Melanoma is a malignancy of pigment-producing cells (melanocytes) located predominantly in the skin, but also found in the eyes, ears, GI tract, leptomeninges, and oral and genital mucous membranes. Melanoma accounts for only 4% of all skin cancers; however, it causes the greatest number of skin cancer-related deaths worldwide. Early detection of thin cutaneous melanoma is the best means of reducing mortality.
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The sequence of events in which normal melanocytes transform into melanoma cells ("melanomagenesis") is poorly understood. It likely involves a multistep process of progressive genetic mutations that (1) alters cell proliferation, differentiation, and death and (2) impacts susceptibility to the carcinogenic effects of ultraviolet radiation. Primary cutaneous melanoma may develop in precursor melanocytic nevi (common, congenital, and atypical/dysplastic types), although more than 60% of cases are believed to arise de novo (i.e.: not from a preexisting pigmented lesion). The development of melanoma is multifactorial and appears to be related to multiple risk factors, including fair complexion, excessive childhood sun exposure and blistering childhood sunburns, an increased number of common and dysplastic moles, a family history of melanoma, the presence of a changing mole or evolving lesion on the skin, and, importantly, older age.
The incidence of melanoma has more than tripled in the white population during the last 20 years, and melanoma currently is the seventh most common cancer in the United States. Approximately 60,000 Americans developed invasive cutaneous melanoma in 2005, with an estimated additional 40,000 or more cases of melanoma in situ. The current lifetime risk for developing invasive melanoma is 1 case per 65 Americans, a 2000% increase since 1930. This risk rises to 1 case per 37 Americans if noninvasive melanoma in situ is included.
While melanoma accounts for roughly 4% of all skin cancers, it is responsible for more than 77% of skin cancer deaths. In the United States, one person each hour dies from metastatic melanoma. Treatment of melanoma in its early stages provides the best opportunity for cure.
Analysis of US Surveillance, Epidemiology, and End Results (SEER) data from 1969-1999 demonstrated a disproportionate burden of melanoma deaths among middle-aged and older white men. While melanoma mortality rates have fallen 39% in women and 29% in men aged 20-44 years over this period, they have increased 70% in men aged 45-64 years and 157% in older men (>65 y). Incidence data generally parallels mortality data and has shown a 3-fold increase in middle-aged men and a 5-fold increase in older men over a similar period.
Melanoma is primarily a malignancy of white individuals. African American persons develop melanoma approximately one twentieth as frequently as white persons, and the prevalence in Hispanic persons is approximately one sixth of that in white persons. However, mortality rates are higher in African Americans and Hispanics, who are more likely to have acral melanoma and advanced disease at presentation. The median age at melanoma diagnosis is 53 years; however, it is the most common cancer in women aged 25-29 years and is second only to breast cancer in women aged 30-34 years.
A changing mole is the most common warning sign for melanoma. Variation in color and/or an increase in diameter, height, or asymmetry of borders of a pigmented lesion are noted by more than 80% of patients with melanoma at the time of diagnosis. Symptoms such as bleeding, itching, ulceration, and pain in a pigmented lesion are less common but warrant an evaluation. Again, because cutaneous melanoma arises de novo (i.e.: not in association with a precursor nevus), the wholesale removal of melanocytic nevi is not warranted for melanoma prevention. However, individuals with numerous moles (common or dysplastic) or a family history of melanoma should be educated regarding the importance of skin self-examination for early detection of skin cancer.
Physician and patient education regarding the warning signs of early melanoma has been achieved successfully through the use of the ABCDE criteria for a changing mole, which are as follows:
- Asymmetry: One half of the lesion does not match the other half.
- Border irregularity: The edges are ragged, notched, or blurred.
- Color variegation: Pigmentation is not uniform and may display shades of tan, brown, or black; white, reddish, or blue discoloration is of particular concern.
- Diameter: A diameter greater than 6 mm is characteristic, although some melanomas may have smaller diameters; any growth in a nevus warrants an evaluation.
- Evolving: Changes in the lesion over time are characteristic; this factor is critical for nodular or amelanotic (nonpigmented) melanoma, which may not exhibit the classic criteria above.
The ABCDEs have the greatest diagnostic accuracy when used in combination. Lesions exhibiting these features should be considered potential melanoma, although severely atypical nevi may be difficult to distinguish clinically.
Four major clinicopathologic (or histogenetic) subtypes of primary cutaneous melanoma have been identified. These include superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma. Distinction among the subtypes is largely based on anatomic site, and whether the melanoma subtype affects the overall prognosis remains controversial. However, molecular analysis has demonstrated different patterns of cell death, oncogene expression, gene amplification, and BRAF mutation frequency among the 4 main histogenetic types.
