White : Diseases of the Skin - Melanocytes, Nevi, and Melanoma

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Gary M. White & Neil H. Cox

Diseases of the Skin

31	Melanocytes, Nevi, and Melanoma

MELANOMA

Familial atypical mole–melanoma syndrome

Etiology and pathogenesis

The familial atypical mole–melanoma (FAMM) syndrome—also called familial atypical multiple mole–melanoma (FAMMM) syndrome, atypical mole syndrome (AMS), dysplastic nevus syndrome, and BK mole syndrome—combines a family history of melanoma with multiple clinically atypical nevi. Patients with FAMM syndrome have a 47–60% increased risk for developing melanoma compared with a person not so affected. A mutation in one of several genes can give rise to this phenotype. Recently, testing has become commercially available to look for one of the melanoma germ line susceptibility loci: CDKN2A. Although this test is of limited practical value at the moment, this area of clinical testing will probably grow signiﬁcantly in coming years.

Figure 31.36 Familial atypical mole–melanoma (FAMM) syndrome. Formerly called the dysplastic nevus syndrome, FAMM syndrome combines a family history of melanoma with multiple clinically atypical nevi. These patients need to be followed closely, photographed if necessary, and subjected to multiple surgical procedures to rid them of any suspect lesions.

Figure 31.37 Familial atypical mole–melanoma (FAMM) syndrome. The family with FAMM syndrome has a genetic predisposition to multiple moles and melanoma. The moles are usually abundant and clinically atypical.

Figure 31.38 Familial atypical mole–melanoma syndrome, close-up view. Note the atypical features of these nevi. Then imagine a patient with hundreds of these!

Table 31.2 THE ABCD CRITERIA FOR ASSESSMENT OF PIGMENTED LESIONS

Letter	Sign
A	Asymmetric shape
B	Irregular border
C	Deep black or two colors
D	7 mm or greater in diameter

Clinical

The body is covered with innumerable large, irregular nevi. These patients often have a large number of nevi (e.g. more than 50), as well as nevi in unusual sites (e.g. the buttocks, dorsum of the feet, and anterior aspect of the scalp) (Figs 31.36 – 31.38).

Differential diagnosis

The relevant concern is melanoma.

Treatment

Education of the patient on sun avoidance, the ABCD warning signs of melanoma (Table 31.2), and monthly self-examination is critically important. Complete skin examination by the physician, initially every 4–6 months, and removal of all suspicious atypical nevi should be done. However, some such patients have hundreds of nevi, and it is clearly impossible to remove them all; in any event, on histologic grounds, it seems that only about 50% of melanomas arise in a preexisting nevus. Dermoscopy and total body photography are therefore used for monitoring and have been shown to allow for very early detection of melanoma in these patients.

Melanoma

Etiology and pathogenesis

Melanoma is the most deadly of the common skin diseases. As of 2002, the lifetime risk of developing melanoma in the USA was 1 in 68. (In 1935, the lifetime risk was 1 in 1500!) In fact, melanoma was the most rapidly increasing malignancy in both sexes during the time period 1973–1997 in the USA. It is the most common cancer among women 20 to 29 years of age in the USA. Data from around the world indicated similar trends for fair-skinned populations. For example, recent data from Sweden shows that the incidence of melanoma in adolescence has doubled in the past 10 years.

Melanoma in children is rare, but when it does occur, it usually develops after puberty. Sometimes adolescents’ reticence about showing their bodies to their parents can cause a delay in seeking medical attention.

A variety of risk factors for melanoma have been identiﬁed and include fair skin, multiple sunburns as a child, many moles (especially if atypical, see earlier), use of tanning beds, and family history of melanoma in a ﬁrst-degree relative. Educational campaigns that emphasize early recognition as well as sunscreen use and the avoidance of tanning are being employed in many countries in the hopes of reducing melanoma morbidity and mortality.

Melanomas may be subdivided into different histogenetic types on clinicopathologic grounds (see later). Additionally, the growth phase of melanoma has been divided into two basic types: radial growth and vertical growth. Initially, the melanoma spreads laterally in two dimensions, forming a flat, black spot on the skin (Figs 31.39 and 31.40). The level of proliferation is low, and the thickness of the melanoma if it is caught and removed in this stage is thin (e.g. less than 0.75mm). At some point, the cells become so abnormal and unregulated that the vertical growth phase is entered. Here, the melanoma grows both up and down, creating a black nodule in the skin. The proliferation level is high, and the thickness is typically greater than 0.75 mm. Obviously, melanomas caught before they enter the vertical growth phase have a much better prognosis.

