Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Advances in the Treatment of Melanoma There are many issues in the management and treatment of melanoma that are controversial. Today we will focus on the main controversy surrounding melanoma, that of SLNB and its role in melanoma. But, first a little background on melanoma. Superficial spreading melanomas are the most common type. They are typified by an initial spreading growth with eventual development of a vertical growth phase, changing slowly over several months to years. Nodular melanomas are the next most common type. They are characterized by extensive vertical growth into the dermis with a minimal radial component. Lentigo malignu melanomas are characterized by a prolonged radial growth phase. They are often larger than 3 cm, and begin as small, freckle like lesion. Acral lentiginous melanomas comprise 2% to 8% of melanomas in Caucasians and 35% to 60% of melanomas in dark-skinned individuals. These melanomas occur on palms/soles and beneath nailbeds, and may appear as flat, tan, or brown stains with irregular borders. Desmoplastic melanomas are frequently amelanotic, making their diagnosis more difficult. They tend to be characterized by infrequent metastasis with a higher local recurrence rate, as well as more frequent perineural involvement. Mucosal melanomas most frequently present in the nose and/or sinuses. They are rare lesions and because of their development in hidden, clinically silent areas, diagnosis often occurs late, requiring more radical treatment and contributing to poorer prognosis. There are different sites in the head and neck region where melanoma can be found. The most common sites are the skin of the cheek, neck, and scalp. Melanoma represents 4% to 5% of skin malignancies. The actual incidence of melanoma is increasing more rapidly than that of any other malignancy, with more than 59,000 cases of invasive melanoma diagnosed in the United States in 2005. In general, melanoma is more common in Caucasians and slightly more common in men, who have somewhat poorer prognosis than women with equivalent lesions. Sun exposure remains one of the most important risk factors in developing melanoma particularly when correlated with skin type. Dr Visosky, in her talk on non-melanoma skin cancers, discussed the pathogenesis of cutaneous malignancies as a result of UV exposure. In addition, increasing numbers of nevi, normal or dysplastic, are also associated with a greater risk of melanoma. Moreover, personal and family history of melanoma are also involved in its development. Those previously diagnosed with melanoma have been reported to have a 30-fold increased risk of the development of a second melanoma. Suspicious lesions are defined by the ABCD criteria. Asymmetry: One half of the lesion does not match the other half. Border irregularity: The edges are ragged, notched, or blurred. Color variegation: Pigmentation is not uniform and may display shades of tan, brown, or black; white, reddish, or blue discoloration is of particular concern. A diameter greater than 6 mm is characteristic, although some melanomas may have smaller diameters; any growth in a nevus warrants an evaluation. Some add an “E” to the ABCD criteria. E refers to Evolving: Changes in the lesion over time are characteristic; this factor is critical for nodular or amelanotic melanoma, which may not exhibit the classic criteria above. During the 1960s, Clark defined landmark histologic levels of invasion. Breslow, on the other hand, demonstrated the importance of tumor thickness. In an analysis of over 17000 melanoma patients from 13 cancer centers, Balch et al identified various clinical and pathologic factors important to predicting outcome of melanoma patients. These factors were incorporated into the AJCC melanoma staging system when it was revised in 2002. For Stages I and II: Tumor thickness and ulceration were the most powerful predictors of survival in patients with localized melanomas. In the graph on the right, the survival of patients with ulcerated tumors—as indicated by the colored lines—was significantly less than patients with non-ulcerated tumors of the same thickness—as indicated by the black line with the box of the corresponding color. For Stage III melanomas, the number of metastatic nodes, tumor burden, either microscopic or macroscopic, and ulceration status were the most powerful predictors of survival And for Stage IV melanomas, anatomic site of distant metastases was the most significant predictor of survival Treatment of the melanoma primary site is wide local excision with resection of normal adjacent tissue to ensure clear margins. Surgical margins of 5mm are currently recommended for melanoma in situ, and margins of 1cm are recommended for melanomas up to 1 mm in depth. Randomized prospective studies show that 2cm margins are appropriate for tumors of 1mm in thickness or greater. A retrospective study