Melanoma is a malignant tumour of melanocytes, which are the cells that make the pigment melanin and are derived from the neural crest. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate. Melanoma occurs predominantly in adults, and more than 50% of the cases arise in apparently normal areas of the skin.
Early signs in a nevus that would suggest malignant change include:
- Darker or variable discoloration
- An increase in size
- The development of satellites
- Ulceration or bleeding are late signs.
Melanoma in women occurs more commonly on the extremities and in men on the trunk or head and neck, but it can arise from any site on the skin surface.
A biopsy, preferably by local excision, should be performed for any suspicious lesions, and the specimens should be examined by an experienced pathologist to allow for microstaging. Suspicious lesions should never be shaved off or cauterized.
Studies show that distinguishing between benign pigmented lesions and early melanomas can be difficult, and even experienced dermatopathologists can have differing opinions. To reduce the chance of this happening a second opinion is sometimes necessary.
Prognosis is affected by clinical and histological factors and by anatomic location of the lesion. Thickness and/or level of invasion of the melanoma, number of actively dividing cells, presence of tumour infiltrating lymphocytes, number of regional lymph nodes involved, and ulceration or bleeding at the primary site affect the prognosis.
Patients who are younger, female, and who have melanomas on the extremities generally have a better prognosis.
Clinical staging is based on whether the tumour has spread to regional lymph nodes or distant sites. For disease clinically confined to the primary site, the greater the thickness and depth of local invasion of the melanoma, the higher the chance of lymph node or systemic metastases and the worse the prognosis. Melanoma can spread by local extension (through lymphatics) and/or by haematogenous route (blood stream) to distant sites. Any organ may be involved by metastases, but lungs and liver are common sites. The risk of relapse decreases substantially over time, though late relapses are not uncommon.
Following is a list of clinicopathologic cellular subtypes of malignant melanoma. These should be considered descriptive terms of historic interest only as they do not have independent prognostic or therapeutic significance.
- Superficial spreading.
- Lentigo maligna.
- Acral lentiginous (palmar/plantar and subungual).
- Miscellaneous unusual types:
- Mucosal lentiginous (oral and genital).
Agreement between pathologists in the histologic diagnosis of melanomas and benign pigmented lesions has been studied and found to be considerably variable. One such study found that there was discordance on the diagnosis of melanoma versus benign lesions in 37 of 140 cases examined by a panel of experienced dermatopathologists. For the histologic classification of cutaneous melanoma, the highest concordance was attained for Breslow thickness and presence of ulceration, while the agreement was poor for other histologic features such as Clark level of invasion, presence of regression, and lymphocytic infiltration. In another study, 38% of cases examined by a panel of expert pathologists had two or more discordant interpretations. These studies convincingly show that distinguishing between benign pigmented lesions and early melanoma can be difficult, and even experienced dermatopathologists can have differing opinions. To reduce the possibility of misdiagnosis for an individual patient, a second review by an independent qualified pathologist should be considered.
The microstage of malignant melanoma is determined on histologic examination by the vertical thickness of the lesion in millimeters (Breslow classification) and/or the anatomic level of local invasion (Clark classification). The Breslow thickness is more reproducible and more accurately predicts subsequent behavior of malignant melanoma in lesions larger than 1.5 mm in thickness and should always be reported. Accurate microstaging of the primary tumor requires careful histologic evaluation of the entire specimen by an experienced pathologist. Estimates of prognosis should be modified by sex and anatomic site as well as by clinical and histologic evaluation.
Clark Classification (Level of Invasion)
- Level I: Lesions involving only the epidermis (in situ melanoma); not an invasive lesion.
- Level II: Invasion of the papillary dermis but does not reach the papillary-reticular dermal interface.
- Level III: Invasion fills and expands the papillary dermis but does not penetrate the reticular dermis.
- Level IV: Invasion into the reticular dermis but not into the subcutaneous tissue.
- Level V: Invasion through the reticular dermis into the subcutaneous tissue.
Treatment Option Overview
Melanomas that have not spread beyond the site at which they developed are highly curable. Most of these are thin lesions that have not invaded beyond the papillary dermis (Clark level I–II; Breslow thickness ≤1 mm). The treatment of localized melanoma is surgical excision with margins proportional to the microstage of the primary lesion; for most lesions 2 mm or less in thickness, this means 1 cm radial re-excision margins.