With the exception of nodular melanoma, the growth patterns of the other subtypes are characterized by a preceding in situ (radial growth) phase that lacks the biologic potential to metastasize and may last from months to years before dermal invasion occurs. While all in situ melanoma may not necessarily progress to invasive melanoma, complete excision is recommended to prevent invasion and effect cure.
Melanoma can occur on any skin or mucosal surface, although a history of cutaneous melanoma does not appear to increase the risk of developing primary intraocular or mucosal melanoma. Melanoma occurs most commonly on the trunk in white males and the lower legs and back in white females. In African American, Hispanic, and Asian persons, the most common site is the plantar foot, followed by subungual, palmar, and mucosal sites.
Melanoma tends to occur at sites of intermittent, intense sun exposure (i.e.: on trunk in males and legs and back in females). The disease shows an increased worldwide incidence in fair-complexioned individuals living in sunny climates and nearer the equator, suggesting a causative role for ultraviolet radiation. Primary risk factors for melanoma include the following: changing mole (most important risk factor), atypical/dysplastic nevi (particularly >5-10), large numbers of common nevi (>100), sun sensitivity/history of excessive sun exposure, melanoma in first-degree relative, male sex, and age older than 50. Importantly, a fair-skin phenotype (blue/green eyes, blond or red hair, light complexion, sun sensitivity) and the occurrence of blistering sunburn(s) in childhood and adolescence are universal risk factors for melanoma. Individuals with these traits have been the focus of preventive efforts worldwide.
The most important aspects of the initial workup for patients with cutaneous melanoma are a careful history, review of systems, and physical examination; also important is a sentinel lymph node biopsy (SLNB) for pathologic staging of the regional nodal basin(s) for primary tumors greater than or equal to 1 mm depth. Recently published data have shown that baseline and surveillance laboratory studies (e.g.: lactate dehydrogenase [LDH] level, liver function tests), chest radiography (CXR), and other imaging studies (e.g.: CT scanning, positron emission tomography [PET] scanning, bone scanning, MRI) are not typically beneficial for stage I/II (cutaneous) melanoma patients without signs or symptoms of metastasis. A metastatic workup should be initiated if physical findings or symptoms suggest disease recurrence or if the patient has documented nodal metastasis based on results from the SLNB.
Practice guidelines developed by the National Comprehensive Cancer Network support the concept that most melanoma recurrences are diagnosed clinically. The current guidelines state that baseline or surveillance CXR and LDH studies may be performed for stage IB/III melanoma on an ”optional” basis every 3-12 months at the discretion of the clinician. Advanced imaging studies should be obtained as clinically indicated for documentation or for suspected metastasis. Current recommendations do not indicate that baseline or surveillance studies are necessary in patients with melanoma in situ (stage 0) or stage IA disease (<1 mm thickness).>
While abnormal laboratory test results are rarely the sole indicator of metastatic disease, serum LDH levels have been incorporated into the American Joint Committee on Cancer (AJCC) 2002 melanoma staging guidelines for the classification of stage IV (distant) disease. Elevated LDH levels are associated with worse survival in this subgroup. Serum S-100 protein levels may also be useful as a tumor marker in patients with metastatic disease.
Studies have confirmed that extensive radiologic studies such as CT scanning, MRI, PET scanning, ultrasonography, and bone scanning have an extremely low yield in asymptomatic patients with primary cutaneous melanoma (AJCC stages I and II) and are generally not indicated. However, maintaining a low threshold for obtaining symptom-directed tests is important. Baseline metastatic staging for melanoma patients with primary tumors greater than 1 mm in depth may include CXR, which typically is repeated every 6-12 months for routine surveillance (optional in the absence of signs or symptoms of metastatic disease).
The criterion standard for melanoma diagnosis is histopathologic examination of clinically suggestive skin or mucosal lesions. An excisional biopsy (fusiform, punch, or deep saucerization technique) with narrow margins is preferred to ascertain the following information: tumor thickness (Breslow depth), presence of ulceration, anatomic level of invasion (Clark level), presence of mitoses, presence of regression, lymphatic/vessel invasion or vascular involvement, and host response (tumor-infiltrating lymphocytes).
Generally, 1-3 mm of normal skin surrounding the pigmented lesion should be removed to provide accurate diagnosis and histologic microstaging. Superficial shave biopsies of suggestive pigmented lesions are discouraged because partial removal of the primary melanoma may not provide an accurate measurement of tumor thickness, which is the most important histologic prognostic factor for cutaneous melanoma. A very important exception to this rule is lentigo maligna. In the case of lentigo maligna, the risk of misdiagnosis is high if small, deep biopsy specimens are taken. Taking large, deep biopsy specimens can be disfiguring. The best diagnostic biopsy technique in this case is often a broad, paper-thin shave biopsy.
