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Familial atypical multiple mole and melanoma (FAMMM)
syndrome: patients have a first- or second-degree relative
with malignant melanoma and typically have at least 50
melanocytic nevi. Mutations in CDKN2A/CDK4. Two or
more cases of melanoma in first-degree relatives may
indicate familial melanoma, autosomal-dominant
transference with variable penetrance.
Xeroderma pigmentosum (XP)
Heterogeneous group of syndromes, mutations in
various DNA repair genes.
UV-induced DNA damage leads to early death
secondary to metastasis.
Typically presents in childhood with multiple BCCs,
SCCs, and melanomas.
Restriction from sunlight exposure is mandatory, with
aggressive surveillance/treatment of skin lesions.
MELANOMA DISEASE BIOLOGY AND
CHARACTERISTICS
Precursor Lesions
Melanoma is caused by multiple processes leading to
malignant transformation of melanocytes.
Congenital melanocytic nevi
Malignant potential correlates with size.
Giant congenital nevi (>40-60 cm): confer an ~6% risk
of melanoma; prophylactic excision (often serially) is
recommended.
Common acquired nevi
Arise in childhood, adolescence and slowly regress in
later years.
The greater the number of nevi, the greater the chance
of melanoma.
Dysplastic or atypical nevi
Often appear in puberty in sun-exposed areas.
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Thought to confer as high as 32× increased risk of
melanoma.
Melanoma in situ/atypical junctional melanocytic
hyperplasia (AJMH)/lentigo maligna
No penetration of atypical cells beyond epidermal
junction.
May arise within dysplastic nevi.
Full excision with 0.5-1.0 cm margins (see Table 7-3).
Genetic Mechanisms
p16/CDKN2A gene: tumor suppressor gene that is mutated
or deleted in the majority of melanoma cell lines; mutations
found in some familial melanomas.
CDK4 gene: cell cycle regulator–like CDKN2A; plays a role
in melanoma progression in a small proportion of familial
and sporadic melanomas.
MCR1: strong association with BRAF-mutant melanomas.
MIT4: missense mutation associated with melanoma and
renal cell cancer.
BAP1: AD mutation associated with mesothelioma,
melanoma, and renal cell carcinoma.
Classification of Melanoma Types
Superficial spreading melanoma
Most common type, ~60%-70% cases; affects both
genders equally.
Upper back in men and lower legs in women are most
common sites.
Irregular borders with color variegation; regression
commonly observed.
Radial growth phase early, vertical growth phase late.
Nodular melanoma
Second most common: ~15%-30% cases.
Most aggressive type; tend to be diagnosed at
advanced stage with poorer prognosis.
More common in men than in women; less clear
association with sunlight exposure.
Typically blue-black, can ulcerate and develop rapidly.
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Vertical growth phase is a hallmark feature; no radial
growth.
Lentigo maligna melanoma (LMM)
Approximately 10% of cutaneous melanomas.
Least aggressive type; ~5% progress to invasive
melanoma.
Most clearly associated with sunlight/UV exposure.
Head, neck, and arms of elderly (sun-exposed areas).
Usually >3 cm in diameter; irregular, asymmetric with
color variegation.
Melanoma precursor lesion is lentigo maligna
(histologically equivalent to melanoma in situ, or
AJMH): radial growth phase only. Transition to vertical
growth phase marks development of LMM.
Acral lentiginous melanoma
Around 2%-8% of melanomas in Caucasians,
35%-60% of melanomas in African-Americans,
Hispanics, and Asians.
*Presents in palms, soles, and beneath nail plate
(subungual); most common site is great toe or
thumb.
Must distinguish from melanonychia, a benign, linear,
pigmented streak in the nail, common in African and
Asian populations. Due to the risk of melanoma, biopsy
of suspect lesions should be performed.
Irregular pigmentation, large size (>3 cm) common.
Long radial growth phase, transition to vertical growth
phase occurs with high risk of metastasis.
Noncutaneous Melanoma
Mucosal melanoma
Mucosal melanomas represent ~1% of melanomas,
most commonly presenting within the genital tract,
anorectal region, and head and neck mucosal
surfaces.
Difficult to detect; typically advanced at the time of
diagnosis with poor prognosis.
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Excision is best for prognosis, but difficult given
anatomy and growth patterns.
Ocular melanoma (choroid ≫ ciliary body > iris)
Represent ~5% of melanomas (most commonly
noncutaneous melanoma).