Figure 31.39 Small, early melanoma. Note the focus of dark pigment that prompted biopsy.

Figure 31.40 Early melanoma. This melanoma illustrates two colors and just barely met the size criteria.

The pathologist plays a signiﬁcant role in the treatment of the patient. The melanoma is graded by the pathologist by thickness, which greatly influences prognosis. Two standards are commonly used: Breslow thickness and Clark level. The Breslow thickness is determined by measuring in millimeters the distance from the stratum granulosum to the deepest cancerous cell, and it is the most important prognostic factor, although the Clark level may provide additional signiﬁcance at thin-skin sites. The Clark level is determined as follows.

•	Level I—no cells have penetrated the dermoepidermal junction (also termed melanoma in situ).
•	Level II—some cells are found in the papillary dermis.
•	Level III—cells ﬁll the papillary dermis.
•	Level IV—cells invade the reticular dermis.
•	Level V—cells invade into fat.

Obviously, the greater the thickness or the deeper the level, the poorer the prognosis. For example, the 10-year survival rates decrease nearly linearly from 100% to 50% for tumor thickness with a range of 0.1–6mm. Other factors have been found to convey a prognosis and include ulceration and axial involvement (versus extremity); for lesions from 2.5 to 3.99mm in thickness, male patients do worse than female ones.

The introduction of sentinel lymph node biopsy (SLNB, discussed further later) represents a signiﬁcant advance for staging melanoma and eliminates the need for routine elective lymph node dissection (for which the overall evidence for beneﬁt is in any event outweighed by the morbidity of the lymphedematous side effects). In SLNB, a radioactive material or blue dye is injected into the skin at the site of the melanoma. This tracer is then located in the draining lymph node basin in the ﬁrst node (occasionally more than one) that drains that area. If this is positive histologically, the patient proceeds to a full lymph node dissection. The morbidity of SLNB itself is extremely low, as only one or two lymph nodes are removed.

Although the term malignant melanoma is commonly used, it is redundant, as there is no such thing as a benign melanoma. The term melanoma is preferred.

Clinical

The classic melanoma is deﬁned by the ABCD warning signs (Figs 31.41 – 31.52, Table 31.2). Any lesion that fulﬁlls two or more criteria should be removed in its entirety for histologic examination. A lesion that is larger than most nevi, is irregularly shaped, with multicolored pigmentation and a notched border, especially with areas of deep black pigment, is characteristic.

Figure 31.41 Melanoma of the buttock. The key features are large size, two colors with one of them dark black, irregular edge, and eroded nodule.

Figure 31.42 Melanoma of the back. Two colors, with one of them being dark black, and an irregular shape are clinical clues here.

Figure 31.43 Melanoma of the sole. Any chronically eroded area should be biopsied. This lesion had pigment visible at one margin.

Figure 31.44 Melanoma of the palm. A large, black spot with an eroded red nodule. Melanoma is the only possibility.

Figure 31.45 Melanoma. This melanoma illustrates the myriad colors that may be seen: red, red-brown, black, and white from regression.

Figure 31.46 Melanoma of the sole in a dark-skinned patient.

Figure 31.47 Melanoma of the vulva. Benign nevi, vulva melanosis, and melanoma may occur in the vulvar region. Any suspicious pigmented lesion should be biopsied. The patient here is 75 years old. (Courtesy of Paul Koonings, M.D.)

Figure 31.48 (a,b) Subungual melanoma. Note the destruction of the nail.

Figure 31.49 Subungual melanoma with Hutchinson sign (pigment spreading from under the nail to involve the adjacent skin, usually of the proximal or lateral nail fold). These lesions are thought to emanate from the nail matrix.

Variants of melanoma

Melanoma has been subdivided on clinicohistologic grounds as follows.

