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The incidence of malignant melanoma appears to be increasing at an alarming rate throughout the world. Some estimates show the global incidence to be doubling every 10 to 17 years. The incidence of melanoma in the United States alone increased by 80% from the years 1973 and 1980 One projection suggest that 1 in 90 Americans will develop melanoma by the year 2000. . Melanoma accounts for 65% of all deaths from skin cancer, reflecting its lethal nature. Fortunately, when detected early, it is a curable disease, with 95% cure rates for lesions less than .76mm in thickness. Because approximately 20% of melanomas originate in the head and neck, the otolaryngologist must be familiar with both cutaneous and mucosal melanoma. This grand rounds will summarize the risk factors, diagnosis and staging of melanoma and address some of the controversies in the treatment of melanoma of the head and neck.
The mortality from melanoma increases as one approaches the equator suggesting that sunlight is a risk factor for the development of cutaneous melanoma. Migration studies have also suggested that sunburn in childhood or adolescence is associated with higher rates of melanoma and this may represent a critical period for ultraviolet exposure . However, the relationship between melanoma and sun exposure is not a simple one. The anatomic distribution of melanoma is different from squamous cell carcinoma, which is more clearly directly related to sun exposure and found on the head, neck and arms. Melanomas can occur anywhere on the body; even in areas never exposed to the sun. Also, if melanoma were directly related to sun exposure, the incidence should increase with age, with multiple primary melanomas occurring in elderly patients. This is clearly not the case with melanoma. Rates of melanoma in persons with outdoor occupations have also been shown to be relatively low. Also, the development of mucosal melanoma does not appear to be related to sun exposure at all. In general, the relationship of melanoma to sunlight is complex, and some have come to the conclusion that it is more dependent on intermittent exposure early in life, rather than simple cumulative exposure.
Approximately 70% of cutaneous melanomas arise in a preexisting mole, so a recent change in the shape, color or size of a mole is an important risk factor. large malignant "precursors" such as congenital nevi, dysplastic nevi, and lentigo maligna must also be considered risk factors and fair-skinned caucasians who do not tan well are at highest risk. Increasing age, immunosupression and a family history of melanoma are other risk factors.
Melanocytes arise from the neural crest tissue during early fetal development and then migrate to the skin and several other peripheral sites. They then reside primarily in the basal layer of the epidermis and synthesize melanin pigment, which protects against ultraviolet irradiation. Recent investigations using cell culture has enhanced our understanding of the biologic features of melanocytes and work in the areas of monoclonal- antibodies have identified antigens on melanocytes in all stages of tumor progression. It is hoped that such investigations could produce specific immunotherapy for melanoma in the future.
Melanoma may be classified histomorphologically as either superficial spreading, nodular, and lentigo maligna types. This once was given significant prognostic value, but, as explained later, the significance of morphology may have been overemphasized in the past. Approximately 50 to 80% of melanomas are of the superficial spreading type, in which the melanoma evolves from a radial growth phase into a vertical growth phase over a period of years. Nodular melanomas appear to evolve over a period of months, beginning in a vertical growth phase from the onset. Lentigo maligna melanoma occurs in later ages from a preexisting lentigo maligna on a sun-exposed area of the body.
As clinicians, we are faced with the task of differentiating malignant melanoma from a variety of nonmalignant lesions that may resemble melanoma. In general, even if the lesion appears benign, if a patient is concerned about a pigmented lesion, the lesion should be removed or biopsied and sent for pathology.
These nevi are called junctional because the nevus cells are located at the junction of the dermis with the epidermis. They are usually small, flat, nonpalpable, brown or black lesions that are the first to appear after birth. As the patient matures, the nevi often grows into the dermis, forming a intradermal nevus.
This is the common “mole” that occurs on the face and trunk. It is dark, elevated or even warty or pedunculated. The elevation is caused by the proliferation of cells in the dermis, elevating the epidermis. These lesions rarely transform to malignancy. H/5>Compound Nevus
This is basically a junctional nevus developing into a intradermal nevus. The center of the lesion is often elevated while the periphery is still in the junctional phase and appears flat. These lesions are often noticed during adolescence and cause concern due to their changing nature but rarely transform.
