The Management of Head and Neck Melanoma

The Management of Head and Neck Melanoma The worldwide incidence of melanoma continues to increase faster than any other cancer.1 It is currently the fifth leading cause of cancer among men and the sixth leading cause among women.2 Fortunately, the management of melanoma is also 1 of the fastest evolving fields in cancer, with promising research taking place at both the molecular and clinical level. Despite these research efforts, many controversies still surround the management of melanoma. What is the optimal evaluation for a newly diagnosed melanoma patient? What are the ideal surgical margins? Does early management of draining nodal basins impact overall survival? Does sentinel lymph node biopsy (SLNB) impart a survival benefit? What is the role of adjuvant interferon-␣2b? The head and neck (HN) region adds further complexity with its rich and often watershed lymphatic system, intricate anatomy, and vital structures such as the carotid artery and facial nerve. The goal of this issue is to review the evaluation and management of patients with HN melanoma. In doing so, the new 2002 American Joint Committee on Cancer (AJCC) staging system will be highlighted, along with the current National Cancer Comprehensive Network (NCCN) practice guidelines. The majority of the monograph chapter will focus specifically on the management of cutaneous head and neck melanoma, which is far more common than mucosal melanoma. Mucosal melanoma and melanoma of unknown primary origin will be discussed briefly as independent sections.

Demographics Despite a recent decline in the overall trend in cancer incidence and mortality, the incidence of cutaneous melanoma continues to rise faster than any other cancer.3 The National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Data estimates that 59,580 new cases of invasive cutaneous melanoma will be diagnosed in 2005. An additional 46,170 in situ cases are estimated that same year. For women Curr Probl Surg 2006;43:781-835. 0011-3840/2006/$30.00 ⫹ 0 doi:10.1067/j.cpsurg.2006.08.003

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under the age of 40, the incidence of melanoma is second only to breast cancer.1 Over the past 50 years, the annual percentage change in invasive melanoma incidence has steadily increased 4.3% each year.3 The lifetime risk for developing invasive melanoma has climbed at epidemic proportions.4 This risk increased from 1 in 1500 for individuals born in 1935, to 1 in 250 in 1980. This trend is expected to continue at a startling rate, with 1 in 39 individuals born in 2010 projected to develop melanoma.5 Melanoma is the most lethal form of skin cancer. In 2005, it will be responsible for an estimated 7770 deaths within the United States.3 This estimate averages to approximately 1 American dying from melanoma every hour. Over the past 50 years, the annual percentage change in mortality rate has increased at a steady rate of 1.8% per year. Melanoma accounts for the second highest increase in mortality rate, especially for men over the age of 65. However, it should not be viewed as a cancer limited to the elderly. Melanoma is known to afflict young adults, with 1 in 4 patients diagnosed before the age of 40.5,6 Consequently, melanoma is responsible for 1 of the leading cancer causes of lost potential life years. Approximately 25% of all cutaneous melanomas arise in the head and neck (HN) region, with more than 9000 cases diagnosed annually. A slight male predominance has been consistently reported throughout the literature.7-9 The median age of diagnosis for patients with HN melanoma is 55 years, slightly younger than the median age of 57 years reported for all melanoma sites.6 However, juvenile cases account for 1.66% of HN melanoma cases, with patients being diagnosed as young as 4 years of age.10,11

Tumor Biology Melanocytes are dendritic cells of neural crest origin, located at the epidermal-dermal junction. Within these cells, cytoplasmic organelles termed melanosomes synthesize melanin, which is distributed to surrounding keratinocytes to form a supranuclear cap that provides protection from damaging ultraviolet radiation (UVR).12 The photo-protective property of melanin results from the absorption of both UVR photons and its oxygen radical by-products.13-15 The protective role of melanin is evident through tanning in which UVR exposure increases melanogenesis. The increased amount of melanin granules is transferred to surrounding keratinoctyes, thereby darkening the skin color. This protective layer of melanin serves as an endogenous sunscreen, persisting for approximately 3 weeks following exposure.15 Whereas cutaneous squamous cell carcinoma (SCC) and basal cell 782

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carcinoma (BCC) are associated with cumulative sun exposure, melanoma development correlates with intermittent and intense exposures common in sunburns.16-18 This difference is thought to be due to intrinsic differences in tumor cell origin. SCC and BCC both arise from keratinocytes that undergo apoptosis in response to severe UVR damage. With repeated low-dose solar exposure, keratinocytes can accumulate a significant amount of unrepaired DNA damage to result in SCC or BCC of the skin. Melanocytes, however, have not been found to undergo apoptosis.19 Gilcrest and colleagues speculate that the absence of apoptosis in DNA-damaged melanocytes represents a protective measure since these cells have a limited ability to proliferate. By escaping apoptosis, the photo-protective role of melanocytes is preserved. However, this protective measure comes at the expense of increased melanoma risk. The appearance of freckles after intense sun exposure supports this theory, because freckles represent clones of mutated melanocytes and carry an increased risk for melanoma.20

Head and Neck Distribution All individuals, regardless of ethnicity, share approximately the same number of melanocytes. It is a difference in the number, distribution, and density of melanin granules within keratinocytes that account for racial variation in skin color.21 Within the human body, melanocyte density varies. The average number of melanocytes per square millimeter squared (mm2) in an adult is 1194 for the face, 1060 for the scalp, and 926 for the neck. This concentration is considerably higher compared with other anatomic sites such as the buttock and abdomen, which contain only 565 and 578 melanocytes/mm2, respectively. The concentration of melanocytes within sun-exposed regions of the body emphasizes the UVR protective role of melanin.22 The majority of HN cutaneous melanomas arise on the cheek, scalp, and neck. Among 857 HN melanoma patients, Fisher and colleagues found that the face and neck region accounted for more than 60% of all primary tumors. An additional 26% arouse from the scalp, with the ear and nose accounting for only 9% and 4% of primary tumors, respectively.6 These results were confirmed by O’Brien and colleagues who reported the face as the most common site (47%), followed by the neck (29%), scalp (14%), and ear (10%).8 The cheek and forehead region contain a 2- to 3-fold greater density of melanocytes compared with other anatomic sites. This difference, coupled with increased sun exposure, is thought to account for the distribution of melanoma within the HN region. Curr Probl Surg, November 2006

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TABLE 1. Cutaneous melanoma risk factors Environmental

Genetic/past medical history

Inability to tan Fair complexion Blue/green eyes Blonde/red hair Freckling History of blistering/peeling sunburns Teenage outdoor summer jobs

CDKN2A (p16) mutation History of prior melanoma Family history of melanoma Actinic keratoses Non-melanoma skin cancer Xeroderma pigmentosa (XP) Atypical (dysplastic) nevus Giant congenital melanocytic nevus Immunosuppression

Etiology and Risk Factors Several environmental and genetic risk factors have been implicated in the development of cutaneous melanoma.23 Numerous risk factors are summarized in Table 1.

Sun Exposure Sun exposure is the leading cause of melanoma.23,24 As noted above, patients with a significant history of sun exposure are at particularly high risk, especially if they experienced intense exposure resulting in blistering sunburns.25 Risk factors for sunburns such as red or blond hair, green or blue eyes, or fair skin consistent with Fitzpatrick skin type I-III share a strong correlation with the development of melanoma.26 Patients previously diagnosed with melanoma are also at increased risk, with 5% to 10% of individuals developing a second primary cancer.27 This risk is life-long and can occur anywhere on the skin. Therefore, long-term, annual follow-up with a thorough total body examination is critical. In addition, adults with more than 100 clinically normal appearing nevi, children with more than 50 clinically normal appearing nevi, and any patient with atypical or dysplastic nevi are at risk.28

Genetics A genetic etiology has also been implicated in the pathogenesis of melanoma.29 CDKN2A, also known as p16, remains the most common chromosomal mutation associated with melanoma.30 Overall, the mutation accounts for only a small percentage of melanoma cases observed. For example, Aitken and colleagues identified the mutation in only 0.2% of the melanoma cases diagnosed in Australia.31 Up to15% of melanoma patients report a positive family history.32 In the 1970s, Clark and colleagues noted the hereditary nature of 784

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cutaneous melanoma when they described several family members afflicted with acquired, large, irregular, and dysplastic nevi, often in sun-protected regions of the body such as the scalp and trunk.33 They coined the term “B-K mole syndrome” after 2 families in their study. During this time period, Lynch and colleagues independently reported a familial association of melanoma among individuals with atypical nevi. They proposed the term “familial atypical multiple mole-melanoma syndrome” or FAMMM syndrome for family members.34 Today, the term “atypical mole syndrome” is applied to familial cases of melanoma. The syndrome is inherited in an autosomally dominant fashion.35 Patients suffering from atypical mole syndrome carry a 10-year melanoma risk of 10.7%, which is significantly greater than the 0.62% risk reported in control patients.36,37 A 56% cumulative risk is estimated in these patients from age 20 to 59 years, with 100% of atypical mole syndrome patients developing melanoma by age 76.38 Another hereditary disorder associated with melanoma is xeroderma pigmentosa (XP). This rare disease is inherited in an autosomally recessive fashion.39 The fibroblasts in XP patients have an impaired ability to repair DNA damaged by ultraviolet light.40 As a result, multiple primary cutaneous malignancies including melanoma, BCC, and SCC develop. Individuals are usually diagnosed with their first cancer before the age of 10. Despite ultraviolet light precautions, careful surveillance, and aggressive treatment, the development of skin cancers is relentless. XP patients ultimately succumb to their disease at an early age.

