resection of bowel mets causing subacute obstruction or bleeding
  • Resection of even brain mets can be considered, if there is otherwise a good response to therapy
• Systemic therapy
  • Nivolumab + ipilimumab

Unusual situations

• Unknown primary melanoma
  • Thorough skin examination - perianal, external genitalia, external auditory canal, scalp, nailbeds
  • Endoscopic evaluation of oral cavity and nasopharynx and anus and rectum
  • Pelvic examination in women
  • Opthalmology
  • PET/CT and MRI brain
  • It is also possible to have previous melanoma that regressed
  • Equivalent or maybe even better survival compared with matched patients with known primary??? (?stronger immune response that resulted in regression of primary)
• Melanoma and pregnancy
  • Prognosis same as non-pregnant patients
  • No therapeutic benefit to early termination
  • Treat exactly the same, just don't use blue dye
  • Examine placenta for melanoma
  • Advise wait 2-3 years until risk of recurrence has settled before next pregnancy
• Ocular melanoma
  • Enucleation or iodine-125 brachytherapy
  • Metastatic spread occurs haematogenously, with metastases almost exclusively in the liver
• Mucosal melanoma
  • Oral cavity, oropharynx, nasopharynx, paranasal sinuses; anal canal, rectum, female genitalia
  • Excise to negative margins when possible
  • APR or exenteration does not improve overall survival

Surveillance

• Most recurrences are detected within the first 5 years after treatment, but recurrences can happen even decades later, from even small lesions
• IA: skin check and lymph node check every six months for two years, then annually
• IB/IIA: skin check and lymph node check every 4-6 months for two years, then annually
• IIB/IIIA: clinical exam every four months for two years, then six-monthly up to five years, then annually. CT chest/abdo/pelvis (and neck for head/neck cancers) every six months for three years, then annually up to five years, then mostly discontinue unless strong patient preference. Regional nodal USS for those with positive SLNB who did not undergo completion dissection.

Recurrence

• Local recurrence
  • Defined as recurrence within 5cm of WLE scar or skin graft
  • Aggressive tumour biology and poor prognosis

Breslow	Recurrence risk
<0.75	0.2%
0.75-1.5	2%
1.5-4	6%
>4	13%

• • Resect to histologically clear margins; aim for 1cm margins and complete resection of scar
  • SLNB technically feasible, and often useful information
• Recurrent in-transit disease
  • Intralesional and systemic therapy
• Regional node recurrence
  • After confirming absence of metastatic disease, perform a therapeutic dissection (above) and then adjuvant immunotherapy
  • Can also recognise that many of these patients will have systemic metastases too, and consider neoadjuvant immunotherapy followed by assessment of response and subsequent therapeutic dissection

Follow-up

• Lifelong surveillance - 8% risk of second melanoma
• Patients with positive nodes should continue to see oncologist
• Patients with low-risk disease can see dermatologist