of melanomas with greater than 4mm thickness showed that excisional margins greater than 2cm have no effect on local recurrence, disease-free relapse, or overall survival rates. There is much controversy surrounding treatment of melanoma. The greatest controversy, however, involves the role of sentinel lymph node biopsy and the necessity of elective node dissection. Management of the regional lymph nodes in early-stage melanoma has remained controversial throughout the last century. The proponents of elective lymph node dissection claim that removal of the regional lymph nodes early in the natural history of the disease can halt the metastatic cascade. However, multiple retrospective, nonrandomized clinical trials have failed to demonstrate an overall benefit for elective lymph node dissection. There have been four randomized controlled studies evaluating elective lymph node dissection in more than 1700 patients with cutaneous melanoma. The first trial was conducted by Veronesi et al in 1980, with a total of 553 patients. After 5 and 10 years, there was no statistically significant difference in overall survival between the two groups. The second and third trials published by Sim and Cascinelli et al also demonstrated that there was no statistically significant difference in overall survival or time to subsequent metastasis. The Intergroup Melanoma Trial, the largest of the four trials, was led by Balch et al in 2000. Four independent predictors of outcome were identified: tumor thickness, tumor ulceration, trunk site, and age greater than 60 years. Furthermore, overall 10-year survival was not significantly different for patients who received elective lymph node dissection or nodal observation. As sound scientific evidence accumulated demonstrating that elective lymph node dissection did not appear to offer a survival advantage for patients, surgeons in the late 20th century began to look for ways to explain the results of these controlled scientific studies. Many believed that one reason no statistically significant survival advantage could be found was that in many cases, the wrong lymph node basin was dissected, due to the unpredictable nature of lymphatic drainage patterns, especially in the head and neck areas. Many surgeons believed that if the correct nodal basin could be identified prior to elective lymph node dissection, a statistically significant advantage could be demonstrated. Thus began a new era of lymphatic mapping and sentinel lymph node identification. As a result of this controversy regarding the management of the regional lymph nodes, Morton et al devised intraoperative lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection as an alternative to either ELND or delayed dissection in the 1990s. This procedure is based on the hypothesis that melanoma metastasizes to regional lymph nodes via a defined connection of dermal lymphatic vessels that can be followed from the skin of the primary tumor to the first or sentinel lymph nodes in the regional basin, which have the highest risk of harboring micrometastatic disease. Sentinel comes from the French word sentinelle, which means to guard over or vigilance. Hence, a sentinel node is the guard node that filters all the lymphatics before it drains to the other nodes in that lymphatic basin. In the nineteenth century, Rudolf Virchow, as seen at left, described the sentinel node concept in his lectures when he pointed out that lymph, which may contain bacteria or tumor cells, drains from a particular body location to a specific lymph node before onward passage to other lymph nodes and eventually to systemic sites. In 1874, French anatomist Marie Philibert Constant Sappey published his comprehensive atlas, including an anatomic study of cutaneous lymphatic drainage. He injected mercury into the skin of cadavers and defined demarcation lines that passed down the midline front and back, and along a horizontal line around the waist at the level of the umbilicus anteriorly, and to the level of the L2 vertebra posteriorly. Sappey's results demonstrated lymphatic drainage based on anatomic location. Braithwaite was the first to use the term “glands sentinel” in reference to a node receiving direct lymphatic drainage from a particular site. Forty years later, Gould et al revisited this concept in a description of direct lymphatic drainage from a parotid malignancy to a “sentinel node” at the confluence of the facial veins. But it wasn’t until the 1980s that Morton et al demonstrated the benefit of lymphatic mapping and selective sentinel lymphadenectomy. Since it was first described in 1992, the sentinel node biopsy technique has been progressively refined. Originally, only the technique of intradermal blue dye injection around the melanoma site was used to identify lymphatics leading to sentinel nodes with a reported success rate of 82%. The addition of preoperative lymphoscintigraphy with radiolabelled sulfur