Risk Factors

Sun exposure is considered the leading cause of melanoma.^15,16 Patients who experienced peeling or blistering sunburns, even during childhood, are at particular risk.¹⁷ Associated factors include blond or red hair, green or blue eyes, and fair skin consistent with Fitzpatrick skin types I through III.¹⁸ 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 poses a greater risk; 5% to 10% of individuals diagnosed with melanoma experience a second primary melanoma.¹⁶ This increased risk remains lifelong, and the melanoma can occur anywhere on the skin. For this reason, long-term follow-up with a thorough total body examination is critical.

Genetics

A genetic component has been implicated in the pathogenesis of melanoma¹⁹; 10% to 15% of patients with melanoma report a positive family history.²⁰ The most common chromosomal mutation associated with melanoma involves CDKN2A, which is also known as p16.²¹ However, the mutation accounts for only a small percentage (0.2%) of melanoma cases observed.²²

B-K mole syndrome is a hereditary form of cutaneous melanoma in which members acquire large, irregular, and dysplastic nevi, often in sun-protected regions of the body, such as the scalp and trunk.²³ A familial association of melanoma among individuals with atypical nevi has also been coined familial atypical multiple mole-melanoma (FAMMM) syndrome.²⁴ Today, the term “atypical mole syndrome” is applied to familial cases of melanoma. The syndrome is inherited in an autosomally dominant fashion.^25,26 The 10-year melanoma risk in this setting is reported to be 10.7%, compared with 0.62% in control patients.^27,28 Fitzpatrick and Ortonne¹⁸ and Greene and associates²⁹ approximated a 56% cumulative risk from age 20 to 59 years, which predicts that 100% of patients with atypical mole syndrome would have melanoma by age 76.

Xeroderma pigmentosa is a rare hereditary disorder also associated with melanoma; it is inherited in an autosomally recessive fashion.³⁰ The fibroblasts in patients with this disease have a reduced or no ability to repair DNA that has been damaged by ultraviolet light.³¹ Consequently, multiple primary cutaneous malignancies, including melanoma, basal cell carcinoma, and squamous cell carcinoma, develop. Individuals are usually diagnosed with their first cancer prior to age 10. Unfortunately for patients with xeroderma pigmentosa, the relentless development of skin cancers—as well as other cancers—ultimately leads to death at an early age.

Congenital Nevi

Congenital melanocytic nevi (CMN) are present at birth or appear within the first 6 months of life³²; an estimated 1% to 6% of children are born with CMN. The nevi are classified by size: small CMN measure less than1.5 mm in diameter and account for the majority of lesions; medium-sized CMN measure between 1.5 and 19.9 mm in diameter; and large CMN, which are also called giant congenital nevi, measure 20 mm or more. This large size can have significant cosmetic and psychosocial implications.²⁸

The risk of melanoma development in small- and medium-sized CMN is similar to that in any other nevi. Melanoma development usually occurs after childhood and arises from the dermoepidermal junction, which makes early detection and intervention feasible. Routine prophylactic removal of small and medium CMN is rarely indicated in the absence of signs or symptoms indicative of malignant progression.

Conversely, giant CMN carry an increased risk for melanoma, with an estimated 5% to 20% of patients with these lesions eventually experiencing cancer.^33,34 Seventy percent of these individuals are diagnosed before age 10 years.³⁵ Melanoma in the setting of giant CMN originates deep within the epidermis, thus potentially delaying the diagnosis and treatment.

Desmoplastic-Neurotropic Melanoma

Desmoplastic melanoma (DM) describes a subtype composed of spindle cells, abundant collagen, and features resembling fibromas.³⁸ Some lesions demonstrate a propensity for perineural and endoneural infiltration, which prompted further subclassification of a desmoplastic neurotropic melanoma (DNM) variant.³⁹

DM/DNM subtypes are rare, accounting for approximately 1% of all cutaneous melanomas.⁴⁰ However, up to 75% of the lesions manifest in the head and neck region, often in the setting of 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 DM/DNMs are amelanotic.^40,41 As demonstrated in Figure 82-1, the neoplasms often lack the typical ABCD criteria for melanoma (described later), and they can have a difficult histologic pattern that requires interpretation by an experienced pathologist. Overall, the atypical and challenging appearance of DM/DNM is thought to result in a delay in diagnosis. This fact provides one explanation for the reason that patients with DM/DNM present with thicker, more aggressive tumors.

Figure 82-1. Desmoplastic melanoma of the nose. Note the amelanotic appearance and the absence of typical ABCD findings associated with other melanoma subtypes.

DM/DNM 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.⁴⁰ Explanations for this high rate include the association with neurotropism and the failure to recognize and adequately clear peripheral atypical junctional melanocytic hyperplasia margins. Although DM/DNM demonstrates greater tumor thickness at the time of diagnosis, the 12.5% rate of regional lymph node metastasis is lower than that for other melanoma subtypes.³⁹

Mucosal Melanoma

Mucosal melanoma is recognized as a distinct subtype from its cutaneous counterpart. The most common site for mucosal melanoma is the head and neck, with 40% to 50% of cases arising in this location.⁴² However, less than 2% of all head and neck melanomas are mucosal in origin. Of the 84,836 melanoma cases registered in the National Cancer Database from 1985 to 1994, only 1074 (1.3%) were of the mucosal melanoma variant.⁴³

Although small case numbers limit research to anecdotal reports, several common trends have been noted throughout the literature. The peak age for mucosal melanoma is during the sixth to seventh decade, which is approximately 10 to 15 years later than that for cutaneous melanoma.^42,44–47 A slight male preponderance has also been reported.^45,47,49 Ethnic differences have been observed; approximately 8.8% of mucosal melanoma cases afflict blacks and Hispanics, a considerable percentage given that less than 3% of all other melanoma variants are diagnosed among this group.⁴⁸ The relative frequency is also exceedingly high in Japan, where mucosal melanoma accounts for 7.5% of all melanoma cases.⁵⁰

Within the head and neck region, the most common site of origin is the nasal cavity, where the anterior nasal septum is most often involved, followed by the inferior and middle turbinates.^46,49,51,52 The second most common site is the oral cavity, where a predilection for the hard palate and maxillary alveolar gingivae has been found. A review of five major mucosal melanoma series by Batsakis and colleagues⁵¹ found laryngeal primary tumors to account for less than 4% of all cases. Within the larynx, the supraglottis was the most common site of origin.

