In Brief

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The worldwide incidence of melanoma is increasing at epidemic proportions, faster than any other cancer. It is currently the fifth leading cause of cancer among men and the sixth leading cause among women. The management of melanoma is also one of fastest evolving fields in cancer, with promising research taking place both at the molecular and clinical level. In fact, recent increased understanding of melanoma biology has prompted major changes in the staging classification system set forth by the American Joint Committee on Cancer (AJCC). Given the association with sun exposure, melanoma is considered a preventable disease. Decreased incidence and mortality ultimately hinges on patient as well as physician education, prevention, early diagnosis, and improved treatment for advanced disease. When treating melanoma, special consideration must be given to the head and neck (HN) region because of the complexity of the rich lymphatic network, the intricate anatomy, and the potential for cutaneous as well as mucosal tumors.

Intense sun exposure is the leading cause of melanoma. Individuals with red or blond hair, green or blue eyes, or fair skin consistent with Fitzpatrick skin type I-III are prone to blistering sunburns and are at particularly high risk. Genetic risk factors include the CDKN2A (p16) chromosomal mutation, familial atypical mole syndrome, and xeroderma pigmentosa. Immunosuppression and large congenital melanocytic nevi measuring greater than 20 cm in diameter also carry significant melanoma risk.

Several histologic subtypes of melanoma are recognized within the HN region. It is important to note that the melanoma subtype itself does not generally influence prognosis after correcting for tumor thickness and other prognostic variables. In general, superficial spreading melanoma (SSM) is the most common type of cutaneous melanoma, and nodular melanoma (NM) is the second most common subtype of the skin. Lentigo maligna (LM) represents intraepidermal or in situ melanoma, and is considered the precursor to invasive lentigo malignant melanoma (LMM). The LM/LMM pattern warrants special comment because this subtype is characterized by asymmetric, subclinical, and often extensive peripheral involvement of atypical junctional melanocytic hyperplasia (AJMH). Therefore, management with adequate wide margins can be challenging from both a functional and cosmetic standpoint. Desmoplastic melanoma and desmoplastic-neurotropic melanoma are locally aggressive, highly infiltrative melanoma variants with a propensity for cranial nerve and skull base involvement. Mucosal melanoma is recognized as a rare, distinct, and separate subtype from its cutaneous counterpart. Fewer than 2% of melanoma cases are mucosal in origin; however, 50% of these cases arise within the HN region, making it the most common location. Lastly, 3% to 8% of melanoma patients present initially with an unknown primary site.

Change in color, size, or shape of a lesion represent the earliest signs for melanoma. The earliest symptom is persistent pruritus. Bleeding, ulceration, and pain represent later signs and symptoms concerning for advanced disease. All patients who present with a suspicious lesion warrant a full body evaluation of the skin and nodal basins by a physician well versed in cutaneous cancers. This thorough examination is important because up to 8% of newly diagnosed patients have multiple primary cutaneous melanomas.

The American Cancer Society has published the ABCD checklist of melanoma warning signs: Asymmetry in lesion appearance, Border irregularity such as scalloped, poorly circumscribed, or ill-defined margins, Color variation within a lesion, or Diameter greater than 6 mm. It is important to realize that a subset of cancers such as nodular, amelanotic, and desmoplastic melanomas lack the common features of the ABCDs. For this reason, any pigmented lesion that fulfills any of the ABCD criteria, has undergone change, or appears different from surrounding nevi on the body necessitates histologic evaluation. The biopsy of potential melanoma is a distinct, 2-staged process. The first stage entails a narrow margin excisional biopsy to obtain both histologic diagnosis and prognostic information. Biopsy results from this first stage then serve as the guide for the second stage, which entails wide local excision (WLE) using a 0.5- to 2-cm margin of normal surrounding tissue, with or without sentinel lymph node mapping and biopsy (SLNB).