colloid and intraoperative gamma probe to the blue dye technique has resulted in much higher sentinel node identification rates, which now approach 100%. The head and neck is a challenging area for accurate lymphatic mapping. Nodes are often small, and drainage to multiple sentinel nodes is common. While most patients with melanomas on the extremities have a median of 1.3 to 1.8 sentinel nodes, a median of 3.8 sentinel nodes is found in patients with intermediate thickness lesions on the head and neck. Various series report a 90% to 95% success rate in identifying the sentinel node in the head and neck region, which is somewhat less than the success rate for detection of the sentinel node at other sites. Because of the close proximity of cutaneous melanomas of the head and neck to the regional lymphatic basins, the radioactive signal from the primary tumor may obscure that from the sentinel nodes in nearby nodal basins. As a result, melanomas of the head and neck are often excised before intraoperative identification of the sentinel nodes in order to decrease the background radioactivity from the primary site. Many variations in the lymphatic drainage patterns make clinical prediction of lymphatic drainage unreliable and biopsy of the sentinel node more difficult in the head and neck. Melanomas frequently are drained by multiple lymphatic channels and nodal basins. Also, only 67% of lesions stain with blue dyes. In addition, up to 60% of patients drain to node sites discordant with clinical prediction. These nonclassic nodes and especially parotid nodes make lymphatic mapping even more challenging. Half of sentinel nodes are located in nonadjacent nodal basins, while 10% to 12% are located in contralateral nodes. Who should be counseled regarding sentinel lymph node biopsy? All studies to date verify that the probability of a positive sentinel node increases with increasing tumor thickness. McMasters et al reported that several variables were independent predictors of sentinel node metastasis; these were not only Breslow thickness, but also Clark level, ulceration, and age. Following a positive sentinel lymph node biopsy, completion lymph node dissection is indicated. An average of 20% to 25% of patients with positive sentinel node will have other positive nonsentinel nodes. There are a number of contraindications to sentinel node biopsy. Among these are: a palpable lymph node, primary tumors larger than 4cm to 5cm, prior neck dissection, and previous radiation to the head and the neck. After excision, the sentinel node is subjected to routine pathologic evaluation using an H&E–stained section. When micrometastasis consists of a single cell or a cluster of fewer than 50 cells, immunohistochemistry may be applied for further confirmation. Metastatic melanomas are known to express a number of surface membrane and cytoplasmic antigens that are detected immunohistochemically by antibodies to paraffin-embedded sections. As a result of phenotypic heterogeneity, multiple stains are a necessity. The S-100 protein is expressed in almost all primary and metastatic malignant melanomas, while the MART-1 protein is a component of a melanocyte-specific complex. The precise function of this protein, however, remains to be determined. Together they are the most effective pair for detecting melanoma in lymph nodes. In addition to immunohistochemistry, there has been much interest in molecular staging of sentinel nodes. Reverse-transcriptase polymerase chain reaction (RT-PCR) has been explored as an alternative means of diagnosis. However, it is suspected that this technique is too sensitive, leading to significant false positive diagnoses. The ultimate prognostic significance of RT-PCR-detected nodal and circulating melanoma cells remains uncertain. More studies are needed to evaluate its efficacy. The controversy with sentinel lymph node biopsy begins with its opponents. Opponents of sentinel lymph node biopsy rely on a number of arguments. First, several publications have recently suggested that sentinel lymph node biopsy should be abandoned as a staging procedure because it may increase the risk of in-transit metastasis. Satellite or in-transit metastases are cutaneous or subcutaneous deposits between the primary melanoma and regional lymph nodes. Estourgie et al cited a 23% incidence of in-transit metastases in patients with a positive sentinel node. This study reported a higher incidence of in-transit metastases during long term follow-up of patients who underwent wide local excision plus sentinel lymph node biopsy versus wide local excision alone. In a review of the literature, Thomas and Clark reported a 4.5% incidence of in-transit metastases after wide local excision vs. 9% after sentinel lymph node biopsy. The incidence decreased to 5.7% in patients who had tumor negative sentinel nodes, and increased to 21% in those who underwent completion lymphadenectomy because of tumor