The presenting signs and symptoms of mucosal melanoma directly correlate with the anatomic site of origin. The majority of patients with nasal cavity primary tumors present with nasal obstruction and epistaxis.^49,51,52 Proptosis, diplopia, pain, and facial deformity are less common and indicate advanced disease. When present, the most common sign of an oral cavity tumor is a mass lesion.⁵² However, oral cavity mucosal melanoma is often asymptomatic, going undiagnosed until a neck mass develops from metastasis.^44,49

Many of the prognostic markers for cutaneous melanoma do not have correlates in mucosal sites.⁴² Consequently, the cutaneous melanoma staging system set forth by the AJCC (see later) may be less applicable to mucosal melanoma. Most patients with mucosal melanoma present with localized disease, and in only 18.7% is regional spread detected at the time of diagnosis. The high percentage of patients with stage I disease is deceiving, because local recurrence is the major reason for treatment failure.⁵¹ Fifty percent of patients have local recurrence, usually within 9 to 12 months of diagnosis, and the overall 5-year survival rate is a dismal 10% to 20%.^45–4751 Rich submucosal vasculature and lymphatics are thought to account for the aggressive behavior of mucosal melanoma.⁵¹

Unknown Primary

Approximately 2% to 8% of cases of melanoma involve unknown primary sites.^43,48,53 In two thirds of the cases, the patients present with regional metastasis in the absence of an identifiable primary lesion or history of melanoma; the remaining third of unknown primary cases involve distant metastasis to sites such as the subcutaneous tissues, lung, and brain.^48,53–55 Several theories have been proposed to explain melanoma of unknown primary origin. The identification of melanocytes and nevus cells within the lymph node capsule and visceral organ epithelium lends credence to the belief that unknown primary cases result from melanoma arising de novo at regional and distant sites.^43,56 Another clinical scenario is that the primary melanoma lesion undergoes complete spontaneous regression.^56,57

The diagnosis of melanoma of unknown origin necessitates a search for the primary site with a total body skin and mucosal evaluation. A history of a previous skin biopsy or a skin lesion that spontaneously disappeared may be helpful. All pathology slides from previously excised lesions should be re-reviewed. The metastatic workup is identical to that for known primary cases (see later). After adjustment of data for tumor stage, melanomas of unknown primary origin share an overall prognosis equivalent to their counterparts with known primary sites.^43,53–55

History

The majority of melanoma lesions are first detected by the patient or his/her significant other.^58,59 Less than one fourth of lesions are diagnosed during routine office physical examination, and these latter lesions tend to be thinner.⁵⁹ Overall, 80% of newly diagnosed melanomas are limited to localized, stage I/II disease.²

The earliest signs of melanoma are a change in color, size, or shape of a lesion, and 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, use of tanning booths, chronic sun exposure, and occupation should be obtained. Schwartz and colleagues⁵⁹ investigated characteristics of 1515 patients with melanoma and found that 81% elicited 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 have multiple primary cutaneous melanomas.^16,60–62

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.⁶³ Under these guidelines, concerning signs for melanoma are as follows:

Although the ABCD checklist is helpful for the identification of melanoma, it does not detect every case.^64,65 It is important to realize that a subset of cancers (e.g., amelanotic, desmoplastic, and nodular melanoma) lack the common features of the ABCD list. In one series, 88% patients with melanoma (615 of 696) recalled change in their pigmented lesions prior to melanoma diagnosis.⁶⁶ Owing to the significance of change, a proposal has been set forth to add “Evolving changes” to the traditional ABCD warning signs.⁶³ Clinicians are hopeful that the new, more comprehensive ABCDE criteria will lead to even further detection of melanoma at an earlier stage.⁶⁶ Another useful screening tool is the “ugly duckling sign,”⁶⁷ whereby any pigmented lesion that appears significantly and singularly different from other surrounding lesions should be viewed with a high index of suspicion, even if the lesion lacks the traditional ABCD criteria.

Biopsy

Any pigmented lesion that demonstrates an ABCD warning sign, has undergone change, or appears different from surrounding nevi on the body necessitates histologic evaluation. The biopsy of a potential melanoma should be considered a two-step process. The first step involves biopsy not only for tissue diagnosis but also to evaluate important prognostic factors such as tumor depth, ulceration, mitotic rate, angiolymphatic invasion, and perineural spread. Ideally, a complete excisional biopsy with a narrow, 1- to 2-mm, clinical margin of surrounding skin is performed. For lesions that are not amenable to excisional biopsy because of large size or anatomic location, punch biopsy or incisional biopsy through the thickest portion of the neoplasm is recommended. Superficial shave biopsy and find-needle aspiration are discouraged, because neither procedure allows the thickness of the tumor, which dictates further diagnostic workup and treatment, to be determined. 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 second biopsy may be necessary.

The pathology results from this biopsy then serve as the guide for the second step, which entails wide local excision (WLE) utilizing a 0.5- to 2-cm margin of normal surrounding skin, with or without sentinel lymph node [mapping and] biopsy (SLNB). The role of SLNB ultimately depends on the final microstaging of the primary lesion and is detailed later. Although obtaining wider margins at the time of the initial biopsy seems efficient and cost effective, it is highly discouraged because clinical accuracy is uncertain and removal of significant amounts of skin surrounding the lesion may compromise the ability to accurately stage regional lymph node basins by means of lymphoscintigraphy and SLNB techniques.⁶⁸ Instead, biopsy with narrow margins in a two-step fashion is advocated.

Metastatic Workup

In an attempt to standardize staging workup for melanoma, a panel of the National Comprehensive Cancer Network (NCCN) has published guidelines.⁶⁹ The metastatic workup performed at our institution, which accords with these guidelines, is summarized in Table 82-1.

Table 82-1 University of Michigan Guidelines for Workup for Cutaneous Melanoma

Adapted from Johnson TM, Bradford CR, Gruber SB, et al. Staging work-up, sentinel node biopsy and follow-up tests for melanoma: update of current concepts. Arch Dermatol. 2004;140:107.

