Clinics in Dermatology (2010) 28, 311–315

Discussion

Excision guidelines and follow-up strategies in cutaneous melanoma: Facts and controversies Ulrike Leiter MD, Thomas Kurt Eigentler MD, Andrea Forschner MD, Annette Pflugfelder MD, Benjamin Weide MD, Laura Held MD, Friedegund Meier MD, Claus Garbe MD ⁎ Center of Dermato-Oncology, Department of Dermatology, University of Tuebingen, Liebermeisterstr. 25, 72076 Tuebingen, Germany

Abstract The ongoing increase in melanoma incidence throughout Caucasian populations worldwide raises the question of an economic and efficient management of primary melanoma and follow-up. The primary treatment of a cutaneous melanoma is surgical excision. An excision biopsy is recommended, and safety margins of 1 cm for tumor thickness up to 2 mm and 2 cm for a higher tumor thickness should be applied at the primary excision or in a two-step procedure. When dealing with facial, acral, or anogenital melanomas, micrographic control of the surgical margins may be preferable to allow reduced safety margins and conservation of tissue. Whereas the treatment for primary melanoma is accepted world wide, follow-up strategies for melanoma patients are discussed controversially, and so far, no international consensus has been reached. © 2010 Elsevier Inc. All rights reserved.

Introduction The incidence of invasive cutaneous melanoma (CM) rose rapidly in populations of predominantly Caucasian origin between the 1940s and the 1980s.1 This trend is still ongoing in many European countries, Canada, the United States of America (USA), Australia, and New Zealand.2 Although surgical excision of the primary melanoma is internationally accepted as the treatment of choice, several questions concerning the follow-up schedule are still debated controversially. In this contribution, we will comment on a few crucial questions.

Recommendation in excision margins and current guidelines Incision Biopsy For a detailed discussion, refer to Pflugfelder et al in this issue (ref). Incision biopsies do not worsen a patient's prognosis but should be avoided. Excision biopsy is preferred to give the dermatopathologist an optimal specimen and to allow evaluation of the excision margins for residual tumor. In case of unclear clinical findings, an incision biopsy is justified to confirm the diagnosis.

Excision margins and current recommendations ⁎ Corresponding author. Tel.: +49 7071 29 83768; fax: +49 7071 29 5187. E-mail address: [email protected] (C. Garbe). 0738-081X/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2009.10.001

Since the beginning of the last century, the recommendation has been to excise a primary melanoma with safety

312

U. Leiter et al.

margins. In 1907, W. Handley3 published a contribution in which he analyzed the pattern of satellite metastases in melanoma and recommended excision of the primary tumor with a margin of 1 inch (2.54 cm) from the edge of the tumor. In the 1970s and 1980s, safety margins of 5 cm, independent of tumor thickness, were the surgical standard.4 The World Health Organization Melanoma Group performed the first surgical trial to compare lower safety margins of 1 and 3 cm in primary melanomas with less than 2 mm of tumor thickness.5 The group found no differences in survival and only slightly increased local recurrence rates in the patients with narrower excision margins. These results led to the recommendation of 1-cm margins in patients with primary melanomas with less than 1 mm tumor thickness. Later comparisons of 5- and 2-cm safety margins in thick primary melanomas revealed no significant advantages for the 5-cm margins.6 A recent trial, however, comparing 1and 3-cm safety margins in thick primary melanoma with 2 mm and more tumor thickness showed an increased rate of local recurrence in those with the small safety margins and a simultaneous trend towards decreased survival rates. These findings indicate that the safety margin cannot be reduced to zero in melanoma.7 Different national guidelines now give uniform recommendations for the excision of primary melanoma.8-11 The safety margins recommended are summarized in Table 1. Recommendations for safety margins are now widely evidence-based. The question of whether a general reduction of safety margins to 1 cm is justified remains open.

