The incidence of melanoma rose by an average of 2.9% each year between 1985 and 2009. In 2012, an estimated 76,250 men and women in the United States were diagnosed with invasive melanoma.¹ The lifetime risk for developing melanoma is estimated to be 1 in 36 for men and 1 in 55 for women. Melanoma is the fifth most common type of cancer in men and the sixth most common type of cancer in women. Mortality rates for melanoma have also increased, although at a slower rate than the increase in incidence. An estimated 9180 men and women will die of melanoma in the United States in 2012.

Risk Factors for Melanoma

Assessment of risk identifies people who may benefit from more aggressive education and surveillance strategies to prevent or detect early-stage melanoma. This section will review risk factors for melanoma, including demographic, environmental, phenotypic, and genetic risks.

Demographic Risk Factors

Age is a risk factor for melanoma; the incidence increases with age. The median age at diagnosis is 61 years, with the majority of cases diagnosed after age 45 years; however, up to 20% of cases are diagnosed in younger patients. The risk for melanoma is greatest in ethnic groups with lighter skin types, with the majority of melanomas in the United States diagnosed in non-Hispanic white patients. The lifetime risk for melanoma is higher in men than in women. The incidence of melanoma varies by age in the sexes. Before age 40 years, incidence rates are higher in women than in men; after age 40 years, rates are almost twice as high in men as in women.

Environmental Risk Factors—Ultraviolet Radiation/Sun Exposure

The majority of melanomas are associated with exposure to UVR, which is the major environmental factor contributing to melanoma risk. Both ultraviolet B (UVB) and ultraviolet A (UVA) radiation are carcinogenic and can induce melanoma. The role of sun and UVR in the development of melanoma is supported by several epidemiological studies demonstrating an increased incidence of melanoma in people who live close to the equator or at higher altitudes and in persons who report increased exposure to UVR. A prospective study has also confirmed the association between UVR exposure and increased melanoma risk.² The risk from UVR varies according to intensity (i.e., sunburn vs. no sunburn), frequency, and age at the time of exposure. Intermittent, intense UVR exposure and sunburns increase melanoma risk; this risk increases as the number of sunburns and intermittent intensive UVR exposures accumulate. Several studies emphasize the increased risk associated with UVR exposure during childhood, but melanoma risk also increases with increasing number of sunburns during all life periods, not just during childhood. The most common anatomic locations of melanoma for men (the trunk) and women (the legs) correspond to areas more commonly exposed to intermittent, intense UVR. Chronic UVR exposure also increases risk for melanoma; a history of chronic exposure (as opposed to intense intermittent exposure) is often noted for melanomas of the upper limbs, head, and neck. Exposure to artificial UVR also increases melanoma risk. Therapy with artificial UVR is used most commonly for the treatment of inflammatory disorders, such as psoriasis or atopic dermatitis. Therapy with oral 8-methoxypsoralen-UV-A increases the risk of melanoma. The recreational use of tanning beds, which emit mostly UVA radiation, is a more common source of exposure to artificial UVR and is a major public health problem.