Patients presenting with localized stage I disease simply require a thorough history and physical examination. Many physicians advocate a screening chest radiograph, because the lung is the most common site for distant metastasis.⁶⁸ Although a chest radiograph is an inexpensive, noninvasive means of metastatic evaluation, the rate of detection of occult pulmonary metastasis on chest radiograph in an asymptomatic patient with stage I or II disease is exceedingly low (0.1%).^70,71 The high false-positive rate, 15%, necessitates additional and costly evaluations. Evidence supporting the use of other screening modalities, such as computed tomography (CT),^72,73 liver-spleen scans, magnetic resonance imaging, and bone scans for patients with limited stage I and II disease is also lacking.^74,75 For this reason, the National Comprehensive Cancer Network panel unanimously agreed that a search for visceral metastases, with either a chest radiograph or blood analysis, is not warranted for a patient with in situ or thin, stage IA lesions. A baseline chest radiograph is considered optional for thicker stage IB and II lesions. Imaging studies (CT, magnetic resonance imaging, positron emission tomography) may be obtained in this setting if there are specific concerning signs or symptoms.⁶⁹ Screening serum lactate dehydrogenase (LDH) measurement carries a 15% false-positive rate, does not correlate with sentinel lymph node (SLN) status, and has not been helpful in detecting occult disease in asymptomatic patients.⁷⁶ For this reason, our institution recommends LDH measurement only when the history or physical examination reveals jaundice, abdominal pain, or other specific findings that raise concern about distant metastasis.⁷⁷

Patients with clinically or radiographically suspicious lymph nodes, satellite lesions, or in-transit metastasis (defined as intralymphatic tumor dissemination between the primacy lesion and draining nodal basin) are considered to have stage III disease and are at higher risk for distant metastasis. Fine-needle aspiration is an accurate and cost-effective means of confirming metastatic melanoma within lymph nodes.⁷⁸ Additional imaging studies should be ordered according to the patient’s history and physical findings. A list of symptoms that warrant a focused investigation of systemic metastasis is summarized in Box 82-2.⁷⁹ Overall, the yield of screening CT in patients with stage III melanoma has been low^77,80–82; however, many physicians obtain the studies to serve as a baseline for future comparison.

Patients with known stage IV disseminated melanoma require a complete evaluation for systemic metastasis. LDH measurements and chest radiography or chest CT are recommended. CT of the abdomen and pelvis, magnetic resonance imaging of the head, and a positron emission tomography scan (whole body) should also be considered. In this setting, workup is often dictated by clinical trial protocols. Unfortunately, greater survival has not been demonstrated for patients who are asymptomatic when diagnosed with their distant, stage IV disease than for their symptomatic counterparts⁷⁶; however, this thorough evaluation may lead to a better quality of life.

Summary of Revisions

The current AJCC staging system for cutaneous melanoma remains founded upon the traditional tumor, node, metastasis (TNM) classification system (Tables 82-2 and 82-3). Stage I and stage II represent localized disease, stage III is regional disease, and stage IV is reserved for distant metastatic disease. The most important predictors for survival now serve as criteria for the definition of melanoma stage and are summarized in Box 82-3. Major revisions of the staging system are highlighted in Box 82-4.

Table 82-2 TNM Classification for Melanoma

Wide Local Excision and Surgical Margins

The standard of care for primary melanoma is complete surgical excision. However, the extent of surgical margins remains an unanswered question despite numerous retrospective studies, clinical trials, and meta-analyses. Historically, WLE included an extensive, 5-cm surrounding margin of normal tissue, a recommendation based on a 1907 autopsy report of a patient with advanced melanoma.⁹⁹ The use of 5-cm surgical margins was routine practice until the 1970s, when Breslow and Macht¹⁰⁰ challenged the concept by successfully treating 35 patients with thin melanomas through the use of narrower margins.

Two prospective, randomized trials investigating surgical margins for cutaneous melanoma have since followed. The World Health Organization (WHO) sponsored an international trial in which 612 patients with thin melanomas (2 mm) were randomly assigned to surgical excision with either 1-cm margins or margins larger than 3 cm.¹⁰¹ At a mean follow-up of 8 years, disease-free survival and overall survival were reported to be equivalent in the two groups. For this reason, the researchers in this study concluded that wide excision did not influence survival for patients with thin melanomas. For patients with melanomas less than1 mm in thickness, they advocated “narrow,” 1-cm margins to the muscular fascia plane.

Within the WHO trial, a subset of 245 patients had tumors measuring 1.1 to 2.0 mm in thickness. Although a difference in disease-free survival and overall survival was not observed with respect to margins, a local recurrence rate of 3.3% was reported among patients undergoing “narrow” excision. This finding prompted the Intergroup Melanoma Surgical Trial, which prospectively randomly assigned 740 patients with intermediate-thickness (1- to 4-mm) melanomas to WLE with either 2-cm or 4-cm margins.¹⁰² Local recurrence rates and 10-year survival were reported to be equivalent in the two groups. This finding led to the recommendation of a 2-cm surgical margin for patients with intermediate-thickness melanomas—those measuring 1.1 to 4.0 mm in.

The latest prospective clinical trial, conducted by the United Kingdom Melanoma Study Group, randomly assigned 900 patients with localized cutaneous melanomas 2 mm or more in thickness to excision with 1-cm or 3-cm margins.¹⁰³ A statistically significant difference was not identified between the two groups when local, regional, and distant recurrences were compared; overall mortality rates were identical in the two groups. However, when all recurrences (local, in-transit, and nodal) were pooled together, the 1-cm margin group had a statistically higher recurrence rate. This is the first clinical trial comparing tumor margins to report a statistically significant difference in tumor recurrence. From a practical standpoint; however, it is the 1-cm versus 2-cm margin that is debated more often in this clinical setting.¹⁰⁴

To date, there is no prospective randomized trial to address the optimal surgical margin for thick (> 4 mm) melanomas. A retrospective study of 278 thick melanomas found that surgical margins greater than 2 cm did not lead to a difference in rates of local recurrence rate, disease-free survival, or overall survival from rates for surgical margins of 2 cm.¹⁰⁴ Within this study, 16% of the tumors involved head and neck subsites.