These nevi are present at birth and are classified as small, medium or giant. Giant congenital nevi have a reported 6-7% lifetime risk of malignant transformation.
Also known as Hutchinson’s freckle, these lesions appear as a flat macule on the sun-exposed areas of middle-aged and older adults (mean age 65). It usually starts as a brown macule but may achieve various shades of pigmentation. The lesion represents an overgrowth of melanocytes at the dermal-epidermal junction and atypical melanocytes can extend far beyond the clinical margin, leading to a high recurrence rate after resection. Some consider this lesion “melanoma-in-situ” and feel the lesion will increase in size until it eventually invades the dermis and become lentigo maligna melanoma. Because there has never been a longitudinal prospective trial looking at the conversion rate to melanoma, the lifetime risk of conversion is unknown. The numbers quoted in the literature vary from as low as 5% to 30 - 50% but are essentially based on anecdotal experience. Epidemiological analyses are imprecise but suggest that the conversion rates are probably lower than the 30 to 50% rates often quoted.
“Dysplastic nevi” is a controversial term used to describe nevi that do not show “typical” features of common nevi. They are usually larger than typical nevi and show irregular color or borders. “Dysplastic nevi” were originally described in family pedigree studies that revealed a Melanoma Syndrome or Familial Atypical Mole and Melanoma Syndrome (FAM-M syndrome). Persons with this syndrome have a very high risk of developing melanoma. Those with a strong family history may approach 100%. In reality, these families are extremely uncommon so the incidence of sporadic “dysplastic nevi” in the general population is of greater concern. Unfortunately, the lack of clear criteria to diagnose a “dysplastic nevi” has led to a large amount of confusion and the 1992 NIH Consensus Conference recommended abandoning the term and using the clinical term “atypical mole” and the pathologic term “nevus with architectural disturbance”. Other lesions that may occasionally resemble melanoma include seborrheic keratoses, pigmented basal cell carcinomas, Kaposi’s sarcoma and blue nevus.
A biopsy of any suspicious lesion must be planned with the possibility of future treatment in mind. The incisions should be well thought out and an excisional biopsy should be performed if possible to allow the pathologist to examine the entire lesion. Curettage or shave biopsies have no place in the treatment of a suspicious lesion. If the lesion is too large to allow excisional biopsy, a punch or incisional biopsy incorporating normal tissue is adequate. Concerns over possible hematogenous dissemination with an incisional biopsy have led to several large studies which have failed to show a decrease in cure rate with incisional biopsy followed by a definitive surgical excision. The ideal pathology report should include the hisopahologic type (superficial spreading, nodular, lentigo maligna, acral), growth phase (radial vs vertical), depth of invasion, tumor thickness and the presence of lymphocytic invasion.
After the diagnosis of malignant melanoma is made, appropriate lab tests include a chest radiograph and liver enzymes, particularly alkaline phosphatase. This is adequate in those patients without symptoms suggesting distant disease because of the low yield of CT scans of the brain, liver and bone scans in patients with a normal chest radiograph and enzymes.
Once melanoma has been confirmed by biopsy, the tumor must be staged to determine prognosis and treatment. The risk of dying of melanoma has been correlated with the level of invasion so histologic staging systems have been developed by Clark (1969) and Breslow (1970). Clark staged by level of invasion:
Breslow’s staging system is based on tumor thickness:
Other histologic features that reflect a poor prognosis include high mitotic activity, microscopic satellites, ulceration, vertical phase growth.
The simplest and most common clinical staging system is a three stage system that is based on location of disease:
Because over 80% of newly diagnosed melanomas are Stage I, the American Joint Committee on Cancer proposed a new four-stage system of classification which combines the various pathologic aspects of melanoma and the TNM system. An overview:
In addition to tumor thickness, a number of other clinical prognostic factors deserve mentioning. Lesions of the scalp, hands and feet have a generally poorer prognosis. Older age and male sex also have been associated with poor prognosis.