Optimum frequency of follow-up examinations Follow-up schedules have been performed to achieve two major objectives: first, to detect recurrences early, and second, to detect subsequent primary melanoma. When follow-up examinations aim at the early detection of recurrences, the period between two follow-up examinations should not exceed 6 months, because a longer time period does not match with the aim of early detection of recurrences. Early detection of locoregional recurrences is associated with a more favorable survival outcome, as is indicated by the current N-staging system.12,13 Early detection of distant metastases allows a greater percentage of surgical treatments with complete removal of all detectable metastases, and this

Table 1 Recommendations for excision margins for melanoma (level of evidence, II) Tumor thickness (Breslow)

Excision margin (cm)

In situ ≤2 mm N2 mm

0.5 1 2

seems likewise to be associated with a more favorable prognosis.14 There is evidence from a prospective study that early detection of recurrences is the basis for a better survival prognosis. 15 One study, however, described a survival benefit in patients with asymptomatic recurrences detected by follow-up examinations, but others did not.16,17 A review12 showed that none of the evaluated studies revealed any benefit in disease-free or overall survival associated with follow-up surveillance, although one study detected a survival benefit of doctor-detected (asymptomatic) recurrences. The authors therefore argued that follow-up surveillance of localized melanoma does not necessarily result in a benefit for patients, because 62% of patients detected their first recurrence themselves.12 Consequently, these authors suggested only infrequent follow-up visits (once or twice yearly) for patients with primary cutaneous melanoma, with a stronger emphasis on patient selfexamination.18,19 If the purpose of follow-up examinations consists in the detection of secondary melanomas, screening examinations once a year are probably sufficient.20-22 Lifelong surveillance is recommended by several authors to detect secondary melanomas.23-25 This kind of surveillance, consisting mainly in nevus screening in follow-up examination using digital dermoscopy, should be preferentially offered to melanoma patients with dysplastic nevus syndrome, and once yearly examinations will be appropriate.21 The intensity of follow-up schedules should reflect the risk of recurrence. One study showed that hazard rates for stage I melanomas did not change substantially, and only annual follow-up visits were recommended.17 Because stage II patients showed a doubled risk of recurrence for the first 2 years, twice-yearly follow-up visits for the first 2 years and annual follow-up afterwards were recommended. Stage III patients showed an initial four to six times increased hazard rate compared with stage I patients, and examinations at 3month intervals for the first year were considered reasonable.17 Because the hazard for stage III patients then decreased quickly, subsequent follow-up every 4 months for the second year and every 6 months thereafter up to 5 years was recommended. A similar strategy was advised independently in a further review.26 We therefore recommend a minimum of two follow-up visits each year for stage I and four times yearly for stages II and III in the first 3 years (Table 2). A 5-year period for more intense follow-up examinations has been proposed by several authors and guidelines.26,27 The intensified surveillance period could also do with three examinations each year, because the difference between 3 and 4 months may be marginal. Some authors proposed a decreasing schedule, starting with examinations every 3 months and then going to examinations every 4 months. These proposals remain arbitrary to a certain degree. The frequency of follow-up visits should reflect the patient's risk of recurrence and should be planned according to the current stage of the disease.

Excision guidelines Table 2

313

Recommendations for the follow-up of melanoma patients (intervals in months)

Stage and tumor thickness

Physical examination

Lymph node sonography

Serum S100 protein levels

Years 1-5

Years 6-10

Years 1-5

Years 1-5

I, ≤ 1 mm I + II, N1 mm III d IV

6 3 3 Individual

6-12 6-12 6

None 6 3-6

None 3-6 3-6

a

Imaging studies Years 1-5 b None None c 6

a

S100 protein is the only parameter suited for detecting recurrences. Abdominal ultrasound imaging and chest radiograph, or computed tomography, magnetic resonance imaging, or positron-emission tomography. c Patients receiving adjuvant therapy should receive imaging studies every 6 to 12 months. d Stage III includes all forms of local and regional metastasis. The new American Joint Committee on Cancer stage IIC (N4-mm tumor thickness and ulceration) should be followed as stage III, because the prognosis is similar. b

Optimum duration of melanoma follow-up Concerning the frequency of follow-up services, most guidelines recommend a duration of 10 years or longer, some of them lifelong (Table 3).28-30,32,38,39 A few guidelines recommended follow-up for only 3 to 5 years after the primary melanoma diagnosis,34 and others recommend a 10year follow-up for thick melanomas.40 A lifelong follow-up was recommended by the national conference of the National Institutes of Health (Bethesda, MD) for stage Ib melanoma Table 3

and above.38 An analysis of hazard rates for recurrences still demonstrates increased rates in stages II and III cutaneous melanoma until the end of this period, where the rates of stage II and III also return to the level of stage I.17 These data may be interpreted in favor of a 10-year follow-up period for the detection of recurrences. Some have proposed shorter follow-up periods,34,37 whereas others have recommended lifelong follow-up examinations. Lifelong examinations are probably not necessary to detect recurrences after 10 years. Particularly in patients with