The majority of melanoma patients present with localized disease, are asymptomatic, and lack clinical findings suggestive of regional or distant spread. The foundation for evaluation of patients presenting with localized stage I disease remains a thorough history and physical examination. For stage II and III patients who lack clinical evidence of regional disease (N-zero neck), chest radiograph (CXR) and screening lactate dehydrogenase (LDH) levels are deemed optional under the National Comprehensive Cancer Network (NCCN) guidelines. All stage III patients with clinically or radiographically suspicious cervical lymph nodes warrant a fine needle aspiration of the enlarged lymph node, CXR, and LDH level. The patient’s history and physical examination dictates whether additional imaging studies are required to evaluate specific distant sites. Patients with known stage IV disseminated melanoma required a complete evaluation for systemic metastasis.

To gain increased understanding of the natural history and behavior of cutaneous melanoma, the AJCC Melanoma Task Force conducted a multi-intuitional study involving 17,600 patients. This investigation is the largest analysis of its kind. In 2002, results from the landmark study were used to revise the AJCC cutaneous melanoma staging system. The goals in modifying the staging system were: 1) to develop categories based on the most important, independent prognostic markers for melanoma, and 2) to provide physicians with a practical classification system that truly mirrored clinical practice.

The 2002 AJCC staging system for cutaneous melanoma remains founded on the traditional Tumor-Node-Metastasis (TNM) classification system, with stage I and II representing localized disease, stage III regional disease in which the melanoma has spread to draining nodal basins, and stage IV reserved for distant metastatic disease, most commonly to the lungs and liver. The T classification is now defined by tumor thickness as measured in even-integer cut points (1.0, 2.0, and 4.0 mm) and ulceration. In fact, ulceration of the primary lesion portends such a poor prognosis that it upstages the patient. Clark’s histologic level of invasion is now only applicable in the staging of thin (≤1 mm) T1 lesions. Three statistically significant prognostic factors were identified for N classification: number of metastatic lymph nodes, tumor burden as represented by microscopic versus macroscopic disease, and primary tumor ulceration. The gross size of the metastatic node was not prognostic and has since been dropped from the N classification. However, satellite metastasis surrounding the primary lesion and in-transit metastasis located between the primary lesion and draining nodal basin were identified as important prognostic markers. Such patients are now classified as stage III regional disease, regardless of the nodal status. Lastly, the M classification is defined by anatomic site of distant metastasis and elevated LDH level.

The standard of care for the treatment of primary melanoma remains complete surgical excision. Current guidelines for surgical margins are: 0.5 cm for melanoma in situ, 1 cm for lesions less than 1.0 mm in thickness, 1.0 to 2.0 cm for lesions 1.0 to 2.0 mm in thickness, and more than 2.0 cm for lesions greater than 2.0 mm in thickness. It is important to realize that these recommendations serve merely as a guideline. Each melanoma case must be individualized.

The most common sites for metastasis of HN cutaneous melanoma are the cervical and parotid lymph node basins. Therapeutic lymph node dissection (TLND) is accepted universally as the treatment of choice for regional disease. Historically, 1 of the most controversial debates in melanoma surrounded treatment of regional nodal basins in the absence of clinical metastasis (prophylactic treatment of the N-zero neck). Nodal status is currently recognized as the single most important prognostic factor for melanoma patients. However, prospective, randomized trials failed to demonstrate an overall survival benefit for patients undergoing elective lymph node dissection (ELND). Therefore, ELND is no longer advocated in the routine treatment of melanoma.

Instead, the procedure has been replaced by SLNB. This technique is a minimally invasive, cost-effective, and efficient means of screening patients for regional metastasis. In doing so, it identifies the 10% to 20% of individuals harboring occult, microscopic nodal disease, who may then benefit from TLND and adjuvant therapy. At the same time, it spares the remaining 80% of individuals without occult disease the cost and morbidity associated with a neck dissection. SLNB is the best staging modality for regional disease, with the highest sensitivity and specificity of any modality currently available. Among major melanoma cancer centers across the country, it is now accepted as standard of care.

