Sebastian G. De La Fuente
Timothy W. Mccardle
Vernon K. Sondak
Presentation
A 37-year-old woman noted a pigmented lesion on her left arm approximately 3 months ago. She sought the attention of a dermatologist who performed an excisional biopsy of the lesion. Pathology was consistent with malignant melanoma, Clark level II, with a Breslow depth of 0.8 mm without ulceration. The tumor mitotic rate was measured at 2 mitoses/mm2. Margins from the biopsy were negative but close (<1 mm). Her physical examination only reveals a well-healed scar at the biopsy site with no palpable lymphadenopathy.
Epidemiology
Approximately 131,810 new cases of melanoma are predicted to be diagnosed in 2012 in the United States, with 55,560 expected to be noninvasive cases (melanoma in situ) and 76,250 invasive melanomas. The incidence of melanoma has been increasing steadily over the last few decades. Melanoma is 10 times more common in whites than in African Americans, with a mean age at diagnosis of 55 years, but it can affect any age group. The most common primary sites are on the extremities of women and on the trunk in men. Currently, malignant melanoma accounts for 5% of all skin cancer but is responsible for most skin cancer–related deaths, with 9,180 deaths predicted for 2012.
Even though the causes of melanoma are not fully understood, it is well established that exposure to sunlight, specifically ultraviolet (UV) radiation, is a significant factor for developing melanoma. While sunburns are primarily due to UVB (280 to 320 nm) radiation, UVA has been shown to induce mutations in various cell lines and is also considered a carcinogen. The highest-risk population is fair-skinned individuals who burn easily with sun exposure. Other risk factors for developing melanoma are shown in Table 1.
TABLE 1. Risk Factors for Malignant Melanoma
Workup
The initial evaluation of patients presenting with suspicious skin lesions should include a complete history and physical examination focusing on the characteristics of the lesion as well as the status of the regional lymph nodes. Suspicious lesions are those presenting with geometric asymmetry, irregular borders, a variety of colors within the same lesion, diameter larger than 6 mm, or lesions that have changed over time (evolution) (Table 2) (Figure 1). The presence of itching, bleeding, or ulceration should also raise concern. Melanoma typically arises de novo from normal skin, but it can also arise in a preexisting nevus. It is important to emphasize that not all melanomas are visibly pigmented. Amelanotic melanomas lack the classic dark or multicolored appearance of most melanomas, which can lead to delays in recognition.
TABLE 2. The ABCDEs of Melanoma Recognition
FIGURE 1 • Malignant melanoma presenting with asymmetry, irregular borders, and a variety of colors.
Suspicious skin lesions should be biopsied to establish the definitive diagnosis. Whenever possible, excisional biopsy with 1 to 2 mm margins of normal skin extending down to subcutaneous fat is recommended. If excisional biopsy is undesirable due to the size of the lesion or its anatomic location (e.g., face, ears, digits, palm, etc.), incisional or punch biopsy may be performed (Figure 2). Shave biopsies should ideally include enough of the underlying dermis to allow determination of the depth of the lesion. Blood tests or imaging studies are generally not necessary in patients who are diagnosed with clinically localized melanomas and no symptoms of metastatic disease, except as needed to evaluate the patient’s overall medical status or suitability for general anesthesia.
FIGURE 2 • Forehead melanoma diagnosed with punch biopsy.
Staging
Staging of melanoma is based on clinical and pathologic features and is determined according to the TNM classification (Table 3). Clinical staging is based on the initial primary tumor biopsy, a complete physical examination, and, where indicated, imaging studies and laboratory tests. Pathologic staging includes the histologic results of definitive surgical procedures such as sentinel node biopsy and radical lymphadenectomy. Patients with clinical stage I and II (localized) melanoma are those with no clinical or radiologic evidence of regional or distant metastases. Clinical stage III patients are those with regional metastases, manifesting as enlarged lymph nodes or satellite or in-transit disease or both. Clinical stage IV is reserved for patients with distant metastases. Pathologic stages I therapeutic and staging purposes, because the statusand II comprise patients with no histologic evidence of nodal involvement after undergoing sentinel lymph node biopsy. Pathologic stage III patients have histologic evidence of metastatic disease in regional lymph nodes or intralymphatic sites.
TABLE 3. Seventh Edition AJCC Staging Classification
The T component of the TNM system, addressing the primary tumor, incorporates the Breslow thickness of the melanoma, the presence or absence of ulceration (Figure 3), and, in melanomas ≤1 mm thick, the mitotic rate. In the case presented above, the patient has a nonulcerated 0.8-mm melanoma with a mitotic rate >1 mitosis/mm2; therefore, her tumor is classified as a T1b melanoma.