•	In situ melanoma—if the melanoma is purely intraepidermal, and no neoplastic cells have penetrated the dermoepidermal junction, the term melanoma in situ or atypical melanocytic proliferation is used (the latter being a vague and less satisfactory term). Lentigo maligna is a speciﬁc variant of in situ melanoma and is discussed separately later. A lesion such as this is not cancerous, in that it cannot metastasize. It is cured if surgically removed.
•	Superﬁcial spreading melanoma (SSM)—this is the most common histogenetic type and comprises more than 70% of all melanomas (Figs 31.53 – 31.56). A radial growth phase predominates, leading to large, flat, black lesions.
•	Nodular melanoma (NM)—if a lesion enters the vertical growth phase from the outset, an NM results (Figs 31.57 and 31.58). Such lesions are nodular proliferations with a variable amount of pigment. If the lesion is predominantly red, often there is a telltale rim of black at the base.
•	Lentigo maligna melanoma (LMM) is a melanoma that has arisen from a lentigo maligna (Fig. 31.59). A lentigo maligna is a melanoma in situ that arises in heavily sun-damaged skin of an older individual (see later).
•	Acral lentiginous melanoma (ALM) is merely a term used to describe melanomas that occur acrally (e.g. on the ﬁngers or soles; Figs 31.42 and 31.60). This type is most common in the darker-skinned patient.
•	Subungual melanoma—deﬁned by its site, but important, and with some additional differential diagnoses beyond the pigmented lesions of the skin in Table 31.1.
•	Desmoplastic melanoma—this refers to a lesion that histologically shows melanoma cells among a dense desmoplastic stroma. It is a much less common histogenetic variant than the others listed here. The most common location is the head and neck, especially underlying an LMM, but it may also occur as a feature of ALM.
•	Rare melanoma variants—some are named according to their morphology, for example polypoid and verrucous melanomas.
•	Amelanotic melanoma—this type is named on the basis of its lack of melanin and is said to account for 2–3% of melanomas, although many actually have a ﬁne rim of pigment when carefully examined, or have histologically detectable pigmentation. Any histogenetic variant of melanoma may be amelanotic but, as it implies poor differentiation, which tends to correlate with rapid growth, amelanotic melanomas are most commonly of nodular type. Such lesions are often misdiagnosed as a vascular lesion (e.g. pyogenic granuloma) or other non-pigmented tumor (Figs 31.57, 31.61, and 31.62). An amelanotic component is particularly common on the sole of the foot. Thin SSM or LMM, or even in situ melanomas, may be amelanotic and have a wide differential diagnosis. Because of the atypical presentation, there is often a delay in diagnosis.

Figure 31.50 Melanoma dorsa of the foot. This small lesion was new and dark. Histologic examination showed a Clark level II melanoma.

Figure 31.51 Melanoma on the arm. The large area represents the superficial spreading (radial) component, with a nodular (vertical) component in the center.

Figure 31.52 Melanoma. Whenever the clinician, whatever the specialty, examines the patient, attention should be given to any pigmented lesions. Can you see the melanomafi (See also Fig. 31.53.)

Figure 31.53 Superficial spreading melanoma of the back (see Fig. 31.52). Any black nevus of diameter 7 mm or greater should be carefully examined and biopsied if there is any suspicion whatsoever.

Figure 31.54 Superficial spreading melanoma with a nodular component.

Figure 31.55 Melanoma of the ear. Note the superficial spreading component at the base and the nodule arising from it. The top of the ear often gets a great deal of sun.

Figure 31.56 Superficial spreading melanoma on the calf. This patient was heavily freckled from chronic sunbathing. Surprisingly, this growing tan patch was a melanoma, 0.6 mm, level II.

Figure 31.57 Amelanotic nodular melanoma on the cheek of an elderly woman.

Figure 31.58 Nodular melanoma of the chest. This melanoma has relatively little pigment in the nodule. The base, however, shows the diagnosis clearly.

Differential diagnosis of pigmented lesions

Refer to Table 31.1 for differential diagnosis of pigmented lesions. A variety of lesions may mimic melanoma; some are illustrated in Figs 31.63 – 31.70. It must be emphasized, however, that if there is any doubt in the clinician’s mind, a complete excision for histologic analysis should be performed.

New technology aids in the detection of melanoma. The use of the dermoscope (termed dermoscopy, dermatoscopy, or epiluminescence microscopy) will magnify cutaneous pigmented lesions, allowing for precise pattern analysis. It is gaining in popularity as an adjunct to clinical evaluation of pigmented lesions; recent studies suggest that the routine clinical use of these devices after adequate training may increase the malignant:benign ratio of histologic specimens.

