Andrew Kroeker
Andrew Shuman
Erin Mckean
Presentation
A 57-year-old caucasian man presents with an irregular pigmented lesion on the left frontotemporal scalp. The patient noticed that the lesion grew over the previous 6 months. Initially, the area of concern was round and uniform in color. As the lesion increased in size, the border became more irregular and began to display different shades of brown. The area has been nontender and without bleeding or ulceration, but the patient describes the lesion as mildly pruritic.
Workup
The diagnostic workup of a suspicious pigmented cutaneous lesion includes a detailed medical history and physical examination. An early symptom frequently associated with malignant lesions is pruritis. Symptoms associated with more advanced lesions include ulceration, pain, and bleeding. A focused history includes questioning the patient about prior sun exposure, the use of tanning beds, work history, a history of significant blistering sunburns, or a personal and family history of skin cancer.
On examination, the mnemonic ABCD(E) has been used in the evaluation of a pigmented lesion suspicious for melanoma. This includes Asymmetric shape, Border irregularity, Color variation, and Diameter >6 mm. Evolution has been added to the screening metric and refers to the change in character over time. A melanoma displaying some of these pathologic characteristics is shown in Figure 1. Although a useful guide, it is important to recognize that some uncommon subtypes of melanoma are not captured by this screening tool. These include desmoplastic, amelanotic, and nodular variants.
FIGURE 1 • Typical melanoma of the head and neck. (Courtesy of Timothy Johnson, MD; University of Michigan Department of Dermatology.
A biopsy should be performed on all lesions that are worrisome to either the patient and/or caregiver. Initially, excisional biopsy with 1 to 2 mm margins that fully encapsulates the suspicious tissue should be undertaken when possible. If complete excisional biopsy is not possible due to size or anatomic constraints, a full-thickness incisional or punch biopsy should be completed in the thickest portion of the lesion. Shave biopsy should be avoided since this limits evaluation of tumor depth and therefore makes appropriate staging more difficult. The specimen should be evaluated by a pathologist experienced in cutaneous disease in order to make an appropriate histologic diagnosis. Once a diagnosis of melanoma is confirmed, a histopathologic template should be reported as recommended by the AJCC. This includes information such as tumor depth, mitotic rate, angiolymphatic invasion, ulceration, and perineural spread. To complete the initial diagnostic workup, any patient diagnosed with melanoma of the head and neck should undergo a comprehensive exam by a dermatologist.
Melanoma arising from the mucosal surfaces of the body is felt to be a distinct pathologic entity from the cutaneous version. This is a rare subtype that accounts for roughly 1% of all cases of melanoma. Unlike the cutaneous version, the incidence of mucosal melanomas is not changing significantly. Common sites include the nasal cavity and the oral cavity; therefore, presenting symptoms include complaints specific to those areas, including epistaxis and nasal obstruction. Many lesions remain asymptomatic during the initial course of disease. The differential diagnosis of a pigmented mucosal lesion includes amalgam tattoos, oral mucosal nevi, melanotic macule, oral mucosal nevi, melanoacanthoma, and mucosal melanoma.
The diagnostic evaluation of mucosal melanoma is similar to cutaneous melanoma. A complete head and neck exam including fiberoptic nasopharyngoscopic examination of all mucosal surfaces should be undertaken. Computed tomography scan of the head and neck and a chest radiograph to evaluate for lung metastases are typically utilized. Much like the cutaneous counterpart, any suspicious pigmented mucosal lesion should be biopsied. Also, similar immunohistochemical stains are also employed, including S-100, vimentin, and HMB-45. There is a distinct AJCC staging profile for mucosal melanoma.
The patient undergoes excisional biopsy of the suspicious lesion. Histopathologic review demonstrates malignant melanoma invading to a depth of 2.7 mm with no microscopic evidence of ulceration. There is no clinical evidence for regional or distant metastatic disease. No second primary lesions were noted on formal cutaneous evaluation. The patient’s melanoma is staged as T2N0M0.
