Introduction

Melanoma is a malignant tumor of melanocytes, cells that are predominantly found in the skin and produce the pigment of the skin. They may also arise from other sites to which neural crest cells migrate, such as rectum, vagina, oesphagus, nasopharynx, iris and oral cavity

Melanoma is a significant clinical problem as there is an increasing incidence, as well as an increasing mortality, despite our best efforts. It is also a serious problem for the patient as this means 1 death per 8.3 diagnoses [1:8]

Once Melanoma is Diagnosed

Once the diagnosis has been secured, and the quality of the pathological report is suitable, the preliminary management of the patient starts with a history and examination as well as a focused and extensive dermatological examination and a specific assessment of the melanoma related risk factors. The clinical stage of the patient will then determine the further workup and specific treatment of the patient.

History – Melanoma Specific Risk Factors

  • A patient who has had a melanoma previously is at risk of a second melanoma, or other non-melanoma skin cancer, this is the most important single risk factor, by 3 orders of magnitude (1500X risk).
  • A family history of melanoma also indicates a significantly increased risk (150 – 700X – depending on the relationship). This is the second most important risk factor.
  • The atypical mole syndrome (B-K Mole Syndrome, FAMM Syndrome) carries a 10% lifetime risk – this is the most important genetic factor.
  • Epidemiological studies show an association between melanoma and sun-exposure, in particular blistering sunburn in childhood and adolescence.
  • Certain sub-populations are at increased risk for melanoma – fair skin and hair colour other than black are risk factors (red is the most at 3.6X), but interestingly, eye colour has no significance.
  • Freckling on exposure to sunlight is associated with 1.9X risk and more than 20 nevi is associated with a 3.4X risk.
  • Immunocompromised patients such as chronic suppressive medication, HIV, Hodgekins etc are at increased risk due to poorer immune surveillance.
  • Impaired DNA repair mechanisms (such as Xeroderma Pigmentosa) place patients at risk.
  • A melanocortin-1 receptor mutation may confer an increased risk. It remains critical to remember that melanoma may occur in ANY ethnic group and in ANY site which contains melanocytes, prior sun exposure notwithstanding

Pathology Report – Cellular Classification

These are now considered descriptive terms and are of academic interest only as they have no prognostic or therapeutic significance.

  • Superficial spreading. (70%)
  • Nodular. (15%)
  • Lentigo maligna. (5%)
  • Acral lentiginous (palmar/plantar and subungual). (10%)
  • Miscellaneous unusual types: Mucosal lentiginous, Desmoplastic, Verrucous & Spindle cell

Pathology Report – Stage Information

The stage is determined on histologic examination by the vertical thickness of the lesion. It is measured in millimeters (to the nearest tenth) and is known as the Breslow’s depth.

The present (7th) AJCC classification is based on 3 clinical issues :

  1. The result of the primary tumour (The T)
  2. The result of the local nodes (The N)
  3. The result of systemic evaluation (The M)

1. Primary tumor (T)

  • TX: Primary tumor cannot be assessed (e.g., shave biopsy or regressed melanoma)
  • T0: No evidence of primary tumor
  • Tis: Melanoma in situ
  • T1        ≤1.0                 a: NO ulceration AND mitosis <1 / mm2

b: with ulceration OR mitoses ≥1/mm2.

  • T2        1.01–2.0          a: No ulceration.

b: with ulceration.

  • T3        2.01–4.0          a: No ulceration.

b: with ulceration.

  • T4        >4.0                 a: No ulceration.

b: with ulceration.

2. Regional lymph nodes (N)

  • NX: Regional lymph nodes cannot be assessed
  • N0: No regional lymph node metastasis
  • N1: 1 Node                 a: Micrometastasis.

b: Macrometastasis.

  • N2: 2–3 Nodes            a: Micrometastasis

b: Macrometastasis.

c: In transit metastases or satellites(s)

  • N3 : ≥4 Metastatic nodes, or matted node OR in transit met(s) / satellite(s) with metastatic node(s).

3. Distant Metastasis (M)

  • MX: Distant metastasis cannot be assessed
  • M0: No distant metastasis
  • M1: Distant metastasis
    • M1a: Metastasis to skin, subcutaneous tissues, or distant lymph nodes
    • M1b: Metastasis to lung
    • M1c: Metastasis to other visceral sites

 Putting it all together – Pathologic staging

Melanoma stage information according to AJCC 7th Edition

Prognosis

The 3 most important factors in the prognosis of melanoma are clearly evident from the above staging system.

  1. Presence of Metastatic disease
  2. Tumour thickness
  3. Presence of ulceration.

Despite these exceptionally important factors, a host of other less important factors may play a role in prognosis, such as age, gender, site and a host of cellular and genetic factors.

What is the survival rate for Melanoma ?

The following survival rates are based on nearly 60,000 patients who were part of the 2008 AJCC Melanoma Staging Database. These are observed survival rates. They include some people diagnosed with melanoma who may have later died from other causes, such as heart disease. Therefore, the percentage of people surviving the melanoma itself may be higher.

Stage IA: The 5-year survival rate is around 97%. The 10-year survival is around 95%.

Stage IB: The 5-year survival rate is around 92%. The 10-year survival is around 86%.

Stage IIA: The 5-year survival rate is around 81%. The 10-year survival is around 67%.

Stage IIB: The 5-year survival rate is around 70%. The 10-year survival is around 57%.

Stage IIC: The 5-year survival rate is around 53%. The 10-year survival is around 40%.

