MELANOMA: HANDS-ON OR HANDS-OFF?

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1 MELANOMA: HANDS-ON OR HANDS-OFF? M SCHAMM MBChB (Pret), FCS (SA) Endocrine and Transplant Surgeon, Department of Surgery, University of the Witwatersrand; and Clinical Head Transplant Surgery, Charlotte Maxeke Johannesburg Academic Hospital Malignant melanoma falls into the category of non-pigmented skin cancers. The lifetime risk of an American developing invasive melanoma is approximately one in 58 overall, and one in 39 for Caucasian men, and one in 58 for Caucasian women. This contrasts dramatically with a lifetime risk of one in for Americans born in This incidence of melanoma has been increasing faster than that of any other cancer in the United States. Statistically significant increases are occurring for tumours of all histologic subtypes and thicknesses. Two topics are discussed in this review: the diagnosis of early malignant melanoma (which pigmented lesions require biopsy); and the role of surgery with regards to the regional nodal basins. Prognosis in melanoma is proportional to the depth of the lesion. Detection at an early stage is therefore important. Melanoma initially grows in a horizontal fashion in the epidermis (radial growth phase). This correlates pathologically with Melanoma in situ. With time, the tumour enters a vertical growth phase, making it an invasive melanoma (into the dermis). The depth of invasion measured from the Stratum Granulosum (granular layer of the epidermis) has been shown to be the factor that best correlates with prognosis. Early forms of melanoma are amenable to surgical cure with a 5-year survival rate of 95%. In contrast, metastatic disease still remains poorly responsive to systemic therapy. An estimated 90% of expenditure for melanoma in the US is related to advanced disease.

2 Significant healthcare savings, as well as lives saved, can be achieved by early diagnosis. The standard way of evaluating a skin lesion to rule out melanoma is by excision biopsy and histopathological examination. The challenge lies in identifying lesions that have a high probability of being a melanoma. DIAGNOSTIC APPROACHES OVER THE YEARS During the past 30 years there has been significant evolution in the diagnosis of early melanoma. Before the 1980s there had been little change in identifying melanoma. The diagnosis was made by identifying clinically macroscopic features, often when they were at an advanced stage. In 1985 the New York University School of Medicine (NYU) devised the ABCD acronym, when they recognised the need to educate both the public and health care providers. The ABCD criteria were intended as a simple tool to be applied by laypersons and physicians to detect early features of melanoma. Asymmetry, Border irregularity, Color variegation and Diameter of >6mm. The sensitivity of the criteria when used singly or in combination is a sensitivity of 57-90% and specificity of 59-90%. The ABCD criteria were intended to differentiate thin, early tumours which otherwise may be confused with a benign pigmented lesion and not comprehensive guide for Dermatologists to stratify pigmented skin lesion. Lesions that are ulcerated or elevated are already suspicious and require assessment regardless of other features. Not all melanomas fulfil all four criteria. It is the combination of features that renders a cutaneous lesion most suspicious. THE IMPORTANCE OF LESION E VOLUTION: ABCD E Lesion evolution is a cardinal feature for cutaneous melanoma! The addition of the E to the ABCD criteria substantially enhances recognition of melanomas at an earlier stage. Evolution may include one or all of the following: Change in size Change in colour

3 Ulceration Bleeding Itching. Other melanoma early diagnostic criteria exist. The most recognised of these is the Glasgow 7- Point Check List however it has been less widely adopted due to its complexity. It includes: 1. Three major a. Change in size b. Shape c. Colour. 2. Four minor criteria a. sensory change b. diameter > 7mm c. presence of inflammation, crusting, bleeding. Other helpful concepts in the early diagnosis of melanoma in suspicious skin lesions. 1. The ugly duckling sign: the pigmented skin lesion that looks different from all its neighbours. 2. The little red riding hood sign: an indicator for patients with fair skin and lightcoloured hair that are likely to suffer from amelanotic melanomas, which can be difficult to see and, therefore, diagnose. SKIN SELF-EXAMINATION (SSE) In the mid-1980s the ABCDs were incorporated into national public and professional education campaigns. Self-examination was encouraged for all individuals, but especially for those at highest risk of melanoma. Melanomas are commonly detected by patients, patients performing SSE were found to be more aware of melanoma and lesions discovered were thinner when compared to patients who did not practice SSE.