The five year survival rates for stage I melanoma have been traditionally felt to differ according to subtype: lentigo maligna melanoma and superficial spreading melanoma were shown to have better survival rates (85-90%) than nodular melanoma (65%). However, the contention that lentigo maligna melanoma carries a more favorable prognosis has been challenged and multivariate analyses have not shown subtypes to be a major prognostic factor.
In the past, surgical excision with margins up to 5cm were accepted as treatment for Stage I melanoma. Recent studies have shown that smaller margins appear to adequate. Due to technical difficulties and problems with interpretation of atypical melanocytes, Mohs micrographic surgery for lentigo maligna and melanoma is controversial and should only be considered experimental at this time. A 1988 prospective study in the New England Journal of Medicine found similar rates of disease free survival in patients with lesions <2mm thick assigned to either 1cm or 3cm margins. There are several similar ongoing prospective trials but current recommendations include conservative margins (1cm) for thin lesions (<1mm) and more extensive margins (up to 3cm) for thicker lesions. Obviously, in the head and neck, important structures such as the eye may make extensive margins unacceptable and must be addresses on an individual basis.
Elective neck dissection in melanoma is exteremely controversial, to say the least and the literature is often conflicting. In general, lesions less than .76mm in thickness rarely metastasize (<2%), regardless of their location and an elective neck dissection is not indicated. Lesions 0.76 to 1.49mm in thickness develop regional mets in about 25% of cases and distant mets in about 8% of cases. In these cases, Medina recommends observation of the neck unless the lesion is associated with poor prognostic features such as nodular configuration, location on the scalp or neck or ulceration. Patients with melanomas 1.5mm to 3.99mm have a higher incidence of cervical mets (57%) but the incidence of systemic disease is still less than 15%. Several studies cite a benefit from elective lymph node dissection in these patients. In patients with lesions thicker than 4mm, the chance of distant mets is greater than 70% and lymph node dissection will not likely influence survival. In these cases, it should only be considered as a palliative procedure.
Neck dissection can also be considered a useful staging procedure in that patients with clinically negative necks with positive nodes histologically behave differently based on the number of positive nodes detected. Patients found to have less than three positive nodes behave similar to Stage I and II patients where prognosis is related to the thickness of the lesion. Patients with three or more positive nodes have a very poor prognosis.
The treatment of the neck in Stage III melanoma with palpable nodes usually requires surgical excision of the primary with a regional neck dissection. A radical neck dissection is usually necessary for extensive lymph node involvement but this is also controversial. Several studies have shown that modifications of the radical neck dissection do not affect survival, but these studies are retrospective in nature. Unfortunately, palpable disease in the neck carries a very poor prognosis, even with neck dissection (<20%). The majority of these patients develop distant mets but a surprising number (26%-34%) develop regional recurrences so adjuvant therapy may be considered.
Melanomas of the neck and face have a particular propensity to metastasize to the parotid so parotidectomy must often be combined with a neck dissection for lesions located on the temporal scalp, forehead or preauricular skin. A lesion of the posterior aspect of the scalp or neck often requires a posterolateral neck dissection, which removes nodes from the posterior triangle, suboccipital and retroauricular areas. This procedure may even be performed bilaterally with minimal morbidity.
Mucosal melanoma is more uncommon and usually more lethal than its cutaneous counterpart. 5 year survival rates range from 10% to 38%, but because there is a noted progressive decline over time, some have even regarded this disease as incurable. The average time of survival after diagnosis (about 3 years) has not significantly improved over the last 40 years, presumably due to the lack of early symptoms, rich blood supply leading to early metastasis and the difficulty in achieving wide surgical margins in the head and neck. Interestingly, mucosal melanoma does not appear to have any relationship to sun exposure.
The most common location in the head and neck is the nasal cavity, followed by the paranasal sinuses. In the oral cavity, the most common areas include the hard palate and the gingiva. The presenting symptoms are nonspecific and the diagnosis is often delayed. Approximately 50% of melanomas which arise in the nasal cavity show no obvious pigment. Interestingly, although pigmentation of the oral cavity mucosa is very common in blacks, melanoma of the oral cavity in blacks is extremely rare. Amalgam tattoos, which represent embedded material from dental work must often be distinguished from melanoma.