Follow-up recommendations of published work on recurrences, secondary melanoma, and current guidelines

First author

Country

Stage

Recommendation

1993

USA

Yearly follow-up for 15 years

Shumate,29 1995 Moloney,30 1996

USA USA

Johnson,31 1998 Dicker,32 1999

USA USA

I, b1.51-mm tumor thickness I, II I, b 0.76-mm tumor thickness All stages I

Kalady,33 2003

USA

Baughan,

28

Poo-Hwu,17 1999 USA

I, b1.0-mm tumor thickness Stages I to III

Roberts,34 2002

UK guidelines

All stages

Garbe,35,36 2006, 2003

German guidelines

All stages

Machet,37 2005

French guidelines

Stages I and II

Houghton,38 2006 USA, ACS guidelines

All stages

Reduction of follow-up thorough education of patients (not further specified) Reduction of follow-up to maximum of 5 years Lifelong follow-up and patient self-examination of skin 3 monthly (year 1 to 3); annually year 4 and 5; thereafter only with special risk factors Long-term follow-up (not further specified) Stage I: annually Stage II: 6-monthly for years 1 and 2; annually thereafter Stage III: 3-monthly for year 1; 4-monthly for year 2; 6-monthly for years 3 to 5; annually year 6 and after All patients should have surveillance due to the risk of late recurrence and/or multiple primaries 3-monthly for 3 years for all patients 6-monthly for year 4-5 for patients with melanoma N1.0 mm thick 10 years of follow-up Stage I: biannually years 1 to 5 Stage II: 3-monthly years 1 to 5; once or twice year 6 onwards Stage III: 3-monthly years 1 to 5; twice yearly thereafter Only clinical examinations 3 monthly: CM≥ 1.5-mm tumor thickness; 6 monthly: CM b1.5-mm tumor thickness for at least 3 years Ia: 3-12 monthly for 5 years; annually thereafter as clinically indicated Ib-III: 3-6 monthly for years 1 to 2; 3-12 monthly for years 3-6; thereafter annually

ACS, American Cancer Society; CM, cutaneous melanoma; UK, United Kingdom.

314 dysplastic nevus syndrome, however, further once-yearly examinations after 10 years are appropriate to detect secondary or multiple primary melanomas. To date, a lifelong follow-up for patients with melanoma is practiced in many melanoma units.26,27,41 Although melanoma can relapse after a long disease-free interval, the most cost-effective benefit might be gained by educating patients to conduct skin self-examinations, because education can be potentially maintained and reinforced lifelong. Analyses show the frequency of late (10 years after primary diagnosis and later) recurrences varies between 1% and 25%.42-46 This assessment is biased, however, because of the retrospective nature of these analyses, and frequencies might therefore be overestimated.42-45,47-49 The probability for recurrences is highest in the first 3 years after the primary diagnosis and declines rapidly thereafter. An intensified follow-up is, therefore, recommended in the first 3 to 5 years and can be reduced afterwards. Surveillance with a total duration of 10 years seems to be appropriate. For the detection of secondary melanomas, further lifelong examinations once a year are recommended.

Staging procedures in melanoma follow-up? The extent of staging procedures strongly depends on the stage of disease and the risk for recurrences. A physical examination and palpation of the regional lymph nodes and drainage basin seem to be sufficient for stage I patients; however, high-risk melanoma patients require the use of imaging techniques and serum analyses.

Conclusions Although there is an internationally accepted consensus derived from evidence-based trials concerning the safety margin, recommendations on surveillance strategies are still discussed controversially. To date, no true evidence is available to support any form of follow-up surveillance in localized melanoma. Follow-up guidelines have been developed in many European countries (such as Germany, the Netherlands, and Switzerland), the USA, and Australia, 35,38,40,50,51 with varying recommendations. An international consensus has, so far, not been reached.

References 1. Grin-Jorgensen CM, Rigel DS, Friedman RJ. The worldwide incidence of malignant melanoma. 2nd ed. Philadelphia: JB Lippincott; 1992. p. 27-39.

