Chapter 18: Nevi and Melanoma

Melanocytic nevi (moles) are common benign skin tumors. In most people, these are primarily of cosmetic significance. However, nevi can occasionally become irritated or subjected to trauma and may need to be removed. Most nevi are benign, but, atypical nevi have some features that resemble malignant melanoma, and in certain circumstances the presence of atypical nevi is a marker for an increased risk of developing malignant melanoma.

Melanoma is a potentially deadly cancer whose incidence is on the rise. It is unique among most serious cancers, because it can be detected by both patients and clinicians with a simple skin examination. The clinician can provide a great service to patients by providing a few simple guidelines for the early detection of melanoma.

Introduction

Melanocytic nevi (moles) are among the most common benign tumors in humans. Nevi are more common in Caucasians. They are less common in Asians and Black individuals. But when they do occur they are more likely to be on the palms and soles. Interestingly, nevi are also less common in patients with the melanocortin-1 receptor (MC1-R) gene pigment variant (red hair, fair skin, always burns).

Nevi appear in early childhood reaching a maximum number in the 3rd to 4th decade of life, with a subsequent decline in number.¹ They are more common on sun-exposed skin, as natural sunlight and artificial ultraviolet light are factors in their induction.

Pathophysiology

Nevi are benign hamartomas of melanocytic nevus cells. They are thought to arise from cells delivered from the neural crest to the skin during embryologic development.

Clinical Presentation

History

Nevi are usually asymptomatic. Patients may bring nevi to a clinician's attention because of new onset, growth, symptoms of pain or itch, interference with activities of daily living, or alarming appearance. They may also bring them to attention because of a cosmetically unacceptable appearance.

Physical Examination

Nevi are small, circumscribed macules, papules, or nodules. They range in color from blue/black through brown, pink to skin colored. Acquired nevi are almost always less than 1 cm in diameter. Melanocytic lesions greater than 1 cm may be congenital nevi, atypical nevi, or melanoma. Nevi may occur anywhere but there is a predilection to sun-exposed skin.

Common presentations of nevi:

• Junctional nevi arise at the skin dermal–epidermal junction; they are typically macular (Figure 18-1).

• Intradermal nevi present with nevus cells confined to the dermis of the skin and are papular (Figure 18-2).

• Compound nevi have both junctional and dermal components and are usually papular.

Less common presentations of nevi:

• Halo nevus (Sutton nevus): These are usually benign melanocytic nevi surrounded by a halo of depigmentation (Figure 18-3), which may be due to a direct cytotoxic effect of lymphocytes surrounding the nevus. The halo usually heralds involution of the nevus over months to years. These lesions most commonly occur in childhood. Patients may have associated vitiligo. Melanoma can masquerade as a halo nevus, and melanomas in other sites may precipitate halo nevi. The presence of a halo nevus warrants a total skin examination and any atypical feature of the nevus itself justifies removal and histopathological examination.

• Blue nevus: These are acquired nevi that range in color from blue to black (Figure 18-4). The onset is usually in childhood, with predominance in Asians. These nevi are benign, but melanoma, especially nodular melanoma may masquerade as a blue nevus. Indications for biopsy include atypical features such as size >1 cm or irregular shape or color, late onset, or a changing lesion.

• Spitz nevus: These are small, typically pink or tan nevi that appear suddenly, primarily in children. They have characteristic dermoscopic and histopathological features. Spitz nevi are unusual in patients over the age of 40; therefore, skin lesions with the dermoscopic features of Spitz nevi are best removed in this age group to exclude melanoma with Spitzoid features.

Features in a nevus that are signs that may indicate a melanoma are listed in Table 18-1.

Laboratory Findings

The histopathologic findings of common acquired melanocytic nevi show mature melanocytes arranged as individual cells or in nests. The margin of the nevus is discrete.

Diagnosis

Common acquired melanocytic nevi present as tan, brown, or black macules or papules or skin-colored papules with uniform colors and borders.

