During the routine physical examination of a 30-year-old, fair-complexioned white man, you discover a 1.5-cm pigmented skin lesion on the posterior aspect of his left shoulder. This lesion is nonindurated, has ill-defined borders, and is without surrounding erythema. Examination of the patient’s left axilla and neck reveals no identifiable abnormalities. No other pigmented skin lesions are observed during your thorough physical examination. According to the patient’s wife, this skin lesion has been present for the past several months, and she believes it has increased in size and become darker during this time. The patient is otherwise healthy.
What is your next step?
What is the most likely diagnosis?
What is the best treatment for this problem?
ANSWERS TO CASE 4: Malignant Melanoma
Summary: A 30-year-old man has a suspicious pigmented skin lesion on his left shoulder.
• Next step: Perform an excisional biopsy.
• Most likely diagnosis: Malignant melanoma.
• Best treatment for this problem: If this proves to be melanoma, wide local excision with an appropriate clear margin is the best initial treatment. Additionally, evaluation and excision of the regional lymph nodes may be appropriate depending on the depth of invasion of the tumor.
1. Learn to recognize the clinical presentation of malignant melanomas.
2. Learn the principles involved in performing biopsies of suspected melanomas.
3. Learn about the treatment and prognosis associated with melanomas.
Melanoma should be considered whenever a patient presents with a pigmented skin lesion, and lesions should be assessed with the following ABCDE approach. A: asymmetry; B: border irregularity; C: color change; D: diameter increase; E: enlargement or elevation.
All suspicious lesions should undergo a diagnostic biopsy and be assessed for depth of tumor invasion. A simple excision can be used to perform a biopsy on small lesions on the extremities. Lesions that are large or involve cosmetically important areas require an incisional biopsy. During the initial biopsy, no attempts are made to achieve a wide margin. Once the melanoma is confirmed and microstaged via biopsy, the patient will require a thorough examination for locoregional metastases and distant metastasis before treatment of the primary melanoma.
APPROACH TO: Pigmented Skin Lesions
MALIGNANT MELANOMA: Cancer of the pigmented cells of the skin.
MALIGNANT MELANOMA STAGING: Surgical staging procedure that depends on the depth of invasion (thickness), ulceration, and lymph node status.
The incidence of cutaneous melanoma is increasing at an alarming rate. In the year 2000, there were 60,000 new cases and 7700 deaths. Melanoma accounts for 4% of all newly diagnosed cancers in the United States and for 1% of all cancer deaths. It is responsible for six out of seven deaths caused by skin cancer. Melanoma is now the fifth most common cancer in men and the seventh most common cancer in women in the United States. The site of occurrence is evenly distributed among the head and neck, trunk, and upper and lower extremities. Risk factors can be divided into environmental, genetic, and other (Table 4–1), with an associated increase in the overall relative risk.
Table 4–1 • RISK FACTORS FOR MELANOMA
Melanocytes, dendritic cells found at the dermal/epidermal junction, are found in the skin, choroids of the eye, mucosa of the respiratory and gastrointestinal tracts, lymph node capsules, and substantia nigra in the brain.
The four types of melanoma are (1) superficial spreading, (2) nodular sclerosis, (3) lentigo maligna, and (4) acral lentiginous. By far the most common is superficial spreading, which accounts for 70% of all cases. It has a slight female predominance and typically has a prolonged radial growth phase (1-10 years) and a late vertical growth phase. In comparison to that for the other types of melanoma, the prognosis is favorable. Nodular sclerosis is the second most common form, accounting for 15% to 30% of all cases. It has no radial growth phase but has an aggressive vertical growth phase that spreads quickly, partially explaining its poorer prognosis. Lentigo maligna occurs in approximately 4% to 10% of patients and has a relatively long radial growth phase (5-15 years) and a good prognosis. Acral lentiginous melanoma represents 35% to 60% of cases occurring in African Americans, Asians, and Hispanics and appears primarily on the palms and soles of the hands and feet and in the nail beds. Similar to nodular sclerosis, it has a very aggressive vertical growth phase and is associated with a poor prognosis.
The incidence of melanoma is directly related to sun exposure. To reduce sun damage, patients should be advised to avoid exposure during the hours of 10 AM to 4 PM, seek shade at all times, and apply sunscreen liberally to protect against ultraviolet (UV) radiation, primarily ultraviolet B (UVB). Other measures include the use of titanium dioxide or zinc oxide for ultraviolet A (UVA) protection, a wide-brimmed hat, sunglasses, darker clothes, and the avoidance of tanning booths and sunlamps.