Diagnosis and Treatment
Classification of melanoma based on traditional TNM stage was recently updated in the seventh edition of the AJCC Cancer Staging Manual. Breslow depth (depth of tumor invasion below the basement membrance) is the primary determinant of T stage and is described in detail in Table 1. Tumor depths of 1.0, 2.0, and 4.0 mm remain as thresholds for the four stages; the updated staging system has removed Clark level. Each stage is further subclassified into either “a” for tumor without ulceration or “b” for tumor with ulceration. For prognostic purposes, further distinction is made within T1 lesions with regards to mitotic figures per mm2 of tissue. Nodal disease staging includes one node for N1 disease, two to three nodes for N2 disease, and greater than three nodes for N3 disease. Selective lymphadenectomy has played an important role in the accurate staging of certain subpopulations with melanoma. Lymphoscintigraphy followed by lymphatic mapping and sentinel lymph node biopsy (SLNB) (sentinel lymphadenectomy) remain important components of melanoma staging and should be used or discussed with the patient in defining occult stage III disease among patients who present with clinical stage IB or II melanoma. Clinical staging is reviewed further in Table 2.
TABLE 1. AJCC TNM Cutaneous Melanoma Guide—2010
aMicrometastasis: diagnosed after SLNB.
bMacrometastasis: clinically detectable nodal metastases confirmed pathologically.
TABLE 2. AJCC Cutaneous Melanoma Staging Guidelines—2010
Melanoma is a disease with a high metastatic potential. However, the propensity for distant metastatic spread is directly related to disease stage. The diagnostic workup of TI disease requires a complete history and physical examination. For more advanced disease, chest x-ray, lactate dehydrogenase, and liver function tests are often employed to exclude distant disease in patients with clinically negative nodal disease and are more strongly recommended in clinically positive nodal disease. Further imaging studies should be ordered as clinical scenarios warrant. Stage IV disease often necessitates a complete metastatic workup including cross-sectional imaging of the brain, neck, chest, abdomen, and pelvis, and/or FDG-PET scans.
Primary Site
Once the diagnosis of melanoma has been confirmed, a wide local excision (WLE) of the lesion should be performed. This is executed with 1-cm margins for lesions <1 mm in depth (T1) and 2-cm margins for lesions >1 mm (T2 to T4). No survival benefit has been shown for wider margins. The depth of excision should include the entire epidermis and dermis, as well as the underlying subcutaneous tissues to the level of the underlying fascia. Extension of the excision into deeper tissue planes should be performed only if tumor invasion is evident. Branches of the facial nerve should be identified and preserved unless they are clinically involved. Tumor margins may be appropriately adjusted when the lesion abuts critical structures such as the eyelids. Meticulous pathologic attention to the tumor margin is crucial, and frozen sections are notoriously unreliable for melanoma. In certain cases, a “square” procedure may be recommended, in which a complete circumferential evaluation of the surgical margin is undertaken in order to ensure clear margins prior to final excision and reconstruction.
Many WLE sites can be closed primarily, although the defect size and location may necessitate reconstruction with skin grafts, local advancement flaps, or larger regional flaps. In general, reconstruction that involves tissue rearrangement should be delayed until pathologic margins are definitively cleared. While some centers report success with Mohs surgery for melanoma, the majority of institutions prefer to await final standard pathologic analysis.
Surgical management is also the mainstay of treatment for mucosal melanoma. However, unlike primary cutaneous disease, complete surgical resection of mucosal lesions is often difficult secondary to tumor site and associated morbidity. Neck dissection is typically performed in N+ cases. Adjuvant radiation therapy may improve locoregional control for mucosal melanoma, although there is no proven improvement in overall survival; chemotherapy is typically only utilized in the palliative setting.
Nodal Disease
Evaluation of cervical metastatic disease has been extensively studied and recommendations continue to evolve. Therapeutic lymphadenectomy is indicated in clinically positive nodal disease. As a general rule, a primary scalp/facial lesion anterior to an imaginary line drawn from one tragus to the other will drain anteriorly through the parotid basin and anterior neck, and lesions posterior to this imaginary line will drain to the posterolateral neck. Therefore, superficial parotidectomy and selective neck dissection are recommended for anterior lesions, and posterolateral neck dissection is recommended for posterior lesions.