Immunosuppression Numerous studies throughout the literature provide supporting evidence for a role of immunosuppression in the development of melanoma. Children suffering from immunodeficiency disorders carry a 3-fold increased risk for melanoma.41 Renal transplant patients requiring immunosuppressive therapy may have a higher incidence of melanoma compared with the general population.42 Although the SEER program for San Francisco has not reported an increased trend in melanoma among men at risk for human immunodeficiency virus (HIV),43 several case series detail aggressive melanomas in this setting.44,45 In addition, higher rates of premalignant, melanocytic nevi are associated with renal transplantation,46 chemotherapy,47 and childhood leukemia.48

Congenital Nevi Congenital melanocytic nevi (CMN) are pigmented lesions present at birth or within the first 6 months of infancy.49 Up to 6% of children are Curr Probl Surg, November 2006

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born with CMN. These nevi are classified according to size, with small CMN measuring less than 1.5 cm in diameter and accounting for the majority of lesions. Medium CMN range between 1.5 and 19.9 cm in diameter. Large CMN, also termed giant congenital nevi, measure 20 cm or greater. The large size of these lesions carries significant cosmetic, as well as psychosocial, implications.50 The CMN classification system is important because nevi size correlates with melanoma risk. The risk of melanoma development from small and medium sized CMN is similar to any other nevus. Cancer development in this setting is usually after childhood. Malignant transformation tends to arise at the dermo-epidermal junction, allowing for obvious changes to the nevus and early detection of cancer. For this reason, routine prophylactic removal of small and medium CMN is rarely indicated in the absence of signs or symptoms concerning for malignant progression. However, large/giant CMN carry an increased risk for melanoma, with development in an estimated 5% to 20% of individuals.51,52 Seventy percent of these patients are diagnosed before age 10.37 Melanoma can originate deep to the epidermis, going unnoticed within the large pigmented lesion, thereby delaying diagnosis until advanced disease has developed. For this reason, prophylactic excision of large CMN is advocated if the nevus is in an anatomic location amenable to surgical excision.

Melanoma Classification Several histologic subtypes of melanoma are encountered within the HN region. Despite the classification system, it is important to realize that melanoma subtype does not generally influence prognosis once tumor thickness and other prognostic variables such as ulceration are taken into account.53

Common HN Melanoma Subtypes The most common type of cutaneous melanoma is superficial spreading melanoma (SSM), accounting for approximately 70% of all cases. SSM commonly arises in the setting of a preexisting nevus, with a diagnosis rendered during the fourth or fifth decade. The characteristic feature of SSM is color variation, which is often haphazard in nature. Black, dark brown, tan, and blue-gray areas of pigmentation are commonly observed. Areas of pink and white represent hypopigmentation secondary to tumor regression. Although SSM lesions are well circumscribed, the borders tend to be scalloped and asymmetric. Nodular melanoma (NM) is the second most common variant, account786

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ing for 15% to 30% of cases. The majority of mucosal melanomas are classified as the nodular subtype (see below). This lesion typically appears as a blue-black or blue-red, raised nodule. For this reason, NM must be differentiated from a hemangioma, blue nevus, pyogenic granuloma, and pigmented BCC. Lentigo maligna (LM) represents intraepidermal or melanoma in situ. Histologically, it is seen in the background of chronic solar damage. LM is considered the precursor to invasive lentigo malignant melanoma (LMM). The exact percentage of LMs that progress to invasive LMM remains unknown54; however, it is speculated that if patients live long enough, all LMs will eventually progress to invasive melanoma. LM/ LMM is commonly found within the HN region. This subtype has been associated with older individuals, but the frequency in younger patients is increasing.28 The LM/LMM pattern warrants special comment because this subtype is often characterized by subclinical and 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. Additionally, amelanotic and invasive desmoplastic melanoma (see discussion here) often arise within LM/LMM.

Desmoplastic-Neurotropic Melanoma In 1971, Conley and colleagues introduced the term desmoplastic melanoma (DM) to describe a melanoma subtype comprised of spindle cells, abundant collagen, and features resembling fibromas.55 Reed and colleagues further noted a propensity for perineural spread among a subset of DMs.56 This prompted further subclassification of a desmoplastic-neurotropic melanoma (DNM) variant. DM/DNM subtypes are rare, accounting for approximately 1% of all cutaneous melanomas.57 However, more than three fourths of the lesions are diagnosed within the HN region. DM/DNM often present as hard, fibrous, subcutaneous lesions within a background of LM/LMM. It is important to note that the clinical presentation and biologic behavior of these tumors are distinct from traditional cutaneous melanomas. Although amelanotic cases account for only 4% to 5% of cutaneous melanomas, up to 73% of DM/DNMs are amelanotic.57,58 In addition, the neoplasms often lack the typical ABCD criteria for melanoma (described herein). They have a challenging histologic pattern that requires combined histopathologic and immunophenotypic evaluation by an experienced pathologist.59 DM/DNM is recognized as locally aggressive and highly infiltrative Curr Probl Surg, November 2006

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melanoma. Tumors are often associated with cranial nerve and skull base involvement. It is estimated that 50% of all cases will recur locally.57 Explanations for this high rate include the association with neurotropism, failure to recognize and adequately clear peripheral AJMH margins, and delay in diagnosis due to the atypical appearance. It is interesting to note that although DM/DNM demonstrate greater tumor thickness at the time of diagnosis, the rate of regional lymph node metastasis is estimated between 8% and 15%, much lower than that of other melanoma subtypes.56

Unknown Primary Three percent to 8% of melanoma patients present initially with an unknown primary site.60-62 Two thirds of these individuals present with regional metastasis in the absence of an identifiable primary lesion or history of melanoma. The remaining one third of cases involve distant metastasis to sites such as the subcutaneous tissues, lung, and brain.61-64 Several theories have been proposed to explain melanoma of unknown primary origin. The identification of melanocytes and nevus cells within lymph node capsules and visceral organ epithelium have led some scientists to propose that unknown primary cases result from melanoma arising de novo at regional and distant sites.61,65 An alternative explanation is that the original primary melanoma site undergoes complete, spontaneous regression secondary to antitumor immune response. Therefore, it is no longer identifiable.65,66 All patients presenting with melanoma of unknown origin warrant a thorough examination of both the total body skin and the mucosal surfaces. A careful history must also be obtained, specifically inquiring about previous skin biopsies, lesions that were “frozen,” skin tags removed, and “moles” that spontaneously disappeared. All pathology slides from previously excised lesions should be re-reviewed. The metastatic evaluation is identical to that of known primary cases described below. After adjusting for tumor stage, melanoma of unknown primary origin shares the same disease-free interval and overall survival rates as their counterparts with known primary sites.61-64

Mucosal Melanoma Mucosal melanoma is recognized as a rare, distinct, and separate subtype from its cutaneous counterpart. Only 1074 (1.3%) of the 84,836 melanoma cases registered in the National Cancer Database from 1985 to 1994 were mucosal in origin.60 Fifty percent of all mucosal melanoma 788

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cases arise within the HN region, making it the most common location.67 However, less than 2% of all HN melanomas are of the mucosal variant. The demographic aspects of mucosal melanoma differ in several respects from cutaneous melanoma. Mucosal melanoma is usually diagnosed during the sixth to seventh decade, approximately 10 to 15 years later than cutaneous melanomas.67-71 Whereas cutaneous melanoma is recognized as a disease among non-Hispanic Caucasians, a substantial number of mucosal melanomas are also diagnosed among African Americans, Hispanics, and the Japanese.61,72 Similar to cutaneous melanoma, a slight male predominance has been reported for mucosal tumors.69,71,73 The nasal cavity (NC) is the most common site for HN mucosal melanoma. Specifically, the origin is most often along the anterior nasal septum, followed by the inferior and middle turbinates.70,73-75 The second most common site is the oral cavity (OC), where a predilection for the hard palate and maxillary alveolar gingivae has been reported. Laryngeal primary tumors account for less than 4% of all cases.74 Within the larynx, the supraglottis was the most common subsite involved. The presenting signs and symptoms for mucosal melanoma are quite different from cutaneous melanoma and correlate directly with the anatomic origin. Patients harboring NC primaries present most often with nasal obstruction and epistaxis.73-75 Proptosis, diplopia, facial pain, and facial asymmetry are less common and raise concern for advanced disease. Patients with OC mucosal melanoma are often asymptomatic, with the cancer going undiagnosed until a neck mass develops from regional metastasis.68,73 The most common local sign for OC tumors is a mass lesion.75 The sparse number of mucosal melanoma cases limits research to anecdotal reports. The paucity of cases simply precludes the ability to conduct meaningful clinical trials. It is recognized that mucosal melanoma does not share the same important prognostic markers as cutaneous melanoma.67 For example, the development of regional metastasis does not impact survival for patients with mucosal melanoma, yet it is the most important prognostic marker for cutaneous variants.70 For this reason, the melanoma staging system set forth by the AJCC and described herein specifically applies to cutaneous, not mucosal, melanoma cases. The majority of mucosal melanoma patients present with localized disease. Only 18.7% will demonstrate stage III, regional spread, at the time of diagnosis. However, the high percentage of patients with localized disease is deceiving because local recurrence is the major reason for treatment failure.74 Fifty percent of patients recur locally, usually within Curr Probl Surg, November 2006

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12 months of diagnosis. Despite the fact that most patients present with stage I/II disease, the overall 5-year survival rate is a dismal 10% to 20%.69-71,74 Mucosal melanoma of the paranasal sinuses portends the worst prognosis, followed in decreasing order by OC, pharyngeal, and NC tumors.70 The rich vasculature and lymphatics of HN mucosa possibly contributes to the aggressive behavior of mucosal melanoma.74

Diagnostic Evaluation History The majority of melanoma lesions are first detected by the patient or his/her partner.76,77 Less than one fourth of lesions are diagnosed during routine office physical examination; however, when lesions are detected by the physician, they tend to be thinner.77 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. Patients should be questioned about a previous personal and family history of melanoma. Information including previous skin biopsies, sun exposure, history of blistering sunburns, tanning booth use, and occupation should be obtained. Johnson and colleagues investigated characteristics of 1515 melanoma patients and found that 81% recalled a history of at least 1 sunburn.77

Physical Examination 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 can have multiple primary cutaneous melanomas.78-81 The differential diagnosis for cutaneous melanoma is quite broad, including: seborrheic keratosis, hemangioma, blue nevus, spitz nevus, pyogenic granuloma, pigmented basal cell carcinoma, and even cutaneous squamous cell carcinoma. To help educate both patients and physicians in early detection of melanoma, the American Cancer Society has published the ABCD checklist.82 Under these guidelines, concerning signs for melanoma include: 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. The ABCD checklist is quite helpful in identifying melanoma; however, it will not detect every case.81,83 It is important to realize that a subset of cancers 790

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such as nodular, amelanotic, and desmoplastic melanomas lack the common features of the ABCDs. For this reason, the Europeans implemented a 7-point checklist that focuses on the importance of change within an existing lesion.84 In 1 series, 88% melanoma patients (615 of 696) recalled change in their pigmented lesion before melanoma diagnosis.85 Due to the significance of change, a proposal has been set forth to add E— evolving changes to the traditional ABCD warning signs.86 Clinicians are hopeful that the new, more comprehensive ABCDE criteria will lead to even further detection of melanoma at an earlier stage.85 A final, useful screening tool is the “ugly duckling sign”87 in which any pigmented lesion that appears significantly and individually different from other surrounding lesions should be viewed with a high index of suspicion. This suspicion should remain high, even if the “ugly duckling” lesion lacks the traditional ABCD warning signs.