Machines using various other techniques such as spectrographic analysis may have diagnostic sensitivity but currently suffer from a lack of speciﬁcity for melanoma.

Figure 31.59 Lentigo maligna melanoma of the cheek.

Figure 31.60 Acral lentiginous melanoma about the nail. Any black lesion on the fingertip (a) would clearly warrant biopsy. The lesion in (b) is much more sinister. It may elude biopsy for some time, mimicking eczema, a wart, or a keratoacanthoma.

Figure 31.61 Amelanotic melanoma of the scalp. This nondescript grouping of flesh-colored papules was initially frozen by a non-dermatologist who didn’t know what the lesion was, but figured freezing would make it go away. It did not. Any unusual growth, pigmented or otherwise, should be biopsied.

Figure 31.62 Amelanotic atypical melanocytic hyperplasia (AMH). Very rarely, a slowly growing red, scaly plaque may represent an amelanotic AMH. This lesion is particularly dangerous, because its serious nature is rarely suspected.

Figure 31.63 Recurrent nevus. When a nevus is only partially removed, usually via a shave biopsy, regrowth in bizarre patterns may occur. This gives rise to the recurrent nevus. The irregularly shaped, pigmented lesion shown here looks just like a melanoma. Note the surrounding white scar from the previous deep-shave excision. Complete excision should be done to verify the diagnosis and because this lesion cannot be monitored effectively for malignant change.

Figure 31.64 Perifollicular sparing of pigment in a nevus. A hair follicle at the edge of a nevus may cause a notch, as the pigment tends to spare this area. This feature is most common on the abdomen, and is benign but may give the appearance of clinical atypia.

Figure 31.65 Nodular blue nevus. This dark nodule may be confused with a nodular melanoma. However, the onset is usually in childhood and the lesion stabilizes after initial growth. Any suspicious growth should be biopsied.

Figure 31.66 Ink drop lentigo. This lentigo, most common on the upper back, appears like ink dropped on the skin. It is a variant of the solar lentigo and results from chronic sun exposure.

Figure 31.67 Seborrheic keratosis occasionally closely resembles a melanoma.

Figure 31.68 Hemangioma. When the venous blood is dark purple, the lesion may mimic a melanoma.

Figure 31.69 Thrombosed angiokeratoma. These lesions may thrombose, mimicking melanomas. Sometimes, unusual haloes of blood surround the lesion. (See also Ch 15).

Figure 31.70 Pigmented streaks in a scar. Streaks of pigment in a melanoma excision may mimic melanoma.

PRACTICE POINTS

•	If at all possible, remove the entire mole if you are suspicious for melanoma. A partial biopsy is not appropriate, as the atypia may be in the part you left in! It may also preclude adequate assessment of thickness, which is the major determinant of subsequent management.
•	Patients who have a history of one melanoma are at higher risk for a second primary. This is one of the key reasons patients are observed so closely.
•	Beware the non-pigmented fleshy nodule on the sole of the foot: it may be an amelanotic melanoma.
•	Always submit any pyogenic granuloma that you remove for histology, and excise rather than curette such lesions if the site or age of the patient is atypical for this diagnosis: it may be an amelanotic melanoma.

Treatment
The current therapy as of this writing is as follows. All atypical pigmented lesions should be immediately completely excised with narrow (e.g. 2mm) margins. Any lesions that are too large may be evaluated by an incisional biopsy in the thickest area.

Wide excision of melanoma is the main deﬁnitive treatment. Recommended excision margins are summarized in Table 31.3. Melanoma in situ should be excised with 2–5-mm margins. A melanoma of less than 1-mm thickness should receive wide excision with 1-cm margins, but guidelines accept that a narrower margin is acceptable for lesions at the thinner end of this spectrum. For melanoma 1–2mm thick, a 2-cm margin is recommended if anatomically possible, with a minimum of 1cm (Fig. 31.60). For tumors >2mm, there does not appear to be any advantage in employing margins greater than 2–3 cm.