The primary goal of melanoma excision is to eliminate local recurrence secondary to persistent disease. The rate of local recurrence from narrow-margin excisions is admittedly low; however, the consequences are potentially fatal. It is estimated that 100% achievement of ideal margins would lead to a reduction in melanoma-related mortality and a 0.4-year increase in life expectancy for patients with melanoma.¹⁰⁵ Although this difference appears small at first glance, it equates to an estimated 11 additional years of life expectancy for patients who would have experienced local recurrence after excision with a 1-cm surgical margin but who instead experienced a disease-free state after excision with a wider surgical margin.

Current guidelines for surgical margins are based on primary tumor thickness (Table 82-4). It is important to realize that these recommendations serve only as guidelines; choices for each case of melanoma must be individualized. The depth of excision includes full-thickness skin and underlying subcutaneous tissue. Resection of fascia, perichondrium, and periosteum is required only in the setting of direct tumor invasion or if the surgical plane was violated during a previous biopsy.¹⁰⁶

Table 82-4 Recommended Surgical Margins for Excision of Primary Cutaneous Melanoma

LMM warrants special comment, because it has a propensity for wide subclinical spread, which often results in pathologically positive margins.¹⁰⁷ Johnson and coworkers¹⁰⁸ and Anderson and colleagues³⁶ have reported on the use of the “square” procedure in the treatment of LM and LMM. This staged procedure entails complete excision of the peripheral margin with permanent-section histologic evaluation of 100% of the peripheral margins surrounding the entire tumor.

Closure and Reconstruction

With the use of judicious undermining, the majority of surgical sites can be closed primarily. Larger defects may require reconstruction with a split-thickness skin graft, a full-thickness skin graft, a local advancement flap, a regional flap, or free tissue transfer. The method of reconstruction depends on anatomic location, skin color and texture, depth of defect, and patient and surgeon preference. Initially surgeons were reluctant to use grafts at excision sites for fear that surveillance within the surgical bed would be hindered and future diagnosis of recurrence delayed. However, the method of closure has not been shown to affect survival.¹⁰⁹ After “clear” margins have been confirmed, surgeons are encouraged to close surgical defects using the technique that they believe will yield the best cosmetic result.

Melanoma of the Ear

Originally, melanoma involving the ear was thought to carry a worse prognosis than that in other head and neck sites.^98,110,111 This increased risk was attributed to rich lymphatics, complex anatomic subdivisions of the auricle, and a paucity of subcutaneous tissue between the thin auricular skin and underlying perichondrium.¹¹² Consequently, full-thickness excision or total auriculectomy was often advocated.

After accounting for tumor thickness, later studies demonstrated that melanoma of the ear carries the same prognosis as that in other sites.^68,113 In addition, outcome differences were not observed between auricular subsites.¹¹² Retrospective reviews did not demonstrate a difference in local recurrence based on the extent of surgical excision, even when perichondrium was preserved.¹¹³ Today, the same prognostic indicators and surgical principles of obtaining wide, clear margins for treatment of cutaneous melanoma can be safely applied to the auricular region.

Therapeutic Lymph Node Dissection

The most common sites for metastasis of head and neck cutaneous melanoma are the cervical and parotid lymph node basins.^114–116 The treatment of choice for regional disease remains a therapeutic lymph node dissection (TLND), which includes draining nodal basins as well as all intervening lymphatics between the primary tumor and the site of regional disease.

The location of the primary tumor dictates the type of TLND and the need for a superficial parotidectomy. Melanomas of the anterolateral scalp, temple, lateral forehead, lateral cheek, and ear, arising anterior to an imaginary coronal plane through the external auditory canals, drain via the parotid nodal basin to the jugular lymph node chain.¹¹⁷ For this reason, a superficial parotidectomy and modified radical neck dissection are both recommended. In the absence of gross tumor involvement or disruption from open biopsy or previous surgical dissection, concerted efforts should be made to preserve the spinal accessory nerve, internal jugular vein, and sternocleidomastoid muscle.¹¹⁷ If the melanoma arises in a more inferior location (e.g., the chin or neck), a superficial parotidectomy is not warranted. Melanomas located on the scalp and occiput—posterior to the imaginary coronal plane through the external auditory canals—can drain to postauricular, suboccipital, and posterior triangle lymph nodes. These nodal basins are not addressed during routine modified radical neck dissection and necessitate a posterolateral neck dissection that includes levels II through V as well as the preceding nodes.¹¹⁸

Elective Lymph Node Dissection

One of the most controversial historic debates about melanoma surrounded the treatment of regional nodal basins in the absence of clinical metastasis (prophylactic treatment of the N0 neck).^114,116 Opponents of elective lymph node dissection (ELND) contend that melanoma metastasis is unpredictable. In Fisher’s⁹ retrospective review of 1444 head and neck patients with melanoma, 16% had distant metastasis in the absence of regional disease. This potential for hematogenous melanoma spread to bypass regional nodal basins theoretically limits the utility of an ELND. Opponents further argue that all four prospective, randomized trials detailed here failed to demonstrate an overall survival benefit for patients undergoing ELND in the absence of regional metastasis.^119–124

The WHO Melanoma Group conducted the first prospective, randomized trial (Trial No.1) between 1967 and 1974, in which 535 patients with stage I and II melanoma of the extremity were enrolled.¹²³ A survival difference was not found between patients who underwent WLE and observation, with TLND reserved for the development of gross nodal metastasis, and patients who underwent WLE and ELND. Similarly, surgeons at the Mayo Clinic randomly assigned 171 patients with stage I disease to (1) WLE and observation, (2) WLE and delayed (30 to 60 days) ELND, or (3) WLE with concomitant ELND.¹²² ELND was not found to provide a survival benefit over observation.

Although both prospective trials represent pioneering research in a challenging area, Balch¹¹⁴ criticized both study designs. At the time of the studies, the prognostic significance of tumor thickness and ulceration was unknown. Later analysis of WHO Melanoma Group Trial No. 1 found significant discrepancy in the distribution of tumor thickness between the two treatment arms. Furthermore, 52% of lesions in the ELND group were ulceration compared with only 19% in the observation group.¹¹⁴ Subsequent reanalysis of these data with respect to tumor thickness and ulceration identified a subset of patients with a 22% better 10-year survival in the setting of ELND. The accuracy of clinical staging within the trial was also questioned because several institutions reported a 30% rate of occult nodal metastasis. This rate is quite high in comparison with rates reported in the literature, which range from 10% to 20%. Lastly, Balch¹¹⁴ argued that the failure to detect a survival benefit with ELND was not surprising, given that both trials included patients with an overall low risk for regional metastasis at the time of diagnosis. Approximately 85% of patients enrolled in WHO Melanoma Group Trial No. 1 were women with extremity melanomas, which are recognized to have a lower rate of metastasis than melanomas at other sites. In addition, the Mayo Clinic study excluded patients with head and neck and midline trunk melanomas.