Family History

A family history of melanoma increases one’s risk for melanoma. The risk for melanoma is 2.62 times greater when a parent has had a melanoma and is 2.94 times greater when a sibling has had a melanoma.⁵ These increased risks apply when first-degree family members have sporadic melanomas, which constitute 90% of all melanomas. Fewer than 10% of patients present with true familial melanomas. In families with autosomal dominantly inherited susceptibility mutations, melanomas develop at an early age and multiple primary melanomas develop; multiple cases of melanoma occur in several family members across different generations on one side of the family, and, in some cases, other associated cancers occur as well. Several genetic loci determine susceptibility to melanoma, with the most important of these being cyclin-dependent kinase 4 (CDK4) and the cyclin-dependent kinase inhibitor 2A gene (p16/CDKN2A), located on chromosome 9p21. The CDKN2A gene encodes two proteins, p16 and p14^ARF, which are cell-cycle inhibitors.⁶ Both proteins are potent tumor suppressors. Both CDNKN2A and CDK4 are highly penetrant susceptibility genes and result in the majority of familial melanomas. The CDKN2A mutation is present in up to 40% of families with three or more cases of melanoma, whereas CDK4 mutations are present in far fewer families. The risk of developing cutaneous melanoma in a person who is a CDKN2A mutation carrier is between 30% by age 5 years and 67% by age 80 years; this risk varies by geographic location and is higher is sunnier regions. The same risk factors that influence the incidence of melanoma in the general population (i.e., total nevus counts, presence of dysplastic nevi, and sunburn) also increase penetrance in CDKN2A mutation carriers. Up to 10% of patients with multiple primary melanomas have also been identified as having a CDKN2A mutation. Pancreatic cancer is also seen in melanoma-prone families with CDKN2A germline mutations.⁷ In contrast to CDKN2A and CDK4, which are high-penetrance melanoma predisposition genes, heritable mutations in the melanocortin-1 receptor (MC1R) gene have lower penetrance. MC1R mutation is commonly associated with a red hair phenotype, but it confers an increased risk of developing melanoma even in the absence of red hair.^3,8 Some familial melanoma occurs in the setting of the familial atypical multiple primary mole and melanoma syndrome, also called the dysplastic nevus syndrome.⁸ A family history of melanoma in multiple first-degree relatives and younger age at diagnosis are important features of this syndrome. Families who present with the familial atypical multiple primary mole and melanoma syndrome may also have CDKN2A mutations. Other heritable disorders that predispose patients to melanoma include xeroderma pigmentosum, a rare inherited disorder in which DNA repair mechanisms are compromised, resulting in an extremely high rate of skin cancers, including cutaneous and conjunctival melanomas, Li-Fraumeni syndrome, BRCA2, or familial retinoblastoma.

Genetic Testing

Genetic testing for CDKN2A is commercially available through several Clinical Laboratory Improvement Amendments–certified laboratories. However, the clinical utility of genetic testing for melanoma susceptibility is limited at this time. For patients thought to be at increased risk of having an inherited susceptibility to melanoma, genetic counseling with a qualified health care provider for education about the risks and benefits of genetic testing can be considered. Skin examinations by trained physicians/providers and patient education regarding skin self-examinations and melanoma risk-reducing behaviors (e.g., use of sunscreen, sun avoidance, and sun protection) remain the standard of care, even in high-risk families.

Etiology and Biological Characteristics

Melanoma arises from the transformation of melanocytes, which are of neural crest origin. Most melanocytes reside in the basal layer of the epidermis or within benign common nevi. Melanocytes synthesize melanin using the enzyme tyrosinase; under normal conditions, they help protect against UV damage. Melanoma induction by UVR is a multistep process involving both UVB and UVA; tumor progression is the consequence of multiple genetic events.

Genetic and Molecular Alterations

Several genetic and molecular alterations contribute to the development of melanoma, and the identification of molecular subgroups of melanoma has resulted in targeted therapies to improve patient outcomes. This section will describe the key pathways involved in melanoma pathogenesis.

CDNK2A

Cell-cycle regulatory proteins are required for the precise regulation of cell growth and division and therefore are critical targets in the malignant transformation of all cells. The observation of frequent deletions in the 9p21 locus in familial primary melanomas led to the identification of the CDNK2A tumor-suppressor gene in familial melanoma.9,10 The CDNK2A gene encodes an inhibitor of the cyclin-dependent kinases, CDK4 and CDK6, which leads to cell-cycle arrest at the G1 phase. If p16 is not expressed, CDK4/CDK6 may phosphorylate the retinoblastoma protein Rb and inactivate its tumor suppressor function. Expression of CDNK2A is silenced in sporadic melanomas via multiple mechanisms, including epigenetic inactivation through promoter methylation CDK4 amplification and cyclin D gene amplification. Loss of p16 expression is associated with disease progression and a poor prognosis.¹¹