Biopsy Any pigmented lesion that fulfills any of the ABCD criteria, has undergone change, or appears different from surrounding nevi on the body, should undergo histologic evaluation. We consider the biopsy of potential melanoma as a distinct, 2-staged 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 narrow 1- to 2-mm clinical margins of surrounding skin, is performed. Some lesions are simply not amenable to excisional biopsy due to large size or anatomic location. In such cases, punch biopsy or incisional biopsy through the thickest portion of the neoplasm is recommended. Shave biopsy and fine needle aspiration are discouraged because the thickness of the tumor, which dictates further diagnostic evaluation and treatment, cannot be obtained. Unfortunately punch and incisional biopsies are subject to sampling error. For this reason, if a diagnosis of melanoma is not rendered following the initial procedure, repeat biopsy is recommended. Biopsy results obtained during the 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 SLNB. The role of SLNB ultimately depends on the final microstaging of the primary lesion and is detailed below. Obtaining wider margins at the time of the initial biopsy may seem both cost and time efficient. However, this practice is highly discouraged because clinical accuracy is uncertain, and removal of significant amounts of skin surrounding the lesion may Curr Probl Surg, November 2006

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TABLE 2. University of Michigan Guidelines for Initial HN Melanoma evaluation Stage 0 (in situ) History & physical examination No routine tests Stage I (mm thickness ⬍1) History & physical examination Consider SLNB for select pts; (see Table 11) Stage I-II (N0; any thickness) History & physical examination SLNB if indicated (see Table 11) CXR Optional LDH levels optional Stage III (N⫹; in transit) History & physical examination FNA neck mass CXR LDH Levels Other imaging studies if clinically indicated Stage IV (distant mets) History & physical examination CXR LDH levels Consider head, chest, abdomen, pelvis CT/MRI if symptomatic Other imaging studies per clinical trial SLNB, Sentinel lymph node biopsy; LDH, lactate dehydrogenase; CXR, chest radiograph; FNA, fine needle aspiration; CT, computed tomography; MRI, magnetic resonance imaging.

preclude accurate regional staging using lymphoscintigraphy and the SLNB technique.88 Instead, biopsy with narrow margins in a 2-staged fashion is advocated.

Metastatic Evaluation The majority of patients presenting with melanoma have localized disease, are asymptomatic, and lack clinical findings suggestive of regional or distant spread. In an attempt to standardize the staging evaluation for cutaneous melanoma, the National Comprehensive Cancer Network (NCCN) published guidelines that are available at: http:// www.nccn.org.89 The staging evaluation performed at our institution incorporates these guidelines and is outlined in Table 2.90 The foundation for melanoma evaluation in the setting of localized stage I disease remains a thorough history and physical examination. The most common site for distant metastasis is the lungs.88 Many physicians advocate a screening chest x-ray (CXR) because the study is viewed as an inexpensive, noninvasive means for metastatic evaluation. However, the incidence of occult pulmonary metastasis in 792

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TABLE 3. Review of systems for melanoma evaluation Skin/lymphatics Lesion change (size, shape, color) Pruritus Mass/nodule/enlarged lymph node Nonhealing skin lesions Easy bruising/bleeding New pigmented skin lesions Constitutional Weight loss/decreased appetite Malaise Weakness/fatigue Fever Respiratory Cough Hemoptysis Pneumonia Pleurisy Chest pain Dyspnea

Neurological/psychiatric Headache Memory disturbance Depression Focal neurologic deficits Visual disturbances Balance problems Blackouts/seizures Numbness Local weakness Paralysis Mood changes Gastrointestinal Cramping/Abdominal pain Bleeding Nausea/anorexia Vomiting Constipation Musculoskeletal Bone pain

Hepatic Abdominal pain Back/scapula pain on inspiration Jaundice Adapted from Johnson TM, Chang A, Redman B, Rees R, Bradford CR, Riba M, et al. Management of melanoma with a multidisciplinary melanoma clinic model, J Am Acad Dermatol 2000; 42:820 – 6.

an asymptomatic patient with stage I or II disease is exceedingly low.91,92 We evaluated 210 patients with a screening CXR and found the true positive rate, defined as the percentage of CXRs interpreted as “positive or possibly melanoma related” to be 0%.93 Yet, the high false positive rate of 7% necessitated additional and costly evaluations. Similarly, evidence supporting the use of other screening modalities such as computed tomography (CT),94,95 liver-spleen scans, magnetic resonance imaging (MRI), and bone scans for patients with limited stage I and II disease is lacking.96,97 For stage II and III patients who lack clinical evidence of regional disease (N-zero neck), CXR and screening lactate dehydrogenase (LDH) levels are deemed optional under the NCCN guidelines. It has been our experience that screening LDH carries a 15% false positive rate, does not correlate with SLN status, and has not been helpful in detecting occult Curr Probl Surg, November 2006

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TABLE 4. Melanoma TNM classification T classification

Thickness

T1

ⱕ1.0 mm

T2

1.01-2.0 mm

T3

2.01-4.0 mm

T4

⬎4.0 mm

Ulceration status a: b: a: b: a: b: a: b:

N classification

No. of metastatic nodes

N1

1 node

N2

2-3 nodes

N3

4 or more metastatic nodes, or matted nodes, or in transit met(s)/satellite(s) with metastatic node(s)

M classification M1a M1b M1c

without ulceration and level II/III with ulceration or level IV/V without ulceration with ulceration without ulceration with ulceration without ulceration with ulceration Nodal metastatic mass a: micrometastasis* b: macrometastasis† a: micrometastasis* b: macrometastasis† c: in transit met(s)/satellite(s) without metastatic nodes

Serum lactate dehydrogenase

Site Distant skin, subcutaneous, or nodal mets Lung metastases All other visceral metastases Any distant metastasis

Normal Normal Normal Elevated

*Micrometastases are diagnosed after sentinel or elective lymphadenectomy. †Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension. From Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001;19:3635-48.

disease in asymptomatic patients.93 For this reason these studies are ordered at our institution only when the history or physical examination reveals jaundice, abdominal pain, or other specific findings concerns for distant metastasis.90 A comprehensive list of concerning symptoms warranting a focused investigation for distant metastasis is summarized in Table 3.98 Patients with stage III disease who present with clinically or radiographically suspicious lymph nodes, satellite lesions, or in-transit lesions (defined by melanoma located more than 2 cm from the primary lesion), carry a significant risk of distant metastasis. Fine 794

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TABLE 5. Proposed stage groupings for cutaneous melanoma Clinical staging* T O IA IB IIA IIB IIC III‡

Tis T1a T1b T2a T2b T3a T3b T4a T4b Any T

N N0 N0 N0 N0 N0 N0 N0 N0 N0 N1 N2 N3

Pathologic staging† M M0 M0 M0 M0 M0 M0 M0 M0 M0 M0

IIIA IIIB

IIIC

IV

Any T

Any N

Any M1

T

N

M

Tis T1a T1b T2a T2b T3a T3b T4a T4b

N0 N0 N0 N0 N0 N0 N0 N0 N0

M0 M0 M0 M0 M0 M0 M0 M0 M0

T1-4a T1-4a T1-4b T1-4b T1-4a T1-4a T1-4a/b T1-4b T1-4b Any T Any T

N1a N2a N1a N2a N1b N2b N2c N1b N2b N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 Any M1

*Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases. †Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial or complete lymphadenectomy. Pathologic stage 0 or stage 1A patients are the exception; they do not require pathologic evaluation of their lymph nodes. ‡There are no stage III subgroups for clinical staging. From Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001;19:3635-48.

needle aspiration has been shown to be an accurate and cost-effective means of confirming metastatic melanoma within a lymph node.99 CXR and LDH should be ordered for all patients diagnosed with regional disease. The patient’s history and physical examination dictate whether additional imaging studies are required to evaluate specific distant sites (Table 3). Patients with known stage IV disseminated melanoma require a complete evaluation for systemic metastasis. Clinical trial protocols often dictate the evaluation in this setting. Unfortunately, a survival benefit has Curr Probl Surg, November 2006

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TABLE 6. 2002 AJCC cutaneous melanoma staging criteria based on the most important prognostic markers of survival* Stages I and II localized disease 1) Tumor thickness (even integer tumor thickness) 2) Tumor ulceration 3) Histologic (Clark’s) level of invasion for thin T1 lesions only Stage III regional disease 1) Number of metastatic lymph nodes 2) Tumor burden (microscopic vs. macroscopic nodal disease) 3) Primary tumor uleration Stage IV distant disease 1) Site of distant metastasis 2) Elevated LDH LDH, Lactate dehydrogenase. *Adapted from Schmalbach CE, Johnson TM, Bradford CR. The management of head and neck melanoma. In: Cummings CW, Flint PW, Harker LA, Haughey BH, Richardson MA, Robbins KT, et al, editors. Cummings Otolaryngology Head & Neck Surgery. Philadelphia: Elsevier Mosby; 2005.

not been found for patients who are asymptomatic when diagnosed with distant, stage IV disease compared with their counterparts who are diagnosed with symptomatic, stage IV disease.90 However, a thorough evaluation for systemic metastasis may lead to improvement in patient quality of life.

