Melanoma

Preface

Malignant melanoma accounts for the greatest number of deaths due to skin disease, and such deaths might be prevented by early diagnosis followed by excision. The non dermatologist physician must be able to evaluate pigmented lesions and appropriately refer for evaluation all potential malignant melanomas. In order to avoid missing some malignant melanomas. In order to avoid missing some malignant melanomas, it is understood that many patient will be referred for what ultimately prove to be benign lesions.

Definition

Cutaneous malignant melanoma is a neoplasm arising from the melanocytes that can occur de novo or from a preexisting lesion such as a congenital, acquired, or atypical (dysplastic) nevus. Noncutaneous primary sites of melanocytes also include the mucosal epithelium, retinas, and leptomeninges. Because melanoma is potentially curable with surgical excision of early, thin lesions, prompt detection, diagnosis, and adequate removal of such lesions are of utmost importance. Education of the public with regard to the technique of routine self-examination and proper methods of sun protection can greatly improve the chances for early detection and adequate treatment of melanoma. A multidisciplinary approach, including primary care physicians, dermatologists, surgeons, oncologists, immunologists, radiologists, pathologists, and epidemiologists is necessary to optimize detection and treatment of this increasingly common cancer.

Pathophysiology

Evidence from epidemiologic studies shows that exposure to solar irradiation is the main cause of cutaneous melanoma in fair-complected persons. 3,4 This causal relation is supported by anatomic differences by sex, migration studies, difference in latitude of residence, and racial differences.

The most common site for melanoma in men is the upper back; in women, the most common sites are the lower legs and upper back. Studies have also shown that persons who immigrated to countries with higher levels of ambient solar radiation have increased rates of melanoma compared with similar people who did not move. Likewise, melanoma incidence and mortality rates in white persons were inversely correlated with distance from the equator. Racial differences also exist with respect to melanoma. The lower rate of melanoma in darkly pigmented persons results from the protective effect of melanin and smaller number of nevi that can serve as precursor lesions for melanoma. The main risk factors for cutaneous melanoma include phenotype (blue eyes, blond or red hair, and fair complexion), cutaneous reaction to sun exposure (freckling, inability to tan, sunburn tendency), history of severe (blistering) sunburns or intense intermittent sun exposures, upper socioeconomic status, family history of melanoma, number and subtypes of nevi (atypical nevi or giant melanocytic nevi), history of prior melanoma, and immunosuppression.

Genetic studies have also shown that 50% of familial melanomas and 25% of sporadic melanomas may be due to mutations in the tumor suppressor gene p16. Linkage studies have identified chromosome 9p21 as the familial melanoma gene. About 8% to 12% of all melanoma cases are familial melanoma. The familial melanoma syndrome (also known as the dysplastic nevus syndrome) has been defined as melanoma in one or more first- or second-degree relatives; large numbers of melanocytic nevi (often 50 to 100 or more), some of which are atypical and varied in size; and melanocytic nevi demonstrating certain histologic features. The mode of inheritance is most likely polygenic. The cumulative risk of developing cutaneous melanoma among persons with a history of familial melanoma is estimated to be approximately 50% by 50 years of age.

Five stages of tumor progression have been suggested:

1. Benign melanocytic nevi

2. Melanocytic nevi with architectural and cytologic atypia (dysplastic nevi)

3. Primary malignant melanoma, radial growth phase

4. Primary malignant melanoma, vertical growth phase

5. Metastatic malignant melanoma

Each step in tumorigenesis is marked by a new clone of cells with growth advantages over the surrounding tissues

Signs and symptoms

Early signs of melanoma include the ABCDEs: asymmetry of lesion; border irregularity, bleeding, or crusting; color change or variegation (some lesions are amelanotic [nonpigmented]); diameter larger than 6 mm or growing lesion; evolving (surface changes (raised, bleeding, crusting) or symptomatic (itchiness or tenderness). About 1% to 2% of primary melanomas arise from mucous membrane melanocytes. Approximately 5% to 10% of patients present with metastatic disease (usually in the lymph node basin) without an identifiable primary lesion. Less than 2% of patients present with visceral metastases in the absence of an unknown primary lesion.