Interference with vision leads to earlier diagnosis.
Melanomas of iris are like cutaneous melanomas in
genetics/behavior; melanomas of the posterior uvea
act more like mucosal melanomas and have a worse
prognosis.
The eye has no lymphatic drainage; therefore, no nodal
metastasis is seen.
The liver is the main site of metastatic disease.
Treatment is by resection, radiation therapy, and
enucleation.
Melanoma With an Unknown Primary
Represent 3% of melanomas; diagnosis of exclusion.
Nodal metastases are the most common presentation.
Prognosis similar to metastatic melanomas with a known
primary.
DIAGNOSIS AND STAGING OF
MELANOMA
Physical examination is 75%-90% sensitive for diagnosing
melanoma. Serial photograph monitoring and use of
dermoscopy significantly enhance diagnostic sensitivity.
Common clinical features of melanoma lesions (ABCDE)
Asymmetry
Border irregularity
Color variation
Diameter >5 mm
Enlarging/evolving lesion
Diagnosis of primary melanoma is made by histologic
analysis of full-thickness biopsy specimens.
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Full-thickness excisional biopsy is preferred for lesions
<1.5 cm in diameter. If possible, excise lesion with 1- to 3mm margins. Partial thickness acceptable for face or acral
sites.
Avoid shave biopsies, since they forfeit the ability to stage
the lesion based on thickness.
Incisional biopsy is controversial; excisional biopsy
preferred.
Permanent sectioning is used to determine tumor
thickness (Breslow depth).
Do not cauterize or freeze the specimen: tissue
destruction makes it impossible to evaluate thickness and
margins.
Wide local excision for tissue diagnosis can disrupt and
decrease efficacy of future lymphatic mapping. Biopsy
scars should be parallel to lymphatic drainage.
Orientation of biopsy incisions should also consider
definitive surgical therapy.
Longitudinal biopsies on extremities; transverse over
joints to prevent contractures.
Place head and neck incisions along relaxed skin
tension lines, keeping facial aesthetic units in mind.
Major Prognostic Factors: T umor thickness, Nodal status,
and Metastases—TNM
*Breslow depth (mm) is a more accurate and better
prognostic indicator than Clark level (invasion through
histologic skin layers) (see Table 7-2).
TABLE 7-2 Melanoma Thickness Grading
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Other Significant Prognostic Factors
Anatomic location: trunk, head, and neck lesions
generally carry worse prognosis than those on the
extremities.
Sex: for a given melanoma, women generally have a better
prognosis if localized.
Ulceration and increased mitotic rate are poor prognostic
signs.
Lymph node involvement or in-transit metastases are
more significant than any other prognostic factors; for stage
IV disease, visceral distant metastases have poorer
prognosis.
The American Joint Committee on Cancer has developed a
staging system based on TNM classification.
MELANOMA TREATMENT
Definitive Management of Melanoma
Wide local excision is the treatment of choice.
Recommended surgical margins depend on tumor
thickness (Table 7-3).
TABLE 7-3 Recommended Surgical Margins for
Melanoma Excision
Subungual melanoma requires amputation proximal to the
DIPJ for fingers and proximal to IP joint for the thumb.
Management of Regional Lymph Nodes
Elective lymph node dissection (ELND) involves removal
of clinically negative lymph nodes from the nodal basin. No
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prospective survival benefit seen except for a subgroup with
1- to 2-mm (intermediate thickness) melanomas.
Sentinel lymph node biopsy (SLNB)
SLN hypothesis: tumor cells migrate to first node
receiving lymphatic drainage from primary tumor; thus,
excision of the sentinel node alone is adequate for
nodal status.
Sentinel node(s) can be detected in >90%-95% of
patients. SLNB is widely considered the standard of
care. Dependent on Breslow thickness, ulceration, and
presence of satellites (Table 7-4).
TABLE 7-4 Indication for Sentinel Lymph Node
Biopsy for Melanoma
SLNB is performed in conjunction with WLE of the
primary tumor. Lymphatic mapping is performed to
determine the first lymph node that drains the primary
tumor site (sentinel node).
On the day of or prior to surgery, preoperative nuclear
imaging is performed with radiolabeled sulfur colloid
solution (technetium-99) injected intradermally at the
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primary tumor. Lymphoscintigraphic imaging localizes
the sentinel node basin(s) (some tumor sites can drain
to multiple basins).