The treatment and prognosis are determined by the microstage and the pathologic stage of the tumor. The American Joint Committee on Cancer (AJCC) revised staging system for melanoma from 2002, introduced some important changes, and included the following: (1) Thickness and ulceration continue to be used for the T classification; however, the level of invasion is no longer used except for T1 lesions. (2) The number of metastatic lesions (rather than the largest dimension) is now used for the N classification as well as whether the nodes are microscopic versus macroscopic. (3) The site of distant metastases and the serum lactate dehydrogenase levels are used for the M classification. (4) All patients with stage I, II, or III disease with an associated primary lesion that is ulcerated should be upstaged. (5) Satellite and in-transit metastases are all combined under stage III disease. (6) The information gained from a sentinel lymph node (SLN) biopsy for staging is used in making clinical management decisions. Table 4–2lists the 2009 melanoma TNM (tumor-node-metastasis) classification and AJCC stage grouping.
Table 4–2 • 2009 AJCC CANCER STAGING CLASSIFICATIONS FOR MELANOMA
Two methods of microstaging for melanomas have been described by Clark and Breslow. The Clark method is based on the level of invasion of the dermal layers (ie, intraepithelial, into or filling the papillary dermis, into the reticular dermis). The Breslow method of microstaging level is based on the depth of invasion, which is the vertical height of the melanoma from the granular layer to the area of deepest penetration. Most studies have shown that in comparison to the Clark method, Breslow depths of invasion are more accurate prognostic indicators; the overall 5-year survival correlates with tumor thickness. The 5-year survival rate for stage I melanoma with a thickness of less than 0.75 mm is more than 96%.
The surgical treatment of melanoma begins with proper management of the primary lesion. Table 4–3 summarizes a treatment plan. Because wide local excision is necessary for treatment of the primary tumor, reexcision of the previous biopsy scar is generally needed. Therefore, orientation of the initial biopsy is extremely important in avoiding unnecessary tissue loss and morbidity. In general, biopsy incisions on the extremities should be oriented longitudinally.
Table 4–3 • SUGGESTED SURGICAL MARGINS
When palpable adenopathy is present, complete lymphadenectomy of the involved lymph node basin should be performed. However, an attempt should be made to obtain a tissue diagnosis (either with fine-needle aspiration or excisional biopsy) before this procedure. Patients with intermediate-depth melanoma (0.76-4 mm) seem to have a longer survival after prophylactic lymph node dissection, suggesting that a subset of patients without clinically evident lymph node involvement may also benefit from regional lymphadenectomy. Because of the morbidity associated with lymphadenectomy, prophylactic dissection is not done routinely, but instead the lymph node basins are generally assessed by SLN biopsy. The SLN is the first node in the lymphatic channel through which the primary melanoma drains and can be identified with greater than 90% accuracy by using the combined technique of vital blue dye and radio lymphoscintigraphy. This approach offers the advantages of identifying patients with regional nodal metastases who may potentially benefit from therapeutic lymph node dissection and avoids exposing patients without regional lymph node metastases to the morbidity associated with a lymphadenectomy. Additionally, the histologic analysis results from an SLN biopsy can be used to stage the disease process more accurately.
All patients with confirmed lymph node metastases should undergo a thorough workup to exclude or identify extranodal spread. Surgery is the primary therapy for patients with nodal involvement, and adjuvant therapy provides minimal benefits for stages I and II disease and only limited benefits for stage III disease. Currently, interferon-2A (Intron-A) is the treatment offered for stage III disease and provides marginal improvements in overall and disease-free survival. However, because of side effects, Intron-A therapy is generally poorly tolerated.
The prognosis for patients with stage IV disease remains dismal, with a median survival of 6 to 9 months. Again, it is essential that a thorough workup be performed to develop a therapeutic plan for all sites of disease involvement. Therapeutic options for patients with stage IV disease are limited. The most promising treatment, now approved by the Food and Drug Administration (FDA) for stage IV melanoma patients, is high-dose interleukin-2, which has a known complete, durable response rate of 9% and a partial response rate of 8%. Molecular therapies targeting the inhibition of BRAF (one of the serine/threonine kinases, when mutated, causes activation of the MAP kinase pathway) have been introduced for the treatment of metastatic melanoma, and early results appear to show promise with some durable clinical responses.