In order to address these concerns, the Intergroup Melanoma Surgical Trial was initiated.¹¹⁹ This prospective, multi-institutional study involved 740 patients with intermediate tumor thickness (1 to 4 mm) melanomas of the trunk, extremity, or head and neck region. Patients were once again randomly assigned to undergo either WLE and observation or WLE and ELND. Cox regression analysis of the results identified ulceration, site, tumor thickness, and age as independent markers for survival. Overall 5-year survival rates were not found to differ in the two treatment groups. However, a significant survival benefit was found in patients 60 years of age and younger who underwent ELND, especially if their tumors were nonulcerated or measured 1 to 2 mm in thickness. Although this subgroup analysis is criticized for the shortcomings of a retrospective review and the failure to randomize by age, patients were prospectively randomized according to tumor thickness and ulceration.

The fourth prospective trial, initiated in 1982 by the WHO Melanoma Group (Trial No. 14), attempted to study patients truly at high risk for occult nodal metastasis.¹²¹ It enrolled 240 patients with trunk melanomas measuring 1.5 mm or more in thickness. A survival difference was not observed between patients randomly assigned to observation and those who underwent ELND. In a multivariate analysis that included sex, age, tumor thickness, and treatment, only sex and tumor thickness were found to have a significant impact on survival. The study did identify a statistically significant 5-year survival difference between patients in whom micrometastasis identified during ELND (47%) and patients in the observation arm who underwent TLND only after the development of gross nodal disease (27%). For this reason, the WHO Melanoma Group advocated early detection of nodal metastasis using procedures such as SLNB (see later).

Statistical power remains one of the greatest challenges in investigating the survival benefits of ELND and early detection of nodal disease in melanoma patients presenting with localized disease in clinical trials conducted to date.¹²⁵ Only 20% of patients with melanoma presenting with localized disease actually have occult nodal metastasis. It is this 20% who would potentially benefit from early removal of nodal basins. Adjuvant melanoma therapy imparts a survival benefit in 25% to 50% of cases. If a similar survival benefit is applied to the ELND group, 25% to 50% of the 20% of patients with occult disease should benefit. In other words, only 5% to 10% of patients undergoing ELND are expected to experience a survival advantage. Detecting this small difference requires an extremely large clinical trial with enrollment numbering in the thousands. McMasters and colleagues¹²⁵ point out that the Intergroup Melanoma Surgical Trial, WHO trial, and Mayo Clinic study lacked adequate statistical power to detect this small survival benefit. For this reason, these researchers concluded that the 4% survival benefit observed in the ELND group of the Intergroup Melanoma Surgical Trial study is clinically significant, despite the fact that statistical significance was not reached.

In summary, numerous prospective, randomized trials failed to demonstrate an overall survival benefit for patients undergoing ELND.^{110,119,121,123,125,126} Therefore, routine ELND is no longer advocated for melanoma. Instead, the procedure has been replaced by SLNB.

Sentinel Lymph Node Biopsy

Sentinel lymph node mapping and biopsy represents a minimally invasive, cost-effective, and efficient means of screening patients for regional metastasis.¹²⁷ Nodal status is currently recognized as the most important prognostic factor for patients with melanoma.⁵ Ten percent to 20% of such patients have occult microscopic nodal disease. In an attempt to identify this small group of patients who need TLND while sparing the remaining 80% of patients without regional disease the morbidity associated with a neck dissection, Morton and colleagues¹²⁶ introduced SLNB for the evaluation of patients with trunk and extremity cutaneous melanoma. The investigators demonstrated that the status of the SLN accurately represented the status of the entire nodal basin from which it was obtained. SLNB is considered the best staging modality for regional disease, with the highest sensitivity and specificity of any modality currently available. In a multivariate model using data from 910 patients with melanoma, Peak and associates¹²⁸ identified an association between SLN positivity and increasing Breslow depth, younger age, higher mitotic rate, angiolymphatic invasion, and location on the trunk/lower extremities. The indications for SLNB are summarized in Box 82-5. Patients who have metastatic disease or who have undergone previous surgical disruption of the lymphatics or resection with wide margins are not deemed candidates for this screening.

The SLN technique introduced by Morton and others has since evolved to include preoperative lymphoscintigraphy.¹²⁹ Approximately 2 to 4 hours before surgery, patients undergo intradermal injection of a radioactive colloid into the four quadrants surrounding the primary melanoma tumor. Lymphoscintigraphy is then performed. This nuclear medicine scan enables the surgeon to determine the number, location, and laterality of nodal basins at risk for metastatic disease (Fig. 82-3). It is particularly helpful in the setting of midline head and neck melanomas, for which there is a risk of bilateral lymphatic drainage.

Figure 82-3. Preoperative lymphoscintigraphy is performed about 3 hours prior to sentinel lymph node biopsy. Approximately 2 µCi of technetium Tc 99m sulfur colloid is injected intradermally into the four quadrants surrounding the primary melanoma lesion located midline on the posterior occiput. The right posterior occiput primary lesion with an overlying shield to limit “shine-through” is denoted by the small arrow. The larger arrow points to two draining sentinel lymph nodes observed in the right posterior triangle of the neck.

Once the patient is under anesthesia, intraoperative lymphatic mapping with isosulfan blue dye (Lymphazurin 1%; Covidien, Mansfield, MA) or methylene blue dye is performed.¹²⁶ Approximately 1 mL of dye is injected into the intradermal layer surrounding the primary melanoma lesion (Fig. 82-4). The primary tumor and draining lymphatics are in close proximity within the head and neck region. Therefore, WLE of the primary tumor is performed first to reduce radioactive “shine-through,” which would render the intraoperative gamma probe useless for the identification of SLNs (Fig. 82-5) Shine-through refers to radioactive counts attributable to the primary site injection rather than sentinel lymph nodes.