Precursor Lesions

Acquired dysplastic nevi are atypical-appearing melanocy-tic tumors that are histologically characterized by intraepidermal melanocytic dysplasia. Dysplastic nevi are important because they are potential histogenic precursors of melanoma and markers of increased melanoma risk. Dysplastic nevi are fairly common; in the United States, 1.8% to 4.9% of white adults have dysplastic nevi. Dysplastic nevi start as rather large moles during the first decade of life. Almost 40% of children from families with dysplastic nevi melanoma have dysplastic nevi, and all children in whom melanoma eventually develops have dysplastic nevi. At least 17% of white adults with melanoma outside the familial melanoma setting have one or more dysplastic nevi, illustrating that dysplastic nevi are markers of risk, as well as potential precursors.

Management for patients who have dysplastic nevi, with or without a personal or family history of melanoma, is controversial. Pathologic confirmation of the clinical diagnosis provides a more solid basis for making further management decisions. For people who have one or two suspected dysplastic nevi, excision is reasonable, but periodic examinations should be offered for a lifetime. Prophylactic removal of suspected dysplastic nevi is not feasible for people who have numerous dysplastic nevi. In patients with many dysplastic nevi, excision for hard-to-monitor areas (scalp, perineum, etc.) should be considered, and serial clinical photography of other lesions should be performed to detect new or changing lesions. Persons with dysplastic nevi should also be instructed on how to practice skin self-examination every 4 to 6 weeks at home.

For the removal of dysplastic nevi, lateral margins of about 2 to 3 mm should be taken to ensure complete removal. Dysplastic nevi can remain unchanged, progress to melanoma, or even regress over time. Only a small fraction of dysplastic nevi ever progress to melanoma, even in the familial melanoma setting. It is probable that both environmental and genetic factors play a role in the transition from dysplastic nevus to melanoma. In Greene and colleagues' study of dysplastic nevi–melanoma kindreds, they found the actuarial probability of melanoma developing in persons who have dysplastic nevi in the familial melanoma setting may be as high as 56% from age 20 to 59 years and 100% by age 76 years.

figure: Atypical nevus

Subtypes

The subtypes of melanoma are distinguished by clinical and pathologic growth patterns: superficial spreading, lentigo maligna, nodular, and acral lentiginous.

Lentigo Maligna and Lentigo Maligna Melanoma

Lentigo maligna (melanoma in situ) ( begins as a tan irregular macule that extends peripherally, with differing shades throughout. It occurs on sun-damaged atrophic skin in elderly persons. Lentigo maligna occurs equally in men and women, usually in the seventh and eighth decades of life. The exact percentage of lentigo maligna that progress to invasive lentigo maligna melanoma is unknown, but it is estimated to be less than 30% to 50%. The lesion can grow slowly for 5 to 15 years in the precursor form before invasion. Although lentigo maligna has a prolonged radial growth phase, when invasion occurs, the result can be lethal. Long-term cumulative rather than intermittent sun exposure is believed to confer the greatest risk for developing lentigo maligna. see the figure below

figure: lentigo maligna melanoma

Lentigo maligna melanoma arises from lentigo maligna, a melanoma in situ (within the epidermis).

Lentigo mamligna elanoma is the least common subtype of melanoma, accounting for 4% to 15% of all melanoma patients. Lentigo maligna melanoma occurs almost exclusively on the sun-exposed skin of the head and neck; the nose and cheeks are the most common sites. Median age at diagnosis is 65 years. The lesion is usually quite large (3 to 6 cm or greater), with a variable nodular area from 1 mm to 2 cm in width. Rarely, lentigo maligna and lentigo maligna melanoma are amelanotic.