Tumor thickness, as defined by the Breslow depth, is the most important histologic determinant of prognosis and is measured vertically in millimeters from the top of the granular layer (or base of superficial ulceration) to the deepest point of tumor involvement. Increased tumor thickness confers a higher metastatic potential and a poorer prognosis. The presence of ulceration microscopically, defined as the loss of epidermis overlying the melanoma, is the next most important histologic determinant of patient prognosis and, when present, should be used to up-stage patients with melanoma.
The melanoma staging system initially developed in 1983 by the AJCC and the International Union Against Cancer (UICC) divided melanoma into 4 stages and incorporated tumor thickness and anatomic level of invasion for stages I and II (localized cutaneous disease), with the later recommendation to follow Breslow depth. Stage III disease involved the regional lymph nodes; stage IV disease included distant skin, subcutaneous, nodal, visceral, skeletal, or CNS metastasis.
Major revisions in the 2002 AJCC/UICC melanoma staging system were made based on a critical analysis of prior versions of the staging protocol. The AJCC formed an international multidisciplinary Melanoma Staging Committee and established a new clinicopathologic database of more than 17,000 patients worldwide to test the validity of the proposed staging changes. Several important modifications in the 2002 AJCC staging system include the incorporation of histologic ulceration and number of lymph nodes involved (instead of size) to better stratify metastatic risk and patient prognosis.
The actual staging classification is beyond the scope of this review, but can be readily found in up to date oncology texts and on-line.
Numerous adjuvant therapies have been investigated for the treatment of localized cutaneous melanoma following complete surgical removal. No survival benefit has been demonstrated for adjuvant chemotherapy, nonspecific (passive) immunotherapy, radiation therapy, retinoid therapy, vitamin therapy, or biologic therapy. Adjuvant interferon (IFN) alfa-2b is the only adjuvant therapy approved by the US Food and Drug Administration for high- risk melanoma (currently defined as stages IIB, IIC, and III), which is associated with a 40-80% chance of relapse and death. Various experimental melanoma vaccines also show promise in the adjuvant setting.
Melanoma vaccines are a theoretically attractive alternative to chemotherapy or immunotherapy with systemic cytokines because they are typically associated with relatively little toxicity (e.g.: fatigue, myalgias, local inflammatory skin reactions). Melanoma vaccines are a type of specific active immunotherapy based on melanoma cell expression of certain HLA- and tumor-associated antigens. Numerous melanoma-associated antigens have been identified, and which of these are the most important in eliciting the necessary cytotoxic and humoral responses to kill melanoma cells remains unclear. In addition, HLA haplotype restriction (mainly to the A2 allele) limits the use of peptide vaccines in many patients. Most current trials for melanoma vaccines are for advanced disease (stages III and IV); trials aimed at prevention are not yet available.
As yet, no large, phase 3 randomized trial has demonstrated a survival advantage for vaccine-treated melanoma patients; however, multiple studies are in progress.
Surgery is the primary mode of therapy for localized cutaneous melanoma. Surgical margins are of paramount importance. Surgery for melanoma greater than or equal to 2 mm thickness (median depth 3 mm) suggests that narrower margins (1 cm) result in higher locoregional recurrence compared with wider margins (3 cm).
Mohs micrographic surgery has been proposed for cutaneous melanoma and has the advantage of providing visualization of 100% of peripheral and deep margins microscopically. Mohs surgery may have certain potential ”niche” indications, including melanomas located in the area of the head, neck, hands, or feet. Mohs surgery may prove useful in completely removing subclinical tumor extension in certain subtypes of melanoma in situ, such as lentigo maligna, desmoplastic melanoma, and acral lentiginous melanoma in situ.
Prophylactic lymph node dissection for primary cutaneous melanoma of intermediate thickness initially was believed to confer a survival advantage on patients with tumors of 1-4 mm in depth. Subsequently, prospective randomized clinical trials have shown no survival benefit for elective lymphadenectomy for melanomas of varying thicknesses on the extremities and marginal, if any, benefit for nonextremity melanomas. The 10-year follow-up data from 2 of the trials conducted by the World Health Organization and the Melanoma Intergroup now suggest a survival benefit for certain subsets of patients studied. In particular, patients in the World Health Organization trial who had occult metastasis detected at the time of wide local excision and immediate elective node dissection had a significantly better 5-year survival rate (48%) compared with those who underwent delayed (therapeutic) lymph node dissection when lymphadenopathy became apparent clinically (27%). The differences in OS rates for all patients who had delayed lymph node dissection was not statistically significant compared with the immediate node dissection group.