The specific staging system for cutaneous melanoma does not apply to mucosal melanoma as survival does not appear to be strongly related to depth of invasion. Treatment usually involves radical surgery and an elective neck dissection is usually not recommended. A recent article by Lee suggests that aggressive local control with surgery significantly affects survival with 45% 5-year survival rates. They also noted that that the disease is usually localized at presentation, local recurrence often occurs before the development of distant mets and that salvage surgery for local recurrence is extremely poor.
The dogma that melanoma is radioresistant has been recently challenged and there is renewed interest in the role of radiation therapy in melanoma. Megavoltage radiotherapy, using a small number of large doses of radiation (24 to 30 Gy in 4 to 5 treatments), was recently investigated at M.D. Anderson. They found locoregional control rates better than treatment with surgery alone and noted good compliance with fewer treatments and no side effects. Numerous studies are currently underway to further delineate the role of radiation therapy in melanoma.
Forty years ago, case reports of spontaneous regression and melanoma regression after blood transfusion sparked an interest in active specific immunotherapy. Melanoma-associated antigens and their associated antibodies have been identified with hopes of developing a specific “melanoma vaccine” . The search for a specific “tumor antigen” is an oversimplified endeavor to say the least but this appears to be the most promising area of adjuvant therapy research.
Rigel DS et. al The rate of malignant melanoma in the United States: are we making an impact? J AM Acad Derm 1987;17:1050-3.
Koh HK et al Lentigo maligna has no better prognosis than other types of melanoma. J Clin Oncol 1984;2:994- 1001.
Medina, JE. Malignant melanoma of the head and neck. Oto Clin N Amer 1993;26:1:73-85.
Ariyan, S Malignant melanoma in: Cancer of the Head and Neck. Mosby 1987:757-83.
NIH consensus conference statement Diagnosis and treatment of early melanoma. JAMA 1992;268:10:1314- 19.
Ang, K K. Et.al. Regional radiotherapy as adjuvant treatment for head and neck malignant melanoma. Arch oto head and neck surg. 1990;116:169-72.
Goepfert, H. Posterolateral neck dissection Arch Otolaryngol 1980;106:618-20
Byers RM. The role of the modified neck dissection in the treatment of cutaneous melanoma of the head and neck. Arch Surg 121:1338-1341, 1986.
O’brein CJ. Et. al. Experience with 998 cutaneous melanomas of the head and neck over 30 years. Am J Surg. 1981;162:310-14.
Turkula LD. Et. al. Limited or selective nodal dissection for malignant melanoma of the head and neck. 1984;148:446-49.
Urist M. et. al. Head and neck melanoma in 534 clinical stage I patients. 1984;200:769-775.
Ackerman AB. Malignant melanoma: a unifying concept. Am J Dermatopathology 1980;2:309-13.
Veronesi U et.al. Thin stage I primary cutaneous malignant melanoma: comparison of excision with marging of 1 or 3cm. N Engl J Med 1988;318:1159-62.
Koh, HK Cutanous Melanoma N Engl J of Med 1991;325:171-82.
Lee, SP et. al. Mucosal Melanoma of the head and Neck: the impact of local control on survival. Laryngoscope 1994;104:121-26.
Chiu, NT et. al. Melanoma of oronasal mucosa. Arch otolaryngol head neck surg. 1996;122:985-88.
Blatchford S. et. al. Mucosal melanoma of the head and neck. Laryngoscope. 1986;96:929-34.
Cohen, LM. Lentigo Maligna and lentigo maligna melanoma. J of Amer Acad Derm. 1995;33:6:923-36.
Demierre, MF. Adjuvant therapy for cutaneous malignant melanoma. J of Amer Acad of Derm 1997;36:5:747- 63.
Wells, KE. Sentinel lymph node biopsy in melanoma of the head and neck. Plast Recon Surg. 1997;100:3:591-94.
Diaz, EM. et al. The posterolateral neck dissection. Anch Oto Head Neck Surg. 1996;122:477-80
Head and Neck 3rd Ed. Edited by Myers. 1996 Sanders.