RAS, RAF, and the Mitogen-Activated Protein Kinase Pathway

The mitogen-activated protein kinase (MAPK) signal transduction pathway, which is composed of RAS, BRAF, MEK (mitogen-activated protein kinase), and extracellular signal-regulated kinase (ERK) signaling, regulates cell growth, survival, and invasion. This pathway is aberrantly activated in many cancers. RAS, a membrane-bound guanosine triphosphatase, is frequently mutated in human cancer but has proven challenging to target therapeutically. RAS mutations are not common in melanoma; they are described in approximately 20% of melanomas and most often in NRAS.12,13 Somatic activating mutations of the serine/threonine kinase BRAF were first described in 59% of melanoma cell lines and in six of nine primary melanomas.¹⁴ The majority of BRAF mutations (80%) are V600E, located in exon 15 and characterized by a single amino acid substitution of valine for glutamic acid at codon 600 that renders the kinase constitutively active. A subsequent study of genome-wide alterations in DNA copy number and BRAF and NRAS mutational status in primary human melanomas demonstrated a correlation between genetic alterations and four unique melanoma subtypes based on anatomic site and UV exposure: mucosal melanoma, acral melanoma, and cutaneous melanomas with and without chronic sun-damaged (CSD) skin (defined by presence of solar elastosis). Approximately 80% of cutaneous melanomas on non-CSD skin (intense intermittent sun exposure) have mutations in either BRAF or NRAS (59% and 22%, respectively). BRAF mutations are less common in melanomas of CSD skin and rare in melanomas of mucosal, uveal, and other noncutaneous origin. V600K BRAF mutations constitute approximately 20% of V600 BRAF mutant melanomas.¹⁵ In addition to V600E and V600K mutations, less common BRAF mutations such as V600D or V600R, K601, and L597 have been reported. Germline mutations in BRAF have not been identified.

Phosphatidylinositol-3-Kinase

The phosphatidylinositol-3-kinase (PI3K) signaling pathway, which is activated by cell surface receptor tyrosine kinases or G-protein coupled receptors, including RAS, is important in cell growth, proliferation, motility, and survival and is frequently altered in cancers. Akt supports cell growth and survival via activation of the mammalian target of rapamycin (mTOR), as well as other activities. PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tumor suppressor that promotes cell cycle arrest and apoptosis and negatively regulates Akt and the PI3K pathway. In melanoma, the most common alterations of the PI3K pathway include NRAS mutations, functional loss of PTEN, and/or Akt overexpression. Alterations of PTEN that result in functional loss include allelic loss/deletion, mutations, and epigenetic silencing. Mutations in PIK3CA, AKT1, and AKT3 are rare. Increased phosphorylated-Akt overexpression, with or without PTEN loss, has been reported in brain metastases compared with extra–central nervous system (CNS) metastases.¹⁶

KIT

KIT (also known as CD117), a receptor tyrosine kinase, plays a critical role in melanocyte development, proliferation, differentiation, migration, and survival. KIT activation leads to activation of downstream targets, including the MAPK, PI3K, and signal transducer and activator of transcription (STAT) signaling pathways and microphthalmia-associated transcription factor (MITF). KIT alterations (mutations and/or copy number increases) have been identified in 28% of cutaneous CSD melanomas, 36% of acral melanomas, and 39% of mucosal melanomas. Of these alterations, activating mutations were present in 17% of cutaneous, 11% of acral, and 21% of mucosal melanomas. Of note, KIT abnormalities were not identified in any non-CSD cutaneous melanomas, which commonly possess NRAS/BRAF mutations.¹⁷

MITF

MITF, a member of the MiT transcription factor family, is required for normal melanocyte development and plays a role in cell cycle progression, motility, and survival. MITF also plays a major role in pigment production, where its expression is induced when alpha-MSH binds MC1R and, in turn, stimulates synthesis of melanin. MITF has been identified as an oncogene in melanoma with amplification demonstrated in melanoma cell lines, as well as in 10% to 20% of human cutaneous primary melanomas and melanoma metastases, but it is absent in benign nevi.¹⁸ Dysregulated MITF acts as an oncogene through altered target gene expression including CDK2, BCL2, MET, CDKN2A, HIF1alpha, and others. Given its interaction with HIF1alpha, the MITF gene has been sequenced in patients with both renal cell carcinoma and melanoma, with identification of a novel germline mutation, MITF E318K, which results in impaired SUMOylation (a posttranslation modification) of the MITF protein and altered target gene regulation.^19,20