Lymphatic mapping and sentinel node biopsy have effectively solved the dilemma of whether to perform regional lymphadenectomy (in the absence of clinically palpable nodes) in patients with thicker melanomas (>1 mm in depth). SLNB for cutaneous melanoma was developed in the early 1990s to allow a selective approach to identifying individuals with occult regional nodal metastasis through localization of the first draining, or sentinel, node. The success of the technique is based on the concept that cutaneous lymphatic flow is well-delineated in melanoma and that the histology of the sentinel node is characteristic of the entire lymph node basin (i.e.: a negative sentinel node obviates the need for further lymph node dissection). Both of these concepts were borne out in the initial studies of the staging technique. A negative sentinel node biopsy result prevents the morbidity associated with an unnecessary lymphadenectomy.
Sentinel node status (positive or negative) is the most important prognostic factor for recurrence and is the most powerful predictor of survival in melanoma patients. In a study of 612 patients with cutaneous melanoma (stage I/II), negative results from SLNB were associated with a nearly 60% increase in 3-year disease-free survival compared with positive SLNB results. Current AJCC 2002 melanoma staging guidelines promote pathologic staging of the regional lymph nodes for cutaneous melanoma of greater than 1 mm depth along with microstaging of the primary melanoma as the most complete means of staging. While SLNB certainly enhances metastatic staging for patients with deeper primaries and provides a more accurate determination of the patient's prognosis, its therapeutic role has yet to be established. The results of the Multicenter Selective Lymphadenectomy Trial and the Sunbelt Melanoma Trial should help to determine whether SLNB provides a therapeutic benefit in patients with cutaneous melanoma.
Patients should be followed regularly after a diagnosis of cutaneous melanoma, particularly in the setting of thicker tumors, because most metastases occur in the first 1-3 years after treatment of the primary tumor. Annual skin examinations are recommended for life because an estimated 5% of patients with a history of melanoma develop new primary melanoma, generally within the first 3 years following diagnosis. The risk of new primary melanoma increases in the setting of multiple clinical atypical/dysplastic nevi, family history of melanoma, and atypical mole syndrome or familial atypical mole-melanoma syndrome.
Prognosis is multifactorial and primarily depends on (1) tumor thickness, (2) the presence or absence of histologic ulceration, and (3) lymph node involvement (most important).
For Cutaneous melanoma (stages I and II), thin primaries (<1 mm) are associated with a 5-year survival rate of 91-95% depending on the presence or absence of histologic ulceration. Intermediate thickness melanoma (1.01-4 mm) is associated with a 5-year survival rate of 63-89%, depending on ulceration and the thickness (1.01-2 mm, 2.01-4 mm) of the primary tumor. Patients with high-risk tumors (>4 mm) have a 5-year survival rate of 67% without ulceration, compared with 45% with an ulcerated primary. Ulceration significantly reduces survival at each tumor stage, even when regional lymph nodes are involved.
In Stage III disease regional lymph node metastasis is associated with a 5-year survival rate of 13-69%, depending on the number of nodes involved, microscopic or macroscopic (matted nodes/gross extracapsular extension) disease, and ulceration of the primary melanoma. A pooled analysis of high-dose adjuvant IFN alfa trial results has shown significantly improved disease-free survival for stage III disease; modest improvement in OS has been observed in 2 prospective randomized studies. Melanoma vaccines/ biologic response modifiers show promise in prolonging disease-free and OS rates in melanoma patients.
In Stage IV disease prognosis for distant metastatic disease is extremely poor, with median survival of only 6-9 months and 5-year survival rates of 7-19%, depending on the site(s) of metastasis. In general, patients with soft tissue, nodal, and isolated lung metastases have slightly better prognoses than those with other visceral metastases and/or elevated LDH levels. However, survival beyond 1 year occurs in only a minority of stage IV patients. Systemic chemotherapy for these patients is the mainstay of treatment, despite low response rates (<20%), which also tend to be of short duration.>
Histopathologic misdiagnosis of melanoma or a delay in the clinical diagnosis and skin biopsy may result in thicker tumors with an increased risk of metastasis. Consensus indicates that skin biopsy results from pigmented lesions suggestive of melanoma should be assessed by a pathologist experienced in the interpretation of melanocytic lesions and a dermatopathologist, whenever possible. These are difficult slides to read and it would be prudent to have subspecialty pathologists see them whenever possible.
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