Figure 82-4. After the administration of anesthesia, intraoperative lymphatic mapping is performed with the use of approximately 1 mL of isosulfan blue dye (Lymphazurin 1%; Covidien, Mansfield, MA) injected into the intradermal layer surrounding the primary melanoma.

Figure 82-5. Wide local excision of the primary melanoma is performed prior to sentinel lymph node biopsy; otherwise, the close proximity of the primary lesion to the draining nodal basins within the head and neck region would cause significant radioactive “shine-through” and difficulty with localization of the sentinel lymph node. Each sentinel lymph node is then identified through the use of a combination of the gamma probe, which detects radioactive activity from the technetium Tc 99m sulfur colloid, and visual cues from the isosulfan blue dye.

Following WLE of the primary melanoma, the surgeon uses handheld gamma probe to identify the site(s) of sentinel lymph node(s). The procedure of identifying and removing sentinel lymph nodes continues until the gamma counts per minute (cpm) in the lymph node basin are equal or less than 10% of the “hottest” sentinel lymph node removed. We advocate this 10% rule because our data suggest that for surgeons using radioactive colloid who routinely terminate the procedure after identifying only the hottest node, or when the cpm values for nodes drop below one-half to one-third the cpm of the hottest node, the false-negative rates are higher.¹³⁰ The SLNs are removed with the use of 1- to 3-cm incisions overlying the areas of increased radioactivity. A preauricular incision is recommended for SLNB in the parotid region. SLNs are then identified through the use of a combination of the gamma probe and visual cues from the blue dye (see Fig. 82-5). Each SLN is individually dissected from surrounding tissue.

At our institution, all SLNs are sent for histologic evaluation using permanent sections. Frozen sections are less reliable, carrying a false-negative rate between 5% and 10%.¹³¹ The evaluation involves serial sectioning (5-µm thick sections) and staining with hematoxylin and eosin. Special melanoma immunohistochemical staining for S-100 protein and melan-A (MART-1 [melanoma antigen recognized by T cells]) are performed for all SLNs with negative response to hematoxylin and eosin staining. This panel was chosen after pathologic evaluation of 99 positive SLNs from 72 patients treated at our institution.¹³² The sensitivities for S-100, melan-A, and HMB-45 monoclonal antibody were found to be 97%, 96%, and 75%, respectively. In addition, HMB-45 stained a smaller percentage of cells (25% to 75%), with weaker intensity compared with S-100 and melan-A; for this reason, we no longer routinely stain for HMB-45.

Patients with a positive SLN result are returned to the operating room within 2 weeks of diagnosis for definitive TLND; patients with a negative result are followed clinically. An alternative to this two-stage technique is immediate TLND on the basis of frozen-section evaluation of the SLNs. However, it is important to realize that the reliability of frozen sections for melanoma analysis has been questioned,¹³³ and permanent sections remain the “gold standard.”

The pathologist plays an extremely critical role in the success of SLNB. Occult lymphatic metastasis from cutaneous melanoma can be difficult to detect and warrants rigorous pathologic analysis, including serial sectioning, special immunohistochemical study when indicated, and interpretation by an experienced pathologist. Wagner and associates¹³⁴ reported the mean tumor volume in SLNs positive for metastatic melanoma to be only 4.7 mm³. Joseph and colleagues⁶⁶ reported the identification of only 73% of metastatic SLNs with the use of standard hematoxylin and eosin staining alone. In our study, 20 of the 97 positive SLNs (21%) tested negative on initial hematoxylin and eosin staining.¹³² This high false-negative rate highlights the importance of immunohistochemical staining for accurate diagnosis of occult nodal disease.

The histologic analysis of SLNs is more thorough, complete, and practical than the traditional evaluation of the entire lymphadenectomy specimen, because the technique provides the pathologist with a limited number of nodes to evaluate thoroughly.¹³⁵ SLNB is particularly helpful in the diagnosis of occult DM/DNM. For this subtype, a focused histopathologic evaluation is of particular importance because the microscopic features are quite variable, often lack resemblance to the primary tumor, are limited to a paucity of tumor cells, and demonstrate inconsistencies on HMB-45 and melan-A staining.¹³⁶

SLNB is a team effort involving experienced surgeons, nuclear medicine staff, and pathologists. The experience and technical skill of the surgeon is vital. Morton and associates¹²⁷ previously suggested a 30-case learning curve. However, long-term follow-up of their international Multicenter Selective Lymphadenectomy Trial (MSLT-1) found the 30-case learning curve to be too shallow. Analysis of the first 25 cases performed at the 10 highest-volume centers in the trial revealed a nodal basin recurrence rate of 10.3%.¹³¹ This false-negative rate dropped to 5.2% after 25 additional cases. The researchers now conclude that a 55-case learning curve is required in order to achieve at least 95% accuracy with SLNB.

An experienced nuclear medicine staff is also necessary, because inappropriate administration of the radioactive tracer can also lead to “shine-through.” Communication between the surgeon and the nuclear medicine team is helpful not only for the interpretation of the lymphoscintigram but also to ensure that the appropriate lesion is mapped, because patients with melanoma often present with multiple pigmented lesions.

A multivariate analysis involving patients with stage I and II melanoma by Gershenwald and coworkers¹³⁷ 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. For patients with stage III melanoma, survival was better in those with occult microscopic disease than in those with palpable macroscopic disease.⁵ This survival difference was so compelling that the AJCC has now incorporated SLNB into the revised staging system for cutaneous melanoma.

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 head and neck region.¹²⁷ The complexity of the head and neck lymphatic system has caused concern about the reliability of the SLNB to accurately reflect the status of the entire nodal basin. The interlacing network of cervical lymphatic vessels is often deemed to be watershed in nature. The complexity of this lymphatic system was demonstrated by O’Brien and colleagues,¹³⁸ who reported a 34% discordance between the clinical prediction of lymphatic drainage and lymphoscintigraphy findings in 97 cases of head and neck cutaneous melanoma. The popularity of SLNB in the head and neck region has also been limited by concern surrounding damage to vital structures such as the facial nerve,¹³⁹ technical difficulties,¹³⁹ and the necessity for nuclear medicine staff as well as pathologists who specialize in SLNB technique.