SLNB is a team effort involving experienced surgeons, nuclear medicine staff, and pathologists. The technique uses a combination of lymphoscintigraphy, radioactive colloid, and isosulfan blue dye to identify the first echelon of draining lymph nodes, which carry the highest probability of harboring occult disease. The histologic analysis of SLNs is more thorough and complete compared with traditional evaluation of the entire lymphadenectomy specimen because the technique provides the pathologist with a limited number of nodes for thorough evaluation. Occult lymphatic metastasis from cutaneous melanoma can be difficult to detect, with tumor cells occupying less that 2% of the entire lymph node volume. Therefore, rigorous pathological analysis including serial sectioning, special immunohistochemical study (S-100 and Melan-A), and interpretation by an experienced pathologist is required.

Although SLNB has a defined role in the evaluation of cutaneous melanoma of the trunk and extremities, several questions have been posed with respect to its application in the HN region. We previously demonstrated that the complexity of HN anatomy does not preclude the use of SLNB for staging of cutaneous melanoma. The reported 17.5% positive SLN rate and 4.5% false negative rate mirror the results achieved in other anatomic sites such as the trunk and extremities. The procedure was performed in both neck and parotid nodal basins with similar safety and accuracy as other non-HN sites. Specifically, no injuries to the facial nerve were reported.

Recent multivariate analysis involving patients with stage I and II melanoma by Greshenwald and colleagues found the pathologic status (positive or negative for metastasis) of the SLN to be the most important prognostic factor for both recurrence and overall survival. This survival benefit was so compelling that the AJCC has now incorporated SLNB into the revised staging system for cutaneous melanoma. The impact that SLNB imparts on overall survival remains to be determined. The answer will hopefully be provided through the multi-institutional Sunbelt Melanoma Trial and Multi-Institutional Selective Lymphadenectomy Trial-I.

Melanoma has traditionally been classified as a radioresistant tumor. Although adjuvant radiation has not been shown to impact survival, researchers at the M.D. Anderson Cancer Center completed a phase II clinical trial supporting the efficacy of large dose, hypofractionated radiation as an adjuvant treatment to surgery for HN cutaneous melanoma patients at high risk for local-regional recurrence. On rare occasion, primary radiation can be used to treat extensive LM/LMM in an elderly patient who is not deemed a surgical candidate or if the lesion is so extensive that surgical resection would leave the patient functionally and socially crippled. Radiation therapy can also be administered as palliative treatment. Similarly, melanoma is relatively chemoresistant. Dacarbazine (DTIC) remains the only chemotherapeutic agent approved for treatment of advance stage IV melanoma. The main role for chemotherapy remains as palliative treatment.

Although numerous clinical trials continue to investigate various combinations of immunotherapy, gene therapy, and melanoma vaccines, high dose interferon-α2b (IFN-α2b) remains the only U.S. Food and Drug Administration (FDA) approved adjuvant treatment for stage III melanoma. IFN-α2b is reserved for patients at high risk for tumor recurrence, including individuals with regional lymph node metastasis or a primary tumor having thickness greater than 4 mm.

The primary goals in melanoma follow-up are early detection of local-regional tumor recurrence, early identification of second primary tumors (including melanoma as well as other skin cancers), continuing patient education, and psychological support. Each follow-up visit should include an inquiry into new or changing skin lesions, a review of systems concerning for distant metastasis, and a thorough examination of the skin and mucosa, with particular attention paid to the original melanoma site and associated draining nodal basins.

Significant advances in the field of melanoma research have been achieved in recent years. Intense efforts in the areas of melanoma vaccination, gene therapy, HLA immunoprinting, and gene profiling at the genomic, as well as the proteomic, level will likely play an important role in future research endeavors. The key to impacting melanoma survival rates ultimately lies in well-organized, multi-institutional studies that enroll patients who are staged accurately and, therefore, share a similar prognosis.