FIGURE 3 • Malignant melanoma, Clark level 4 with a Breslow depth of 6 mm presenting with an area of ulceration in the center of the lesion.
Other histopathologic features have prognostic implications and should be routinely described on the pathology report. These include the presence or absence of regression, microsatellitosis, vertical growth phase, angiolymphatic invasion, and tumor-infiltrating lymphocytes (Table 4) (Figure 4).
TABLE 4. Histopathologic Factors Associated with Melanoma Prognosis
FIGURE 4 • Malignant melanoma in vertical growth phase (i.e., nests within the dermis are larger than the largest intraepidermal nests and mitotically active). A non-brisk lymphocytic host response is present.
Surgical Management
The fundamental principle in the treatment of primary cutaneous melanoma consists of wide excision of skin and subcutaneous tissues down to or including fascia with a radial margin measured from the edges of the biopsy scar or of any residual pigmented lesion. This excision margin is determined by the depth and anatomical location of the primary tumor (Table 5). Wide excision done by itself (i.e., without an accompanying lymph node biopsy or dissection) can often be performed under local anesthesia, with intravenous sedation if necessary. The resected specimen is oriented and sent for permanent pathologic examination. In most cases, the resulting defect can be closed primarily, but skin grafts or local skin flaps may be needed when primary closure is not feasible.
TABLE 5. Recommended Surgical Margins for Invasive Melanoma Based on Prospective Randomized Trials*
*Randomized trials included only patients with primary melanomas located on the trunk and proximal extremities. In other locations, (e.g., hands, face, etc.), 1.0 cm margins may be acceptable even for thicker tumors.
The most common first site for metastatic disease is in the lymph node basin draining the primary tumor site. Before the development of sentinel lymph node biopsy, most patients presenting with melanomas of 1.5 mm or greater in Breslow thickness were subjected to elective regional lymphadenectomy. This was done for both therapeutic and staging purposes, because the status of regional lymph nodes is the most important prognostic factor for survival. The observation in clinical trials that elective lymphadenectomy did not provide survival benefit and was associated with significant morbidity, such as lymphedema, wound infection, and nerve injuries, led to the development of lymphatic mapping and the sentinel lymph node biopsy procedure in the early 1990s. Current guidelines recommend sentinel lymph node biopsy for patients with clinically node-negative melanomas that are at least 1 mm in thickness. If the primary melanoma is <1 mm deep, sentinel lymph node biopsy is considered in patients of young age, in the presence of ulceration, or with tumors with mitotic rate of at least 1/mm2. If only a partial biopsy has been done, especially if substantial residual pigmented lesion is present, this may also be an indicator for sentinel lymph node biopsy in thin tumors.
Sentinel lymph node biopsy involves preoperative radionuclide lymphoscintigraphy and intraoperative injection of isosulfan blue dye. Preoperative lymphoscintigraphy, utilizing intradermally injected tracers such as 99mTc-sulfur colloid, permits determination of the lymphatic drainage patterns and allows identification of those basins at risk for melanoma metastasis (Figure 5A). A new technique that combines single photon emission computed tomography with computer tomography (SPECT/CT) for localization of sentinel nodes provides considerably more anatomic detail than conventional lymphoscintigraphy (Figure 5B,C).
FIGURE 5 • A: Conventional planar lymphoscintigraphy in a patient with a 2.1-mm nonulcerated melanoma of the temporal scalp. Images are taken after injecting 99mTc-sulfur colloid intradermally into the primary melanoma site. Note the anatomical landmarks defined on the scan by the technologist (ear, sternocleidomastoid muscle, and clavicle) for orientation purposes.
B: Sagittal image from 3D SPECT-CT lymphoscintigraphy of the same patient as in (A), demonstrating uptake in upper and lower cervical lymph nodes and more clearly demonstrating the relationship of the nodes to the ear, sternocleidomastoid muscle, and clavicle.
C: Axial image from 3D SPECT-CT lymphoscintigraphy of the same patient as in (A) and (B), showing the relationship of the upper sentinel lymph node to the undersurface of the sternocleidomastoid muscle.