The adoption of dermoscopy has enhanced the ability of the clinician to differentiate normal nevi from atypical nevi and melanomas (Figures 18-5 and 18-6).² Dermoscopy uses an illuminated, high quality 10×-magnifying lens coupled to a device to remove surface reflection. This is done either using a set of cross-polarizing filters (polarized dermoscopy) or by direct contact with the skin using a coupling liquid such as an alcohol-based hand cleansing gel. The limitation of dermoscopy is that it is learning intense, but there are a number of algorithms that have been designed to assist clinicians in making the decision to biopsy suspicious lesions.

The easiest is the 3-point algorithm that uses 3 simple criteria for the analysis of a melanocytic neoplasm: (1) the presence of an atypical pigment network; (2) asymmetry of any structure; and (3) the presence of any structure that is blue or white. The presence of 2 or more criteria warrants a removal of the lesion for histopathologic examination.² A full body dermoscopic examination typically takes about 2 to 3 minutes.

Differential Diagnosis

• ✓ Table 18-2 lists the differential diagnosis for common acquired nevi, which primarily includes other pigmented tumors.

Management

Nevi are usually asymptomatic. Patients who have more than 50 nevi are at increased risk for developing melanoma and they should have a full body skin examination annually.³ They should be counseled on sun precautions and how to perform self-examination.

If feasible, clinically suspicious nevi should always be removed in their entirety so that the entire lesion can be examined histopathologically. Clinically suspicious lesions often have one or more of the following features of the ABCDE rule (Table 18-1). Melanocytic lesions are also suspicious for melanoma if they are painful or pruritic or if the lesion becomes eroded in the absence of trauma. Dermoscopy aids in the evaluation of nevi and other cutaneous neoplasms.

Indications for Consultation

Consideration for referral for regular screening should be given in patients with multiple nevi, especially if the clinician is uncomfortable with dermoscopy.

Depending on the surgical skills of the clinician, patients may be referred for excision of particularly large nevi or nevi in cosmetically sensitive areas.

Patient Information

American Academy of Dermatology: www.aad.org/skin-conditions/dermatology-a-to-z/nevi

Introduction

Atypical nevi (dysplastic nevi) may occur sporadically as isolated "ugly ducklings" (nevi that appear different from other nevi on the body) or as multiple lesions as in the case of atypical nevus syndrome. They can appear in adulthood or childhood and are not uncommon, occurring in up to 5% of Caucasians. They are present in virtually every patient with familial cutaneous melanoma and in 30% to 50% of patients with sporadic primary cutaneous melanoma. Risk factors include a history of sun exposure, but atypical nevi can occur in sun-protected skin. Unlike common acquired nevi, new atypical nevi continue to appear throughout a patient's lifetime.

Atypical nevus syndrome describes an autosomal dominant phenotype of patients with multiple nevi of different sizes and colors. Patients with atypical nevi have an increased risk for melanoma. The general population has a 1.93% life-time risk for melanoma. The following are the approximate life-time risks (%) of melanoma for patients with atypical nevi.

• 5% for one atypical nevus with increasing risk for additional atypical nevi

• 18% for atypical nevus syndrome

• 100% for atypical nevus syndrome with two blood relatives with melanoma

Pathophysiology

Atypical nevi are often thought of as melanoma precursors, but this concept is controversial. Most authorities consider atypical nevi as potential markers for an increased risk for developing melanoma de novo. The other important significance of atypical nevi is the potential histopathologic ambiguity and the risk of under diagnosis of melanoma.

Clinical Presentation

History

Patients often have a history of multiple acquired nevi. There may be a family history of melanoma or removal of nevi.

Physical Examination

Atypical nevi present as pink to black macules or papules with variegated color, variable shape, and irregular borders (Figure 18-7). Table 18-3 lists the clinical presentation of atypical nevi as contrasted with common typical nevi. The difficult patient is one without a "signature nevus," meaning a specific type of mole pattern that most if not all nevi adhere to. Some patients have multiple, even hundreds of atypical nevi ranging in size from millimeters to centimeters and having a variety of colors ranging from pink to black. In these patients, every nevus is an exceptional nevus (an ugly duckling).

Laboratory Findings

The histopathological findings of atypical nevi may be the same as benign common nevi, but typically will include degrees of mild to severe architectural disorder and/or mild to severe cytological atypia.

