Management of Cutaneous Head and Neck Melanoma

Risk Factors

Sun exposure is considered the leading cause of melanoma. Patients who experienced peeling or blistering sunburns, even during childhood, are at particular risk. Sun beds and tanning booths are associated with early-onset melanoma; increasing risk is associated with both early age of first use as well as with greater use. First use of a tanning bed before age 35 years alarmingly increases the risk for melanoma by up to 75%. The World Health Organization (WHO) now classifies tanning booths as a category I carcinogen. In fact, the risk of developing melanoma from tanning booth exposure exceeds the risk of developing lung cancer from cigarette smoking. Other associated factors include blond or red hair, green or blue eyes, or fair skin consistent with Fitzpatrick skin types I through III. Adults with more than 100 clinically normal-appearing nevi, children with more than 50 clinically normal-appearing nevi, and any patients with atypical or dysplastic nevi are also at risk. A prior history of melanoma places a patient at increased risk, with 5% to 10% of individuals developing a second primary melanoma.

Genetics

The genetic aspect of melanoma remains complex, with over 33,000 mutations identified. An inherited chromosomal abnormality at the CDKN2A locus, which encodes for the p16 tumor suppression gene, is the most common germline mutation. A point mutation in the serine-threonine protein kinase BRAF is present in approximately 42% of melanomas, the majority being the V600E substitution. Additional melanoma mutations include NRAS (25% of tumors) and c-KIT (19%).

Some 10% to 15% of melanoma patients report a positive family history. Xeroderma pigmentosum (XP) is a rare hereditary disorder that is also associated with melanoma; it is inherited in an autosomal recessive fashion. The fibroblasts in XP patients have a reduced or absent ability to repair DNA damaged by ultraviolet light. B-K mole syndrome is a hereditary form in which individuals acquire large, irregular, dysplastic nevi, often in sun-protected regions of the body, such as the scalp and trunk. A familial association of melanoma among individuals with atypical nevi has also been coined familial atypical multiple mole-melanoma (FAMMM) syndrome. Today the term atypical mole syndrome is applied to familial cases of melanoma. The syndrome is inherited in an autosomal dominant fashion.

Congenital Nevi

Congenital melanocytic nevi (CMNs) are present at birth or appear within the first 6 months of life ; an estimated 1% to 6% of children are born with CMN. The nevi are classified by their adult size: small CMNs are less than 1.5 cm in diameter and account for the majority of lesions; medium CMNs measure between 1.5 and 19.9 cm in diameter; and large CMNs, which are also called giant congenital nevi , measure 20 cm or more. This large size can have significant cosmetic and psychosocial implications.

The lifetime risk of melanoma development in small- and medium-sized CMNs is estimated to be between 0% and 4.9%. Routine prophylactic removal of small- and medium-sized CMNs is rarely indicated in the absence of signs or symptoms indicative of malignant progression. However, giant congenital nevi carry a higher risk for melanoma, with an estimated 4.5% to 10% of patients going on to develop cancer. Seventy percent of these individuals are diagnosed before the age of 10 years. Melanoma in the setting of giant congenital nevi may develop below the dermoepidermal junction, which makes identification more difficult and delays diagnosis.

Desmoplastic Melanoma

DM is rare, accounting for less than 4% of all cutaneous melanomas. However, up to 51% of the lesions present in the HN region and may arise in association with LM/LMM. The clinical presentation and biologic behavior of these tumors are distinct from those of other cutaneous melanomas. Although amelanotic cases account for only 4% to 5% of cutaneous melanomas, up to 73% of DMs are amelanotic. As demonstrated in Fig. 80.1 , the neoplasms often lack the typical ABCD criteria for melanoma (described later) and can have a difficult histologic pattern that requires interpretation by an experienced pathologist. Overall, the atypical and challenging appearance of DMs may result in a delay in diagnosis and thicker Breslow depth at diagnosis.

DM is known to be locally aggressive and highly infiltrative, often leading to cranial nerve and skull base involvement. Local recurrence has been reported in up to 50% of cases. Explanations for this high rate include the association with neurotropism and the failure to recognize and adequately clear peripheral AJMH margins. Although DM demonstrates greater tumor thickness at the time of diagnosis, there is a lower risk of regional lymph node metastasis for the “pure” desmoplastic pattern compared with the mixed desmoplastic pattern, which behaves similar to conventional melanoma subtypes. The incidence of nodal metastasis found by SLNB has been reported as low as 1% for purely DM; however, the rate of cervical lymph node metastasis can reach as high as 22% in the setting mixed DM. For this reason, SLNB is used primarily in the setting of mixed DM, not pure DM. This difference in metastatic rate highlights the need for accurate and complete histopathologic evaluation of the primary tumor for development of a treatment plan.

Unknown Primary

Approximately 2% to 8% of melanoma cases involve unknown primary sites. Two-thirds of these patients present with regional metastasis in the absence of an identifiable primary lesion or history of melanoma; the remaining third of such cases involve distant metastasis to sites such as the subcutaneous tissues, lung, and brain.

Patients diagnosed with melanoma of unknown origin require a search for the primary site with a total body skin and mucosal evaluation. A history of a previous skin biopsy or skin lesion that spontaneously disappeared may be helpful. All pathology slides from previously excised lesions should again be reviewed. The workup for metastasis is identical to that for known primary cases, as described further on. After adjustment for tumor stage, melanomas of unknown primary origin share an overall prognosis equivalent to that of their counterparts with known primary sites.