Our experience in staging 80 cases of head and neck cutaneous melanoma demonstrated that the complexity of the head and neck anatomy does not preclude the use of SLNB for the staging of cutaneous melanoma.¹⁴⁰ SLNB in the head and neck region accurately predicted the status of the nodal basin. Fourteen of 80 patients (17.5%) had a positive sentinel lymph node. Of 66 (4.5%) patients with negative SLNB results, only 3 experienced regional recurrence. The 17.5% positivity rate of SLNs and the 4.5% false-negative rate both mirror the results that SLNB achieved in other anatomic sites, such as the trunk and extremities.^135,141 Similar success in the application of SLNB for head and neck cutaneous melanoma has been reported by others,^142,143 and the technique has been applied successfully in pediatric head and neck cases.¹³

Approximately 25% to 30% of head and neck cutaneous melanomas drain to lymph nodes within the parotid bed.^138,140 Potential injury to the facial nerve from SLN biopsy has led some surgeons to advocate superficial parotidectomy over the mapping procedure.¹³⁹ In our retrospective analysis, staging with SNLB was successful in 28 of 30 (93.3%) patients whose tumors were draining to the parotid nodal basin.¹⁴⁰ One patient required a superficial parotidectomy owing to the location of the SLN deep to the facial nerve, and a second patient experienced significant bleeding from surrounding parotid tissue, which could have put the facial nerve at increased risk. A total of 39 nodes from the parotid basins of these 28 patients were removed without facial nerve injury. Continuous facial nerve monitoring for SLNB within the parotid nodal basin can be helpful when the biopsy is performed within the parotid bed.

Concern has also been expressed that SLNB causes inflammation and fibrosis that could place the facial nerve at increased risk when reoperation is required to definitively treat the parotid basin in the setting of a pathologically positive SLN.¹³⁹ In our experience, all patients with a positive parotid SLN underwent superficial parotidectomy as a subsequent procedure without facial nerve injury. Our findings are consistent with those of other reports demonstrating that SLNB can reliably and safely be performed within the parotid nodal basin.^144,145

Other researchers have suggested that SLNB increases the risk of in-transit metastasis (ITM), which is defined as intralymphatic tumor dissemination within cutaneous or subcutaneous tissue located between the primary lesion and draining nodal basin.^146–150 It is theorized that ITM develops when melanoma cells detach from the primary lesion and become lodged in the dermal plexus of lymphatics prior to reaching the lymph nodes. ITM presents a therapeutic challenge and carries a poor prognosis, as indicated by the changes to the AJCC staging system previously described.⁵ Original reports citing increased ITM following SLNB must by viewed with caution, because the studies often entailed pooled data from small cohorts and failed to control for important prognostic factors such as tumor thickness and ulceration.^61,148 A later prospective review comparing 4412 patients undergoing WLE alone, WLE with SLNB, or ELND identified a correlation between ITM and increasing Breslow depth, Clark level, and T stage.⁶¹ A statistically significant difference between ITM and tumor recurrence was not found among the treatment groups, once adjustment of data was made for T stage, age, sex, tumor thickness, and site. Additional studies have concluded that it is the tumor biology, rather than the surgical procedure (SLNB; ELND), which dictates melanoma metastatic behavior.^148,151 Finally, a correlation between ITM and SLNB was not reported with MSLT-1, thus negating this concern.¹³¹

The impact of SLNB on overall survival remains to be determined. The answer will hopefully be provided through the multi-institutional Sunbelt Melanoma Trial, which is a prospective, randomized clinical trial that utilizes SLN staging to determine the need for adjuvant therapy.¹⁵² While we await these results, McMasters and colleagues¹⁵³ outline the following four compelling reasons to use of SLNB for accurate regional staging of cutaneous melanoma.

The fifth and final analysis of MSLT-I will provide additional insight into the potential therapeutic benefit of SLNB.¹³¹ Publication of the MSLT-I interim analysis is exciting in that it is the first randomized, prospective trial to demonstrate that SLNB accurately identifies occult nodal metastasis that would lead to advanced, palpable nodal disease if left in situ. The researchers argue that there is no reason not to perform SLNB because a zero mortality rate was reported, and the complication rate for SLNB (10%) was significantly lower than that for TLND (37%). Morton and colleagues¹³¹ concluded that SLNB should be considered the standard of care for regional staging of primary cutaneous melanoma—the key term being “staging.” At present SLNB is a diagnostic tool for regional staging, not a therapeutic modality. Although it is not 100% accurate, SLNB is the most reliable means for regional staging. It is more sensitive and specific than CT, magnetic resonance imaging, positron emission tomography, ELND, and clinical examination.¹⁵⁴ McMasters astutely points out that we do not expect a survival benefit from any other cancer staging test, and therefore we should not ask the same of SLNB.

Surgical Management of Distant Metastasis

Patients with stage IV melanoma involving distant sites have an exceedingly grave prognosis. Surgical treatment has a limited role in the setting of disseminated disease. It has successfully been used as a means of palliative treatment in patients suffering from brain, lung, gastrointestinal, subcutaneous soft tissue, and distant lymph node metastasis.¹⁶¹ Success of surgery in the palliative setting depends heavily on appropriate patient selection; it should be considered only if clearly identifiable and specific symptoms are associated with a metastatic lesion. Other considerations are surgical morbidity, expected quality of life, expected survival, and, most important, the patient’s wishes.¹⁶² It is imperative that the patient and his or her family understand that the goal of surgery is palliative in nature.

Several prognostic markers have been identified in patients with disseminated stage IV melanoma.^162,163 These markers are reflected in the AJCC staging system previously described above and should serve as a guide for the consideration of surgical resection of distant tumors. Patients with metastatic disease limited to one or two isolated sites experience a better prognosis as than patients who have multiple metastatic lesions. A short disease-free interval is associated with an overall poor prognosis. Patients in whom distant metastasis develops within a year of initial diagnosis have a poor prognosis, even when complete resection of the metastatic lesion is achieved.¹⁶² Lastly, the anatomic site of the metastatic lesion is of importance. Patients with metastatic spread to nonvisceral sites (e.g., distant subcutaneous tissues, lymph nodes) have a better prognosis than those with visceral metastasis. Within the group of patients suffering from visceral metastasis, individuals with pulmonary lesions experience better survival than those with lesions at other visceral sites.