Stage IIIA: The 5-year survival rate is around 78%. The 10-year survival is around 68%.

Stage IIIB: The 5-year survival rate is around 59%. The 10-year survival is around 43%.

Stage IIIC: The 5-year survival rate is around 40%. The 10-year survival is around 24%.

Stage IV: The 5-year survival rate for stage IV melanoma is about 15% to 20%. The 10-year survival is about 10% to 15%.

Treatment Options Overview

Stage 0 Melanoma

Stage 0 melanoma (in situ) may be treated by excision with microscopically free margins. Most surgeons recommend margins of 0.5cm. No further work up is required, but continued screening for a second malignancy is critical. The lifetime risk of a second melanoma is in the order of 10-15%.

Stage I Melanoma (GOAL = CURE)

Surgery of the Primary Lesion : Stage I melanomas are treated with adequate radial excision margins.

  • For T1 lesions, 1cm margins appear adequate
  • T2 lesions should have radial margins of 2cm.
  • Excision depth should be limited to the subcutaneous tissue, and not include the deep fascia as this has shown no added benefit, and may possibly result in metastatic spread.

Lymph Node Surgery : Elective regional lymph node dissection is of no benefit for patients with stage I melanoma. However, lymphatic mapping and sentinel lymph node biopsy for patients who have high risk tumors may be beneficial

Further Workup: CT scans have a low detection rate. Even lower rates are found for chest x-rays, bone and liver scans and ultrasonography. Even PET scans have a low detection rate. Blood workup is similarly of almost no value

Stage II Melanoma (GOAL = CURE)

Surgery of the Primary Lesion : Stage II melanoma requires the surgical margins to be 2 cm. In melanomas >4mm thick, there was controversy about whether to extend the margins to 3cm. Recent literature (Surgical Clinics or North America, 2010) suggest the margins should be reduced to 2 cm even for thick lesions.

Lymph Node Surgery :

  • Lymphatic mapping (lymphoscintigraphy) and sentinel lymph node biopsy is specifically recommended to assess the presence of occult metastasis.
  • Therapeutic regional lymph node dissection for positive SNLB is done within 3 weeks.

Bio-Chemotherapy: A relapse-free survival advantage was shown for all patients who received high-dose interferon (including stage II patients) when compared with the observation, as was a statistically significant overall survival benefit. The greatest benefit was seen in the node-negative (stage IIB) subset. .

Further Workup :PET scans (CT/PET combination) have revolutionized the hunt for metastatic disease in T2 and T3 lesions and it is presently the investigation of choice. Further investigations (as above) are not warranted.

Stage III Melanoma (GOAL = DISEASE FREE TIME)

Surgery of the Primary Lesion: Stage III melanoma is surgically treated with wide local excision of the primary tumor with 1 cm or 2 cm margins, depending on tumor thickness and location, as above.

Lymph Node Surgery: In these patients with positive nodes, a surgical clearance of the involved basin is mandatory.

Bio-Chemotherapy: All stage III patients require adjuvant therapy. Multi-centre trials have presented conflicting reports regarding the overall survival benefits with high dose interferon therapy, but disease free survival is improved by its use. High-dose chemotherapy has not been shown to improve survival.

For patients with in-transit/satellite lesions (stage IIIC) of the extremities, isolated hyperthermic limb perfusion (ILP) with melphalan (L-PAM) with or without tumor necrosis factor-alfa (TNT-alfa) has resulted in high tumor response rates and palliative benefit. The addition of interferon-gamma has not been of any benefit.2 Exciting, novel strategies are currently undergoing trial: Intra-tumoral injections of replication-competent oncolytic viruses and the monoclonal therapy, ipilimumab.

Stage IV Melanoma and RECURRENT Melanoma (GOAL = PALLIATION)

Most often this is diagnosed by PET scans. Blood LDH levels may be used as a baseline marker to assess response rates and recurrence in patients with liver or GIT mets. Isolated metastases to the lung, gastrointestinal tract, bone, or occasionally the brain may be palliated by resection with occasional (very occasional) long-term survival. The primary tumour (if it can be found) and the local lymph nodes (if involved) are resected for palliative benefit only.

Radiation therapy may provide symptomatic relief for metastases to brain, spinal cord, bones, and viscera. Melanoma is a radio-resistant tumour and high dose-per-fraction therapy is required.

Chemotherapy: Advanced melanoma is refractory to most standard chemotherapy The response rate to dacarbazine (DTIC) is poor and usually short-lived, ranging from 3 to 6 months – overall survival is unchanged. Multi-drug combination regimens have not demonstrated any advantage over dacarbazine. The much touted drug, temozolomide has not been shown to be better than dacarbazine and was thus not approved by the FDA.

Immunotherapy: Response to IL-2 regimens is in the 10% to 20% range. Approximately 5% of patients may obtain a complete remission and be long-term survivors. Attempts to improve on this therapy have included the addition of lymphokine-activated killer cells, but only Level III data exist for this strategy

Monoclonal Antibodies: Among patients receiving ipilimumab, a survival benefit was shown at 1 year for stage IV. Side effects and treatment mortality remain high however.

Cellular inhibitors : BRAF Inhibitors (Vemurafenib) has shown some promise but has variable response rates, form modest to exceptionally good. Other novel and very exciting therapies are still in their infancy, although they show promise for the future. Currently several large trials are underway investigating : Multikinase inhibitor sorafenib (Nexavar), Kit Inhibitors, MEK, AKT and P13 Kinase Inhibitors.