Prognostic Factors and Tumor Staging To gain increased understanding of the natural history and behavior of cutaneous melanoma, the AJCC Melanoma Task Force conducted a multi-intuitional study, comprised of 13 major cancer centers and 17,600 patients.100 This investigation marks the largest analysis of its kind. In 2002, results from the landmark study were used to revise the AJCC cutaneous melanoma staging system.100,101 The goal in modifying the classification system was 2-fold. First, the Staging Committee wanted to develop categories based on the most important, independent prognostic markers for melanoma. This goal was established in an attempt to better identify cohorts of patients sharing similar survival rates, thereby leading to increased homogeneity for future, meaningful clinical trials. The second goal was to provide physicians with a practical classification system that truly mirrored clinical practice. For this reason, the Committee used physician input related to both clinical management and research protocols. 796

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TABLE 7. Revisions to the AJCC staging system 1) Tumor thickness (Breslow depth measured in mm) and ulceration are now utilized in T classification. Clark’s histologic level of invasion is now only applicable in the staging of thin (ⱕ1 mm) T1 lesions. 2) The number of metastatic lymph nodes, as opposed to the gross size of the metastatic node, defines the N category. 3) The technique of sentinel lymph node mapping and biopsy (SLNB) is now incorporated into the staging system. Delineation of occult (microscopic/ subclinical) nodal metastasis vs. clinically/radiographically apparent (macroscopic) nodal metastasis is outlined within the N category. 4) Both anatomic site of distant metastasis and elevated LDH level are utilized in the M classification. 5) Ulceration of the primary lesions upstages the patient. 6) Primary lesions with surrounding satellite metastasis or in-transit metastasis are defined as stage III regional disease regardless of the nodal status.

Summary of Revisions The 2002 AJCC staging system for cutaneous melanoma remains founded on the traditional Tumor-Node-Metastasis (TNM) classification system (Tables 4 and 5). Stages I and II represent localized disease, stage III is regional disease in which the melanoma has spread to draining nodal basins, and stage IV is reserved for distant metastatic disease, most commonly to the lungs and liver. Table 6 summarizes the most important predictors for melanoma survival, all of which are now used in classifying tumor stage. The comprehensive, multiinstitutional study conducted by the AJCC led to 6 major revisions in the staging system (Table 7).

T Classification/Localized Disease Tumor thickness and ulceration emerged as the 2 most important predictors for outcome when multivariate analysis of 13,581 patients with localized disease was performed.100 Overall, tumor thickness was the most powerful prognostic indicator for this subgroup. Tumor thickness was previously incorporated in the 1997 version of the staging system. However, the 0.75-mm cut point between T1 and T2 lesions was empirically based on the Breslow classification.102 The revised staging system now uses practical, even-integer cut points of 1.0, 2.0, and 4.0 mm to delineate T stage, since these cut points represent the best statistical fit in correlating tumor thickness and survival. In the 1997 staging system, the histologic level of invasion, as represented by the Clark scale was incorporated into the T classification. Curr Probl Surg, November 2006

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798 TABLE 8. Survival rates for melanoma TNM and staging categories Pathologic Thickness TNM stage (mm) IA IB IIA IIB IIC IIIA IIIB

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IIIC

IV

Total

T1a T1b T2a T2b T3a T3b T4a T4b N1a N2a N1a N2a N1b N2b N1b N2b N3 M1a M1b M1c

1 1 1.01-2.0 1.01-2.0 2.01-4.0 2.01-4.0 ⬎4.0 ⬎4.0 Any Any Any Any Any Any Any Any Any Any Any Any

Ulceration No Yes or level IV, V No Yes No Yes No Yes No No Yes Yes No No Yes Yes Any Any Any Any

No. ⴙ nodes 0 0 0 0 0 0 0 0 1 2-3 1 2-3 1 2-3 1 2-3 4 Any Any Any

Nodal size

Distant metastasis

— — — — — — — — — — — — — — — — Micro — Micro — Micro — Micro — Macro — Macro — Macro — Macro — Micro/macro — Any Skin, SQ Any Lung Any Other Visceral

No. of patients 4,510 1,380 3,285 958 1,717 1,523 563 978 252 130 217 111 122 93 98 109 396 179 186 793 17,600

Survival ⴞ SE 1-Year

2-Year

5-Year

10-Year

99.7 ⫾ 0.1 99.8 ⫾ 0.1 99.5 ⫾ 0.1 98.2 ⫾ 0.5 98.7 ⫾ 0.3 95.1 ⫾ 0.6 94.8 ⫾ 1.0 89.9 ⫾ 1.0 95.9 ⫾ 1.3 93.0 ⫾ 2.4 93.3 ⫾ 1.8 92.0 ⫾ 2.7 88.5 ⫾ 2.9 76.8 ⫾ 4.4 77.9 ⫾ 4.3 74.3 ⫾ 4.3 71.0 ⫾ 2.4 59.3 ⫾ 3.7 57.0 ⫾ 3.7 40.6 ⫾ 1.8

99.0 ⫾ 0.2 98.7 ⫾ 0.3 97.3 ⫾ 0.3 92.9 ⫾ 0.9 94.3 ⫾ 0.6 84.8 ⫾ 1.0 88.6 ⫾ 1.5 70.7 ⫾ 1.6 88.0 ⫾ 2.3 82.7 ⫾ 3.8 75.0 ⫾ 3.2 81.0 ⫾ 4.1 78.5 ⫾ 3.7 65.6 ⫾ 5.0 54.2 ⫾ 5.2 44.1 ⫾ 4.9 49.8 ⫾ 2.7 36.7 ⫾ 3.6 23.1 ⫾ 3.2 23.6 ⫾ 1.5

95.3 ⫾ 0.4 90.9 ⫾ 1.0 89.0 ⫾ 0.7 77.4 ⫾ 1.7 78.7 ⫾ 1.2 63.0 ⫾ 1.5 67.4 ⫾ 2.4 45.1 ⫾ 1.9 69.5 ⫾ 3.7 63.3 ⫾ 5.6 52.8 ⫾ 4.1 49.6 ⫾ 5.7 59.0 ⫾ 4.8 46.3 ⫾ 5.5 29.0 ⫾ 5.1 24.0 ⫾ 4.4 26.7 ⫾ 2.5 18.8 ⫾ 3.0 6.7 ⫾ 2.0 9.5 ⫾ 1.1

87.9 ⫾ 1.0 83.1 ⫾ 1.5 79.2 ⫾ 1.1 64.4 ⫾ 2.2 63.8 ⫾ 1.7 50.8 ⫾ 1.7 53.9 ⫾ 3.3 32.3 ⫾ 2.1 63.0 ⫾ 4.4 56.9 ⫾ 6.8 37.8 ⫾ 4.8 35.9 ⫾ 7.2 47.7 ⫾ 5.8 39.2 ⫾ 5.8 24.4 ⫾ 5.3 15.0 ⫾ 3.9 18.4 ⫾ 2.5 15.7 ⫾ 2.9 2.5 ⫾ 1.5 6.0 ⫾ 0.9

From Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001;19:3635-48.

FIG 1. Survival curves of 1528 melanoma patients with lymph node metastases subgrouped by actual number of metastatic lymph nodes. (From Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001;19:362234.)

However, recent analysis by Balch and colleagues found the histologic level of invasion to be prognostic only for thin T1 lesions.100 For tumors up to 1 mm without ulceration, invasion to Clark level II or III is considered T1a, whereas invasion into the reticular dermis (level IV or V) is considered T1b. With the exception of T1 lesions, the Clark level of invasion is no longer used in staging melanoma. Tumor ulceration was the second most important prognostic indicator for patients with localized disease. It is important to note that ulceration is not a visible crater on gross examination, but rather a histologic diagnosis in which intact epidermis overlying the melanoma is absent. Patients with ulcerated primary lesions were found to have significantly lower survival rates compared with their nonulcerated counterparts (Table 8). Closer analysis revealed that the survival of patients with an ulcerated tumor mirrored that of nonulcerated patients in the next highest T category, as opposed to their original T category. For this reason, ulceration warrants upstaging of tumors. The prognostic significance of Curr Probl Surg, November 2006

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FIG 2. Survival curves of 1429 patients with lymph node metastases subgrouped by presenting clinical stage. Survival rates calculated from the time of primary melanoma diagnoses were significantly different for the 2 groups (P ⬍ 0.0001). (From Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001;19:3622-34.)

ulceration,103 as well as the correlation between ulceration and mitotic rate, has been reported.104,105 Although mitotic rate was not evaluated during the revision of the AJCC staging system, it may emerge as an important prognostic marker in the future.

N Classification/Regional Disease Similar multivariate analysis was performed for more than 1000 melanoma patients diagnosed with lymph node metastasis. Three statistically significant prognostic factors were identified: number of metastatic lymph nodes, tumor burden as represented by microscopic vs. macroscopic disease, and primary tumor ulceration. The gross diameter of metastatic nodes was previously used to define the N category in the 1997 staging system. However, this most recent study failed to find a meaningful predictive value for metastatic nodal size, and it is no longer incorporated into melanoma staging.100,106,107 800

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TABLE 9. Five-year survival rates for stage III (nodal metastases) patients stratified by number of metastatic nodes, ulceration, and tumor burden Microscopic 1ⴙ Node Melanoma ulceration % ⴞ SE No. Absent Present

2-3 Nodes % ⴞ SE

No.

Macroscopic >3 Nodes

1ⴙ Nodes

% ⴞ SE No. % ⴞ SE

No.

2-3 Nodes % ⴞ SE

No.

>3 Nodes % ⴞ SE

No.

69 ⫾ 3.7 252 63 ⫾ 5.6 130 27 ⫾ 9.3 57 59 ⫾ 4.7 122 46 ⫾ 5.5 93 27 ⫾ 4.6 109 52 ⫾ 4.1 217 50 ⫾ 5.7 111 37 ⫾ 8.8 46 29 ⫾ 5.0 98 25 ⫾ 4.4 109 13 ⫾ 3.5 104

From Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001;19:3622-34.