Superficial Spreading Melanoma

Superficial spreading melanoma (SSM) represents approximately 70% of all melanomas and is the most common type of cutaneous melanoma occurring in light-skinned people. It affects adults of all ages, with the peak incidence in the fourth and fifth decades of life. SSM, not uncommonly, can arise in a preexisting melanocytic nevus. The usual history is that of a slowly changing mole over 1 to 5 years. SSM most commonly affects intermittently sun-exposed areas with the greatest nevus density, such as the upper backs of men and women and lower legs of women.

Clinically, SSM starts as a deeply pigmented macule or plaque with intact skin markings. The earliest change in SSM can be a focal area of darkening within a preexisting nevus. Pigment variegation ranges from black and blue-gray to pink or gray-white. Absence of pigmentation within an SSM often represents regression of the melanoma, and the borders are often extremely irregular. The SSM subtype usually manifests with the classic early signs of melanoma (ABCDEs). see the picture below

 

figure: superficial spreading melanoma

Nodular Melanoma

The second most common subtype of melanoma is nodular melanoma.Nodular melanoma represents 15% of all melanomas. The median age at onset is 53 years. Clinically, nodular melanoma manifests as a uniform blue-black, blue-red, or amelanotic nodule. About 5% of nodular melanomas lack pigment (amelanotic melanoma). The most common sites for nodular melanoma are the trunk, head, and neck. It is more common for nodular melanoma to begin in normal skin rather than in a preexisting lesion. Rapid growth is also a hallmark of nodular melanoma. see the picture below

figure: nodular melanoma on the forearm

Acral Lentiginous Melanoma

Acral lentiginous melanoma accounts for 10% of melanomas overall; however, they are the most common types among Japanese, African Americans, Latin Americans, and Native Americans. The median age for occurrence is 65 years, with equal gender distribution. The most common site of melanoma in African Americans is the feet, with 60% of patients having subungual or plantar lesions. Overall, acral lentiginous melanoma can occur on the palms or soles or beneath the nail plate; the sole is the most common site in all races. The average size at diagnosis is 3 cm, which may be related to delayed diagnosis. Clinically, the lesion is characterized by a tan, brown-to-black, flat macule with color variegation and irregular borders. Unlike lentigo maligna melanoma, development of acral lentiginous melanoma does not seem to be associated with sun exposure.

Subungual melanoma is a rare variant of acral lentiginous melanoma. Most subungual melanomas involve the great toe or thumb and generally arise from the nail matrix. Hutchinson's sign is the finding of pigmentation on the posterior nail fold and is associated with advanced subungual melanoma

Demoplastic Melanoma

Desmoplastic melanoma is a rare subtype of melanoma that is locally aggressive and has a high rate of local recurrence. It most commonly develops on sun-exposed skin of the head and neck of elderly persons in the sixth or seventh decade of life. Desmoplastic melanoma has a male predominance ratio of approximately 2 : 1. Approximately one half of desmoplastic melanomas develop in association with a lentigo maligna. Desmoplastic melanoma can manifest clinically as a pigmented macule with or without a nodular component or as a flesh-colored nodule without any surrounding pigmentation. Desmoplastic melanomas often invade perineurally and are, therefore, often symptomatic. Most desmoplastic melanomas are deeply invasive at the time of diagnosis, at least 5 to 6 mm thick. They have a propensity to recur and deeply invade locally.

figure: demoplastic melanoma

Diagnosis

As with nonmelanoma skin cancers, biopsy is indicated for all suspicious pigmented lesions. Surface epiluminescence microscopy (dermatoscopy) and ultrasound are evolving adjunctive noninvasive diagnostic techniques. According to the American Academy of Dermatology (AAD) guidelines, whenever possible the lesion should be excised with narrow margins for diagnostic purposes. An incisional biopsy technique is appropriate when suspicion for melanoma is low, the lesion is large, or it is impractical to perform a complete excision. A repeat biopsy should be performed if the initial biopsy specimen is inadequate for accurate histologic diagnosis or staging. Fine needle aspiration cytology should not be used to assess the primary tumor. Histologic interpretation should be performed by a pathologist experienced in the microscopic diagnosis of pigmented lesions. The differential diagnosis is listed in