Diagnosis

Atypical nevi present as pink to black macules or papules with variegated color and irregular borders. They are usually greater than 6 mm in diameter.

Differential Diagnosis

• ✓ The differential diagnosis for atypical nevi is listed in Table 18-2.

Management

Nevi that are changing in shape, border, size, or pigmentary features should be biopsied. The observation of these changes often originates from the patient,⁴ but ideally originates from baseline photographs, such as from total body photography or digital dermoscopy.

Patients with atypical nevus syndrome have an increased risk for melanoma and require regular skin examinations, preferably with baseline full body photography to reduce unnecessary biopsies over time.⁵ Patients with atypical nevi and familial melanoma should be examined every 3 months. Close family members should also be examined once the diagnosis of atypical nevus syndrome is established.

Because of the possibility of ambiguity on histopathology, atypical nevi with moderate to severe degrees of architectural disorder or cytological atypia should be excised with at least 5 mm margins, especially in the case of severe architectural disorder or cytological atypia.

Patients should be given color-illustrated pamphlets that depict the clinical features of atypical moles and malignant melanoma. These brochures are available through the Skin Cancer Foundation and the American Academy of Dermatology. Patients with atypical nevi should be instructed to monitor their nevi monthly. Patients should not sunbathe and should use sunscreens and sun protective clothing when outdoors. They should not use tanning salons.

Indications for Consultation

Patients with atypical nevi should be referred for regular screening by a dermatologist skilled in dermoscopic examination. In addition, full body photography should be performed as a base-line benchmark for future examinations.

Patient Information

Skin Cancer Foundation: www.skincancer.org/skin-cancer-information/dysplastic-nevi

Introduction

Congenital melanocytic nevi (CMN) are nevi present at birth or that appear very shortly after birth (tardive CMN). They are present in 1% of Caucasian infants and have no gender predilection. They vary widely in size and incidence (Table 18-4). Five percent of patients with congenital nevi have multiple congenital nevi. CMN are benign tumors, but they do have a limited risk for developing melanoma.

Clinical Presentation

History

Most CMN are present at birth and they grow in proportion to the rest of the body. They are usually asymptomatic, but often visually disconcerting to parents.

Physical Examination

CMN are brown or black. They are usually palpable with well-defined borders, but may have irregular contours. The surface can be smooth (Figure 18-8) but may also have a pebble-like surface. Lesions may also be cribriform, lobular, rugose, or bulbous. They commonly have dark terminal hairs. Giant CMN are often surrounded by smaller satellite nevi. Dermoscopy of CMN is often difficult because atypical features are common. Giant CMN involving the scalp or midline can be associated with deep involvement including muscle, bone, dura mater, and leptomeninges.⁶ Neurocutaneous melanocytosis may be complicated by seizures, focal neurologic defects, or obstructive hydrocephalus. Melanoma most often arises in giant CMN, and is usually advanced because of the difficulty following these lesions through observation.

Laboratory Findings

The histopathological findings of CMN include benign features of junctional and dermal nevi, and in some instances a "neural" component with neuroid tubes and corpuscles. There may also be melanocytic aggregates resembling blue nevi.

Diagnosis

CMN present at birth with brown to black plaques usually with well-defined borders.

Differential Diagnosis

• ✓ Common acquired melanocytic nevi: Small CMN are virtually indistinguishable clinically from common acquired nevi except for their size

• ✓ Other melanocytic nevi: Congenital blue nevi have a deep blue color and nevus spilus presents with multiple 2- to 3-mm dark brown nevi on a large light brown patch

• ✓ Other pigmented congenital lesions: Becker's nevus, pigmented epidermal nevus, and café-au-lait spots

Management

Melanoma that develops in a large CMN has a poor prognosis because it usually is detected late. The lifetime risk of developing a melanoma in a small CMN is estimated to be as high as 1% to 5%. However, this risk estimate comes from retrospective data and the actual risk is unknown. The risk is higher in large or giant CMN and has been estimated to be as high as 6.3%. Half of patients who develop melanomas in congenital nevi will develop the melanoma between the ages of 3 and 5 years. For this reason, many advocate prophylactic staged excision of the CMN early in life.⁷ However, the value of excision of CMN has been questioned because it is usually impossible to remove all the nevus, poor cosmetic results are common, and there are attendant medical and psychological risks to repeated large excisions.⁶

Indications for Consultation

Patients with atypical nevi and congenital nevi should be referred to dermatology for evaluation and long-term monitoring of their nevi.