Interferon

Despite myriad clinical trials involving adjuvant regimens, high-dose interferon-α 2b remains the only adjuvant treatment approved by the U.S. Food and Drug Administration (FDA) for stage III melanoma. It functions as a biologic response modifier; the mechanism of action includes direct antiproliferative effects, immune stimulation through the enhancement of natural killer cells, increased histocompatibility antigen expression on melanoma cells, macrophage phagocytosis, and enhanced T-cell–mediated cytotoxicity.^107,183 Although all three types of interferon (α, β, and γ) demonstrate antitumor activity,¹⁸³ Interferon-α 2b is the only treatment that is currently approved for the adjuvant treatment of patients with melanoma at high risk for recurrence after surgery.

Three large clinical trials involving adjuvant interferon-α 2b have been conducted by the Eastern Cooperative Oncology Group (ECOG).^184–186 In brief, ECOG trial E1684 was the first study to demonstrate the efficacy of interferon-α 2b.¹⁸⁴ The regimen consisted of high-dose interferon (20 million units/m²/day) administered intravenously, 5 days a week, for 4 weeks. Maintenance treatment followed, consisting of 48 weeks of subcutaneous interferon-α 2b (10 MU/m²/day) administered 3 days a week. The prolonged disease-free survival rate and overall survival rate in the interferon-α 2b arm of E1684 ultimately led to FDA approval of the adjuvant therapy.

Although the follow-up trial E1690 did not confirm the efficacy of high-dose interferon-α 2b,¹⁸⁵ the results require careful interpretation.¹⁵³ Unlike in E1684, patients enrolled in E1690 did not require pathologic staging with ELND or SLNB, nor were they stratified according to ulceration. In addition, a disproportionate number of individuals from the observation arm crossed over into the interferon-α 2b arm to receive salvage therapy for recurrent disease. Any therapeutic benefit provided to this subgroup by interferon-α 2b went unrecognized, because the crossover patients remained in the observation arm for the purposes of statistical analysis.

The latest and largest of the three studies, ECOG 1694,¹⁸⁶ once again confirmed the efficacy of high-dose interferon-α 2b. In fact, the difference between rates of relapse-free and overall survival observed in the high-dose interferon-α 2b control arm in the GMK ganglioside vaccine treatment arm was so compelling that the Data Safety Monitoring Committee terminated the trial early.

With close follow-up, dose modification, and pharmacologic intervention, the majority of patients with melanoma are able to tolerate the 1-year course of interferon-α 2b.^{153,175,185,186} Almost all individuals experience flulike symptoms (fevers, chills, malaise) during the initial treatment course. Severe and intolerable chronic fatigue occurs in 20% to 30% of patients, and an additional 2% to 10% experience neurologic and psychiatric side effects, including depression, anxiety, suicidal ideation, and difficulty with cognition. Myelosuppression, thyroid dysfunction, and elevated liver enzyme values require close monitoring. Contraindications include a history of myocardial infarction or dysrhythmia, liver disease, central nervous system disorders, and severe psychiatric illness.¹⁷⁵ Approximately 50% of patients require a dose reduction or delay as a result of these side effects. The majority of patients with melanoma are willing to accept these side effects, given the potential benefit of interferon-α 2b.¹⁸⁷

Although clinical trials continue to investigate alternative dosages and schedules,^188,189 high-dose interferon-α 2b remains the only proven adjuvant treatment for melanoma, with relapse-free survival prolonged by approximately 10%.¹⁹⁰ It remains the standard of care for adjuvant therapy against which all interventions must be compared, ideally in the setting of prospective, randomized trials.¹⁹¹ Every patient with regional lymph node metastasis or a primary tumor thickness greater than 4 mm should be informed of the option to receive postoperative interferon-α 2b. To enable the patient to make an educated decision, the surgeon must have an objective discussion about the side effects of interferon-α 2b and the opportunities to enroll in other clinical trials.

Interleukin-2 and Other Cytokines

Interleukin-2 (IL-2) is another form of immunotherapy that is used in the primary treatment of disseminated stage IV disease. Unlike interferon, IL-2 lacks direct antitumor activity and in vitro activity.¹⁰⁷ However, in vivo, IL-2 stimulates the host’s immune system by activating effector cells such as natural killer cells, monocytes, cytotoxic T cells, and helper T cells. It also induces cytokines such as interferon-γ and tumor necrosis factor-α.^107,192

Rosenberg and colleagues,¹⁹³ of the Surgery Branch of the National Cancer Institute, successfully used high-dose IL-2 to treat 134 patients with melanoma. An overall response was observed in 17% of patients; 10% experienced a partial response, and an additional 7% had complete regression. The therapeutic benefit was substantial, lasting between 2 and 8 years.

The side effects of IL-2 are significant and potentially lethal. Acute toxic effects include myocardial infarction, arrhythmia, respiratory distress, hypotension, capillary leak syndrome, nephrotoxicity, hepatic toxicity, and sepsis.^192,194 Others are anemia, thrombocytopenia, nausea, emesis, diarrhea, myalgia/arthralgia, skin erythema, and pruritus. Only patients who demonstrate excellent cardiopulmonary health and performance status should be considered for clinical trials involving IL-2.

Subsequent efforts to enhance the response to IL-2 by altering the schedule and dose and by combining it with other therapeutic agents (e.g., lymphokine-activated killer cells) have not proved beneficial.^{107,182,192,194} In addition to IL-2, other cytokines have been studied alone and in combination with various chemotherapeutic agents, including IL-1, IL-4, IL-6, and tumor necrosis factor-α.¹⁹² Significant therapeutic benefit has not been demonstrated for any.

Future Immunotherapy Investigations

Significant advances in the field of melanoma research have been achieved in recent years.^{175,182,183,195,196} Intense efforts in the areas of melanoma vaccination, gene therapy, and HLA immunoprinting will likely play important roles in future research endeavors. Until therapeutic efficacy achieves that of interferon-α 2b, all other adjuvant agents should be administered to high-risk patients only in the setting of well-designed clinical trials. Given the heterogeneous melanoma patient population, myriad immunotherapy regimens, and the limited survival of high-risk patients with melanoma, multi-institutional studies with accurate clinical staging will be imperative.