In many countries, any patient with a melanoma of 1mm or greater may also be investigated by SLNB and, if positive, this is followed by complete lymph node dissection of the regional node basin; however, although undoubtedly a highly important tool for staging melanoma, there remains controversy about the beneﬁt of this procedure in terms of eventual outcome, as some would argue that all melanomas affecting local nodes have already metastasized further (and there is currently no deﬁnitive chemotherapeutic option for those in whom this suspicion exists). The likelihood of ﬁnding metastatic melanoma in the sentinel lymph node is approximately 1% if the thickness of the tumor is less than 0.8 mm, 8% if it is between 0.8 and 1.5mm, 23% if 1.5–4.0mm, and 36% if 4 mm or greater. A negative lymph node ﬁnding has a better prognosis. For example, in one study, distant metastases were present in 2.0% of sentinel node (SN)-negative patients and in 24% of SN-positive patients. Highly statistically signiﬁcant differences were found between SN-negative and SN-positive patients in both the 3-year disease-free survival rate (86.3% versus 49.2%) and the 3-year disease-speciﬁc survival (92.3% versus 77.1%).

Table 31.3 SUGGESTED SURGICAL MARGINS FOR EXCISION OF MELANOMA

Thickness (histologically measured)	Excision margin (clinically measured)
In situ	2–5 mm (at least with clear margins)
< 1 mm	0.5–1 cm (1 cm if > 0.76 mm thick)
1–2 mm	1–2 cm
2.1–4 mm	2–3 cm (usually 2 cm)
> 4 mm	2–3 cm

Figure 31.71 Multiple primary melanomas. This woman presented for evaluation of the large pigmented lesion on her sole. For completeness, all three pigmented lesions were removed. Surprisingly, all three were separate melanomas! The largest one was a thick melanoma Clark level IV. The other two were a primary melanoma Clark level II and a melanoma in situ.

All patients diagnosed with a melanoma should have a complete skin examination to look for a second primary (Fig.31.71). Obtaining a chest radiograph has a very low likelihood of ﬁnding disease (e.g. 0.1% in one study), but some still maintain its beneﬁt, if only to provide a baseline. UK guidelines suggest that imaging is not indicated for stage 0 (in situ), I (less than 1mm thick, or less than 2mm without ulceration), or IIA (less than 2mm thick, or less than 4mm without ulceration) melanomas (all these stages assuming no lymph node disease or metastasis).

Initial blood tests (full blood count, liver function, and lactate dehydrogenase), and radiographic scanning of the body (liver ultrasound at least, computed tomography of chest, abdomen, and pelvis if higher risk) is recommended for patients with thicker tumors and/or nodal disease (stage IIB or greater) to rule out metastasis and to serve as a baseline. However, routine follow-up blood analysis and chest radiography are of minimal value in detecting recurrence. In one study, when recurrence did occur, it was signaled by symptomatology in 68%, history and physical examination in 26%, and chest radiography in 6%.

Interferon alfa-2b is the only adjuvant treatment that has reliably been shown to reduce the recurrence of melanoma. It does, however, have many side effects, including headache, nausea, fatigue, weight loss, myelosuppression, and depression, as well as high cost. There is no consensus on strict criteria for recommending treatment with interferon alfa-2b. Therefore it should be recommended for patients where the risk of recurrence outweighs the expected side effects.

Figure 31.72 Melanoma of the foot. Primary melanoma with local cutaneous metastases. The patient presented with a swollen foot, and had about 100 small, black nodules on the dorsum of the foot and lower leg. The larger lesion on the dorsum of the foot had been present for 3 years, but the patient had assumed it was an injury from a bite or splinter.

Figure 31.73 Metastatic melanoma. (a) Primary melanoma with local spread on the sole. (b) Non-pigmented metastatic nodules from a primary melanoma of the ankle excised previously.

Figure 31.74 Metastatic melanoma. On routine follow-up in a man with a prior melanoma, this nondescript, new pink nodule was noted. Excision was positive for metastatic melanoma.

Follow-up

The patient without atypical moles or a family history can be seen routinely (e.g. every 3–6 months for 2 years, then yearly) for inspection and palpation of the scar, surrounding tissue, and regional lymph nodes, as well as a complete skin examination. Monthly self-examination is critically important, and relatives should be encouraged to have a complete skin examination. Three percent of patients develop a second primary melanoma within 3 years. Recurrence within the scar or in regional lymph nodes may be reduced by surgical excision. Even thin melanomas may give rise to metastases years after diagnosis, so patients should arguably have at least an annual follow-up for the rest of their life to look for both new primaries and metastatic disease. A minimum of 3 years follow-up is recommended for those with thin (less than 1mm thick) melanoma, and at least 5 years for all others.