Apoptotic Pathways

The process of apoptosis, or programmed cell death, is critical to cellular responses to stress and is a major pathway of cell death induced by radiation therapy and traditional chemotherapy. Melanoma cells can be resistant to therapies that have efficacy in other tumor types; this resistance is related, in part, to their ability to evade normal apoptotic signals. The two major apoptotic pathways are the extrinsic pathway, which is induced on activation of cell-membrane–associated death receptors by their associated ligands, and the intrinsic pathway, which is dependent on mitochondrial membrane permeability in response to cellular stress signals. Both pathways result in the activation of caspases that are critical effectors of apoptosis. Melanomas evade both intrinsic and extrinsic apoptotic pathways, which are critical determinants of tumor response to traditional cytotoxic therapies. The cytochrome c-associated factor Apaf-1 is downregulated in advanced melanomas and influences the death response of melanoma cells to cytotoxic agents.²¹ In addition, Fas and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) death receptors are downregulated by a variety of mechanisms, leading to impaired activation of the extrinsic apoptotic pathway. Therapeutic strategies aimed at circumventing impaired apoptotic pathways in melanoma are likely to require multiple interventions to ensure the continued activation of effective death pathways, given the variety of resistance mechanisms present in melanoma cells.

Prevention and Early Detection

Identification of people at high risk for melanoma introduces the possibility of reducing incidence and mortality through primary and secondary prevention. Primary prevention consists of protection from UV light. Secondary prevention consists of early detection and treatment of melanoma through regular self-skin examinations and clinical skin examinations by a trained health care practitioner.

Primary Prevention

UVR exposure is the only modifiable risk factor for melanoma. Protection from UVR is the primary strategy to decrease melanoma risk; optimal use of sunscreen and sun protection results in a decreased risk of melanoma.²² Protection from UVR can mitigate one’s risk for skin cancer, regardless of the age at which it is implemented. Standard recommendations to decrease UVR exposure include avoidance of the sun between the peak hours of 10 am to 4 pm, seeking shade whenever possible, covering the skin surface with sun-protective clothing including wide-brimmed hats, long-sleeved shirts, long pants, and sunglasses, and using broad-spectrum sunscreen with a sun protection factor (SPF) of 15 or greater to cover exposed skin surfaces. Regular application of SPF 15+ sunscreen in adults has been demonstrated to decrease melanoma risk in a randomized trial.²³ Appropriate type, timing, frequency, and amount of sunscreen applied are important factors in effective primary prevention. The United States Food and Drug Administration (FDA) has legislated regulations for over-the-counter sunscreens (http://www.fda.gov/forconsumers/consumerupdates/ucm258416.htm). Highlights of these new regulations are that sunscreen products that protect against both UVA and UVB radiation will be labeled “broad spectrum” and “SPF 15” (or higher) on the front label; sunscreen products that are not broad spectrum or that are broad spectrum with SPF values from 2 to14 will be labeled with a warning; and the front label must limit water resistance claims to either 40 minutes or 80 minutes, based on standard testing to determine how much time a user can expect to get the declared SPF level of protection while swimming or sweating. Sun-protective clothing guards the skin from UVR more effectively than sunscreen. As opposed to sunscreen, which is frequently applied unevenly and insufficiently, sun-protective clothing provides uniform and constant protection for the areas it covers. The UVR-protective properties of clothing vary according to the thickness, color, and type of fabric. Most regulatory agencies have adopted the UV protection factor as the standard of measurement of UV protection for clothing. Clothing can achieve a UV protection factor >500, which is vastly superior to sunscreen. Barriers to the implementation of sun protection behaviors include discomfort from sun-protective clothing, inconvenience of applying sunscreen, and denial of personal risk for skin cancer. Furthermore, studies indicate that tanning may be an addictive behavior. Recent legislation may help to decrease access of minors to indoor tanning salons; however, modifying exposure to natural UVR remains a challenge.

Secondary Prevention

Patients with early-stage disease have an excellent prognosis after complete excision of the melanoma. Strategies to improve detection of early-stage melanoma include regular self-skin examinations and skin examinations by a trained medical practitioner. Self-skin examination, defined as a careful and deliberate self-conducted examination of all areas of the skin for changes in spots or moles, may reduce mortality from melanoma but are performed by only a small percentage of patients ²⁴ and are not recommended for prevention in the general public. The majority of melanomas are detected by patients or their partners. Physician recommendation is one of the strongest determinants of self-skin examination and cancer screening. Health care practitioners may increase compliance by strongly recommending regular self-skin examination and by educating patients to examine their skin with confidence. Offering patients full-body photography can improve their ability to diagnose new and changing nevi during self-skin examination. Full-body photography can aid both patients and physicians by providing a fixed reference point to compare new or changing lesions. Although no strong evidence exists that skin cancer screening in the general population by primary care providers or self-examination reduces skin cancer morbidity and mortality, some evidence indicates that screening for melanoma with skin examinations by experienced physicians reduces melanoma mortality because experienced physicians are more likely to detect melanomas at an earlier stage than are patients. Regular screening skin examinations provide an opportunity for physicians to educate patients and their families about melanoma and to increase efforts aimed at primary prevention.