U. Leiter et al. 2. Lens MB, Dawes M. Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol 2004;150:179-85. 3. Handley WS. The pathology of melanotic growths in relation to their operative treatment. Lancet 1907;i:927-96. 4. Kaufmann R. Surgical management of primary melanoma. Clin Exp Dermatol 2000;25:476-81. 5. Veronesi U, Cascinelli N, Adamus J, et al. Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med 1988;318:1159-62. 6. Ringborg U, Andersson R, Eldh J, et al. Resection margins of 2 versus 5 cm for cutaneous malignant melanoma with a tumor thickness of 0.8 to 2.0 mm: randomized study by the Swedish Melanoma Study Group. Cancer 1996;77:1809-14. 7. Thomas JM, Newton-Bishop J, A'Hern R, et al. Excision margins in high-risk malignant melanoma. N Engl J Med 2004;350:757-66. 8. Dummer R, Panizzon R, Bloch PH, Burg G. Updated Swiss guidelines for the treatment and follow-up of cutaneous melanoma. Dermatology 2005;210:39-44. 9. Dummer R, Hauschild A, Jost L. Cutaneous malignant melanoma: ESMO clinical recommendations for diagnosis, treatment and followup. Ann Oncol 2008;19(Suppl 2):ii86-8. 10. Garbe C, Hauschild A, Volkenandt M, et al. Evidence and interdisciplinary consensus-based German guidelines: surgical treatment and radiotherapy of melanoma. Melanoma Res 2008;18:61-7. 11. Essner R, Lee JH, Wanek LA, Itakura H, Morton DL. Contemporary surgical treatment of advanced-stage melanoma. Arch Surg 2004;139: 961-6. 12. Francken AB, Bastiaannet E, Hoekstra HJ. Follow-up in patients with localised primary cutaneous melanoma. Lancet Oncol 2005;6: 608-21. 13. Kleeberg UR. Wishful thinking, unicentric empiricism and the everyday world of the medical melanomologist. Melanoma Res 1997;7(Suppl 2):S143-S149. 14. Essner R. Surgical treatment of malignant melanoma. Surg Clin North Am 2003;83:109-56. 15. Garbe C, Paul A, Kohler-Spath H, et al. Prospective evaluation of a follow-up schedule in cutaneous melanoma patients: recommendations for an effective follow-up strategy. J Clin Oncol 2003;21:520-9. 16. Mooney MM, Mettlin C, Michalek AM, Petrelli NJ, Kraybill WG. Lifelong screening of patients with intermediate-thickness cutaneous melanoma for asymptomatic pulmonary recurrences: a cost-effectiveness analysis. Cancer 1997;80:1052-64. 17. Poo-Hwu WJ, Ariyan S, Lamb L, et al. Follow-up recommendations for patients with American Joint Committee on Cancer Stages I-III malignant melanoma. Cancer 1999;86:2252-8. 18. Basseres N, Grob JJ, Richard MA, et al. Cost-effectiveness of surveillance of stage I melanoma. A retrospective appraisal based on a 10-year experience in a dermatology department in France. Dermatology 1995;191:199-203. 19. Hofmann U, Szedlak M, Rittgen W, Jung EG, Schadendorf D. Primary staging and follow-up in melanoma patients–monocenter evaluation of methods, costs and patient survival. Br J Cancer 2002;87:151-7. 20. Argenziano G, Mordente I, Ferrara G, Sgambato A, Annese P, Zalaudek I. Dermoscopic monitoring of melanocytic skin lesions: clinical outcome and patient compliance vary according to follow-up protocols. Br J Dermatol 2008;159:331-6. 21. Bauer J, Blum A, Strohhacker U, Garbe C. Surveillance of patients at high risk for cutaneous malignant melanoma using digital dermoscopy. Br J Dermatol 2005;152:87-92. 22. Haenssle HA, Krueger U, Vente C, et al. Results from an observational trial: digital epiluminescence microscopy follow-up of atypical nevi increases the sensitivity and the chance of success of conventional dermoscopy in detecting melanoma. J Invest Dermatol 2006;126:980-5. 23. Brobeil A, Rapaport D, Wells K, et al. Multiple primary melanomas: implications for screening and follow-up programs for melanoma. Ann Surg Oncol 1997;4:19-23.