4.1 A 50-year-old man is noted to have a growing pigmented lesion of the right forearm. On biopsy, it is noted to be malignant melanoma. Which of the following is the most likely type of melanoma?
A. Superficial spreading
B. Nodular sclerosis
C. Acral lentiginous
D. Lentigo maligna
4.2 Which of the following is the most accurate predictor of clinical prognosis during microstaging of a melanoma?
A. Breslow depth of invasion
B. Clark level of invasion
C. T-cell infiltration
D. Diameter of the primary tumor
E. Patient age
4.3 Based on the current consensus, which of the following is the most appropriate surgical margin for a 2.1-mm-deep melanoma?
A. 0.5 cm
B. 1 cm
C. 2 cm
D. 4 cm
E. 5 cm
4.4 A 30-year-old man had a melanoma biopsied from his left forearm. The initial pathology finding revealed this lesion with a maximal depth of 1.5 mm and microscopically uninvolved margins. Which of these is the most appropriate treatment?
A. Thorough skin examination, wide local excision with 2-cm margin, and interferon therapy
B. Thorough skin examination, wide local excision with 2-cm margin, and PET scan
C. Thorough skin examination, wide local excision with 1-cm margin, PET scan, and interferon therapy
D. Thorough skin examination, wide local excision with 4-cm margin, lymphoscintigraphy, and SLN biopsy
E. Thorough skin examination, wide local excision with 2-cm margin, lymphoscintigraphy, and SLN biopsy
4.5 Which of the following is the most appropriate strategy for a 33-year-old man with a 1.2-mm-thick melanoma on the left shoulder?
A. Wide local excision of the melanoma followed by alpha-interferon therapy
B. Lymphoscintigraphy, SLN biopsy, and wide local excision of the melanoma, and alpha-interferon therapy
C. Wide local excision followed by axillary SLN biopsy
D. Lymphoscintigraphy, SLN biopsy, and wide local excision of the melanoma
E. Wide local excision of the melanoma and radiation therapy
4.1 A. Superficial spreading is the most common form of melanoma and consists of 70% of all cases. It has a slight female predominance and typically has a prolonged radial growth phase and a late vertical growth phase. In comparison to that for the other types of melanoma, the prognosis is favorable. Ulcerations can occur with several melanoma types and is not individually classified.
4.2 A. Although Breslow and Clark staging both use depth of invasion, the Breslow criterion is considered to reflect the prognosis more accurately. Patient age and tumor diameter are not independent prognosticators for melanomas.
4.3 C. Margins of 2 to 3 cm are considered adequate for a tumor with a depth between 2.0 and 4 mm.
4.4 E. Thorough skin examination is important for all patients with skin cancers. Wide local excision with adequate margins (2 cm) in this case is the mainstay of treatment for this intermediate-depth melanoma, and in this patient without obvious regional and distant metastases, lymphoscintigraphy and SLN biopsy may be beneficial for regional lymph node staging and treatment.
4.5 D. Lymphoscintigraphy is needed to identify the appropriate lymphatic drainage basins and the location(s) of the SLNs. A lesion in this location could have SLNs in the axillary and/or supraclavicular region, and a lymphoscintigraphy is the best way to identify the appropriate lymph node drainage basin(s). SLN biopsy is beneficial in identifying the subset of patients with intermediate-depth melanoma who may potentially benefit from identification and resection of involved regional lymph nodes. Radiation therapy is usually reserved for the treatment of symptomatic recurrences and selective patients with close resection margins. Alpha-interferon treatment is not indicated in patients without documented lymph node involvement.
A full-thickness biopsy should be performed on all suspicious pigmented skin lesions.
Asymmetry, Border irregularity, Color change, Diameter increase, and Enlargement or Elevation is more suspicious for malignant melanoma.
The Breslow system is more accurate than the Clark system for microstaging.
Excision of the melanoma with adequate skin margins remains the mainstay of therapy, and in patients with prior excisions, the margins are measured in a radial fashion from the edge of the biopsy scar or edge of the melanoma; therefore, planning of the initial skin biopsy incision is important.
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Shepherd C, PuzanovI, Sosman JA. B-RAF inhibitors: an evolving role in the therapy of malignant melanoma. Curr Oncol Rep. 2010;12:146-152.