Pathology

Melanoma can arise in a preexisting nevus or de novo. It is likely that both the stepwise evolution of melanocytic nevi to melanoma and the de novo onset of melanoma from malignant conversion of epidermal melanocytes are mechanisms of tumorigenesis.

Melanoma Histopathology

The histopathologic diagnosis of melanoma relies heavily on the presence of specific alterations in growth patterns relative to those of benign nevi. Melanocytes are easily identified and differentiated from keratinocytes by the presence of halos that surround melanocytes on well-prepared routine hematoxylin and eosin–stained sections. In normal skin, the melanocytes are usually located in the basal layer of the epidermis, where the ratio of melanocytes to keratinocytes varies from approximately 1 : 4 in areas exposed to the sun to 1 : 30 in nonexposed areas. Benign nevi are characterized by the presence of nevus cells that are arranged in clusters or nests. Their nuclei are small, without prominent nucleoli or mitoses. Nevic melanocytes are arranged uniformly and predominantly as nests and occasional single units at the rete tips of the dermoepidermal junction and within the dermis. Nevus cells “mature” or diminish in size as they descend into the dermis. Significant alterations in these basic growth patterns are cause for concern, and when they occur, a diagnosis of melanoma must be considered. In contrast to nevi, and with few exceptions, melanomas are asymmetric and poorly circumscribed. Melanocytes, as nests and single units, may be present at all levels of the epidermis, a pattern known as Pagetoid spread. Dermal melanocytes do not “mature” evenly and are characterized by enlarged nuclei with prominent nucleoli. Melanoma in situ is defined as an irregular proliferation of uniformly atypical melanocytes confined to the epidermis. Invasive melanoma is defined as the presence of melanoma cells, at a minimum, within the papillary dermis.

Melanoma has been conceptualized as growing first in a radial growth phase with little risk of metastatic behavior. This phase is followed by the vertical growth phase with the capacity for metastasis.²⁵ Different clinical and histologic features are associated with these two phases. Histologically, the radial growth phase refers to a progressive intraepidermal proliferation of melanocytes in which they are largely confined to the epidermis and the superficial dermis, without forming a tumor in the dermis, and without having competence for metastasis. This radial growth phase precedes the vertical growth phase of melanoma in all subtypes except nodular melanoma, which lacks prominent radial growth. Approximately one third of melanomas arise in association with a preexisting nevus. Distinguishing between melanoma and a benign nevus can be challenging, particularly when attempting to distinguish special types of nevi such as a Spitz nevus, cellular blue nevus, combined nevus, or deep penetrating nevus from a melanoma, or when attempting to distinguish a nevus from a nevoid melanoma.²⁶ In these instances, the histologic differences may be subtle, and interpretation by an experienced dermatopathologist is necessary.

Clinical Manifestations, Patient Evaluation, and Staging

Clinical Presentation

The clinical presentation of melanoma includes the physical appearance of the pigmented lesion and the history of any change in shape, size, color, or surface. More than 70% of melanomas are associated with an increase in size and change in color of a pigmented lesion. Most patients report having had a preexisting mole at the site of the melanoma. Itching, burning, or pain in a pigmented lesion should increase suspicion, although melanomas are often not associated with local discomfort. Bleeding and ulceration are signs of advanced melanoma. Most melanomas are varying shades of brown, but they may also be black, blue, or pink. The “ABCDEs” for the recognition melanoma are Asymmetry, Border irregularity, Color variegation, Diameter greater than 6 mm, and Evolving characteristics. In patients with numerous pigmented lesions, practitioners can improve detection of melanomas by looking for the “ugly duckling,” that is, the nevus that deviates in size or color from the patient’s general pattern of nevi.²⁷ Full-body photography provides patients and practitioners with a fixed reference of the appearance of the patient’s skin and can facilitate the detection of new or changing lesions. Dermoscopy, which is widely available in dermatology practices, allows examination of skin lesions without obstruction from skin surface reflections. With appropriate training, dermoscopy improves the sensitivity and specificity of melanoma diagnosis among pigmented lesions.²⁸ Most recently, computerized devices that apply diagnostic algorithms to images of pigmented lesions have been used to improve clinical detection of melanomas.