Excision guidelines 24. Goggins WB, Tsao H. A population-based analysis of risk factors for a second primary cutaneous melanoma among melanoma survivors. Cancer 2003;97:639-43. 25. Kang S, Barnhill RL, Mihm Jr MC, Sober AJ. Multiple primary cutaneous melanomas. Cancer 1992;70:1911-6. 26. Ross MI. Staging evaluation and surveillance for melanoma patients in a fiscally restrictive medical environment. A commentary. Surg Clin North Am 1996;76:1423-32. 27. Tsao H, Cosimi AB, Sober AJ. Ultra-late recurrence (15 years or longer) of cutaneous melanoma. Cancer 1997;79:2361-70. 28. Baughan CA, Hall VL, Leppard BJ, Perkins PJ. Follow-up in stage I cutaneous malignant melanoma: an audit. Clin Oncol (R Coll Radiol) 1993;5:174-80. 29. Shumate CR, Urist MM, Maddox WA. Melanoma recurrence surveillance. Patient or physician based. Ann Surg 1995;221:566-9. 30. Moloney DM, Gordon DJ, Briggs JC, Rigby HS. Recurrence of thin melanoma: how effective is follow-up? Br J Plast Surg 1996;49:409-13. 31. Johnson TM, Hamilton T, Lowe L. Multiple primary melanomas. J Am Acad Dermatol 1998;39:422-7. 32. Dicker TJ, Kavanagh GM, Herd RM, et al. A rational approach to melanoma follow-up in patients with primary cutaneous melanoma. Scottish Melanoma Group. Br J Dermatol 1999;140:249-54. 33. Kalady MF, White RR, Johnson JL, Tyler DS, Seigler HF. Thin melanomas: predictive lethal characteristics from a 30-year clinical experience. Ann Surg 2003;238:528-35. 34. Roberts DL, Anstey AV, Barlow RJ, et al. U.K. guidelines for the management of cutaneous melanoma. Br J Dermatol 2002;146:7-17. 35. Garbe C, Hauschild A, Volkenandt M, et al. Brief guidelines: malignant melanoma of the skin. J Dtsch Dermatol Ges 2006;4:344-9. 36. Garbe C, Schadendorf D. Surveillance and follow-up examinations in cutaneous melanoma. Onkologie 2003;26:241-6. 37. Machet L, Nemeth-Normand F, Giraudeau B, et al. Is ultrasound lymph node examination superior to clinical examination in melanoma followup? A monocentre cohort study of 373 patients. Br J Dermatol 2005;152:66-70.

315 38. Houghton AN, Coit DG, Daud A, et al. Melanoma. J Natl Compr Canc Netw 2006;4:666-84. 39. Jonsson H, Nystrom L, Tornberg S, Lenner P. Service screening with mammography of women aged 50-69 years in Sweden: effects on mortality from breast cancer. J Med Screen 2001;8:152-60. 40. National Institutes of Health Consensus Development Conference Statement on Diagnosis and Treatment of Early Melanoma, January 2729, 1992. Am J Dermatopathol 1993;15:34-43. 41. Tsao H, Rogers GS, Sober AJ. An estimate of the annual direct cost of treating cutaneous melanoma. J Am Acad Dermatol 1998;38: 669-80. 42. Callaway MP, Briggs JC. The incidence of late recurrence (greater than 10 years); an analysis of 536 consecutive cases of cutaneous melanoma. Br J Plast Surg 1989;42:46-9. 43. Crowley NJ, Seigler HF. Late recurrence of malignant melanoma. Analysis of 168 patients. Ann Surg 1990;212:173-7. 44. Gutman M, Klausner JM, Inbar M, Rozin RR. Late recurrence of stage I malignant melanoma. J Surg Oncol 1989;42:96-8. 45. Leman JA, Mac Kie RM. Late (N 10 years) recurrence of melanoma: the Scottish experience. Br J Dermatol 2003;148:372-3. 46. Schmid-Wendtner MH, Baumert J, Schmidt M, et al. Late metastases of cutaneous melanoma: an analysis of 31 patients. J Am Acad Dermatol 2000;43:605-9. 47. Shaw HM, Beattie CW, McCarthy WH, Milton GW. Late relapse from cutaneous stage I malignant melanoma. Arch Surg 1985;120: 1155-9. 48. Briele HA, Beattie CW, Ronan SG, Chaudhuri PK, Das Gupta TK. Late recurrence of cutaneous melanoma. Arch Surg 1983;118:800-3. 49. Tahery DP, Moy RL. Lack of predictive factors in late recurrence of stage I melanoma. Int J Dermatol 1992;31:629-31. 50. Summary of the NIH consensus diagnosis and treatment of early melanoma. Pa Nurse 1992;47:9. 51. Consensus conference. Follow-up of patients surgically treated for stage I melanoma. Paris, France, 30 March 1995. Ann Dermatol Venereol 1995;122:250-391.