Patients are typically injected 1 to 2 hours prior to the operation, allowing enough time for the tracer to travel to the basin of interest. The sentinel lymph node is identified intraoperatively with the aid of a handheld gamma counter. Additionally, intradermal administration of 0.5 to 1 mL of isosulfan blue dye (Lymphazurin 1%) around the intact tumor or biopsy site immediately preceding the procedure facilitates localization of the sentinel lymph node during surgery. The combination of dye and radiolabeled colloid solution allows the surgeon to identify the sentinel lymph node in more than 98% of cases. Removed nodes are then carefully evaluated using hematoxylin and eosin staining and immunohistochemistry techniques with antibodies to one or more melanoma marker epitopes such as S100, HMB45, and MART-1/Melan-A. Complications of sentinel lymph node biopsy include hematoma, wound infection, and seroma, although serious adverse effects are very uncommon.
Follow-up
Controversy exists among clinicians regarding the frequency and duration of postoperative surveillance in patients with history of melanoma. Most experts would recommend following these patients every 3 to 6 months for the first 3 years and annually thereafter. This schedule is influenced by a variety of factors such as the stage of the primary melanoma, number of lymph nodes involved, any prior history of melanoma, the presence of multiple atypical moles, or a family history of the disease. For asymptomatic patients, some authors recommend a chest x-ray and lactate dehydrogenase (LDH) levels every 6 to 12 months, but their value has never been shown, and we do not routinely obtain these tests.
The main goal of any surveillance program includes identification of new primary or recurrent disease at an early stage that would allow potential curative resection. Skin cancer education including potential deleterious effects of sun exposure and the need for appropriate protection, such as sun avoidance, protective clothing, and broad-spectrum sunscreens, should be promoted among melanoma patients and their families. Routine self–skin examination and assessment of lymph node basins is of great value, since many patients presenting with recurrence find the disease themselves.
Presentation Continued
A 75-year-old man with a history of a thin mela noma in the thigh 2 years ago presents with enlarged ipsilateral inguinal nodes. At the time of the original diagnosis, he was treated with excision with adequate resection margins, but a sentinel lymph node biopsy was not performed. The patient did not have complaints other than occasional headaches and a few episodes of visual changes.
Workup
The use of routine blood work and imaging studies for patients with clinical stage I or II disease is of low yield. Patients presenting with more advanced stages or with symptomatology of metastatic disease should be evaluated more extensively. Currently available blood tests such as LDH serum levels have low sensitivity and specificity. In patients with stage IV disease at presentation, elevated serum values of LDH are associated with reduced survival rates. Regardless of the stage of the original melanoma, patients with suspected recurrence should undergo a complete physical examination including a full dermatologic evaluation and assessment of all lymph node groups. In patients with prior surgery, the status of the scars at the primary and lymph node resection sites as well as the presence of lymphedema should be documented. When a melanoma patient presents with an enlarged lymph node, the preferred diagnostic modality is a fine needle aspiration (FNA) of the node. If this cannot be performed or if the FNA is nondiagnostic, an open biopsy is the next step, orienting the incision so as to facilitate a subsequent lymph node dissection.
The use of imaging studies in the initial staging of the patient with advanced or recurrent disease includes computed tomography and positron emission tomography (PET) scans. PET scanning is sensitive for detecting metastatic melanoma deposits as small as 5 to 10 mm in size but is nonspecific. The use of PET/CT fusion scans provides improved anatomic definition but does not eliminate false-positive results. Pelvic CT scans are often recommended in the setting of inguinofemoral lymphadenopathy to evaluate for the presence of intrapelvic disease. Brain magnetic resonance imaging (MRI) is recommended when patients have neurologic symptoms and for patients with palpable nodes or distant disease.
Surgical Management of Node-Positive Disease
The current recommendation for melanoma patients with regional lymph node metastases and no evidence of distance disease is complete lymphadenectomy, which includes removal of all nodes of the involved nodal basin. In patients with inguinal metastasis, such as the case above, superficial inguinal node dissection (inguinofemoral lymphadenectomy) is indicated at a minimum. This technique involves en bloc resection of all inguinal lymphatic tissue contained within the femoral triangle, as well as the node-bearing tissue superior to the inguinal ligament but superficial to the external abdominal oblique aponeurosis. The decision making about adding a pelvic node dissection, that is, performing a superficial and deep inguinal node dissection (ilioinguinal lymphadenectomy), remains controversial. Some authors recommend routine biopsy of Cloquet’s node to predict involvement of pelvic lymph nodes. In our experience, we have found this approach to be of very limited value. Radiographic evidence of pelvic nodal metastasis is an absolute indication for ilioinguinal lymphadenectomy, but we tend to perform this in most patients with palpable inguinal nodes.