Determining melanoma stage is important for planning appropriate treatment and assessing prognosis. The American Joint Commission on Cancer (AJCC) has revised the four-stage system, reflecting new findings that the Clark level (level of invasion according to depth of penetration of the dermis) offer little prognostic information for tumors thicker than 1 mm, whereas histologic ulceration consistently worsens prognosis across all tumors depths. There are now a and b (nonulcerated and ulcerated, respectively) categories for each primary tumor level, for a total of eight. A new stage, IIC, has been added, which represents clinically localized melanoma with the worst prognosis (thick, ulcerated primary tumors). The main changes of the revised AJCC staging system include simplified tumor-thickness thresholds from 0.75, 1.5, and 4.0 mm to 1.0, 2.0, and 4.0 mm; reassignment of thick tumors (>4.0 mm) from stage III to stage II; and elimination of the Clark level as a criterion except in tumors 1.0 mm thick. Additional staging criteria include presence or absence of microscopic ulceration, number of nodal metastases, metastatic burden, serum lactate dehydrogenase (LDH) level, and sentinel lymph node status.

Eighty-five percent of melanoma patients have localized disease (stages I and II) on presentation. About 15% of patients have regional nodal disease, and only about 2% of patients have distant metastases at diagnosis. Prognosis for stages I and II melanoma can be affected by many factors. Factors associated with an improved prognosis include younger age, female gender, extremity lesions, and histologically negative nodes. Histologic variables associated with a less-favorable prognosis include increasing tumor thickness, deeper level of invasion, increased mitotic rate, ulceration, diminished lymphoid response, evidence of tumor regression, microscopic satellites, vascular invasion, and non–spindle-cell type tumors.

Treatment

According to the AAD's 2001 guidelines, surgical management of primary cutaneous melanoma should focus on obtaining an excision margin based on histologic confirmation of tumor-free margins.

1. Melanoma in situ: 0.5-cm margins

2. Melanoma with Breslow's thickness <2 mm: 1.0-cm margins

3. Melanoma with Breslow's thickness ≥2.0 mm: 2.0-cm margins

In certain circumstances, surgical management needs to be tailored to the individual case. Primary melanomas near a vital structure might require a reduced margin, and aggressive histologic features can suggest a more worrisome tumor and warrant a wider margin. Surgical excision at sites such as the fingers, toes, soles, and ears also need separate surgical considerations.

Mohs' micrographic surgery might prove useful for excision of melanoma, especially lesions located on the head, neck, hands, and feet. However, there are no formal recommendations pending additional studies. Studies suggest that the current recommendation of 0.5-mm margins for lentigo maligna (melanoma in situ) is often insufficient. Mohs' micrographic surgery and margin-controlled excision of lentigo maligna offer lower recurrence rates and allow tissue to be conserved. Despite adequate surgical resection of the primary melanoma, approximately 15% to 36% of patients with stages I and II melanoma will have some form of recurrence or metastasis during their clinical course.

Routine laboratory tests and imaging studies are not required for asymptomatic patients with primary cutaneous melanoma 4 mm or less in thickness for initial staging or routine follow-up. Indications for such studies are directed by a thorough medical history and complete physical examination. However, some studies have suggested that a chest x-ray and serum lactate dehydrogenase (LDH) might help detect occult metastases and alter further clinical management.

Prevention and screeening

Primary prevention of melanoma requires reduction of known risk factors in at-risk populations. The most important modifiable behavior for melanoma prevention is reduction of ultraviolet exposure. Education of the public regarding sun protection, risk factors for developing skin cancer, and skin self-examination is essential. The American Academy of Dermatology's skin cancer awareness initiatives such as Melanoma Monday (an annual countrywide event offering free skin cancer screenings conducted by dermatologists to raise awareness about melanoma and encourage Americans to begin a lifelong habit of regular skin examinations) and Sun Smart programs have been particularly effective in creating positive change in society's approach toward the sun.