Cutaneous Melanoma

Author Credentials 

Original Author:
George H. Yoo, MD
Associate Professor / Vice Chair
Department of Otolaryngology-Head and Neck Surgery
Wayne State University
5E University Health Center
540 East Canfield Avenue
Detroit, MI 48201

Updated by:
Arnaud F. Bewley, MD
Assistant Professor
Department of Otolaryngology
University of California – Davis
2521 Stockton Blvd. Suite 7200
Sacramento, CA 95819

Module Summary

In general, melanoma is treated by primary surgical excision. The melanoma intergroup study did not demonstrate a benefit of elective node dissection. Adjuvant IFN alpha-2b has a role in high-risk melanoma. Although sentinel node biopsy is widely used, controversy exists on its effectiveness in head and neck melanoma. The management of patients with metastatic melanoma has changed significantly with the evolving use of targeted and immunotherapy.

Module Learning Objectives 
  1. Review the basic embryology, anatomy, pathogenesis, immunology, and incidence of melanoma.
  2. Clinically differentiate melanoma from nevus.
  3. Determine appropriate resection margin goals based on tumor characteristics.
  4. Accurately performing staging and understand its implications.
  5. List the indications for and type of elective neck dissection and parotidectomy.
  6. Describe the role and controversies of sentinel lymph node biopsy.
  7. Explain the role of adjuvant interferon alpha-2b (IFN alpha-2b) and radiation therapy.
  8. Describe the evolving role of targeted and immunotherapy in the treatment of metastatic melanoma.

Embryology

Learning Objectives 

1.    Describe which progenitor cells melanomas are derived from.

References 

1.    Wolf GT, Sullivan MJ. Management of head and neck melanoma. In: Cummings CW, Fredrickson JM, et al., editors. Otolaryngology: head and neck surgery. 2nd ed. St. Louis: Mosby-Year Book; 1993:419-41.

Anatomy

Learning Objectives 
  1. List the anatomic layers of the skin.
  2. Understand the high-risk sub-units of the face.
  3. Describe the cutaneous lymphatic drainage of the head and neck.
References 

1.    Wolf GT, Sullivan MJ. Management of head and neck melanoma. In: Cummings CW, Fredrickson JM, et al., editors. Otolaryngology: head and neck surgery. 2nd ed. St. Louis: Mosby-Year Book; 1993:419-41.

Pathogenesis

Learning Objectives 
  1. Identify genetic mutations and pathways that have been implicated in melanoma.
  2. Understand the role of immune tumor regulation in melanoma.
  3. Describe the role of immunotherapy in the treatment of metastatic melanoma.
  4. Describe the role of targeted therapy in the treatment of metastatic melanoma.
References 
  1. Rosenberg SA: Progress in human tumour immunology and immunotherapy. Nature. 2001;411:380-4.
  2. Smith C, Cerundolo V: Immunotherapy of melanoma. Immunology. 2001;104:1-7.

Basic Science

Learning Objectives 

1.    Understand basic and applied immunology along with immunotherapy-based clinical trials for melanoma.

References 

1.    Parmiani G, Castelli C, Santinami M, Rivoltini L: Melanoma immunology: past, present and future. Curr Opin Oncol. 2007;19:121-7.

Incidence

Learning Objectives 
  1. Describe current incidence trends for melanoma.
  2. Understand the association of the following factors with the development of melanoma.
    1. Ultraviolet light exposure (UV-B)
    2. Sunburns in childhood
    3. Fair skin (blue-green eyes)
    4. Immunosuppression
    5. Large congenital nevi (>20 cm)
    6. Sporadic or inherited genetic disposition
    7. Previous melanomas
  3. Understand differences in clinical behavior between head /neck and trunk / extremity melanoma.

Genetics

Learning Objectives 
  1. Understand the genetic basis for differences in the following types of melanoma:
    1. Spontaneous melanoma
    2. Familial melanoma syndrome
    3. Dysplastic nevi syndrome
    4. Xeroderma pigmentosum
References 
  1. Greene MH: The genetics of hereditary melanoma and nevi. 1998 update. Cancer. 1999;86:2464-77.
  2. Autier P, Dore JF. Influence of sun exposures during childhood and during adulthood on melanoma risk. EPIMEL and EORTC Melanoma Cooperative Group. European Organization for Research and Treatment of Cancer. Int J Cancer. 1998;77(4):533-7.
  3. Greenlee RT, Hill-Harmon MB, Murray T, Thun M: Cancer statistics, 2001. CA Cancer J Clin. 2001;51:15-36.