Primary cutaneous melanoma has historically been classified into four subtypes on the basis of distinct clinical and histologic features. These subtypes include superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM), nodular melanoma (NM), and acral lentiginous melanoma (ALM) (Fig. 69-1). The classification excludes multiple subtypes of melanoma, such as desmoplastic melanoma (DM), mucosal melanoma, and uveal melanoma. Although histologic subtype does not directly correlate with clinical behavior, recent studies of genotype-phenotype correlation have demonstrated a higher prevalence of BRAF mutation in SSMs and a higher prevalence of KIT mutation in LMMs.

Superficial Spreading Melanoma

SSM is the most common histologic subtype among most groups of patients; in black patients, ALM is most common. SSM may occur on any area of the body, but it most commonly occurs on the trunk and proximal extremities of young to middle-aged adults. SSM is more commonly associated with intense, intermittent sun exposure. Clinically, the lesions are often asymmetric; have irregular or indistinct borders; display various shades of brown, black, pink or other colors; and are larger compared with other nevi on the patient’s skin. Patients frequently note a change in size or color. In its early stages, SSM is flat. As dermal invasion progresses, the lesion may first become raised and then ulcerate or bleed. SSM can be associated with BRAF mutation.

Lentigo Maligna/Lentigo Maligna Melanoma

Lentigo maligna (referring to in situ disease) and LMM (referring to disease with an invasive dermal component) occur most commonly on the chronically sun-exposed areas of the head and neck and dorsal extremities. This subtype occurs more commonly in elderly persons who have accumulated years of sun exposure. Clinically, the lesion presents as a poorly defined brown to black macule that may display variegated colors. Patients frequently notice a change in size or color. Early lesions are flat, and more advanced lesions may have a palpable component. The clinically sun-damaged skin correlates with the pathologic finding of solar elastosis. LMM can be associated with KIT mutation.

Nodular Melanoma

NM can occur anywhere on the body and often appears as a symmetrical nodule that may or may not have a dark color. NM often defies early detection because it more frequently lacks the striking color changes seen with other clinical-pathological subtypes. Consequently, NM constitutes a large portion of deeply invasive melanomas with a poor prognosis.

Acral Lentiginous Melanoma

ALM accounts for only 2% to 3% of all melanomas but is the most common subtype of melanoma in black patients and darker-skinned patient groups. ALM presents on the palms of the hands, soles of the feet, and nail units as a pigmented macule that can display variegated color and a palpable component in its more advanced stages. ALM does not result from UVR exposure. ALM is often detected at more advanced stages, resulting in a worse prognosis; public health efforts aimed at early detection may improve outcomes in susceptible individuals. ALM, like LMM, can also be associated with KIT mutation.

Desmoplastic Melanoma

DM accounts for approximately 1% of all cases of melanoma. DM clinically presents as a firm papule, nodule, or plaque without distinguishing color characteristics and nondescript features that can easily be mistaken for a scar, fibroma, or cyst. DM occurs most commonly on the head and neck of elderly persons, but it may occur anywhere. Because of its nondescript clinical features, DM is often diagnosed at more advanced levels of dermal invasion. DM exhibits an increased risk for local recurrence after wide excision.

Most DMs stain strongly and diffusely with S100 but are negative or only focally positive for other melanoma markers such as HMB45. DM must be differentiated from other malignant spindle cell tumors of muscle, epithelial, neural, or fibroblastic origin, typically through the use of a panel of immunohistochemical markers. The tumors may display varying degrees of desmoplasia; the presence of a pure DM (as opposed to mixed, with desmoplastic components) has prognostic significance and should be noted on the pathology report.

Staging

Biopsy Technique

A biopsy should be performed on any skin lesion suspicious for melanoma. Obtaining adequate biopsy specimens is essential because staging of the primary melanoma depends on three microscopic features: Breslow depth or thickness, mitotic rate, and presence or absence of ulceration. Excision of the entire lesion is preferred; partial biopsies increase the risks of both misdiagnosis (false negative or false positive) and microstaging inaccuracy (either the biopsy transects the base of the melanoma or fails to sample the deepest portion of the melanoma). Performing a partial biopsy may be necessary and reasonable in cosmetically or functionally sensitive anatomic locations or if the lesion is large. Shave biopsies can compromise histologic interpretation and proper measurement of thickness and should be avoided.