Currently, there is no conclusive evidence that prophylactic complete regional lymphadenectomy is beneficial in patients with clinically negative nodal disease. However, approximately 15% to 20% of patients at initial presentation harbor occult metastatic disease. It is accepted that in early lesions (depth <1.2 mm) without clinical evidence of nodal disease, there is generally no indication for lymphadenectomy. With lesions between 1.0 and 3.5 mm depth of invasion, SLNB may be warranted.
Sentinel node biopsy involves preoperative intradermal injection of a radiolabeled colloid tracer. This is followed by lymphoscintigraphy to map the nodal drainage basins of interest. At the onset of surgery, the surgeon injects the lesion intradermally with blue dye to assist in the visual confirmation of the sentinel nodes. Intraoperatively, once the primary lesion has been completely excised, the surgeon uses the nuclear medicine imaging, the presence of blue dye within the nodes of interest, as well as the scintigraphy probe to assist in localization of the sentinel lymph nodes. Typically, specimens are processed for pathologic review by permanent section, which usually involves both traditional H&E staining and melanoma-specific immunohistochemical stains. Patients with known metastatic disease or those who have previously undergone WLE or had surgical manipulation in the area of concern are not candidates for SLNB. In the hands of a surgeon experienced in head and neck oncology, sentinel nodes within the parotid bed and neck can be safely and successfully excised with appropriate facial nerve dissection and monitoring.
Adjuvant and Palliative Treatment
The role of immune modulators in melanoma has been studied extensively. Adjuvant interferon α2b has been shown in some studies to increase disease-free and overall survival in stage III disease. This therapy is not without significant side effects, and close monitoring, appropriate patient selection, and counseling by a medical oncologist are crucial.
Distant metastatic disease confers a very poor prognosis. There is a limited role for surgery in management of these difficult cases, although there may be a role for surgical palliation in specific clinical scenarios.Specific prognostic indicators are used in stage IV disease and include the number and location of anatomic sites involved with distant disease, as well as the length of time elapsed from primary excision to recurrence; mean 5-year survival in stage IV disease is approximately 6% to 7% (Figure 2).
FIGIRE 2 • Cutaneous melanoma––5-year survival based on AJCC TNM stage
Melanoma is generally resistant to external beam radiation and cytotoxic chemotherapy. Adjuvant radiation therapy may play a role in the prevention of local disease recurrence in selected cases; however, there is no evidence for an overall survival benefit. The use of chemotherapy remains controversial, as no regimen has been shown to alter long-term survival. The primary role for both chemotherapy and radiation is in the palliative setting. Recent advances in targeted therapies, including both monoclonal antibodies that promote an antitumor T-cell response and inhibitors of gene products associated with oncogene function, have shown promise toward improving survival in stage IV disease.
The patient undergoes WLE with 2-cm margins followed by local tissue rearrangement. Sentinel lymph nodes located in this superficial parotid lymphatic basin and in level 2 of his right neck were biopsied and sent for permanent pathology.
Discussion
The lifetime risk of developing melanoma is almost 40 times greater than it was just 75 years ago. The incidence of melanoma continues to rise faster than any other malignancy. It affects people of all ages, with approximately one-quarter of new cases diagnosed in patients <40 years of age. The head and neck is a frequent primary site, with close to one-quarter of all cases occurring in this region. Risk factors implicated in the development of melanoma involve both environmental exposures and genetic predisposition. Both fair skin and a history of significant sun exposure are correlated with increased incidence of melanoma. Furthermore, the presence of numerous and/or large congenital nevi and a prior personal or family history of melanoma correspond to an increased relative risk. Although present in a minority of cases of melanoma, genetics also play an important role. The most common mutation involves the p16 tumor suppressor gene. The autosomal recessive disorder, Xeroderma pigmentosa, also confers a significantly increased risk of melanoma.