In the operating room, a lymphangiography dye (eg,
methylene blue) can be injected intradermally at
periphery of primary tumor site prior to excision.
Mark edges of the lesion before injection to avoid
obscuration with dye.
Potential sentinel nodes will appear blue when
exploring the nodal basin, giving secondary
confirmation to localization of 99Tc with gamma
detection probe.
Dye injection may briefly interfere with pulse-
oximeter readings; alert anesthesiologist at the
time of injection.
Caution: risk of allergy or anaphylaxis with dye
injection.
Following primary tumor excision, drapes, instruments,
gowns, and gloves are changed and regional lymph
nodes identified by lymphoscintigraphy are explored.
Nodes demonstrating maximal counts with gamma
detection probe are excised.
Histologic analysis of sentinel node with
immunohistochemical staining identifies
micrometastases. Permanent sections are required;
frozen sections cannot reliably differentiate normal
from neoplastic melanocytes.
Surveillance and Treatment of Melanoma Recurrence
Asymptomatic patients should be seen every 3-6 months
with clinical lymph node exam (depending on pathological
stage) for 2 years, then annually. All patients should be
educated on and should receive thorough review of
symptoms.
Imaging surveillance: CT of chest, abdomen, and pelvis
considered for stage IIB and higher and regional nodal US
every 4 months for positive SLNB without CLND; CLND
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does not offer survival benefit (MLST-2 trial). PET-CT for intransit/satellite metastases.
Local recurrence: defined as regrowth within 2 cm of
surgical scar; incidence 3%-5%; usually due to incomplete
excision of primary or hematogenous dissemination.
Resection is treatment of choice. Offered imaging,
lymphatic mapping, and SLNB. Aggressive therapy
warranted as local recurrences can indicate disseminated
disease.
In-transit metastases: >2 cm from primary but not beyond
regional nodal basin, presumed due to lymphatic spread.
Imaging, SLNB, and systemic therapy typically warranted.
Resection considered for limited disease.
Radiation therapy: can treat portions of unresectable
metastases to brain or bone.
Cytokine therapy: interferon-α (IFN-α) and interleukin-2
(IL-2) produce tumor response, albeit transient. Little or no
improvement in overall survival.
Immunotherapies: checkpoint inhibitors (nivolumab,
pembrolizumab, ipilimumab) have largely replaced cytokine
therapy and prolong life in nearly half of all patients.
Targeted therapy: melanomas that harbor BRAF mutations
treated with BRAF inhibitors (dabrafenib, encorafenib,
vemurafenib) or MEK inhibitors (trametinib, cobimetinib,
binimetinib) or in combination and extend overall survival.
Chemotherapy: less effective than immunotherapy or
targeted therapy, not used as initial treatment in advanced
disease. Dacarbazine (DTIC), carmustine, cisplatin, and
tamoxifen in combination are most frequently used.
LESS COMMON SKIN CANCERS
Merkel Cell Carcinoma (MCC)
Rare, malignant neuroendocrine tumor arises from cells of
neural crest origin in dermis.
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Incidence increasing; 2000 cases per year in the United
States; 70% survival at 5 years.
Risk factors include median age 75-80; UV exposure; fair
skin; immunosuppression.
Merkel cell polyomavirus implicated in 80% of MCC cases;
positive prognostic factor.
Pink to red-brown, firm, subcutaneous nodule; 50% involve
the head and neck.
Has very aggressive, radial spread, high local recurrence,
regional, and systemic metastasis.
Treatment: WLE with up to 3 cm margins; SLN biopsy with
dissection in select patients.
Advanced disease: adjuvant radiation, avelumab (PD-L1
inhibitor) and pembrolizumab (PD-1 inhibitor) are both FDA
approved.
Microcystic Adnexal Carcinoma
Slow-growing firm, flesh-colored to yellow nodule primarily
on the head and neck.
Pathophysiology debated; favor dual follicular and eccrine
differentiation.
Tumor is invasive and locally destructive; treat with Mohs or
standard excision.
Sebaceous Gland Carcinoma
Malignant tumor derived from adnexal epithelium of
sebaceous glands.
Most are periocular; sebaceous gland carcinomas
elsewhere are rare.
Yellowish to pink, slowly growing papulonodule on eyelid
(resembles chalazion).
SOFT TISSUE SARCOMAS
EPIDEMIOLOGY
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