Prognostic Factors and Microstaging

Wallace Clark, Jr., initially described an inverse correlation between increasing anatomic levels (I-V) of microinvasion into the dermis or subcutaneous tissue and survival in 1967. Alexander Breslow subsequently established the correlation between tumor thickness in millimeters and survival. Multivariate statistical analysis has identified several features of the primary melanoma that have prognostic significance. These factors have been incorporated in the seventh (2010) edition of the American Joint Committee on Cancer (AJCC) staging system. In a multifactorial analysis of more than 27,000 patients with localized melanoma (either clinically or pathologically), the most powerful and independent prognostic characteristics of the primary melanoma were tumor thickness, ulceration, and mitotic rate for melanomas ≤1 mm.²⁹ Additional clinical factors that have been associated with outcome (but that are not included in the AJCC staging system) are also outlined in the following sections.

Thickness

In virtually all studies analyzing the prognosis of patients with stages I and II melanoma, thickness of the primary melanoma is the strongest predictor of outcome. Increasing melanoma thickness correlates with increasing risk of local recurrence, regional metastasis, and distant metastasis and with poor melanoma-specific survival. Thickness is measured using a micrometer and is measured from the distance from the top of the granular layer to the deepest level of invasion, excluding adnexal extension. Thickness is included in the AJCC “T” staging of melanoma, given its prognostic value across all thicknesses; a thickness of 1 mm or less is associated with excellent prognosis.

Ulceration

Melanomas with histologic ulceration are more biologically aggressive; ulceration confers a significantly worse prognosis and a higher risk of developing metastatic disease compared with nonulcerated melanomas of equivalent thickness. Melanoma ulceration also correlates with increased tumor thickness, mitotic rate, and increasing age. Histologic ulceration is defined as the loss of continuity of the epithelium over the tumor surface. The presence or absence of ulceration is included in the AJCC “T” staging of melanoma given its prognostic value across all thicknesses.

Dermal Mitotic Rate

Tumor mitotic rate is a reflection of the proliferation rate of the primary melanoma. Although mitotic rate is a continuous variable, a threshold of at least 1 mitosis/mm² has been identified to have the most significant correlation with survival; melanomas with at least 1 mitotic figure/mm² have a worse prognosis than do those with no mitotic figures. The mitotic rate has been shown in several studies to be an independent factor in predicting both incidence of sentinel node metastases and survival and is now included in the AJCC “T” staging of melanomas ≤1.00 mm in thickness only.30,31 Pathologists begin the mitotic count with the most active tumor focus; this “hot spot” technique is the recommended method of assessment. Adjacent fields are inspected until a total of 1 mm² has been examined. The mitotic rate should be reported as “mitoses/mm².”

Several other histologic features of the primary melanoma have prognostic importance but are not included in the current AJCC “T” staging. The presence of tumor-infiltrating lymphocytes (TILs) is associated with a more favorable prognosis. Melanomas should be routinely assessed for lymphocytic infiltration in the vertical growth phase and classified as brisk, nonbrisk, or absent with regard to TILs. TILs are termed brisk if they infiltrate the entire invasive component diffusely or across the base of the VGP. TILs are reported as absent if no lymphocytes are present or if they are present but do not infiltrate the tumor. When lymphocytes infiltrate the melanoma only focally, the term “nonbrisk” is used. The absence of TILs is predictive of a higher risk sentinel lymph node (SLN) metastasis in patients undergoing SLN biopsy (SLNB) for primary cutaneous melanoma but is not predictive of survival.³² Microsatellites are a relatively uncommon feature in melanoma and are defined as any discontinuous nest of metastatic melanoma cells >0.05 mm in diameter that is clearly separated by normal dermis (not fibrosis or inflammation) from the main invasive component of melanoma by a distance of at least 0.3 mm. The presence or absence of microsatellites should be routinely reported because it confers a worse prognosis and is incorporated into the AJCC “N” stage. Lymphovascular invasion is defined by the presence of melanoma cell(s) in the lymphovascular channel. Lymphovascular invasion in the primary melanoma is associated with a higher risk of lymph node metastasis but is not an independent predictor of survival for melanoma in general.^33,34

The anatomic site of the primary melanoma has been reported to correlate with survival, with trunk and head and neck sites having a worse outcome than extremity sites; anatomic site is not included in the current AJCC staging system. Although older patients have thicker melanomas and a higher incidence of ulcerated melanomas, age (especially age greater than 60 years) has been reported as an independent adverse prognostic factor, even after multivariate adjustment for other factors.35,36 Finally, men have a worse prognosis compared with women who have a similar melanoma presentation and stage; this finding that has been consistent across many studies.