positive sentinel nodes. They concluded that sentinel lymph node biopsy increased the risk of in-transit metastases by two to four fold. However, there is substantial evidence to the contrary. In an interim analysis of the randomized Multicenter Selective Lymphadenectomy Trial, the incidence of in-transit metastases in the sentinel lymph node biopsy group was 8%, while in the wide local excision alone group it was 9%. Moreover, a review of more than 4,000 patients by Kang et al treated during a 30-year period, did not show an increased incidence of in-transit metastases after sentinel lymph node biopsy vs. wide local excision or elective neck dissection. When patients with similar primary risk factors were compared, there was no association between sentinel lymph node biopsy and in-transit metastases. There was also no survival disadvantage, either disease free or overall, in those sentinel lymph node biopsy patients who subsequently developed in-transit metastases. Proponents of sentinel lymph node biopsy argue for the importance of identifying patients who qualify for treatment with interferon alfa-2b. However, the effects of this treatment regimen are modest at best and have been shown to increase only disease-free survival. Moreover, recent meta-analysis reassessing these trials grouped together failed to reveal a statistically significant overall survival advantage. This observation, combined with the significant toxicity and economic costs related to the required 12-month treatment regimen, has resulted in little enthusiasm for the use of interferon in patients with high-risk melanoma. IFN alfa 2b therapy is still the only FDA approved adjuvant therapy for high risk melanoma patients. The indication for IFN-alpha 2b is based on the Eastern Cooperative Oncology Group Trial E1684, which demonstrated a disease free and overall survival benefit for treatment with interferon. In study E1694, patients were treated with either adjuvant high dose IFN or the GM2 ganglioside vaccine. The study was stopped early based on interim analysis that showed superiority of IFN treatment in terms of both disease free and overall survival. Even if current adjuvant therapy is imperfect, there is still value in staging patients for adjuvant therapy trials. One major goal of sentinel lymph node biopsy is to identify homogeneously staged patient populations for entry into clinical trials. Only by entry of patients with similar prognoses will meaningful interpretation of adjuvant therapy results be possible. Advancement in the area of adjuvant therapy depends on rigorous clinical trials with more homogenous populations to better distinguish between natural disease course and therapeutic intervention. By far, the most powerful argument against sentinel lymph node biopsy is that it has not been shown to improve overall survival. Although sentinel lymph node biopsy has been shown to increase disease free survival, no randomized prospective trials so far have demonstrated that sentinel lymph node biopsy improves survival. Findings by Gutzmer et al in a retrospective analysis of 673 melanoma patients support this argument. Most opponents of sentinel lymph node biopsy argue that unless sentinel lymph node biopsy can be shown to improve overall survival for patients with melanoma, it should not be performed. The best evidence that suggests that sentinel lymph node biopsy in conjunction with surgical therapy may offer a survival benefit comes from the Intergroup Melanoma Trial, comparing completion lymph node dissection in subjects with positive sentinel nodes to observation with therapeutic lymph node dissection performed at the time of gross nodal involvement. The trial demonstrated improved 10-year survival for completion lymph node dissection in prospectively stratified subsets of patients with nonulcerated melanomas, melanomas 1-2mm thick, or melanomas on the trunk. The impact of the pathologic status of sentinel node on survival rates is currently being elucidated. The evidence for performing sentinel lymph node biopsy in intermediate thickness melanoma is strong and continues to accumulate. First, sentinel lymph node biopsy is minimally invasive, performed at the same time as wide local excision of primary melanoma and has been shown to be cost effective and less morbid compared with elective lymph node dissection. McMasters et al in the Sunbelt Melanoma Trial, compared the morbidity associated with sentinel lymph node biopsy and completion lymph node dissection. Overall, 4.6% of patients undergoing sentinel lymph node biopsy and 23.2% of patients undergoing completion lymph node dissection experienced complications after their respective procedure. Hematoma and seroma formation was the most frequent complication at 2.3% and 6% for sentinel lymph node biopsy and completion lymph node dissection respectively. Second, prognostic information is invaluable for therapeutic guidance, patient counseling, and