History

The majority of melanoma lesions are first detected by the patient or the patient's significant other. Less than one-fourth of lesions are diagnosed during routine office physical examination; when found by a health care provider, however, lesions tend to be thinner. Overall, 80% of newly diagnosed melanomas will be limited to localized stage I/II disease.

The earliest signs of melanoma are a change in the color, size, or shape of a lesion. Pruritus is the earliest symptom. Later signs and symptoms, which are usually associated with a more advanced lesion, include bleeding, ulceration, and tenderness. Patients should be questioned about a personal and family history of melanoma. Information about previous skin biopsies, sun exposure, history of blistering sunburns, tanning booth use, chronic sun exposure, and occupation should be obtained. Johnson and colleagues investigated the characteristics of 1515 melanoma patients and found that 81% reported a history of at least one sunburn.

Physical Examination

All patients presenting with a suspicious lesion warrant full evaluation of the skin and nodal basins by a physician who is well versed in cutaneous cancers. Thorough evaluation is imperative, because up to 8% of newly diagnosed patients will have multiple primary cutaneous melanomas. The differential diagnosis for cutaneous melanoma is broad and includes seborrheic keratosis, hemangioma, blue nevus, Spitz nevus, pyogenic granuloma, pigmented basal cell carcinoma, and cutaneous squamous cell carcinoma.

The American Cancer Society has published the ABCD checklist to educate both patients and physicians about the early detection of melanoma. Under these guidelines, concerning signs for melanoma include the following:

• A symmetry in appearance

• B order irregularity, such as scalloped, poorly circumscribed, or ill-defined margins

• C olor variation within a lesion, such as shades of black, red, white, or blue

• D iameter greater than 6 mm

Although the ABCD checklist is helpful for the identification of melanoma, it will not detect every case. It is important to realize that a subset of cancers (e.g., amelanotic, desmoplastic, and nodular melanomas) lack the common features of the ABCDs. In one series, 88% melanoma patients (615 of 696) recalled change in their pigmented lesion prior to melanoma diagnosis. Due to the significance of change, a proposal has been set forth to add E —evolving changes—to the traditional ABCD warning signs. Clinicians are hopeful that the new, more comprehensive ABCDE criteria will lead to even better detection of melanoma at an earlier stage. Another useful screening tool is the “ugly duckling sign,” or any pigmented lesion that appears significantly and singularly different from other surrounding lesions. Such a lesion should be viewed with a high index of suspicion even if it lacks the traditional ABCD criteria.

Biopsy

Any pigmented lesion that demonstrates an ABCD warning sign, has undergone change, or appears different from surrounding nevi necessitates histologic evaluation. Ideally, a complete excisional biopsy with a narrow 1- to 3-mm clinical margin of surrounding skin is performed. This allows for the diagnosis and evaluation of important prognostic factors such as Breslow depth, ulceration, mitotic rate, and angiolymphatic/perineural invasion. For lesions that are not amenable to excisional biopsy due to their large size or anatomic location, punch biopsy or incisional biopsy through the thickest or darkest portion of the neoplasm is recommended. Superficial shave biopsy, frozen section biopsy, and fine-needle aspiration are strongly discouraged because the thickness of the tumor, which dictates staging and treatment, may not be accurately obtained. It is important to realize that punch and incisional biopsies are subject to sampling error. If a diagnosis of melanoma in this setting is not rendered, a repeat biopsy may be necessary. The pathology results from this biopsy then serves as the guide for treatment, which entails wide local excision (WLE) using a 0.5- to 2-cm margin of normal surrounding skin with or without SLNB. Although obtaining wider margins at the time of the initial biopsy seems efficient and cost-effective, it is highly discouraged because the removal of significant amounts of skin surrounding the lesion may compromise the ability to accurately stage regional lymph node basins using lymphoscintigraphy and SLNB techniques. Instead, excisional biopsy with narrow margins for diagnosis is advocated.

The American Academy of Dermatology (AAD) and National Comprehensive Cancer Network (NCCN) recommend standardized reporting for melanoma pathology. This information allows for accurate staging and associated treatment planning. Key components to the report include the following:

• Tumor (Breslow) depth of invasion

• Mitotic rate

• Margin status

• Ulceration, which is a histologic diagnosis

• Melanoma subtype to include pure versus mixed desmoplasia if applicable

• Clark level of invasion for thin melanomas measuring up to 1 mm in depth of invasion

• Vertical growth pattern

• Tumor-infiltrating lymphocytes (TILs)

• Angiolymphatic invasion

• Tumor regression

• Neurotropism

• Microsatellitosis

Melanoma remains a histopathologic diagnosis using traditional hematoxylin and eosin (H&E) staining and melanoma-specific immunohistochemical staining such as HMB-45, S-100, and MART-1 (Melan-A).

Advances have been made in gene profiling, including comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). A diagnostic reverse-transcription polymerase chain reaction assay is commercially available to assist in differentiating melanoma from benign lesions such as Spitz nevi, junctional nevi, and blue nevi (myPath Melanoma test; Myriad Genetics, Inc., Salt Lake City, UT). Gene expression profiling (GEP) is also commercially available to help stratify high- versus low-risk melanoma metastasis in stage I and II disease (DecisionDx-Melanoma; Castle Biosciences, Inc., Friendswood, TX). However, testing sensitivity and specificity remains low and rigorous validation is still required for the mentioned tests to become standard of care.