The most important predictive marker for patients with nodal metastasis was the number of positive lymph nodes. Survival curves are depicted in Fig 1. The greatest difference in 5-year survival rates was used to subclassify the N category. Patients with 1 metastatic node are now categorized as N1, patients with 2 or 3 metastatic nodes as N2, and patients with 4 or more nodes as N3. Tumor burden was identified as the second most important prognostic indicator for patients with regional metastasis. Patients identified with microscopic nodal disease (also referred to as occult or subclinical nodal disease), either through SLNB or elective lymphadenectomy, were found to have a significantly better survival compared with individuals diagnosed clinically or radiographically with gross, macroscopic disease (Fig 2). This difference was so compelling that microscopic versus macroscopic nodal disease is now a subclassification within the N category. In addition, the AJCC Melanoma Committee strongly recommends staging with SLNB for patients with T2N0M0, T3N0M0, and T4N0M0 disease before entry into clinical trials.101 It is the Committee’s hope that identification of occult nodal disease will lead to accurate staging and increased homogeneity among investigational cohorts. Ulceration was identified as the only primary tumor characteristic indicative of outcome for patients with stage III disease. Depth of invasion, as represented by tumor thickness, was no longer prognostic once adjustment was made for regional metastasis (P ⫽ 0.16). Intralymphatic metastasis is new a criterion now used in classifying stage III regional disease. The presence of satellite metastasis surrounding a primary lesion, and in-transit metastasis identified between the primary melanoma and draining nodal basin, emerged as poor prognostic indicators.100,107,108 Both findings portend a prognosis similar to nodal metastasis. Under the new staging system, satellite metastasis and in-transit metastasis are classified as N2C disease, even in the absence of nodal Curr Probl Surg, November 2006

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TABLE 10. Recommended surgical margins for primary cutaneous melanoma Tumor thickness (mm)

Surgical margin (cm)

In situ ⬍1.0 1.01–2.0 ⬎2.0

0.5 1.0 1.0–2.0 2.0

disease (N-zero). If synchronous nodal metastasis is found along with satellite or in-transient metastasis, the prognosis is exceedingly poor. These patients are automatically upstaged to N3 disease regardless of the number of positive lymph nodes. Overall 5-year and 10-year survival for patients with metastatic nodal disease was 49% and 37%, respectively.100 However, reported survival rates for stage III patients were quite broad, ranging from a dismal 13% in the setting of an ulcerated primary lesion with macroscopic disease identified in 4 lymph nodes to a promising 69% survival in the setting of a nonulcerated primary tumor with microscopic disease confined to 1 lymph node (Table 9). This finding confirms previous studies that demonstrated that stage III disease represents a heterogeneous group of patients.106,109 It further highlights the critical impact on survival afforded by the early diagnosis of regional metastasis, as well as the necessity for accurate pathologic staging of all patients enrolled in clinical trials.

M Classification/Distant Metastasis A total of 1158 patients in the study were diagnosed with disseminated stage IV disease at the time of presentation. The most significant prognostic factor correlated to anatomic site of distant metastasis. Patients with skin, subcutaneous tissue, or distant lymph node involvement (M1a) had a slightly higher survival rated compared with patients with lung metastasis (M1b). Overall, patients with metastasis involving other visceral organs (M1c) had the worst prognosis. Previous studies have also identified elevated LDH as a poor prognostic marker.110-113 For this reason, any patient with elevated LDH and distant metastasis, regardless of site, is classified as M1c. Overall survival for patients with distant metastasis is extremely grave, measured in months as opposed to years. The median survival time following diagnosis of disseminated disease is only 6 to 8 months, with a dismal 5-year survival rate of 6%.110,114 For this reason, the AJCC staging system does not subclassify stage IV melanoma. 802

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Anatomic Site The anatomic site of the primary lesion is not used within the formal staging system. However, prognostic differences have been reported in the literature.6,115 A review of 6300 cutaneous melanomas treated at the Duke Medical Center identified the worst 10-year survival rate among HN primary tumors (54%) compared with trunk (61%), lower extremity (71%), and upper extremity (76%) sites.115 A 50% tumor recurrence rate has been reported for HN cutaneous melanomas.116,117 One explanation for this aggressive behavior and higher local recurrence is the development of thicker melanoma lesions within the HN region compared with other sites. In addition, the surgeons may be reluctant to clear tumor margins adequately and to remove peripheral AJMH in the HN region due to the visible anatomic location and related psychosocial implications.

Surgical Management of the Primary Tumor Wide Local Excision and Surgical Margins The standard of care for primary melanoma treatment is complete surgical excision. However, the extent of surgical margins remains an unanswered question despite numerous retrospective studies, meta-analyses, and clinical trials. Historically, an extensive 5-cm margin of surrounding normal tissue was practiced. However, this recommendation was based on a 1907 autopsy report of a patient with advanced melanoma.118 The use of a 5-cm surgical margins was routine practice until the 1970s when Breslow and Macht challenged the concept by successfully treating a cohort of 35 patients with thin melanomas using narrower margins.119 Several prospective, randomized trials investigating surgical margins for cutaneous melanoma have since followed. The World Health Organization (WHO) conducted an international trial in which 612 patients with thin melanomas (up to 2 mm) were randomized to surgical excision with 1-cm vs. greater than 3-cm margins.120 At a mean follow-up of 8 years, the disease-free survival and overall survival rates were reported to be equivalent between the 2 groups.121 The WHO concluded that wide excision did not influence survival for patients with thin melanomas; for patients with melanomas less than 1 mm in thickness, the authors 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 “narCurr Probl Surg, November 2006

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row” excision. This finding prompted the Intergroup Melanoma Surgical Trial, which prospectively randomized 740 patients with intermediate thickness (1-4 mm) melanomas to WLE with 2-cm vs. 4-cm margins.122 Local recurrence rates and 10-year survival rates were reported to be equivalent between the 2 groups. This finding led to the recommendation of a 2-cm surgical margin for patients with intermediate melanomas measuring 1.1 to 4.0 mm in thickness. The most recent prospective clinical trial conducted by the United Kingdom Melanoma Study Group randomized 900 patients with localized cutaneous melanomas of at least 2 mm in thickness to 1-cm vs. 3-cm margins.123 A statistically significant difference was not identified between the 2 groups when local, regional, and distant recurrences were individually compared. Overall mortality rates were found to be identical between the 2 arms. However, when all recurrences (local, in-transit, and nodal) were pooled together, the 1-cm margin group experienced 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 vs. 2-cm margin that is debated more often in the clinical setting.124 No prospective randomized trial has investigated 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 local recurrence rate, disease-free survival, or overall survival when compared with margins less than 2 cm.125 Within this study, 16% of the tumors involved HN 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 has been estimated that 100% achievement of ideal margins would lead to a reduction in melanoma-related mortality and an increase of life expectancy of melanoma patients by 0.4 years.126 Although this difference appears small at first glance, it equates to an estimated 11 additional years of life expectancy for those individuals who would have recurred locally following a 1-cm margin, but instead achieved a disease-free state following a wider surgical margin. Current guidelines for surgical margins are based on primary tumor thickness (Table 10). It is important to realize that these recommendations serve merely as a guideline. Each melanoma case must be individualized. The depth of excision includes full thickness skin and underlying subcutaneous tissue. Resection of fascia, perichondrium, and periosteum 804

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is required only in the setting of direct tumor invasion or if the surgical plane was violated during a previous biopsy.127 LMM warrants special consideration because it has a propensity for wide subclinical spread, which often results in positive margins.128 In an attempt to address this challenge, we developed the “square” procedure.”53,129 This staged procedure entails complete excision of the peripheral margins using a double-bladed instrument, followed by permanent histologic evaluation of 100% of the peripheral margins surrounding the entire tumor.

Closure and Reconstruction The majority of surgical sites can be closed primarily with the use of wide undermining. Larger defects may require reconstruction with a split thickness skin graft, full thickness skin graft, local advancement flap, or regional flap. The method of reconstruction depends on the anatomic location including skin color and texture, depth of the defect, and patient, as well as surgeon, preference. Initially surgeons were reluctant to graft excision sites for fear that surveillance for future melanoma recurrence within the surgical bed would be hindered. However, the method of closure has not been shown to impact survival.130 Once clear margins have been confirmed, surgeons are encouraged to close surgical defects using the technique that they think will yield the best cosmetic result.

Auricular Melanoma Originally, auricular melanoma was thought to carry a worse prognosis compared with other sites within the HN region.117,131,132 This increased risk was attributed to rich lymphatics, complex anatomic subdivisions of the ear, and a paucity of subcutaneous tissue between the thin auricular skin and underlying perichondrium.133 For these reasons, full thickness excision or total auriculectomy was often advocated. Research conducted over the past decade has led to a shift in the treatment paradigm for auricular melanoma. After accounting for tumor thickness, recent studies have demonstrated that melanoma in this region carries the same prognosis as other HN sites.88,134 Outcome differences were not observed between auricular subsites.133 In addition, retrospective reviews failed to demonstrate a difference in local recurrence based on the extent of surgical excision, even when perichondrium was preserved.134 Today, the same prognostic indicators and surgical principles of obtaining wide, clear margins for treatment of cutaneous melanoma can be applied safely to the auricle. Curr Probl Surg, November 2006

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Surgical Management of Regional Lymph Nodes Therapeutic Lymph Node Dissection The most common sites for metastasis of HN cutaneous melanoma are the cervical and parotid lymph node basins.7,135,136 Therapeutic lymph node dissection (TLND) is accepted universally as the treatment of choice for regional disease. The neck dissection must include all draining nodal basins as well as the intervening lymphatics between the primary tumor and the site of regional disease. The location of the primary tumor dictates the specific type of TLND, as well as the need for a superficial parotidectomy. 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.137 Melanomas of the anterolateral scalp, temple, lateral forehead, lateral cheek, and ear, arising anterior to an imaginary coronal plane through the external auditory canals (EACs), drain via the parotid nodal basin to the jugular lymph node chain.137 For this reason, melanomas anterior to this coronal plane require a superficial parotidectomy and modified radical neck dissection (MRND). If the melanoma arises in a more inferior location, such as 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 EACs, can drain to postauricular, suboccipital, and posterior triangle lymph nodes. These nodal basins are not addressed during routine MRND. In this situation, a posterolateral neck dissection, which extends to the midline of the posterior neck, is required.138

Elective Lymph Node Dissection 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). Melanomas measuring less than 1.0 mm in thickness have an excellent prognosis, with a 5-year survival rate approaching 95% to 99%. For this reason, elective treatment of the neck is considered unnecessary for the majority of thin stage I melanomas since the risk of occult nodal metastasis is less than 5%. Conversely, melanomas measuring greater than 4.0 mm in thickness have an extremely poor prognosis. The high 70% rate of systemic metastasis is thought to negate any benefit that may be gained by electively treating regional nodal basins.88 The real controversy sur806

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TABLE 11. University of Michigan considerations for melanoma sentinel lymph node mapping and biopsy

