Epidemiologic studies of malignant melanoma have shown a steady rise in the incidence of this disease in various parts of the world in the last few decades. This incidence is the fastest growing among all cancers, now surpassing transverse colon carcinoma, oropharyngeal carcinoma, renal carcinoma, or uterine carcinoma. It is estimated that over 76,000 new cases of cutaneous melanoma will be diagnosed in the United States in 2016. And although it accounts for only 1% of all skin cancers diagnosed, it does account for the vast majority of skin cancer deaths with an estimated 10,000 deaths predicted for 2016. The lifetime risk of melanoma is presently 2% for all women and 3% for all men. (1) As our understanding of melanoma has increased over the years, we can now differentiate low-risk from high-risk patients on the basis of multifactorial analyses of large numbers of patients.

DIFFERENTIAL DIAGNOSIS

Staging of melanoma begins with a careful history and thorough physical examination. Although an experienced clinician may be able to diagnose malignant melanoma by appearance, diagnosis is often not made until histologic examination has occurred. Furthermore, there is a wide range of pigmented nevi, which must be included in the differential diagnosis. Therefore, a review of the various pigmented lesions is essential for making a differential diagnosis.

All infants are born with nevi, but the lesions usually are not apparent at birth because they have not yet produced pigment. Melanocytes produce pigment over the ensuing few weeks or months, as a response to circulating hormones. As the nevi develop, they undergo maturation that leads to the following various forms.

Junctional Nevus

Junctional nevi are small flat lesions that first appear after birth and are smooth, nonpalpable, and light to dark brown or black (Figure 4.1A). They are called junctional because the nevus cells are located at the interface of the epidermis and dermis. As the person develops and matures, the nevus cells grow and push into the dermis to develop into the common adult intradermal nevus.

Figure 4.1 The various types of nevi in the differential diagnosis of melanoma: (A) flat smooth junctional nevus, (B) compound nevus with central thickening, (C) mature uniformly thickened intradermal nevus, (D) deeper blue-colored nevus, (E) speckled congenital nevus, and (F) halo nevus.

Compound Nevus

As the nevus matures, the central portion pushes into the dermis, causing this central portion to elevate and appear thicker (Figure 4.1B). This nevus is called compound because the central portion is intradermal and thick, while the periphery is still junctional and flat. Compound nevi often are seen during adolescence, and the changes in such moles may cause concern to the patient, family, or primary care physician.

Intradermal Nevus

The intradermal nevus is the common adult mole of the face or trunk that is elevated because of the maturation and proliferation of the nevus in the dermis, which now pushes up the overlying epidermis (Figure 4.1C). It may be light or dark, usually is elevated, and may be sessile or pedunculated.

Blue Nevus

Most nevi appear brown or black because the melanin is superficial and absorbs light. When the nevus contains melanin that is located more deeply, blue wavelengths of light pass through the less pigmented epidermis and are reflected back to the eye as a blue nevus (Figure 4.1D).

Congenital Nevus

Congenital nevi differ from others in that they already produce pigment at birth (Figure 4.1E). The controversy regarding congenital nevi is whether or not they are precursors of malignant melanoma. We do not know the true incidence because we do not know the total number of patients in the normal population who have congenital nevi but never consult a physician, let alone have it removed for examination. On the basis of available information regarding the potential for malignant transformation, it is a good policy to remove congenital nevi if it can be done without much difficulty. Since malignant transformation does not usually occur before adolescence, if the lesion is to be excised, it should be done before adolescence.

Halo Nevus

Halo nevi are moles with a surrounding area of skin devoid of any pigmentation (Figure 4.1F). This is a benign lesion seen in normal patients as well as patients with melanoma. It is believed to be an autoimmune response by T cells that attack and destroy the melanocytes, leaving a ring of depigmentation.

Dysplastic Nevus (Atypical Nevus)

The atypical nevus is a clinical diagnosis of a nevus with melanocytes involving the epidermis and dermis, which have features that are suspicious for malignancy. Clinically, it is large (>6 mm), with a macular surface, irregular margin, and variegated color. It may have a background of erythema (Figure 4.2). These are benign lesions with histologic features that are abnormal. At various times they have been called atypical nevi or dysplastic nevi. However, an NIH Consensus Conference in 1992 recommended the descriptive term atypical nevus be applied for the clinical diagnosis, and the histologic term dysplastic nevus be used to describe the histologic degree of atypia and architectural disorder (2).

Figure 4.2 Atypical (dysplastic) nevus.

CLINICAL DIAGNOSIS

The clinician is faced with the task of differentiating the malignant melanoma from a number of other lesions that may clinically resemble melanoma, such as seborrheic keratosis (Figure 4.3A), pyogenic granuloma (Figure 4.3B), or pigmented basal cell carcinoma. Sometimes this differentiation may be more difficult because of a recent growth, bleeding into a lesion, or peripheral inflammation. In these cases, only microscopic examination of the tissue provides the proper diagnosis.

Figure 4.3 Additional nonmalignant lesions are (A) the seborrheic keratosis and (B) the pyogenic granuloma.

Extensive or radical surgical procedures should not be performed without the proper diagnosis of a malignant melanoma, because clinical impressions are not uniformly correct. Epstein et al. (3) reviewed 559 patients with black lesions that they believed might be melanomas. They found their diagnosis of melanoma was correct only a third (38.7%) of the time. Indeed, the most common diagnoses were benign nevi (35%), pigmented basal cell cancer (30%), and benign angiomas or vascular lesions (13%). Only 2% of all the lesions were found to be melanoma.