management of emotional distress. Sentinel node status is the most important predictor of recurrence and survival of patients with melanoma. In fact, in a report by Gershenwald et al, the hazard ratio for survival associated with a positive sentinel node was 6.53, much greater than that for any other prognostic factor. Third, as demonstrated earlier, sentinel lymph node biopsy may indeed improve survival. More evidence to this end was provided by Yee et al in an analysis of 975 patients from the Sydney Melanoma Unit who underwent sentinel lymph node biopsy. The difference in the 5-year disease free and overall survival between patients with positive and negative sentinel node biopsy was highly significant. This is corroborated by a study conducted by Leong et al that evaluated 412 patients who underwent sentinel lymph node biopsy. Patients with positive sentinel node status were nearly twice as likely to die as patients with negative sentinel nodes. The 5 year overall survival rate for sentinel node-positive patients was 60% compared to 87% for sentinel node-negative patients Finally, before the advent of sentinel lymph node biopsy, the pathologic nodal status of patients with melanoma was known only after elective lymph node dissection. However, after the 4 prospective randomized trials failed to demonstrate an overall survival benefit for elective node dissection, many believe that lymphadenectomy offers no therapeutic benefit for patients with melanoma. The important distinction between elective and completion lymph node dissection is often overlooked or obscured. In the WHO Programme 14 Trial of elective LN dissection, overall, there was no difference in survival for the two randomized arms. When the survival of patients with positive lymph nodes was compared, a different picture emerges. The overall survival of patients with nodal micrometastases removed at completion lymph node dissection was significantly greater than that of patients who underwent lymphadenectomy for palpable lymph nodes in the observation arm. Node dissection offers increased survival in patients with node metastases. These results lend support for procedures like sentinel node biopsy aimed at early identification of patients with occult node metastases, who can then undergo completion node dissection. In a study conducted by Morton et al, patients who underwent completion dissection for metastases identified by sentinel lymph node biopsy survived for longer than patients who underwent delayed dissections Sentinel lymph node biopsy is a diagnostic staging test to determine the pathologic status of the regional lymph nodes and accurately identify the presence of nodal metastasis. The presence of a positive sentinel node is the single most important prognostic factor in determining the likelihood of survival. Patients should be offered the option of sentinel lymph node biopsy, when appropriate, to determine the status of the regional lymph nodes. Patients identified with positive sentinel nodes are then eligible for adjuvant treatment with IFN alpha 2b, still the only FDA approved adjuvant therapy for melanoma. Furthermore, sentinel lymph node biopsy provides patients the opportunity for early therapeutic lymph node dissection and has recently been shown to increase survival in subsets of patients. Case Presentation: RD is a 60-year-old male who was referred to the Michael E. DeBakey VA Medical Center ENT Clinic for situ lentigo maligna melanoma of the left face by Dermatology. The patient reports that the lesion had been present for approximately one year. Past medical history: Coronary artery disease, hyperlipidemia, tinnitus, gout and hypertension. He denied any allergies. Current medications consist of the following: Allopurinol, Atenolol, Felodipine, Lisinopril, Simvastatin, and aspirin. Social History: Distant history of smoking, quit 25 years ago. Family History: Noncontributory. Physical Exam was notable for a slightly hypopigmented 5 x 4 mm area just inferior to his left eye. There were no other notable lesions on his face. His labs and CXR were normal. The patient was taken to the OR on 7/15/05 and underwent wide local excision with 1 cm margins. The area was left open pending permanent sections prior to taking him back to the OR for definitive closure. Pathology results revealed a positive superior margin. He was taken back to the OR a week later 7/21/05 and underwent further excision in the superior portion of the defect with 1 cm margins. Again the defect was left open pending final pathology. Pathologic exam revealed margins free from tumor. On 7/28/05, the patient returned to the operating room for closure of his 2.5 x 1.2 cm defect. An elliptical shaped full thickness skin graft was taken from the patient’s left neck and was used to close the defect. Since then, the patient has done well and his skin graft healed nicely. 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