4 Main predictors of thorough SSE: Having been advised to do so by a physician. Availability of a partner to help. Availability of wall and hand-held mirror. The use of photographic examples of lesions with the ABCDE characteristics. Nationwide mass screening has been undertaken. The first Monday in May has been recognised as Melanoma Monday with associated public events undertaken each year. OFFICE BASED SCREENING Total skin examination (TSE) has also been shown to enhance earlier detection of melanoma. It is a non-invasive, quick and sensitive (89-97%) screening procedure when performed by a physician trained to identify skin cancers. When performed by a Dermatologist a sensitivity of 93,3%, a specificity of 97.8%, positive predictive value of 54%, and a negative predictive value of 99.8% can be achieved with TSE. Regular screening is associated with detection of thinner and smaller melanomas. MODERN TECHNOLOGY TO AUGMENT DETECTION OF MELANOMA In the 1990s light based visual technologies were adopted. Dermoscopy or epilumininescence microscopy was developed, and is now a well-established tool that uses a hand-held lighted magnifier to analyse skin lesions. The 10-fold magnification, using cross polarising light filters, allows identification of newly defined and descriptively named subsurface structures, eg. dots, streaks, veils, networks. A systemic review of the diagnostic accuracy of dermoscopy to detect melanoma improved the sensitivity and specificity of clinical diagnosis from 71% to 90%. However, the results depend on the experience of the clinician.

5 Piccolo et al. reported that dermatologists with five years of experience using dermoscopy had a 92% sensitivity rate and a 99% specificity rate using dermoscopy, whereas inexperienced users had a 69% sensitivity rate, and a 94% specificity rate 1. Three criteria have been shown to be especially important in distinguishing malignant from benign pigmented lesions: asymmetry, atypical pigment network and blue-white structures. Changes in melanocytic lesions over time an also be appreciated through side-by-side dermoscopic comparisons. This approach appears sensitive for early melanoma detection, in that a relatively higher percentage of melanomas were detected as in situ. Dermoscopy can increase or decrease the confidence that a melanocytic lesion is benign or malignant, thereby improving the early detection of melanoma, while reducing the need for unnecessary biopsies. Regular follow up and monitoring is needed to identify slow-growing melanomas with subtle changes. The downside of dermoscopy is its potential to miss very early or featureless amelanotic melanomas. Total body photography (TBP) is useful for following patients at high risk for melanoma. One of the goals is to detect subtle changes over time in lesions that may otherwise go unnoticed by clinical examination; this is especially useful in a patient with hundreds of lesions. NEWER TECHNOLOGIES Digital Capture and Analysis. Computer-Augmented Image Analysis. Digital Dermoscopy. Multispectral Digital and Image Analysis. Laser-based Enhanced Diagnosis. Reflectance Confocal Microscopy. Optical Coherence Tomography. Diagnostic Ultrasound. Using mrna to Diagnose Melanoma. Cellular Electrical Resistance (Bio-impedance).