Staging Classification

The 7th edition of the AJCC staging system was adopted in 2009 and is based on a study of patient outcomes from the AJCC Melanoma Database, which consisted of a total of 38,918 patients with melanoma, including 7972 patients with stage IV melanoma.²⁹ The data were merged from prospective databases of patients from 17 major medical centers, stand-alone cancer centers, and cancer cooperative groups. Box 69-1 and Tables 69-1 and 69-2 list the current melanoma TNM categories and the stage groupings, respectively. The 15-year survival curves for patients with stage I to IV melanoma are shown in Figure 69-2.The distinction between clinical and pathologic staging is worth noting.

Box 69-1

American Joint Committee on Cancer TNM Definitions

Primary Tumor (T)

Tx: Unable to assess (e.g., curettage or severely regressed melanoma)

T0: No evidence of primary tumor

Tis: Melanoma in situ

T1: 0.1- to 1.0-mm thick

T1a: Without ulceration and mitosis <1/mm²

T1b: With ulceration or mitoses ≥1/mm²

T2: 1.01- to 2.0-mm thick

T2a: Without ulceration

T2b: With ulceration

T3: 2.01- to 4.0-mm thick

T3a: Without ulceration

T3b: With ulceration

T4: >4.0 mm thick

T4a: Without ulceration

T4b: With ulceration

Regional Lymph Nodes (N)

NX: Patients in whom the regional nodes cannot be assessed (e.g., previously removed for another reason)

N0: No regional lymph node metastasis

N1: metastasis in one node

N1a: Micrometastasis (clinically occult)

N1b: Macrometastasis (clinically apparent)

N2: Metastasis in two to three nodes or in-transit metastases without nodal metastases

N2a: Micrometastases (clinically occult)

N2b: Macrometastases (clinically apparent)

N2c: In-transit met(s)/satellite(s) without metastasis in nodes

N3: Metastasis in four or more regional nodes, matted notes, or in transit metastasis or satellite(s) with metastasis in node(s)

Distant Metastases (M)

M0: No detectable evidence of distant metastasis

M1a: Skin, subcutaneous, distant lymph node metastases

M1b: Lung metastases

M1c: All other visceral metastases, or distant metastases at any site with elevated serum lactate dehydrogenase

From American Joint Committee on Cancer. Cancer staging manual. 7th ed. New York: Springer-Verlag; 2010.

Table 69-1

American Joint Committee on Cancer Pathologic Stage Grouping *

Stage	Grouping
Stage 0	TisN0M0
Stage IA	T1aN0M0
Stage IB	T1bN0M0
	T2aN0M0
Stage IIA	T2bN0M0
	T3aN0M0
Stage IIB	T3bN0M0
	T4aN0M0
Stage IIC	T4bN0M0
Stage IIIA	T1–4aN1aM0
	T1–4aN2aM0
Stage IIIB	T1–4bN1aM0
	T1–4bN2aM0
	T1–4aN1bM0
	T1–4aN2bM0
	T1–4a/bN2cM0
Stage IIIC	T1–4bN1bM0
	T1–4bN2bM0
	Any T N3M0
	Any T, any N, M1

^*Note that the stage groupings involve upstaging to account for melanoma ulceration, where thinner melanomas with ulceration are grouped with the next greatest T substage for nonulcerated melanomas.

From American Joint Committee on Cancer. Cancer staging manual. 7th ed. New York: Springer-Verlag; 2010.

Table 69-2

American Joint Committee on Cancer 5-year Survival Rates of Pathologically Staged Patients

	IA	IB	IIA	IIB	IIC	IIIA	IIIB	IIIC
Ta: nonulcerated	T1a 97%	T2a 91%	T3a 79%	T4a 71%		N1a N2a 78%	N1b N2b 48%	N3 47%
Tb: ulcerated*		T1b 94%	T2b 82%	T3b 68%	T4b 53%		N1a N2a 55%	N1b N2b N3 38%