Patient Information

The Association for Large Nevi and Related Disorders: www.nevus.org

Introduction

Malignant melanoma is a cancer of melanocytes. The cancer incidence is on the rise, afflicting over 68,000 people in the United States annually and causing 8000 annual deaths.⁸ It is the fifth most frequently diagnosed cancer in men (lifetime risk of 2.67%) and the sixth most common in women (lifetime risk of 1.79%).⁸ Malignant melanoma attracts a great amount of publicity, because it is one of the most common potentially lethal malignancies of young adults. From 1970 to 2009 in Olmsted County, Minnesota, the incidence of melanoma increased by 8-fold among young women and 4-fold among young men (although there was no increase in mortality).⁹ It is the easiest malignancy to diagnose early, and there are national educational campaigns in most countries emphasizing the importance of self-examination of the skin.

Melanoma can occur at any age but is rare in childhood. Lifetime risk factors (in roughly decreasing risk) include genotypes with specific risk enhancement (eg, CDKN2A), atypical nevus syndrome (especially if two immediate family members have a melanoma history), family history of melanoma in first-order relatives, prior personal history of melanoma, one or more atypical nevi, large numbers of common nevi, advancing age, outdoor occupations or aviation flight occupation, fair skin, history of blistering sunburn, and a history of commercial tanning.³

Pathophysiology

Most melanomas begin as de novo lesions, although some authors state up to 30% arise in preexisting nevi. The cancer genetics for melanoma are complex, but certain oncogenes have become important because of their frequencies and because of potential therapeutic implications for targeted therapy (eg, vemurafenib for BRAF mutation). Other mutations in addition to BRAF (most common in superficial spreading melanoma) include KIT (most common in lentigo maligna melanoma and acral-lentiginous melanoma), NRAS, and CDKN2A (the most common specific mutation in familial melanoma).¹⁰ About 20% to 40% of familial melanoma cases are associated with a CDKN2A mutation.

Clinical Presentation

History

Patients often have a history of a change in size, shape or color or pruritus in a new or existing nevus.

Physical Examination

Melanoma can occur on any skin surface irrespective of sun exposure. The most common locations in men are the trunk (55%), especially the upper back, followed by the legs, arms, and face; in women, the most common location is the legs (42%), followed by the trunk, arms, and face.⁸

Melanomas typically have the features as listed in Table 18-1. Figure 18-9 demonstrates many of these features.

Main Types of Melanoma

• Superficial spreading melanoma can occur in sun-exposed or nonexposed skin. It is characterized by a superficial radial growth phase that occurs before an invasive vertical growth phase (Figure 18-10). These melanomas account for about 70% of melanomas and have an excellent prognosis when detected early.

• Lentigo maligna melanoma occurs most commonly in sun-damaged skin of the head and neck of elderly patients (Figure 18-11). These account for 10% to 30% of melanomas, depending on the patients' age demographics and latitude.¹¹ These are very often diagnosed as in situ lesions.

• Nodular melanoma: These melanomas, representing 10% to 15% of melanomas, lack a radial growth phase (Figure 18-12). They grow rapidly over months and are often advanced at the time of diagnosis.

• Acral lentiginous melanoma occurs on the palms and soles (Figure 18-13). It accounts for only about 5% of melanomas in Caucasians, but is the most common cause of melanomas in Asians and Blacks. It is often advanced at diagnosis because of patients' inattentiveness to the sole of the foot.

Other Presentations of Melanoma

• Melanoma in situ (MIS) is a proliferation of malignant melanocytes confined to the epidermis. The American Cancer Society estimated that 46,770 cases of MIS occurred in the United States in 2010. The most common subtype of MIS is lentigo maligna which occurs in sun-exposed skin and accounts for 80% of MIS.¹¹

• Metastatic melanoma from an unknown primary: This occurs in about 3% to 5% of all melanoma patients. If the metastasis is limited to skin or lymph nodes, the prognosis is actually better than patients with visceral metastases from a known primary.