Hutchinson’s Freckle

Hutchinson’s freckle is a flat, brown, macular lesion that may grow at various rates and achieve different shades of pigmentation (Figure 4.4). This lesion occurs most commonly on the face, neck, and other sun-exposed surfaces of adults in middle age or later. On histologic examination, this lesion appears as an overgrowth of melanocytes at the epidermis–dermis junction. Although lentigo maligna is an in situ melanoma, invasive melanoma may develop within a Hutchinson’s freckle and is then called lentigo maligna melanoma.

Clinical cues that may raise suspicion for a diagnosis of melanoma can be easily remembered by the acronym ABCDE: Asymmetry of the lesion; Border irregularity; Color variegation, Diameter greater than 6 mm; Evolution of the lesion (Figure 4.5).

Figure 4.4 Hutchinson’s freckle, on the sun-exposed surfaces, showing a deeper pigmentation.

Figure 4.5 ABCDE acronym for changes leading to suspicion of diagnosis of melanoma.

CLASSIFICATION

Melanoma is most commonly located on the skin, but may also occur in the mucosa of the oral cavity, nasopharynx, esophagus, vagina, and rectum. However, the current staging systems were developed for cutaneous melanomas, and therefore the discussions in this chapter will be limited to cutaneous melanoma.

Melanoma can be classified both morphologically (by clinical appearance) and histologically (by microscopic appearance).

Morphologic Classification

Melanoma can be classified morphologically into lentigo maligna, superficial spreading, nodular lentiginous, and acral lentiginous. Lentigo maligna melanomas represent 4% to 10% of all melanomas, and arise from lentigo meligna, also known as Hutchinson’s freckle. It is commonly located on sun-exposed areas, in adults with light complexion, with a peak incidence in the seventh decade of life (4). Superficial spreading melanomas (SSM) are the most common variant and represent approximately 50% to 80% of all cutaneous melanomas (Figure 4.6). They are characterized by radial (horizontal) growth for up to several years before vertical growth begins. It is also the variant most likely to arise from, or be contiguous with, a preexisting melanocytic nevus. SSM has a tendency to affect a younger patient population, with peak incidences found in the fourth and fifth decade of life. This subtype presents most classically with ABCD features and is often <1.5 cm in diameter (4).

Nodular melanomas are the second most common variant, accounting for approximately 20% to 30% of all melanoma cases. Unlike both SSM and lentigo maligna, nodular melanomas may be nonpigmented, and present as an elevated, dome-shaped nodule. It is seen most commonly in the fifth and sixth decades of life, and enters the vertical growth phase early in its development (4).

Acral lentiginous melanomas account for 2% to 8% of all melanomas, and appear on the palms of the hands, soles of the feet, subungual areas of the fingers and toes, and web spaces. It is the most common type of cutaneous melanoma in African Americans, Asians, and Hispanics. Acral lentiginous melanomas do not seem to be associated with sun exposure, and are often diagnosed in older patients, with peak incidence in the seventh decade of life. These lesions are often thicker at the time of their diagnosis, most often because they are associated with a lower clinical suspicion due to erroneous misdiagnosis as a fungal infection, leading to a higher staging and poorer prognosis (4).

Desmoplastic melanomas are uncommon variants, representing approximately 1% of all melanomas. They are commonly seen in sun-damaged skin of older patients. This lesion is often nonpigmented, with the appearance of a hypertrophic scar in a location where the patient does not recall having had an injury.

Figure 4.6 Morphologic Classification. Typical lesions representative of the various morphologic types of melanoma.

Histologic Classification

Histologic classification of melanoma focuses on the depth of invasion of the primary melanoma. The earliest correlation between depth of melanoma with prognosis was described in 1965 by Mehnert and Heard (5). Later, Clark et al. (6) described a modification of this system to classify the tumor by its depth of invasion into the dermis, referred to as Clark’s level staging (Table 4.1).

However, the difficulty with the Clark’s classification system lies in the subjective nature in the determination of the depth of invasion. For example, multiple pathologists examining the same histologic slide of a melanoma with a mid-dermal invasion may disagree on the Clark level of invasion—whether it is a deep level II, a level III, or a superficial level IV. It is because of this difficulty that Breslow subsequently reported a quantitative and reproducible method of measurement. Breslow’s method measures the lesion’s depth of invasion through the lens of the microscope by millimeters thickness from the epidermal surface to the deepest tumor cell (Figure 4.7). In addition to Breslow thickness, histologic features of the primary melanoma are included, specifically the presence of ulceration and mitotic rate per high-powered field (7). The presence of ulceration on the surface of the lesion is associated with a higher risk of recurrence and is therefore a higher designated group in the staging. The presence of mitotic figures greater than 1 per high-powered field is associated with a higher risk of recurrence only in lesions less than 1.0 mm in thickness. However, in the updated staging system by the American Joint Committee on Cancer (AJCC) in 2017, mitotic rate was removed as a staging criterion for T1 lesions. Nevertheless, it remains an overall prognostic factor, and should still be recorded for all patients with T1 to T4 primary cutaneous melanomas, even though it does not upstage the T1 lesions.

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