Clinically localized melanoma ⱖ 1 mm No significant comorbidities No previous wide excision (usually) 0.75–0.99 mm, with Ulceration Extensive regression to 1 mm Young age High mitotic rate Any site, any age, any number of basins After discussion of risks and benefits

rounded elective treatment of the neck for patients with intermediate thickness (1.0-3.9 mm) melanomas. Opponents of elective lymph node dissection (ELND) contended that melanoma metastasis is unpredictable. In Fisher’s retrospective review of 1444 HN melanoma patients, up to 16% developed distant metastasis in the absence of regional disease.7 The potential for hematogenous melanoma spread to bypass regional nodal basins theoretically limits the utility of an ELND. Opponents further argue that all 4 prospective, randomized trials failed to demonstrate an overall survival benefit for patients undergoing ELND in the absence of regional metastasis.139-142 In 1967 the WHO Melanoma Group conducted the first prospective, randomized trial (No. 1) between 1967 and 1974.141 A total of 535 patients with stage I and II melanoma of the extremity were enrolled. No difference in survival benefit was found between patients who underwent WLE and observation, with TLND reserved for the development of gross nodal metastasis, compared with patients who underwent WLE and ELND. Similarly, surgeons at the Mayo Clinic randomized 171 patients with stage I disease to: 1) WLE and observation, 2) WLE and delayed (30-60 days) ELND, or 3) WLE with concomitant ELND.139 ELND was not found to provide a survival benefit compared with observation. Although both prospective trials represent pioneering research in a challenging area, both study designs have been criticized.135 At the time of the studies, the prognostic significance of tumor thickness and ulceration was unknown. Later analysis of the WHO Melanoma Group Trial No. 1 found significant discrepancy in the distribution of tumor thickness between the 2 treatment arms. Furthermore, 52% of lesions in the ELND group were ulcerated compared with only 19% in the observation group.135 Subsequent re-analysis of these data with respect to tumor thickness and ulceration identified a subset of patients with a 22% Curr Probl Surg, November 2006

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FIG 3. Preoperative lymphoscintigraphy is performed approximately 3 hours before SLNB. A total of 2 ␮Ci of technetium Tc 99m sulfur colloid (CIS-US, Inc., Bedford, MA) is injected intradermally into the 4 quadrants surrounding the primary melanoma lesion located midline on the posterior occiput. (A) The right posterior occiput primary lesion with an overlying shield. (B) Lateral views taken 45 minutes after injection. An SLN is observed in the right posterior triangle. Reprinted from Schmalbach C, Johnson T, Bradford C. In: Cummings Otolaryngology, The Management of Head and Neck Melanoma. 4th Ed. Elsevier Inc. pp 563-564, 2005 with permission.

improved 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 compared with reports in the literature that range from 10% to 20%. Last, Balch argues 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.135 808

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FIG 4. After administration of anesthesia, intraoperative lymphatic mapping is performed using approximately 1 mL of isosulfan blue dye (Lymphazurin 1%, Hirsh Industries, Inc., Richmond, VA) injected into the intradermal layer surrounding the primary melanoma. Reprinted from Schmalbach C, Johnson T, Bradford C. In: Cummings Otolaryngology, The Management of Head and Neck Melanoma. 4th Ed. Elsevier Inc. pp 563-564, 2005 with permission.

Approximately 85% of patients enrolled in the WHO Melanoma Group Trial No.1 were women with extremity melanomas, a group that is recognized to have a low rate of metastasis compared with other sites. In addition, the Mayo Clinic excluded patients with HN and midline trunk melanomas. To address these concerns, the Intergroup Melanoma Surgical Trial (IMST) was initiated.142 The IMST was a prospective, multi-institutional study of 740 patients with intermediate tumor thickness (1-4 mm) melanomas of the trunk, extremity, and HN region. Patients were once again randomized to WLE and observation vs. WLE and ELND. Cox regression analysis identified ulceration, site, tumor thickness, and age as independent markers for survival. Overall 5-year survival rates were not found to be different between the 2 treatment groups. However, a significant survival benefit was found in patients 60 years of age and younger who underwent ELND, especially if their tumor was nonulcerated or measured 1 to 2 mm in thickness. Although this subgroup analysis Curr Probl Surg, November 2006

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FIG 5. Wide local excision of the primary melanoma is performed before SLNB. Otherwise, the close proximity of the primary lesion to the draining nodal basins within the head and neck region will cause significant radioactive shine-through and difficulty in localizing the SLN. Each SLN is then identified using a combination of the gamma probe, which detects radioactive activity from the Tc 99m sulfur colloid, and visual cues from the isosulfan blue dye. Reprinted from Schmalbach C, Johnson T, Bradford C. In: Cummings Otolaryngology, The Management of Head and Neck Melanoma. 4th Ed. Elsevier Inc. pp 563-564, 2005 with permission.

is subject to the shortcomings of retrospective review, and it is criticized because patients were not randomized on age, patients were randomized prospectively on tumor thickness and ulceration. The fourth prospective trial was initiated in 1982 by the WHO Melanoma Group (No. 14). In an attempt to study patients truly at high risk for occult nodal metastasis, 240 patients with trunk melanomas measuring greater than 1.5 mm in thickness were enrolled.140 A difference in survival was not observed between patients randomized to observation vs. ELND. In a multivariate analysis including sex, age, tumor thickness, and treatment, only sex and tumor thickness were found to have a significant impact on survival. However, this study did identify a statistically significant 5-year survival difference for patients with micrometastasis identified during ELND (47%) compared with patients in the observation arm who underwent TLND only after the development of 810

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gross nodal disease (27%). For this reason, the WHO Melanoma Group advocated early detection of nodal metastasis using procedures such as SLNB. Statistical power remains 1 of the greatest challenges in investigating the survival benefits of ELND and early detection of nodal disease.143 Only 20% of melanoma patients presenting with localized disease actually harbor occult nodal metastasis. It is only 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 extremely large clinical trial enrollment, numbering in the thousands. McMasters and colleagues point out that the IMST, WHO, and Mayo Clinic trials lacked adequate statistical power to detect this small survival benefit. For this reason, the group concluded that the 4% survival benefit observed in the elective lymph node dissection (ELND) group of the IMST study is clinically significant, despite the fact that statistical significance was not reached. In summary, numerous prospective, randomized trials have failed to demonstrate an overall survival benefit for patients undergoing ELND.139-146 Therefore, routine ELND is no longer advocated for melanoma. Instead, the procedure has been replaced by SLNB.

Sentinel Lymph Node Biopsy Sentinel lymph node biopsy represents a minimally invasive, costeffective, and efficient means of screening patients for regional metastasis. Nodal status is currently recognized as the single most important prognostic factor for melanoma patients.101 Ten percent to 20% of individuals harbor occult, microscopic nodal disease. In an attempt to identify this small group of patients who warranted TLND, while sparing the remaining 80% of patients without regional disease the morbidity associated with a neck dissection, Morton and colleagues introduced SLNB for the evaluation of patients with trunk and extremity cutaneous melanoma.146 These investigators demonstrated that the status of the SLN accurately represented the status of the entire nodal basin from which it was obtained. 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 the standard of care.147-149 Curr Probl Surg, November 2006

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Success of SLNB hinges on appropriate patient selection. Patients presenting with palpable regional disease or distant metastasis are not candidates for SLNB because additional prognostic information will not be gained. In addition, patients who have undergone previous neck dissection or resection of the primary site with wide margins are not deemed candidates due to lack of accuracy. Guidelines for SLNB practiced at our institution are summarized in Table 11. The SLN technique has evolved to include preoperative lymphoscintigraphy by nuclear medicine.150 Approximately 2 to 4 hours before surgery, patients undergo intradermal injection of a radioactive colloid into the 4 quadrants surrounding the primary melanoma tumor. Lymphoscintigraphy is then performed to guide the surgeon in determining the number, location, and laterality of nodal basins at risk for metastatic disease (Fig 3). It is particularly helpful in the setting of midline HN melanomas that have the potential for bilateral lymphatic drainage. Once under anesthesia, intraoperative lymphatic mapping with isosulfan blue dye (Lymphazurin 1%, Hirsch Industries, Inc., Richmond, VA) is performed.146 Approximately 1 mL of dye is injected into the intradermal layer surrounding the primary melanoma lesion (Fig 4). Unlike melanoma of the trunk and extremity, the primary tumor and draining lymphatics are in close proximity within the HN region. Therefore, WLE of the primary tumor is performed first to reduce radioactive “shine-through,” which will render the intraoperative gamma probe useless in identifying SLNs (Fig 5). Following WLE of the primary melanoma, nodal basins at risk for metastasis are evaluated for increased radioactivity using a handheld gamma probe. A 1- to 3-cm incision was made overlying the areas of increased radioactivity. A preauricular incision is recommended for SLNB in the parotid region. Facial nerve monitoring is also recommended in this setting. SLNs are then identified using a combination of the gamma probe and visual cues from the blue dye (Fig 5). Each SLN is individually dissected from surrounding tissue. Within the parotid bed, gentle dissection in the anticipated direction of the facial nerve is imperative. The staging procedure is considered complete when all nodal basins demonstrate minimal background radioactivity (⬍10%) relative to the primary lesion and sentinel nodes. Histopathologic protocols for SLN evaluation vary from institution to institution. At the University of Michigan, all SLNs are sent for histologic evaluation using permanent sections. We do not use frozen sections because this practice is less reliable, carrying a false negative rate between 5% to 10%.151 Our evaluation includes serial sectioning (5-␮m 812