Patient Evaluation

Learning Objectives 
  1. List clinical features that are suspicious for melanoma including the following:
    1. ABCDs of melanoma:
      1. Asymmetric (irregularly shaped)
      2. Border irregularity
      3. Color variation (color changes within the lesion)
      4. Diameter (>6 mm)
References 

1.    Carli P, de Giorgi V, Palli D, Giannotti V, Giannotti B: Preoperative assessment of melanoma thickness by ABCD score of dermatoscopy. J Am Acad Dermatol. 2000;43:459-66.

Pathology

Learning Objectives 
  1. List the different types of melanoma.
    1. Describe the clinical and pathologic features that are characteristic of the following types of melanoma:
      1. Superficial spreading
      2. Nodular          
      3. Lentigo maligna
      4. Acral lentiginous
  2. Understand the association of melanoma tumor thickness with behavior.
    1. List Clark’s levels and the how they are defined
    2. List Breslow’s levels and how they are defined.
  3. Describe which pathologic features are associated with poor prognosis and increased metastatic potential.
  4. List several Immunohistochemical markers for melanoma.
References 
  1. Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970;172(5): 902-8.
  2. Friedman RJ, Heilman ER: The pathology of malignant melanoma. Dermatol Clin. 2002;20:659-76.

Medical Therapies

Learning Objectives 
  1. List the indications for the use of interferon alpha-2b in the adjuvant setting. 
    1. Describe the adverse effects of interferon therapy.
    2. Describe the adverse effects of radiation therapy.
  2. Summarize the evolving role of BRAF and MEK inhibition for metastatic melanoma.
    1. Describe the survival benefits that have been demonstrated with BRAG and MEK inhibition.    
  3. Understand the role of PD-1 inhibition in the treatment of metastatic melanoma.
References 
  1. Parmiani G, Castelli C, Santinami M, Rivoltini L: Melanoma immunology: past, present and future. Curr Opin Oncol. 2007;19:121-7.
  2. Flaherty LE: Rationale for intergroup trial E-3695 comparing concurrent biochemotherapy with cisplatin, vinblastine, and DTIC alone in patients with metastatic melanoma. Cancer J Sci Am 2000;6 Suppl 1:S15-20.
  3. O'Day SJ, Kim CJ, Reintgen DS: Metastatic melanoma: chemotherapy to biochemotherapy. Cancer Control. 2002;9:31-8.
  4. Flaherty et al. Combined BRAF and MEK inhibition in melanoma  BRAF V600 mutations. NEJM. 2012;367(18):1694-703.
  5. Wolchok JD et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. NEJM. 2017;377(14):1345-1356.

Surgical Therapies

Learning Objectives 
  1. Understand that primary surgical resection is the primary mode of therapy.
    1. Describe the surgical principles of wide local excision
      1. List margin goals based on depth of invasion.
  2. Describe the appropriate use of sentinel lymph node biopsy in treating melanoma.
    1. Understand the appropriate indications for sentinel lymph node biopsy
      1. Summarize the survival benefits associated with sentinel lymph node biopsy
        1. Understand why there is some controversy over the use of sentinel node biopsy for melanomas in the head and neck.
    2. List the surgical steps of a sentinel lymph node biopsy
  3. Understand the role of completion neck dissection and parotidectomy in patients with positive a sentinel lymph node.
    1. Explain the controversies surround the oncologic of completion lymphadenectomy
    2. Describe the levels of the neck that should be addressed based on the location of the primary.
  4. Describe the management of patients with nodal metastasis
    1. Understand the principles of therapeutic lymphadenectomy for melanoma
    2. List the indications for adjuvant radiation therapy or interferon therapy.
  5. Describe reconstruction options after primary tumor resection.
References 

Margin Delineation

  1. Balch CM, Soong SJ, Smith T, Ross MI, Urist MM, Karakousis CP, et al.: Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol. 2001;8:101-8.
  2. Hayes AJ, Maynard L, Coombes G, Newton-Bishop J, Timmons M, Cook M, Theaker J, Bliss JM, Thomas JM; UK Melanoma Study Group. Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up of survival in a randomized trial. Lancet Oncol. 2016 Feb;17(2):184-92.
  3. Ringborg U, Andersson R, Eldh J, Glaumann B, Hafstrom L, Jacobsson S, 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.
  4. Urist MM, Balch CM, Soong SJ, Milton GW, Shaw HM, McGovern VJ, et al.: Head and neck melanoma in 534 clinical stage I patients. A prognostic factors analysis and results of surgical treatment. Ann Surg. 1984;200:769-75.
  5. Veronesi U, Cascinelli N, Adamus J, Balch C, Bandiera D, Barchuk A, 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.