6 MelaFind uses fully automated multi-spectral imaging to provide a rapid, nonoperator-dependent diagnosis of lesions. Elbaum and colleagues demonstrated a specificity of 68% to 85% and a sensitivity of 95% to 100% in the differentiation of malignant melanoma in situ and invasive malignant melanoma from dysplastic and other atypical nevi 2. Several systems, such as Dermogenius Ultra, FotoFinder, and Microderm, have been developed to use machine vision to perform automated analysis of conventional or dermoscopic images of lesions. One example, SolarScan, is an automated dermoscopy image analysis system. In the diagnosis of melanoma, Menzies and colleagues reported that SolarScan (sensitivity 85%, specificity 65%) performed as well as or better than experts (sensitivity 90%, specificity 59%), dermatologists (sensitivity 81%, specificity 60%), trainees (sensitivity 85%, specificity 36%), and general practitioners (sensitivity 62%, specificity 63%) 3. THE IMPACT AND NEED FOR LYMPH NODE DISSECTION Lymph node metastases are common in melanoma patients. The status of the regional lymph nodes is the most important prognostic indicator for patients with melanoma. Sentinel Lymph node biopsy is a minimally invasive, low morbidity staging procedure recommended by the American Joint Committee on Cancer (AJCC), and is widely accepted and recommended by the Society of Oncology (SSO), and the American society of Clinical Oncology (ASCO) in clinically node negative patients with melanomas > 1mm. Sentinel lymph node biopsy was developed as technique to surgically assess the regional lymph nodes, while sparing node negative patients unnecessary complete nodal dissection. According to the incubator hypothesis the primary melanoma spreads primarily to sentinel lymph nodes in the regional basin, where the metastatic melanoma cells may survive and grow slowly, or stay latent before spreading to distant sites. If the regional metastatic disease could be removed prior to systemic spread the patient could be cured.

7 THE MLST 1 TRIAL In the MSLT 1 trial, 2001 clinically node negative patients were randomised to either SLNB (+) dissection of the nodal basin if SLN+), or observation of nodal basin. Among patients who did not have nodal metastases (either on SLNB or observation), there was no treatment related difference in the 10 year MSS in the intermediate thickness group, or those with thick melanomas 4. Distant disease-free survival in node positive patients was significantly improved in the intermediate thickness group who received immediate lymphadenectomy vs delayed lymphadenectomy (hazard ratio for distant metastases, 0.62; 95% CI, 0.42 to 0.91, P = 0.02). The benefit was not observed in the patients with thick melanomas (hazard ratio, 0.96; 95% CI, 0.56 to 1.64, P = 0.88) 4. Treatment effect of SLNB with immediate lymphadenectomy in the subgroup of patients with nodal metastases showed that among intermediate thickness melanomas, both disease-free (estimated treatment effect was 1.17 (P < 0.001)) and distant disease-free survival (estimated treatment effect was 0.73 (P < 0.04)) was improved in the biopsy group 4. The treatment effects on the disease-free survival, distant disease-free survival, and melanoma specific survival indicate an increase in survival times by factors of 3.2, 2.1, and 2.0 respectively 4. The NCCN has stratified clinical Stage I patients into a group of patients at very low risk for nodal involvement for whom SLNB is not indicated. In a study by Mozzillo et al 5, sentinel node-positivity in the groin was related to deep node involvement in 6.1% of patients, a finding similar to that of Santinami et al 6, who reported a figure of 8.6% for involved nodes in the iliac basin. Involvement of deep nodes cannot be predicted by histological or clinical features. Conventional imaging and PET have been reported to have limited utility.

8 OUTCOMES AFTER SUPERFICIAL VS. COMPLETE NODAL DISSECTION Management of patients with clinically node positive lymph node metastases to the groin is by ilio-inguinal or combined superficial and deep groin dissection. Superficial groin dissection (SGD) only is still performed in some centres. Disagreement exists about the extent of surgical dissection, and whether an iliacpelvic lymphadenectomy is mandatory. Many support the idea that iliac-pelvic involvement indicates systemic disease, and that an aggressive surgical approach will not improve melanoma specific survival. Indeed, the therapeutic value of elective lymph node dissections and the role of adjuvant therapy for node-positive disease have been two of the most studied and least agreed on issues in the treatment of melanoma. Numerous studies have concluded that the extent of groin dissection, regardless of the presence or absence of deep lymph node involvement, has no effect on survival. Since 2001, the more conservative approach, without sectioning of the inguinal ligament has reduced post-operative morbidity. Hughes et al 7, found no evidence that deep groin dissection caused greater morbidity than superficial dissection. Data from three major cancer institutions (MSK New York, Netherland Cancer Institute, Amsterdam, MD Anderson Cancer Center, Houston) have demonstrated that survival can be achieved in a substantial number of patients with deep nodal metastases, with five-year survival rates ranging from 24-43%. In these studies the number of metastatic nodes, the thickness of the primary melanoma and the presence of ulceration were independent prognostic factors 6. Therapeutic lymphadenectomy is the treatment of choice for clinically detectable and cytologically or pathologically proven regional lymph node involvement in patients with melanoma. This approach is associated with long-term disease free survival in a subset of patients. Even if patients develop distant metastases, aggressive regional therapy at presentation can prevent morbidity.