The most common complications following inguinofemoral and ilioinguinal lymphadenectomy include wound infections and seroma, lymphedema, and deep vein thrombosis. Preoperative antibiotics are routinely used, but postoperatively antibiotics are only given if signs or symptoms of infection develop. To prevent the femoral vessels from being exposed in the event of a wound disruption, the sartorius muscle is often detached from its origin on the anterior superior iliac spine and transposed, suturing it to the inguinal ligament to cover the femoral vessels. The severity of lymphedema can be minimized by the use of fitted gradient compression stockings, using limb measurements obtained preoperatively, in the first few months postoperatively and as needed thereafter. Typically, inguinal lymphadenectomy patients are kept on bed rest overnight but are asked to ambulate starting on postoperative day 1. Frequent leg elevation when the patient is not ambulating helps as well. Low molecular weight heparin administration and early ambulation may decrease the rate of postoperative DVT.
Adjuvant Therapy and Treatment of Metastatic Disease
The majority of patients with early-stage melanoma will be cured by excision alone. Current recommendations for adjuvant therapy for patients with stage IIB or III melanoma include interferon alpha therapy or enrollment in clinical trials. Interferon alpha treatment has been consistently shown to improve relapse-free survival by approximately 20% to 30%, and in some analyses overall survival by a smaller amount. Recently, a large European randomized trial involving more than 1,250 patients with stage III melanoma showed a statistically significant improvement in relapse-free survival, but not overall survival, in patients treated with pegylated interferon. Due to its much longer half-life, pegylated interferon allows weekly injections as opposed to daily or three times per week injections for standard interferon, but in the European study it was given for 5 years rather than one. Whenever possible, patients with melanoma should be referred for clinical trials that may allow developing better therapies for the future.
Adjuvant radiation therapy can be considered in certain situations. For desmoplastic melanoma with neurotropic spread, radiation to the primary site is often used. Radiation to the regional node basin is also often recommended in the face of risk factors for postlymphadenectomy regional recurrence, which include extracapsular extension, four or more involved lymph nodes, maximum nodal metastasis size ≥3 cm, or recurrent disease in the nodal basin after complete lymphadenectomy. Radiation therapy is also used in the treatment of brain metastases and may be useful in palliating other symptomatic metastases.
Dramatic changes in the management of patients with metastatic melanoma have occurred over the last few years with the introduction of two new targeted agents. Ipilimumab, an antibody directed against cytotoxic T-lymphocyte antigen 4 (CTLA4), has been shown to improve overall survival for patients with unresectable metastatic melanoma when given alone or combined with dacarbazine. More recently, selective inhibition of the mutant BRAF V600E protein with vemurafenib was shown in a phase III study to dramatically prolong progression-free and overall survival compared to dacarbazine. About 50% of patients with metastatic melanoma have tumors that harbor the BRAF V600E gene mutation, so patients with metastatic disease should routinely have their tumors undergo mutational analysis to determine if targeted therapy is an appropriate consideration. Patients treated with vemurafenib or other selective BRAF inhibitors such as dabrafenib develop cutaneous squamous cell carcinomas, particularly keratoacanthoma-type lesions, at a greatly increased frequency.
TAKE HOME POINTS
· Early recognition and treatment are associated with more favorable outcomes.
· The presence of ulceration and the mitotic count determines T1a versus T1b in melanomas ≤1 mm, and these factors influence surgical decision making in these patients.
· The most important prognostic factor for clinically localized melanoma is the status of the lymph nodes draining the primary site.
· Postoperative surveillance relies mostly on physical examination, with imaging studies performed when metastatic disease is suspected.
· New therapies have shown improved overall survival in patients with metastatic disease.
· Whenever possible, patients with advanced melanoma should be referred for clinical trials that would allow developing even better therapies for the future.
SUGGESTED READINGS
Gershenwald JE, Ross MI. Sentinel-lymph-node biopsy for cutaneous melanoma. N Engl J Med. 2011; 364;1738–1745.
Morton DL, Cochran AJ, Thompson JF, et al. Multicenter Selective Lymphadenectomy Trial Group. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg. 2005;242:302–311.
Paek SC, Griffith KA, Johnson TM, et al. The impact of factors beyond Breslow depth on predicting sentinel lymph node positivity in melanoma. Cancer. 2007;109:100–108.
Rao NG, Yu HH, Trotti A III, et al. The role of radiation therapy in the management of cutaneous melanoma. Surg Oncol Clin N Am. 2011;20:115–131.
Sondak VK, Flaherty LE. Targeted therapies: improved outcomes for patients with metastatic melanoma. Nat Rev Clin Oncol. 2011;8:513–515.
Zager JS, Hochwald SN, Marzban SS, et al. Shave biopsy is a safe and accurate method for the initial evaluation of melanoma. J Am Coll Surg. 2011;212:454–460.