Sentinel Lymph Node Biopsy (SNL)

  1. Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, Foshag LJ, Cochran AJ. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127(4): 392-9.
  2. Alex JC, Krag DN, Harlow SP, Meijer S, Loggie BW, Kuhn J, et al.: Localization of regional lymph nodes in melanomas of the head and neck. Arch Otolaryngol Head Neck Surg. 1998;124:135-40.
  3. Eicher SA, Clayman GL, Myers JN, Gillenwater AM: A prospective study of intraoperative lymphatic mapping for head and neck cutaneous melanoma. Arch Otolaryngol Head Neck Surg. 2002;128:241-6.
  4. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, et al.: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355:1307-17.
  5. Erman AB, Collar RM, Griffith KA, Lowe L, Sabel MS, Bichakjian CK, Wong SL, McLean SA, Rees RS, Johnson TM, Bradford CR. Sentinel lymph node biopsy is accurate and prognostic in head and neck melanoma.  Cancer. 2012 Feb 15;118(4):1040-7.
  6. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Nieweg OE, Roses DF, Hoekstra HJ, Karakousis CP, Puleo CA, Coventry BJ, Kashani-Sabet M, Smither BM, Paul E, Kraybill WG, McKinnon JG, Wang HJ, ELashoff R, Faries MB, MSLT Group. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609.
  7. Faries, M. B., et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. New England Journal of Medicine. 2017; 376(23): 2211-2222.

Adjuvant Therapy

  1. O’Brien CJ, Petersen-Schaefer K, Stevens GN, Bass PC, Tew P, Gebski VJ, Thompson JF, McCarthy WH. Adjuvant radiotherapy following neck dissection and parotidectomy for metastatic malignant melanoma. Head Neck. 1997;19:589-594.
  2. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14:7-17.
  3. Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS, et al.: High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol. 2001;19:2370-8.
  4. Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, et al.: High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000;18:2444-58.

Neck Dissection / Parotidectomy

  1. Veronesi U, Adamus J, Bandiera DC, Brennhovd IO, Caceres E, Cascinelli N, et al.: Inefficacy of immediate node dissection in stage 1 melanoma of the limbs. N Engl J Med. 1977;297:627-30
  2. Balch CM, Soong S, Ross MI, Urist MM, Karakousis CP, Temple WJ, et al.: Elective neck dissection: long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol. 2000;7:87-9
  3. Balch CM, Soong SJ, Bartolucci AA, Urist MM, Karakousis CP, Smith TJ, Temple WJ, et al.: Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg. 1996;224:255-63
  4. Caldwell CB, Spiro RH: The role of parotidectomy in the treatment of cutaneous head and neck melanoma. Am J Surg. 1988;156:318-22.
  5. O'Brien CJ, Petersen-Schafer K, Papadopoulos T, Malka V: Evaluation of 107 therapeutic and elective parotidectomies for cutaneous melanoma. Am J Surg. 1994;168:400-3.
  6. Vaglini M, Belli F, Santinami M, Cascinelli N: The role of parotidectomy in the treatment of nodal metastases from cutaneous melanoma of the head and neck. Eur J Surg Oncol. 1990;16:28-32.

Staging

Learning Objectives 
  1. Understand the staging system for melanoma.
    1. List the T-stage criteria for melanoma
    2. List the N-stage criteria for melanoma
    3. List the M-stage criteria for melanoma

Case Studies

T2N0M0 melanoma: A healthy 60-year-old male comes in with a left temporal pigmented lesion that was 3 x 3 mm. Excisional biopsy shows a 2.1-mm-deep melanoma with an ulcer. Physical examination reveals a scar in the left temporal face area and no palpable lymph nodes in the parotid gland or in the neck. Patient underwent a wide local excision with a 2-cm resection margin and a sentinel node biopsy. The sentinel node had melanoma cells present. How would you manage this patient in the adjuvant setting?

Review

Review Questions 

A healthy 60-year-old male comes in with a left temporal pigmented lesion that was 3 x 3 mm. Excisional biopsy shows a 2.1 mm deep melanoma with an ulcer.

  1. What laboratory and radiological tests would you order?
  2. How large should your margins be?
  3. Is there a benefit in doing elective node dissection for intermediate melanoma?
  4. If you perform a sentinel node biopsy, what percentage of patients will have a positive node if they are stage N0?
  5. What percentage of patients will have a sentinel node biopsy that was a false negative (defined as a negative sentinel node biopsy intraoperatively and a positive sentinel node based on permanent sections)?
  6. What is the definition of high risk?
  7. If the sentinel lymph node is positive, what would you counsel then regarding the benefit of a completion lymphadenectomy.
  8. Should the patient developed distant metastatic disease, what are they’re treatment options.
Resources 

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