9 Approximately 20 to 40 percent of patients with clinically apparent (macroscopic, N1b or N2b) metastatic involvement of regional nodes are alive at 10 years following therapeutic lymphadenectomy 6. NCCN RECOMMENDATION 8 In the absence of clinical or radiologic evidence, patients with melanoma metastatic to inguinal nodes are at risk for pelvic node involvement and candidates for elective pelvic lymph node dissection when there are more than three superficial nodes involved, when the superficial nodes are clinically positive, or when Cloquet s node is positive. In the setting of inguinal lymphadenopathy, a pelvic dissection is recommended if the PET/CT or pelvic CT scan reveals iliac and/or obturator lymphadenopathy 8. One measure of the completeness of a regional lymph node dissection is the number of lymph nodes examined. However, the NCCN committee felt that available retrospective evidence to date was insufficient to mandate that a specific number of nodes be required to deem a lymph node dissection adequate for any designated lymph node basin. As a measure of quality control to ensure adequacy of lymphadenectomy, the committee recommended that the operative note fully describe the anatomic boundaries of the lymph node dissection 8. SUMMARY Lymph node dissection should be considered more than a staging or palliative procedure for melanoma metastatic to regional lymph nodes. The outcomes of patients with regional lymph node metastasis vary widely, with the most powerful predictor of both overall and disease-free survival after lymph node dissection being the number of positive lymph nodes. However, even patients with multiple positive lymph nodes can enjoy significant long-term survival after lymph node dissection. Therefore, aggressive surgical therapy of regional lymph node metastases is warranted, and each individual s risk of recurrence should be weighed against the potential risks of adjuvant therapy.

10 Although the number of positive nodes is by far the most powerful predictor of survival, there clearly is not one factor that can be used to absolutely predict who will survive or who won t survive. Further advances in the molecular staging of the lymph nodes may improve the ability to stratify these patients but are probably going to still incompletely predict the outcomes of patients, since it is in all likelihood determined by tumour biology. REFERENCES 1. Piccolo D, Ferrari A, Peris K, Diadone R, Ruggeri B, Chimenti S. Dermoscopic diagnosis by a trained clinician vs. a clinician with minimal dermoscopy training vs. computer-aided diagnosis of 341 pigmented skin lesions: a comparative study. Br J Dermatol. 2002;147: Elbaum M, Kopf AW, Rabinovitz HS, et al. Automatic differentiation of melanoma from melanocytic nevi with multispectral digital dermoscopy: a feasibility study. J Am Acad Dermatol. 2001;44: Menzies SW, Bischof L, Talbot H et al. The performance of SolarScan: an automated dermoscopy image analysis instrument for the diagnosis of primary melanoma. Arch Dermatol Nov;141(11): Donald L. Morton, M.D., John F. Thompson, M.D, et al, for the MSLT Group. Final Trial Report of Sentinel-Node Biopsy versus Nodal Observation in Melanoma. N Engl J Med 2014; 370: Nicola Mozzillo, Corrado Caracò,Ugo Marone, et al. Superficial and deep lymph node dissection for stage III cutaneous melanoma: clinical outcome and prognostic factors. World J Surg Oncol. 2013; 11: 36. Published online 2013 Feb 4.doi: / Santinami M, Carbone A, Crippa F, et al. Radical dissection after positive groin sentinel biopsy in melanoma patients: rate of further positive nodes. Melanoma Res Apr;19(2): Hughes TM, Thomas JM: Combined inguinal and pelvic lymph node dissection for Stage III melanoma. Br J Surg 1999, 86: