Malignant Melanoma

Malignant melanoma (MM) is a malignant neoplasm of epidermal melanocytes. Melanoma is the third most common skin cancer and represents from 3% to 5% of cutaneous malignancies. Oral MMs are extremely rare and represent less than 2% of all reported melanomas. The incidence of melanoma has been steadily increasing in both the United States and around the world. Although MM has long been among the most feared cancers, in many instances, it now can be cured if detected early enough.

Epidemiology

Melanoma generally occurs in all adult age groups. The average age of persons affected by MM is 50-55 years. The incidence in the United States is estimated to be 4.5 out of 100,000. Recently, the incidence has risen proportionately more in young adults. In the United States it is estimated that 34,000 new cases are diagnosed each year, with 7,200 deaths per year attributed to MM (based on 1995 statistics). The tumor exhibits a slight male predilection.

Etiology and Pathogenesis

Most melanomas are believed to develop de novo from melanocytes within normal skin or mucosa. Ultraviolet radiation has been implicated as a major causative factor in the development of MM. Several cutaneous melanocytic lesions with the ability to undergo malignant transformation have been identified as possible precursor lesions to MM.

Five cutaneous lesions have been identified which possess the potential to undergo malignant transformation into melanoma. The dysplastic melanocytic nevus is thought to be the most frequent precursor lesion to MM and accounts for about 20% of the cases of this malignancy. They occur in about 2% of white adults. More than half of superficial spreading melanomas (SSM) are thought to have a nevus or "mole" precursor of one type or another.

Dysplastic nevi (DN) are clinically and histologically atypical nevi. They appear as 5 to 12 mm diameter macular lesions with irregular or indistinct borders and variable pigmentation. DN usually appear on the trunk and rarely occur before puberty. Most common benign nevi such as lentigo simplex or junctional nevi never give rise to melanoma. However, melanomas commonly arise from pre-existing nevi. DN are felt to represent the transition stage from benign nevi into MM. Malignant transformation of benign nevi follows a sequence different from the normal evolution and differentiation of nevi. A sequence of increasingly abnormal melanocyte growth accompanied by cytologic abnormalities signals the possibility of malignant transformation. This flawed evolution of normal benign nevi usually starts in a junctional nevus and continues to progress through the compound and dermal stages into a lesion which is finally termed a dysplastic nevus. The evolution of benign nevi into DN appears to center around the migration of melanocytes from the basal layer of the epidermis, as seen in early benign nevi, down into the dermis, as seen in later dermal or dysplastic nevi. Accompanying the migration of the melanocytes, there are also corresponding changes in the melanocyte population including hyperplasia, hypertrophy and increasing atypia and dysplasia. The histologic diagnostic features of DN have been outlined below and include the following:

DN are thought to be able to progress into the radial growth phase of SSM. Evidence for DN being a step in the progression of benign common nevi (BCN) into MM has been found. A cytologic study by Schmiegelow, et al. has given some insight into this process. The DNA content of melanocytes, in the progression of BCN to DN and finally into MM, steadily increases as does the variability of melanocyte nuclear areas within a given lesion. In addition, DN have a significantly larger proportion of nuclei with hyperdiploid and tetraploid DNA content indicating increased proliferative activity.

The rate at which DN progress into MM has been estimated to be about 10%. Most DN are completely stable over long periods of time. Nevertheless, the presence of DN is believed to represent a significant increase in a patient's overall risk in developing MM. Such a patient should be followed closely every 3 to 6 months for any changes in these lesions. Patient education plays an important role in the early detection of malignant transformation of BCN or DN. Patients should be taught to be aware of the following warning signs in any nevus or "mole":

Patients should also be instructed to report any new pigmented lesions which occur after the age of 40.

The exact etiological agent which causes BCN to undergo transformation into MM is not certain. Ultraviolet (UV) light is considered to be an inducing and/or releasing factor in most types of MM. This theory is due to the fact that the highest incidences of MM generally occur in those countries near the equator with strong sunlight. The highest incidence of MM is reported in Australia and Arizona while the lowest numbers are seen in European countries. Any specific cytologic information about the role of UV light has not been clearly established, clinically or in the laboratory (as is the case for diseases like xeroderma pigmentosum). Most of the evidence for the role of UV light in MM is indirect; i.e., patients with xeroderma pigmentosum develop MM at an early age and patients with solar lentigenes also appear to have an increased incidence of MM.

At best, the strongest correlation between UV light exposure and MM is seen in the Lentigo maligna melanoma (LMM) variant. This is due to the the fact that LMM is almost exclusively confined to sun-exposed skin surfaces. Solar degeneration of the upper dermis of the lesion, along with its association with a lentigo maligna precursor, are also characteristic of LMM and are highly suggestive of a UV light etiology.

There also has been an indication that long-wave UV radiation, coupled with systemic psoralens therapy, may induce the formation of pigmented macules which sometimes show cytologically atypical melanocytes.

Additional observations linking UV light exposure with MM come from a "high risk" group of individuals. The group consists of patients with blond or red hair, freckles, blue eyes, poor tanning ability, a tendency of repeated sunburn (Type I skin), indoor occupation (unaccustomed skin) and recreational vacations in sunny climates. Studies have shown that patients which fit this profile appear to demonstrate an increased risk of developing MM which is thought to be induced by exposure to UV light.

The importance and exact role of UV light as an inducing factor in MM has been debated by other studies. Serious arguments against a direct relationship between MM and UV light have been raised. The key features of these arguments have been outlined by Illig:

It is generally agreed that, in addition to the role of UV light, there are genetic predisposing factors associated with the risk of developing MM. Genetic factors seem to play a part in the role of DN and MM. Dysplastic nevus syndrome (DNS) occurs in familial and sporadic patterns and appears to represent an increased genetic risk factor in developing MM. There are four categories of DNS: types A through D. Type D represents the highest familial risk. Studies have shown that the gene for familial DNS lies on chromosome 1 with autosomal dominant inheritance. Persons with this genetic characteristic who exhibit DN and have a history of MM in two or more family members have a lifetime risk approaching 100%. Patients with DNS represent the highest risk group for MM and require very close monitoring by dermatologists to prevent the progression of DN into MM.

Other significant precursor lesions of MM are congenital nevi (CN). They account for about 15% of all cases of MM. Congenital nevi occur in approximately 10% of all newborns and have been divided into three groups according to size at the time of presentation:

CN appear as round, brown to black, round to oval plaques (often with coarse hair). Of the three sizes of CN, the large and medium types appear to hold the greatest risk of progressing into MM. The lifetime risk of melanoma in patients with large CN is estimated to be 5% to 20%. It is recommended that all large and most medium-sized CN should be evaluated for excision. The risk of small CN transforming into MM in normal individuals is about 1 in 170,000. For this reason, it is usually agreed that small CN should be monitored unless the patient has additional risk factors for MM. In this case, excision should be considered. It should be noted that obtaining an accurate history of a pigmented lesion's presence at birth may be quite difficult. This fact should be taken into consideration when trying to determine if a nevus is congenital or acquired.

Congenital-nevus-like nevi (CNLN) are acquired (non-congenital) nevi which clinically and histologically resemble CN. CNLN are a recently-identified group of precursor lesions and markers for MM. They are darkly pigmented lesions which usually occur on acral surfaces and mucous membranes. The exact histologic differences between CN and CNLN are not known at this time and the exact degree of risk for transformation of CNLN into MM is also unknown.

Lentigo maligna (LM) or Hutchinson's freckle is a precursor lesion to LMM. It is considered by many to be malignant melanoma in situ. LM starts as an unevenly pigmented macule which extends peripherally and may be several centimeters in diameter. It is light brown to brown with minute black flecks. There also may be depigmented areas of spontaneous regression. LM usually arises in individuals over 50 years old and almost always occurs on exposed areas, especially the face. Progression of LM to LMM occurs in about one third of all cases after the lesion has been present for 10 to 15 years and has reached a size of about 4 to 6 cm.

Clinical Presentation

Four common forms of MM have been described. Superficial spreading melanoma (SSM) is the most common variety and accounts for about 55% to 75% of all cases of MM. SSM usually begins in middle age and can occur anywhere on the skin (demonstrates no specific site predilection). Clinical appearance of SSM closely follows the guidelines of the "ABCD" mnemonic useful in identifying melanomas.

SSM exhibits two different growth phases, radial (horizontal) and vertical. In the radial growth phase, malignant melanocytes grow in the epidermis and may also be present in the dermis. The proliferating melanocytes grow in all directions: outward, peripherally and downward. However, the net direction of growth in the radial growth phase is peripheral, thus producing a superficially proliferating lesion confined largely to the epidermis. In the later vertical growth phase the net direction of growth is downward, towards the papillary dermis, and is therefore perpendicular to the radial phase. Vertical tumor growth leads to melanocyte proliferation first through the papillary dermis and then into the reticular dermis. SSM will usually remain in the radial growth phase for up to several years before making the transition to the vertical phase. The prognosis of a SSM in the vertical growth phase (which produces a lesion that is more than 4.0 mm in thickness) is death in 75% to 80% of affected patients due to metastatic disease. In contrast, the mortality rate due to a SSM which is completely excised while confined to the radial growth phase (thickness of less than 0.85 mm) is about 1%. Therefore, early diagnosis of MM before progression to the vertical growth phase is a key component in the reduction of mortality from this tumor.

The histologic appearance of MM is variable with regard to cell morphology, melanin content and host response. The two cell types known to occur in MM are the epithelioid type and the spindle-cell type. For each variant of MM, one cell type appears to be dominant. SSM shows a predominance of epithelioid malignant melanocytes over the spindle-shaped cell type. The epithelioid type cells tend to lie in alveolar formations or "nests" while the spindle-shaped type are arranged in irregularly branching formations. The amount of melanin in a given MM tumor varies greatly. In SSM, melanin is usually scanty. The degree of inflammatory infiltrate in MM varies as well. A florid lymphohistiocytic infiltrate in SSM is usually seen only when the malignant melanocytes penetrate the basement membrane.

Nodular melanoma (NM) is the second most common variety (comprising 15% to 30% of malignant melanomas). The clinical appearance of these lesions is usually a uniformly blue-black nodule, round to irregular in shape, slightly elevated, and embedded beneath the skin surface. It differs from the other melanoma variants by its lack of a horizontal growth phase. NMs have a history of rapid growth (usually over weeks to months) and ulceration is fairly common. Due to the lack of the radial growth phase, NMs have a much higher potential and rate of metastasis (as well as a worse prognosis than SSM). The tumor is in a vertical growth phase from the outset and may already be highly invasive at the time of presentation. NM is characterized histologically by nodules of large, epithelioid melanocytes which grow in an expansile manner within the dermal connective tissue. Spindle-shaped cells are seen occasionally and a considerable amount of melanin pigment is usually present as well.

Acral lentiginous melanoma (ALM) represents 5% to 10% of malignant melanomas. It is the most common variety of MM in dark-skinned people and usually affects the palms, soles, and nailbeds. When mucous membranes are affected it is termed mucosal lentiginous melanoma. The clinical presentation of ALM is usually characterized by irregular borders and coloration; papular or nodular areas may be present on a macular background. ALM exhibits both radial and vertical growth phases. Its prognosis is somewhat poorer than SSM (probably due to delayed recognition). ALM is characterized histologically by a lentiginous radial growth phase followed by a deep vertical growth phase composed of predominantly spindle-shaped cells. Also seen is psoriasiform epidermal hyperplasia, prominent desmoplasia and an intense lymphohistiocytic host response.

Lentigo maligna melanoma (LMM) accounts for 5% to 12% of malignant melanomas. It is more common in women than in men and occurs almost exclusively in fair, usually elderly Caucasians. LMM affects the sun exposed body surfaces, especially the face, and is probably related to ultraviolet light exposure.

It is widely believed that LMM is preceded by a slowly growing lesion known as lentigo maligna or Hutchinson's freckle. Lentigo maligna is a black to brown pigmented lesion with irregular borders. Pigment cells are usually confined to the basal cell layer of the epidermis. Some consider lentigo maligna as a melanoma in situ or simply believe lentigo maligna is the prolonged radial growth phase of LMM. This is due to the fact that often after 10 to 15 years about 30% to 50% of lentigo maligna lesions start to exhibit nodular areas of vertical growth and invasion. This signifies progression into LMM. The malignant melanocytes of the vertical phase of LMM are usually of the spindle-shape cell type and may exhibit neurotropism and grow along small nerves. A lymphohistiocytic host response is commonly seen. LMM exhibits a slow rate of growth coupled with a lateness of metastases. There is a tendency for metastases to be limited, at first, to regional lymph nodes. These growth characteristics give LMM a survival rate of 90% to 94%, the highest among the melanomas.

A variant of MM is the amelanotic or nonpigmented melanoma and represents only about 2% of melanomas. This nodular lesion may appear pinkish in color. Amelanotic melanomas are thought to be less differentiated than pigmented MM and are unable to produce melanin. The lack of differentiation may be responsible for the aggressive behavior of amelanotic melanomas; 75% of which have already metastasized at the time of presentation. It is also believed that amelanotic melanomas are frequently overlooked or ignored by both patients and clinicians as unimportant or benign due to their lack of the more characteristic identifying features consistent with pigmented melanomas.

Medical Management and Treatment

The treatment of MM usually consists of excision. A 1 cm margin is usually considered adequate for small melanomas (those with a histologic depth of invasion less than 1 mm). For larger lesions, or those with a histologic depth of invasion greater than 1.24 mm, surgical removal of regional lymph nodes is recommended by some sources (although elective lymph node dissection in the absence of clinical involvement is still a controversial issue). Chemotherapy, radiation therapy, and immunotherapy do not appear to have had a significant impact on survival of metastatic MM.

There are several criteria which may be used in evaluating the prognosis of MM. It is widely believed that the best single indicator for the prognosis of MM is the total thickness of the tumor in the vertical growth phase. The Breslow system is used to classify MM on the basis of the actual total tumor thickness as measured from the outermost layer of the stratum granulosum to the deepest identifiable point of tumor invasion in the dermis. Survival rates based on tumor thickness should be correlated with site and sex data for greatest accuracy.

Level of tumor invasion is another important indicator of the prognosis of MM. The Clark system is generally used to grade tumor invasion based on the deepest histologic cutaneous structure the tumor infiltrates. The table below shows five year survival (FYS) rates for MM based on the Breslow and Clark grading systems.

Malignant Melanoma Classification and Five Year Survival (FYS) Rates

Clark System	FYS Rate
Level I - Tumor in situ Tumor is confined to the epidermis and is entirely above the basement membrane.	100% - 98%
Level II Invasive cells are only present in the papillary dermis. The tumor is usually still considered to be in the radial growth phase.	96% - 72%
Level III Tumor cells are found throughout the papillary dermis with impingement on the reticular dermis. The tumor has entered the vertical growth phase.	90% - 46%
Level IV Tumor cells are clearly seen between the collagen bundles of the reticular dermis.	67% - 31%
Level V Tumor cells show invasion of the subcutaneous fat.	48% - 12%

Breslow System*	FYS Rate
0.00 - 0.76 mm	98% - 99%
0.76 - 1.49 mm	85%
1.50 - 2.49 mm	84%
1.50 - 2.49 mm	84%
4.00 mm	44%

* Total tumor thickness as measured from the outermost layer of the stratum granulosum to the deepest identifiable point of tumor invasion in the dermis.

It is extremely rare to see metastasis from MM in Level I tumors which are usually less than 0.76 mm in total thickness. Level III or greater malignant melanomas are usually over 2.0 mm in thickness and commonly metastasize. Regional lymph nodes will usually be affected first. Metastases via the blood stream are also common and usually occur after regional lymph node involvement. When hematogenous spread occurs, almost every body organ may be affected—especially the lungs (88%), central nervous system (75%), gastrointestinal tract (73%), heart (70%), and liver (63%). Staging of MM and five year survival (FYS) rates are as follows:

Stage I - local disease with no metastases: 89% FYS
Stage II - invasion of regional lymph nodes: 30% to 61% FYS
Stage III - disseminated disease with distant metastases: less than 5% FYS

In general, MMs of the extremities have a better prognosis than do sites on the head, neck or trunk. Women appear to have a better prognosis than men for every site and thickness of MM. Histologically, melanomas that exhibit lymphocytic infiltration around the tumor, especially at its base, during the vertical growth phase have a much better prognosis than those which do not exhibit this infiltrative host response.

The number of mitoses per square millimeter is also an important prognostic indicator. A malignant melanoma with no observed mitoses per square millimeter is associated with the best prognosis. An intermediate mitotic rate of 1 to 6 per mm² indicate a somewhat poorer prognosis, while mitotic rates greater than 6.1 per mm² have an extremely poor prognosis.

Oral Malignant Melanoma

Malignant melanoma of the oral mucosa is quite rare and occurs in about one out of every two million persons annually in the United States, and accounts for less than 2% of all reported MM. The most common intraoral sites for MM is the palate and the maxillary gingiva/alveolar ridge. The average age for oral MM is 55 years. Oral MM generally has a poorer prognosis than cutaneous MM (FYS rate between 4% to 38% overall). Some possible explanations for the poorer prognosis of oral MM include the delay in initial detection of these lesions, and early invasion of oral MM into underlying bone in sites involving the palate or gingiva.

The differential diagnosis for a pigmented macular lesion of the oral mucosa would include: amalgam tattoo, focal deposit of hemosiderin pigment (ecchymotic macule), oral melanotic macule (focal melanosis), oral melanoacanthoma, acquired (e.g., compound or junctional) melanocytic nevus, congenital (e.g., blue) melanocytic nevus, and malignant melanoma. It is recommended that any equivocal pigmented oral lesion be excised and submitted for biopsy in order to rule out MM.

Authored by F. John Firriolo, DDS, PhD

Dr. Firriolo is an Associate Professor in the Division of Oral Diagnosis and Oral Medicine at the University of Louisville, School of Dentistry.

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