Melanomas with a Breslow thickness of 2 mm or more are still curable in a significant proportion of patients, but the risk of lymph node and/or systemic metastasis increases with increasing thickness of the primary lesion. The local treatment for these melanomas is surgical excision with margins based on Breslow thickness and anatomic location. For most melanomas more than 2 mm to 4 mm in thickness, this means 2 cm to 3 cm radial excision margins. These patients should also be considered for sentinel lymph node biopsy followed by complete lymph node dissection if the sentinel node(s) are microscopically or macroscopically positive. Sentinel node biopsy should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping. Patients with melanomas that have a Breslow thickness more than 4 mm should be considered for adjuvant therapy with high-dose interferon. High-dose interferon regimens have substantial side effects, and patients should be monitored closely. Adjuvant therapy with lower doses of interferon have not been consistently shown to have an impact on either relapse-free survival or overall survival. Adjuvant chemotherapy does not improve survival. A multicenter phase III randomized trial (EORTC-18832 ) of patients with high-risk primary limb melanoma did not show a benefit from isolated limb perfusion with melphalan in regard to disease-free survival or overall survival when compared to surgery alone.
Some melanomas that have spread to regional lymph nodes may be curable with wide local excision of the primary tumour and removal of the involved regional lymph nodes. Melanoma that has spread to distant sites is rarely curable with standard therapy, though high-dose interleukin-2 (IL-2) has been reported to produce durable responses in a small number of patients.
In patients with systemic metastasis confined to one anatomic site, long-term survival is occasionally achieved by complete resection of all metastatic disease. All patients with distant metastasis are appropriately considered candidates for clinical trials exploring new forms of treatment, including combination chemotherapy, biological response modifiers (such as specific monoclonal antibodies, interferons, IL-2, or tumor necrosis factor-alpha), vaccine immunotherapy, or biochemotherapy (chemoimmunotherapy).
Malignant melanoma has been reported to spontaneously regress; however, the incidence of spontaneous complete regressions is less than 1%.
Recurrent melanoma is resistant to most standard systemic therapy, and all newly diagnosed patients should be considered candidates for clinical trials. Deciding on further treatment depends on many factors, including prior treatment and site of recurrence, as well as individual patient considerations. Surgery is the most efficacious therapy for isolated recurrence in sites where it can be accomplished (including lymph node, skin, brain, lung, liver, and gastrointestinal sites).Although advanced melanoma is relatively resistant to therapy, several biologic response modifiers and cytotoxic agents have been reported to produce objective responses.
ROLE OF CHEMOTHERAPY
The objective response rate to dacarbazine (DTIC) and the nitrosoureas, carmustine (BCNU) and lomustine, is approximately 10% to 20%. Responses are usually short-lived, ranging from 3 to 6 months, though long-term remissions can occur in a limited number of patients who attain a complete response. Other agents with modest single-agent activity include vinca alkaloids, platinum compounds, and taxanes.
The two biologic therapies that appear most active against melanoma are interferon-alpha and interleukin-2 (IL-2). Response rates for interferon range from 8% to 22% and long-term administration on a daily or a three-times-per-week basis appears superior to once per week or more intermittent schedules. Response to IL-2 regimens is similar and is in the 10% to 20% range. Attempts to improve on this with the addition of lymphokine-activated killer cells (autologous lymphocytes activated by IL-2 ex vivo) and by tumour-infiltrating lymphocytes (lymphocytes derived from tumour isolates cultured in the presence of IL-2) have not improved response rates or durable remissions sufficiently to merit the expense and complexity of these therapies. Phase II studies testing combinations of interferon and IL-2 have demonstrated high response rates, but a phase III comparison of interferon and IL-2 compared with IL-2 alone in 85 patients did not show any benefit for the combination.
For patients with recurrent melanoma presenting in the extremities as in-transit or satellite metastases, surgical resection remains standard treatment for limited-volume disease. For multiple in-transit and/or satellite lesions, hyperthermic isolated limb perfusion (ILP) with melphalan has been associated with overall tumor response rates of approximately 80% to 90%, with complete response rates ranging from 7% to 82%.
Role of Radiotherapy
Although melanoma is a relatively radiation-resistant tumour, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that patients with multiple brain metastases, bone metastases, and spinal cord compression may achieve symptom relief and some shrinkage of the tumor with radiation therapy.
Summary of Treatment Options for Recurrent Melanomas
- Resection of isolated single or localized metastases from skin, visceral, or brain sites in selected patients is sometimes associated with prolonged survival.
- Hyperthermic isolated limb perfusion for in-transit and/or satellite extremity recurrences. Isolated limb infusion is being studied as a minimally invasive regional chemotherapy technique for extremity recurrences.
- Palliative radiation therapy for bone, spinal cord, or brain metastases.
- Palliative biologic therapy and/or chemotherapy in phase I and II clinical trials.
- Palliative treatment with interleukin-2 or interferon can occasionally result in prolonged survival.
www.cancer.gov (National Cancer Institute, USA website)
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