• Primary mucosal melanoma of the head and neck: This rare subtype occurs in about 1% of melanomas.

• Vulvo/vaginal melanoma: These account for a small number of melanomas. However, melanoma in this location is important because the detection is often delayed.

• Subungual melanoma: Subungual melanoma accounts for up to 3% of melanomas. It most commonly presents with pigmentary changes of the nail bed. The diagnosis is aided by dermoscopy. Early diagnosis is essential as the prognosis is otherwise poor compared to other melanoma locations.

• Primary ocular melanoma: Ocular melanoma is extremely rare. Lesions may be uveal, ciliary, or choroidal and are not amenable to biopsy. Patients usually present with visual loss or pain. The diagnosis is based on physical findings.

• Pediatric melanoma: Accounts for 1% to 4% of melanoma. Thirty percent of pediatric melanomas arise in association with a giant congenital melanocytic nevus.¹² In two-thirds of the cases the melanomas develop within the congenital nevus.¹³

• Amelanotic melanoma is a variant of melanoma. It usually presents as a pink lesion (Figure 18-14). Dermoscopy will sometimes show a pigment network or globules not apparent on clinical examination. These lesions usually are outliers (ugly ducklings) but sometimes are masked by other pink lesions, particularly in patients with atypical nevus syndrome. They are often nodular and may be confused with pyogenic granulomas.

• Desmoplastic melanomas account for 1% of melanoma. These most commonly present as flesh-colored or pink papules or nodules, most commonly on the head, neck, palms, and soles. Although often invasive at the time of diagnosis, the prognosis is better than for comparably thick nodular melanomas. The cell of origin is controversial and this tumor may in fact be a soft tissue sarcoma.

• Familial melanoma: 5% to 10% of melanomas occur in familial clusters. Up to 40% of patients with familial melanoma have a gene mutation in the CDKN2A suppressor gene. These patients also are at increased risk for pancreatic cancer. Indications for genetic screening include individuals with three or more primary melanomas or family members affected by two melanomas or two pancreatic cancers.¹⁰

Laboratory Findings

The histopathological findings of a melanoma include an irregular distribution of atypical cells in nests and individually with disruption of normal architecture, violation of boundaries, and a host response evident by an inflammatory infiltrate.

A report of melanoma should include the Breslow depth, which is a measurement of thickness of the tumor measured from the surface of the skin to the deepest level of tumor invasion. Tumor staging is based on the Breslow depth, with 1.0, 2.0, and 4.0 mm being thresholds for T category staging.¹⁴ Other features important for staging include the number of mitoses and the presence of ulceration. Additional prognostic factors not incorporated into the current American Joint Committee on Cancer (AJCC) staging classification, which have shown prognostic significance in some studies, include radial and vertical growth phases, regression, angiolymphatic invasion, angiotropism, perineural invasion, and tumor-infiltrating lymphocytes. The Clark classification, which is an older measurement of tumor invasion, is not used any more. Atypical melanocytic hyperplasia is a term that describes lesions that are ambiguous histopathologically and may be difficult to distinguish from melanoma. Most experts treat these lesions as MIS.

Diagnosis

Most melanomas present with one of more features as listed in the ABCDE rule (Table 18-1).

Dermoscopy is of limited usefulness in patients with nevi that have borderline dermoscopic features or are completely featureless structurally. In these patients if there is clinical uncertainty one is obligated to remove the lesion. An alternative is to follow the patient with serial photography,⁵ an approach that many experts suggest as standard of care for patients with atypical nevus syndrome.

Differential Diagnosis

• ✓ Table 18-2 lists the differential diagnosis for pigmented lesions.