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thick sections) and staining with hematoxylin and eosin (H&E). All SLNs negative on H&E staining are then subjected to melanoma-specific immunohistochemical staining (IHCS) for S-100 and Melan-A (MART1). This panel was chosen after pathologic evaluation of 99 positive SLNs from 72 patients treated at our institution.152 The sensitivities for S-100, Melan-A, and HMB-45 were found to be 97%, 96%, and 75%, respectively. In addition, we found that 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 return to the operating room within 2 weeks of diagnosis for definitive TLND. Patients with a negative biopsy are followed clinically. An alternative to this 2-staged technique is immediate TLND based on frozen section evaluation of the SLNs. However, it is important to realize that the reliability of frozen sections for melanoma analysis has been questioned,151,153 and permanent sections remain the “gold” standard. The pathologist plays an extremely critical role in the success of the SLNB. Occult lymphatic metastasis from cutaneous melanoma can be difficult to detect, with tumor cells occupying less that 2% of the entire lymph node volume.151 Therefore, rigorous pathological analysis including serial sectioning, special immunohistochemical study when indicated, and interpretation by an experienced pathologist is necessary. Wagner and colleagues reported the mean tumor volume in positive SLNs to be only 4.7 mm3.154 Joseph and colleagues reported identification of only 73% of metastatic SLNs using standard H&E staining alone.155 In our study, 20 of the 97 positive SLNs (21%) were negative on initial H&E staining.152 This high false negative rate highlights the importance of IHCS for accurate diagnosis of occult nodal disease. From a practical standpoint, the histologic analysis of SLNs is more thorough, cost-effective, and complete compared with traditional evaluation of the entire lymphadenectomy specimen because the technique provides the pathologist with a limited number of nodes to evaluate thoroughly.156 In an effort to further increase SLNB sensitivity, Morton and colleagues are investigating the utility of carbon dye as a mapping adjunct. Unlike isosulfan blue dye, the carbon remains as a permanent marker to aid the pathologist in identifying the specific intranodal site of lymphatic drainage, which is the most likely area for occult metastatic disease.157 We have found SLNB particularly helpful in the diagnosis of occult DM/DNM. Here, a focused histopathologic evaluation is particularly important because the microscopic features of metastatic DM/DMN are quite variable, often lack resemblance of the primary tumor, are limited to Curr Probl Surg, November 2006

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a paucity of tumor cells, and demonstrated inconsistencies on HMB-45 and Melan-A staining.158 SLNB is a team effort involving experienced surgeons, nuclear medicine staff, and pathologists. The experience and technical skill of the surgeon is vital and may account for some of the variability observed in HN cutaneous melanoma SLN studies.159 Morton and colleagues previously suggested a 30 case learning curve.150 However, long-term follow-up of their international Multicenter Selective Lymphadenectomy Trial (MSLT-I) 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%.151 This false negative rate dropped to 5.2% after 25 additional cases. The authors now conclude that a 55 case learning curve is required to achieve at least 95% accuracy with SLNB. An experienced nuclear medicine staff is necessary because inappropriate administration of the radioactive tracer can lead to “shine through, ” which renders the handheld gamma probe useless in the operating room. Communication with the nuclear medicine team is critical not only in interpreting the lymphoscintigram, but also in ensuring that the appropriate lesion is mapped since patients with melanoma often present with multiple pigmented lesions and significant solar changes. 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.160 For stage III melanoma, a survival benefit was found in patients with occult microscopic disease compared with their counterparts who had palpable, macroscopic disease (Table 9).101 This survival benefit 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 HN region.150,161,162 The complexity of the HN lymphatic system has caused concern surrounding the reliability of the SLN to represent the status of the entire nodal basin accurately. The interlacing network of cervical lymphatic vessels is often deemed watershed in nature. The complexity of this lymphatic system was demonstrated by O’Brien and colleagues who reported 34% discordance between the clinical prediction of lymphatic drainage and lymphoscintigraphy findings in 97 cases of HN cutaneous melanoma.163 The popularity of SLNB in the HN region has also been limited by concerns surrounding damage to vital structures such as the facial nerve,164 814

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technical difficulties,161,164 and the necessity for nuclear medicine staff as well as pathologists who specialize in SLNB technique. Our experience in 80 patients with HN cutaneous melanoma demonstrated that the complexity of HN anatomy does not preclude the use of SLNB for staging of cutaneous melanoma.159 SLNB accurately predicted the status of the nodal basin in this region. Fourteen (17.5%) of 80 patients were identified with a positive SLNB. Only 3 (4.5%) of 66 patients developed regional recurrence following a negative SLNB. The 17.5% positivity rate of SLNs and the 4.5% false negative rate both mirror the results of SLNB achieved in other anatomic sites such as the trunk and extremities.156,165 Similar success in the application of SLNB for HN cutaneous melanoma has been reported by others,166,167 and the technique has successfully been applied in pediatric HN cases.11 Approximately 25% to 30% of HN cutaneous melanomas drain to lymph nodes within the parotid bed.159,163 Potential injury to the facial nerve from SLNB has led some surgeons to advocate superficial parotidectomy over the mapping procedure.164 In our retrospective analysis, 28 (93.3%) of 30 patients draining to the parotid nodal basin successfully underwent staging using SLNB.159 One patient required a superficial parotidectomy due to the location of the SLN deep to the facial nerve. A second patient experienced significant bleeding from surrounding parotid tissue, which could have placed the facial nerve at increased risk. A total of 39 nodes from 28 parotid basins were removed without facial nerve injury. Continuous facial nerve monitoring for SLNB within the parotid nodal basin can be helpful when performing the biopsy with 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 treat the parotid basin definitively in the setting of a positive SLN.164 In our experience, all patients with a positive parotid SLN underwent a superficial parotidectomy as a subsequent procedure, without facial nerve injury. Our findings are consistent with other reports demonstrating that SLNB can be performed reliably and safely within the parotid nodal basin.132,168 Other authors 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.169-174 It is theorized that ITM develops when melanoma cells detach from the primary lesion and become lodged in the dermal plexus of lymphatics before reaching the lymph nodes. The development of ITM presents a therapeutic challenge and carries a poor Curr Probl Surg, November 2006

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prognosis as indicated by the new changes to the AJCC staging system cited above.101 Original reports citing increased ITM following SLNB must be 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.169,175 A more recent prospective review comparing 4412 patients undergoing WLE alone, WLE with SLNB, and ELND identified a correlation between ITM and increasing Breslow depth, Clark level, and T stage.175 A statistically significant difference between ITM and tumor recurrence was not found among the treatment groups, once adjustment was made for T stage, age, sex, tumor thickness, and site. Additional studies have concluded that it is the tumor biology, as opposed to the surgical procedure (SLNB; ELND), which dictates melanoma metastatic behavior.176,177 Finally, a correlation between ITM and SLNB was not reported with MSLT-I, thus negating this concern.151 The impact that SLNB imparts on overall survival remains to be determined. The answer will hopefully be provided through the multiinstitutional Sunbelt Melanoma Trial, which is a prospective, randomized clinical trial that uses SLN staging to determine the need for adjuvant therapy.178 While we await these results, McMasters and colleagues outlined 4 compelling reasons to use SLNB for accurate regional staging of cutaneous melanoma.148 First, the SLNB technique provides important prognostic information to the physician, patient, and family members in guiding subsequent treatment options. Second, SLNB helps identify patients harboring nodal metastasis, who then may benefit from early TLND. Third, SLNB identifies patients who are candidates for adjuvant treatment such as interferon-␣2b. Fourth, SLNB provides the most accurate means of regional staging. In doing so, the technique enables the identification of a homogeneous population of patients for enrollment into clinical trials. Regional metastasis is recognized as the most important prognostic factor in melanoma. Without accurate pathologic staging, stratification is impossible, and the results of clinical trials will remain inconsistent and difficult to interpret. The fifth and final analysis of MSLT-I will provide additional insight into the potential therapeutic benefit of SLNB.151 Recent publication of the MSLT-I interim analysis is exciting because it is the first randomized, prospective trial to demonstrate that SLNB accurately identifies occult nodal metastasis, which will lead to advanced, palpable nodal disease if left in situ. The authors argue that there is no reason not to perform SLNB because a zero mortality rate was reported, and the complication rate of SLNB (10%) was significantly lower than for TLND (37%). Morton 816

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concluded that SLNB should be considered standard of care for regional staging of primary cutaneous melanoma—the key term being “staging.” At the present time 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, MRI, PET, ELND, and clinical examination.179 McMasters astutely points out that we do not impart a survival benefit for any other cancer staging test, and therefore we should not ask the same of SLNB.

Future SLNB Investigations SLNB research endeavors hold exciting and great promise in the future. In an effort to further investigate the therapeutic potential of SLNB, recent research efforts have focused on identifying markers of both the primary lesion and the SLN that are predictive of tumor containing non-SLNs.180-182 Absence of these markers would then allow identification of the subset of SLNB positive patients who may not warrant further treatment with a formal TLND. Unfortunately, current studies have failed to identify a consistent and 100% accurate marker. For this reason, the future MSLT-II trial is designed to investigate the indications for TLND following a positive SLNB. Specifically, it will determine whether immediate TLND provides a survival benefit over postoperative, diligent, ultrasonographic monitoring of the draining nodal basins.151 Molecular staging of melanoma is also gaining increased interest. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis of SLNs for melanoma-associated genes such as MART-1, tyrosinase, microphthalmia-associated transcription factor (MIFT), and tyrosinaserelated protein 2 (TRP-2) has proven helpful in identifying a subset of patients harboring occult nodal disease at a submicroscopic level that cannot be detected with traditional IHCS.183-185 In 1 study, 30% (49 of 162) of patients had negative SLNs on IHCS but at least 1 melanoma marker identified with RT-PCR.186 This subset of patients experienced an increased rate of tumor recurrence. Currently, RT-PCR lacks specificity. The high false positive rate may be from the inability to differentiate melanoma cells from occult benign nevus cells.187 Through future research efforts, molecular staging may prove helpful in the identification of a subset of high-risk melanoma patients who develop nodal or distant metastases despite presentation with a thin primary tumor. This information has the potential to change the manner in which these individuals are counseled both with respect to adjuvant therapy and follow-up surveillance.188 Curr Probl Surg, November 2006

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Surgical Management of Distant Metastasis Patients with stage IV melanoma involving distant sites have an exceedingly grave prognosis. Surgical treatment has a limited role. Operation has been used as a means of palliative treatment in patients suffering from brain, lung, gastrointestinal, subcutaneous soft tissue, and distant lymph node metastasis.189 The success of surgery in the palliative setting is heavily dependent on appropriate patient selection. Surgery should be considered only if clearly identifiable and specific symptoms are associated with a metastatic lesion. In selecting patients, it is also important to consider surgical morbidity, expected quality of life, expected survival, and most importantly, the patient’s wishes.190 The patient and family must understand that the goal of surgery is palliative in nature. Several prognostic markers have been identified in patients with disseminated stage IV melanoma.190,191 These markers are reflected in the AJCC staging system described above and should serve as a guide when considering surgical resection of distant tumors. Patients with metastatic disease limited to 1 or 2 isolated sites experience a better prognosis compared with patients with multiple metastatic lesions. In addition, a short disease-free interval between initial diagnosis and the development of distant metastasis correlates with a poor overall prognosis, even when complete resection of the metastatic lesion is achieved.190 Last, the anatomic site of the metastatic lesion is of importance. Patients with metastatic spread to nonvisceral sites such as distant subcutaneous tissues or lymph nodes have a better prognosis compared with individuals with visceral metastasis. Within the group of patients suffering from visceral metastasis, individuals with pulmonary lesions experience improved survival compared with other visceral sites.