Metastatic melanoma

Melanoma may recur at the surgical site, in transit to regional lymph nodes, in the locoregional nodes, or at distant sites (Figs 31.72 – 31.74). Multiple pigmented cutaneous lesions may occur. Diffuse hyperpigmentation and melanuria can develop. Late metastasis (after 10 years) may rarely occur. Measurement of plasma melanin metabolites may be able to detect occult metastases, as may polymerase chain reaction (PCR) of blood to detect tyrosinase gene expression (and thus circulating melanocytes).

Various chemotherapeutic regimens are used for treatment. Dacarbazine plus tamoxifen increases survival, especially in women. High-dose bolus interleukin-2 is used, but side effects are severe. Various combinations of chemotherapeutic drugs are currently being investigated, as are vaccines and other biological agents.

Lentigo maligna

Etiology and pathogenesis

Lentigo maligna (LM) is a melanocytic proliferation in actinically damaged skin that may progress to melanoma. The terminology of freckles, lentigines, LM, and LMM is often poorly understood, so has been listed in Table 31.4.

Table 31.4 TERMINOLOGY OF FRECKLES AND LENTIGINES

Feature	Freckle	Lentigo	Lentigo maligna	Lentigo maligna melanoma
Increased pigment	+	+	+	+
Increased melanocytes	-	+	+	+
Cytologically atypical (malignant) melanocytes in epidermis	-	-	+	+
Cytologically atypical (malignant) melanocytes in dermis	-	-	-	+

Figure 31.75 Lentigo maligna melanoma on the cheek. Note the Favre–Racouchot comedones as well (both secondary to too much sun).

Lentigo maligna has typically been viewed as a melanocytic dysplasia, an in situ precancer, that is histologically conﬁned to the epidermis (including extension down the hair follicle). However, invasion into the dermis may occur, creating LMM. Once invasion has occurred, the prognosis based on thickness is the same as for other types of melanoma.

Clinical

A slowly enlarging, irregularly pigmented, irregularly shaped macule on the face of an older adult is characteristic (Figs 31.75 and 31.76). A Wood’s light may be helpful in delineating the extent of the lesion. An amelanotic form occurs; a raised hypopigmented area within LM should be viewed as suspicious in the same way that a blacker nodule should be.

Treatment

Surgical excision with clear margins is the treatment of choice, if feasible. A margin of 0.5cm for small lesions and 1.0cm for larger lesions has been recommended, due to the difﬁculty that may arise in identifying a deﬁnite transition between dysplastic malignant versus chronically sun-exposed melanocytes. Staged excision (vertical excision with initial 2–3-mm margins examined by rush permanent sections, prepared and read within 24h, followed by further excision as guided by histologic ﬁndings) can provide a 5-year disease-free survival of 95%.

Figure 31.76 Lentigo maligna melanoma. This lesion grew over 37 years. (Courtesy of Michael O. Murphy, M.D.)

Several other treatments may be considered in selected patients for whom surgery is contraindicated or would have signiﬁcant morbidity (most patients being elderly). Topical imiquimod can be used; a typical treatment regimen is 5% imiquimod applied 5 days per week to the clinical lesion and for 2cm around it for 12 weeks. However, biopsies afterward show residual disease, or even complete lack of effect, in some patients, so resolution of clinically apparent pigment cannot be safely accepted as implying a cure. Cryotherapy (ideally with a thermocouple) has been used, as has CO2 laser. However, follicular recurrences may occur if treatment is inadequate in depth. Fractionated radiation therapy using superﬁcial X-rays is a simple and effective method with very good results for LM, especially in older patients, but results are less good if invasion has occurred (which may not be apparent in a sampling biopsy). All these non-surgical or destructive modalities require close follow-up with biopsy of any recurrent pigmentation.

Merely following LM with the idea that invasion may be treated if it occurs is not recommended. Cases have been reported where life-threatening melanoma developed.

PRACTICE POINTS

•	Determining adequate excision of a lentigo maligna (LM) is difﬁcult, as adjacent sun-damaged melanocytes also appear abnormal, termed ‘never-ending’ surgical margins.
•	Results of radiotherapy for LM without invasion are excellent; this or topical imiquimod may be considered in patients in whom excision would be difﬁcult.
•	A raised hypopigmented area within an LM is as suspicious as a black nodule.