Histologic subtypes exist within cutaneous melanoma. Common variants include superficial spreading and nodular subtypes. The term lentigo maligna correlates to melanoma in situ and is thought to be the precursor to invasive lesions known as lentigo malignant melanoma. Less common subtypes include amelanotic, desmoplastic, and desmoplastic-neurotropic melanoma. The utility of these subclassifications is limited, however, as prognosis is more highly correlated with the depth of tumor invasion than histologic subtype. It is also important to recognize the distinction between cutaneous melanoma and melanoma originating in mucosal surfaces of the body. Mucosal melanoma is thought to behave more aggressively and carries a poorer overall prognosis than cutaneous primary disease. Furthermore, a small percentage of melanomas will present with regional or distant metastatic disease in the absence of a known primary site. After an attempt to find the primary lesion is made, these cases should be approached similarly to patients with known primary lesions and metastatic disease.
Surveillance
Early identification of local and regional recurrence as well as new primary lesions is the primary goal of oncologic surveillance. It is important to instruct patients about the warning signs of melanoma and the need to perform monthly self-examinations. Although late recurrence (>10 years from the time of initial diagnosis) is relatively uncommon, it still occurs with moderate regularity and therefore necessitates indefinite surveillance. Follow-up guidelines from the National Comprehensive Cancer Network vary based upon stage. Melanoma in situ lesions require, at minimum, annual skin examinations by a health care provider indefinitely. More advanced-stage cancers require a focused history and physical exam every 3 to 6 months for 2 years, then every 3 to 12 months for 2 years, followed by annual exams indefinitely. Imaging and laboratory studies may be used to evaluate any concerning symptoms, or at the discretion of the individual provider.
Case Conclusion
The patient is seen in postoperative follow-up to discuss the final pathology and staging. Both sentinel lymph nodes were negative for melanoma. No adjuvant therapy is recommended. He is scheduled for routine follow-up in 3 months’ time.
TAKE HOME POINTS
· Surgery is the primary treatment modality for melanoma.
· Timely identification and excision of malignant lesions is crucial.
· Surgery requires in-depth anatomical knowledge and experience in order to dissect and preserve critical neurovascular structures, and to appropriately respect aesthetic issues while remaining oncologically sound.
· Appropriate histopathologic and clinical staging is necessary for both risk stratification and selection of appropriate treatment modalities.
SUGGESTED READINGS
Balch CM, Gershenwald JE, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199–6206.
Balch CM, Soong SJ, Smith T, 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;8:101–108.
Barth A, Wanek LA, Morton DL. Prognostic factors in 1,521 melanoma patients with distant metastases. J Am Coll Surg. 1995;181:193–201.
Brand CU, Ellwanger U, Stroebel W, et al. Prolonged survival of 2 years or longer for patients with disseminated melanoma, an analysis of related prognostic factors. Cancer. 1997;79:2345–2353.
Byers RM. Treatment of the neck in melanoma. Otolaryngol Clin North Am. 1998;31:833–839.
Chang AE, Karnell LH, Menck HR. The national cancer database report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. Cancer. 1998;83:1664–1678.
Flaherty KT, Puzanov I, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–819.
Hodi FS, O’Day SJ, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–723.
Kirkwood JM, Ibrahim JG, Sosman JA, 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;19:2370–2380.
Morton DL, Thompson JF, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355:1307–1317.
Rigel DS, Friedman RJ, Kopf AW, et al. ABCDE—an evolving concept in the early detection of melanoma. Arch Dermatol. 2005;141:1032–1034.
Schmalbach CE, Johnson TM, Bradford CR. The management of head and neck melanoma. Curr Probl Surg. 2006;43:781–835.
Schmalbach CE, Nussenbaum B, et al. Reliability of sentinel lymph node mapping with biopsy for head and neck cutaneous melanoma. Arch Otolaryngol Head Neck Surg. 2003;129:61–65.
Stern SJ, Guillamondegui OM. Mucosal melanoma of the head and neck. Head Neck. 1991;13:22–27.
Surveillance, Epidemiology and End Results. (2003). http://seer.cancer.gov.
Wagner Marcus MD, Morris Christopher G. MS002E Mucosal melanoma of the head and neck. Am J Clin Oncol. 2008;31:43–48.
Wornom IL, Smith JW, Soong SJ, et al. Surgery as palliative treatment for distant metastases of melanoma. Ann Surg. 1986;204:181–185.