Radiation Therapy Melanoma has traditionally been classified as a radioresistant tumor.192,193 Although adjuvant radiation has not been shown to impact survival,194 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.195-197 Local-regional control was achieved in 88% of patients, an improvement over the historical control rates of 50% to 70%.8,198 Late radiation complications were rare (3 of 174 patients) and included moderate neck fibrosis, mild ipsilateral hearing loss, and transient exposure of external auditory canal cartilage. Although an overall survival benefit has not been 818

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demonstrated, local-regional control is of great importance because recurrence can significantly impact the quality of life by causing pain, wound breakdown, and socially debilitating cosmetic disfigurement, especially in the HN region.199,200 Ultimately, the survival benefit achieved with adjuvant radiation therapy will be determined through the prospective, randomized phase III clinical trial (E3697) currently under investigation by the Radiation Therapy Oncology Group.199 Until this randomized phase III clinical trial is completed, most authors advocate the use of adjuvant radiation for patients demonstrating adverse prognostic markers such as neurotropism, extracapsular spread (ECS), multiple node involvement (⬎4), or tumor recurrence.201-203 These patients are often eligible to receive adjuvant interferon-␣2b (see discussion herein). Interferon is thought to act as a radiosensitizer; therefore, it is common practice to delay radiation until the 4-week induction phase of interferon therapy is complete.204 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.205 Radiation therapy can also be administered as palliative treatment. Patients suffering from painful, systemic stage IV disease, such as brain metastasis, bone metastasis, spinal cord compression, and isolated, symptomatic visceral metastasis have gained benefit from such treatment.201

Chemotherapy Melanoma is a relatively chemoresistant tumor.206-212 A small subset of patients is thought to benefit from chemotherapy; however, a regimen that definitively impacts survival has not emerged. The challenge lies in the limited number of stage IV patients, the inherently short survival period for this group, and the vast number of treatment options being studied in phase I and II trials. The main role for chemotherapy remains as palliative treatment in the setting of disseminated stage IV disease. Dacarbazine (DTIC) was the first chemotherapeutic agent to show significant activity against melanoma. Today it remains the only agent approved for treatment of advance stage IV melanoma. Unfortunately, response rates following DTIC administration are modest at best, ranging from 10% to 20%.26,76,102,109,130 This prognosis has not changed over the past 2 decades, despite dedicated research efforts using a host of chemotherapeutic agent regimens. Overall, fewer than 5% of individuals experience a complete response with DTIC. Curr Probl Surg, November 2006

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Immunotherapy Classically, immunotherapy is divided into 2 categories. Specific immunotherapeutic agents upregulate the antibody and cytotoxic T-cell immune response specifically to the patient’s tumor or to known melanoma antigens. The majority of melanoma vaccines fall into this category. In contrast, nonspecific immunotherapeutic agents stimulate the host’s immune system without targeting melanoma tumor antigens. Examples include interferon, interleukin, and microbacterial products such as Bacille Calmette-Gu’in (BCG) and Cryptosporidium parvum. These agents are often administered as an adjuvant to specific immunotherapeutic agents in an attempt to augment the immune system.204,208

Interferon Despite myriad clinical trials involving adjuvant regimens, high dose interferon-␣2b (IFN-␣2b) remains the only U.S. Food and Drug Administration (FDA) approved adjuvant treatment for stage III melanoma. It functions as a biologic response modifier. Mechanisms of action include direct antiproliferative effects, immune stimulation through enhancement of natural killer cells (NKCs), increased histocompatibility antigen expression on melanoma cells, macrophage phagocytosis, and enhanced T-cell mediated cytotoxicity.128,212 Although all 3 types of interferon (IFN-␣, IFN-␤, IFN-␥) demonstrate antitumor activity,212 IFN-␣2b is the only treatment currently approved for adjuvant treatment of melanoma patients at high risk of recurrence following surgery. Three large clinical trials involving adjuvant IFN-␣2b have been conducted by the Eastern Cooperative Oncology Group (ECOG).213-215 In brief, ECOG trial E1684 was the first study to demonstrate the efficacy of IFN-␣2b.213 The regimen consisted of high dose interferon (20 million units[MU]/m2/d) administered intravenously, 5 days per week for 4 weeks. Maintenance treatment followed, consisting of 48 weeks of subcutaneous IFN-␣2b (10 MU/m2/d), administered 3 days per week. The prolonged disease-free survival rate and overall survival rate in the IFN-␣2b arm of E1684 ultimately led to FDA approval of adjuvant high dose IFN-␣2b. Although the follow-up trial E1690 failed to confirm the efficacy of high dose IFN-␣2b,214 the results require careful interpretation.148 Unlike E1684, patients enrolled in E1690 did not require pathologic staging with ELND or SLNB, nor were they stratified on ulceration. In addition, a disproportionate number of individuals from the observation arm crossed over into the IFN-␣2b arm to receive salvage therapy for recurrent 820

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disease. Any therapeutic benefit provided to this subgroup by IFN-␣2b went unrecognized since the crossover patients remained in the observation arm for the purposes of statistical analysis. The most recent and largest of the 3 studies, ECOG 1694,215 once again confirmed the efficacy of high dose IFN-␣2b. In fact, the relapse-free and overall survival benefit observed in the high dose IFN-␣2b control arm compared with 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 melanoma patients are able to tolerate the 1-year course of IFN-␣2b.148,204,214,215 Almost every individual experiences flu-like symptoms (fevers, chills, malaise) during the initial treatment course. Severe and intolerable chronic fatigue is experienced in 20% to 30% of patients. An additional 2% to 10% of patients experience neurologic and psychiatric side effects including depression, anxiety, suicidal ideation, and difficulty with cognition. Myelosuppression, thyroid dysfunction, and elevated liver enzymes require close monitoring. Contraindications include a history of myocardial infarction or dysrhythmia, liver disease, CNS disorder, and severe psychiatric illness.204 Approximately 50% of patients require a dose reduction or delay as a result of these side effects. Despite these risk factors, the majority of melanoma patients are willing to accept the side effects given the potential benefit of IFN-␣2b.216 While clinical trials continue to investigate alternative dosages and schedules,217,218 only high dose IFN-␣2b is FDA approved and used as routine adjuvant therapy within the United States. Given the toxicities associated with IFN-␣2b, the adjuvant therapy is reserved for patients at high risk for tumor recurrence. Candidates include patients with regional lymph node metastasis or a primary tumor thickness greater than 4 mm. All patients should be informed of the option to receive postoperative IFN-␣2b. To make an educated decision, an objective discussion including the side effects associated with IFN-␣2b, as well as the opportunity to enroll in other clinical trials, must be provided.

Interleukin-2 and Other Cytokines Interleukin-2 (IL-2) is another form of immunotherapy used in the primary treatment of patients with disseminated stage IV disease. Unlike interferon, IL-2 lacks direct antitumor activity and in vitro activity.128 However, in vivo, IL-2 stimulates the host immune system by activating effector cells such as NKCs, monocytes, cytotoxic T cells, and helper T Curr Probl Surg, November 2006

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cells. It also induces cytokines such as IFN-␥ and tumor necrosis factor (TNF)-␣.128,219 Rosenberg and the National Cancer Institute Surgery Branch successfully used high dose IL-2 to treat 134 melanoma patients.220 An overall response was observed in 17% of patients, with 10% experiencing a partial response, and an additional 7% experiencing complete regression. The therapeutic benefit was substantial, lasting between 2 and 8 years. IL-2 side effects are significant and potentially lethal. Acute toxicities include myocardial infarction, arrhythmia, respiratory distress, hypotension, capillary leak syndrome, nephrotoxicity, hepatic toxicity, and sepsis.219 Other toxicities include 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, the dose, and by combining other therapeutic agents such as lymphokine-activated killer (LAK) cells have not proven beneficial.128,208,219 In addition to IL-2, other cytokines have been studied alone and in combination with various chemotherapeutic agents. The list includes IL-1, IL-4, IL-6, and TNF-␣.219 To date, substantial therapeutic benefit has not been demonstrated.

Follow-up and Surveillance The primary goals in melanoma follow-up are: 1) early detection of local-regional tumor recurrence, 2) early identification of second primary tumors (including melanoma as well as other skin cancers), 3) continuing patient education, and 4) psychological support.193 Each follow-up visit should include an inquiry into new or changing skin lesions. A review of systems (Table 3) concerning distant metastasis should be asked.98 A thorough examination of the skin and mucosa is required, with particular attention paid to the original melanoma site and associated draining nodal basins. Photodocumentation and dermoscopy have proven helpful in monitoring change in patients who have a substantial number of nevi.221 This vigilant monitoring is particularly important among elderly patients where a change in nevus appearance is more likely to be a melanoma compared with younger patients.221 Each follow-up visit should be viewed as an opportunity to re-educate patients on the ABCDE melanoma warning signs and the importance of monthly skin self-examination. Studies have demonstrated that melanoma patients who practice monthly self-examination are diagnosed with thinner lesions at the time of recurrence.221 Sun education including the use of sunscreen, avoidance of 822

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peak sun hours, shade seeking, sun protective clothing, and the potential risks of tanning booths should all be emphasized.

Conclusion Over the past few decades, melanoma has escalated into a problem of epidemic proportions. Fortunately, significant research advances have been achieved in recent years.204,208,212,222,223 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. Given the association with sun exposure, melanoma is considered a preventable disease. Decreased incidence and mortality hinges on patient as well as physician education, prevention, early diagnosis, and improved treatment for advanced disease. Ultimately, the key to impacting melanoma survival rates lies in wellorganized, multi-institutional studies that enroll patients who are staged accurately and therefore share a similar prognosis.

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