Management

The first step in management of a suspected melanoma is confirmation of the diagnosis with a skin biopsy. The purpose of the biopsy for a suspected melanoma is to make the diagnosis and to provide staging information. The most important staging information is thickness.¹⁴ Ideally a suspicious lesion should be excised in its entirety with at least 2 mm of normal appearing skin at the margin (allowing the pathologist to examine the lesion margin).¹⁵

Partial biopsies are subject to sampling error and should be avoided except in limited circumstances such as in a large facial lesion in which a total excision may result in an unacceptable scar. Even in that circumstance best practice would be to obtain multiple biopsies from several parts of the lesion.

Shave biopsies are acceptable if the lesion is suspected to be thin (less than 1 mm in thickness) and the biopsy method can remove the entire lesion to a depth of more than 1 mm and include at least 2 mm of normal skin at the margin. This results, in effect, in more of a saucerization biopsy than a shave biopsy.

Surgical Management

Melanoma in situ: This is typically treated with surgical excision. Lentigo maligna (the most common subtype of melanoma in situ) should be excised with a wide local excision with 5 to 7 mm margins after verifying margins using a Wood's lamp or dermoscopy. Mohs micrographic surgery is often used for ill-defined or large lesions of lentigo maligna. The advantage of Moh's surgery is that 100% of the peripheral margin is examined following the excision. Disadvantages are unique technical problems resulting from freeze artifacts and the presence of benign melanocytic hyperplasia common to sun-damaged skin. Alternative therapies for lentigo maligna include radiotherapy, cryosurgery, and topical treatment with imiquimod, or long-term close observation.¹⁶

Invasive melanoma: In areas where there are cosmetic or anatomic limitations, the margin of excision may deviate from the standard resection margins. The National Comprehensive Cancer Center guidelines stipulate surgical margins based on tumor thickness (Table 18-5).¹⁵ The depth of excision is typically down to fat, but preserving muscular fascia.

Sentinel node biopsy: The AJCC Melanoma Staging Committee has recommended that patients with more advanced stages of melanoma (Table 18-5) and with clinically uninvolved regional nodes have sentinel node biopsy performed.¹⁴ The sentinel node status is of prognostic value, even if only microscopic metastases are seen.¹⁴ However, at the time of this writing, there is no proven therapeutic benefit from sentinel node biopsy, and there is potential morbidity and opportunities for misdiagnosis and therapeutic misadventures.

Monitoring of Patients with Asymptomatic Melanoma

There are no clear data to guide clinicians regarding follow up and laboratory testing.¹⁵ It is reasonable to recommend an annual history and physical examination with attention to skin and lymph nodes. In addition, patients should be educated on the importance of interval self-examination of skin and lymph nodes. Baseline laboratory tests and imaging studies are not recommended, nor is there a clear role for surveillance laboratory testing or imaging studies.

Melanoma survival depends on early diagnosis. Most melanomas begin as thin lesions and early diagnosed melanoma with a thickness of less than 0.75 mm has a 5-year survival prognosis exceeding 98%.¹⁷ Patients with melanomas with thicknesses between 1 mm and 2 mm have 10-year survival rates of less than 70% and those with melanomas greater than 4 mm in thickness have 10-year survival rates of less than 20%. The web site www.melanomaprognosis.org has more detailed information for prognosis based on the AJCC melanoma data base.

Primary Prevention and Detection

Ultraviolet radiation exposure, including radiation from commercial tanning beds, increases the risk of malignant melanoma. For this reason as well as for primary prevention of other skin cancers patients should be counseled on the value of sun safe behavior, including sun protective clothing, shade, and use of sun screens.

Indications for Consultation

Patients with melanoma who are candidates for sentinel node lymph biopsies should be referred to a surgeon that has expertise in the procedure. Patients should also be referred to dermatology for a total body examination and follow-up examinations. Patients with positive sentinel lymph nodes or with melanomas with a poor prognosis should be referred to oncology.

Patient Information

• American Academy of Dermatology: www.aad.org/skin-conditions/dermatology-a-to-z/melanoma

• Skin Cancer Foundation: www.skincancer.org/skin-cancer-information/melanoma

• Melanoma Research Foundation: www.melanoma.org

• American Society of Clinical Oncology: www.cancer.net/patient/Cancer+Types/Melanoma/ci.Melanoma.printer