Contents
Melanoma is the most malignant neoplasm of the skin and mucous membranes, originating from melanocytes of pigmented nevi or unchanged skin. It arises as a result of their excessive stimulation due to exposure to ultraviolet radiation and gives early metastases both through the lymphatic and blood vessels.
Melanoma – frequency of occurrence
Melanoma is a disease that accounts for nearly 75% of deaths from skin malignancies. The proportion of skin melanoma patients has been increasing steadily among the white population – from 3 to 7% per year – over the past 30 years. The increased number of cases is due to earlier detection.
In white people, the number of people suffering from melanoma increases significantly as people move towards the equator. This is especially true of the white population in Australia (mainly Queensland), where the highest increase in incidence is recorded (approx. 40 cases per 100 inhabitants), and in the USA (mainly California, Florida, Hawaii). A high increase in the incidence of melanoma can also be noticed among the Jewish population in Israel (approx. 000%) and the white population in New Zealand (approx. 11%).
African and Asian population – here the incidence of lymphoma decreases. In Europe, the incidence of cutaneous melanoma is geographically declining towards the south due to the darker skin color of the Mediterranean. Among the inhabitants of northern Europe, the number of people suffering from melanoma is about 6%. A higher incidence of melanoma was also observed among the population of Switzerland and Tyrol.
DIG. 23.1. Melanoma from a lenticular spot. Lentigo maligna melanoma.
DIG. 23.2. Melanoma superficially spreading. Superfi cial spreding melanoma.
DIG. 23.3. Nodular melanoma. Nodular melanoma.
DIG. 23.4. Nodular melanoma. Nodular melanoma.
The causes of melanoma
The main causes of melanoma are:
• high exposure to ultraviolet radiation,
• practicing climbing and other sports in high mountains.
1. The largest number of people suffering from melanoma is recorded in Europe, specifically in Norway. This is largely related to the growing tendency to travel and sunbathe intensively.
2. High risk of melanoma is observed in both women and men, but mortality is higher in men. This is due to the unfavorable location of tumors, resulting in their later detectability and the predisposition to the development of more aggressive forms. However, the mortality rate is lower than the melanoma incidence rate. This is due to better diagnosis of melanoma, and thus earlier treatment initiation and large-scale public educational campaigns.
Factors influencing the formation of melanoma:
• overexposure and hypersensitivity to ultraviolet radiation (especially in childhood);
• sunburn;
• prolonged exposure to the sun;
• malignant transformation of melanocytes;
• having a large number of moles (atypical, dysplastic);
• predisposition to the formation of freckles;
• having a fair complexion, eye and hair color – the degree of pigmentation depends on the type of melanin and determines how the action of UV rays affects the skin and, consequently, the development of melanoma;
• intense but interrupted exposure to UV rays (often responsible for sunburn);
• patient’s age;
• low immune system of the patient;
• frequent use of a solarium or therapeutic UVA radiation;
• family predisposition to the occurrence of melanoma;
• previous history of skin cancer;
• the development of melanoma may be related to HPV infections and retroviruses;
• the influence of hormones that are activated in the period of puberty and the puerperium or the use of contraceptives;
• the influence of chemical substances / compounds (melanoma often occurs in people from highly industrialized cities);
• previous organ transplants undergoing immunosuppression;
• AIDS.
The location of the melanoma
90% of melanoma malignum (MM) develops in the skin, but it can also attack the meninges of the brain, the eyeball or mucous membranes.
• pigments, mainly hairless (naevi pigmentosi), especially in the area of a congenital giant nevus (naevus congenitalis giganteus);
• malignant lentil spots (lentigo maligna);
• junction nevus;
• mixed dermal-epidermal nevus (compound nevus);
• it can very rarely develop from a blue birthmark (naevus coeruleus malignus).
In addition, melanoma can arise de novo from unchanged skin. A large percentage of melanomas arise on the basis of atypical moles and a group of atypical moles.
DIG. 23.5. Nodular melanoma.
DIG. 23.6. Subungual melanoma.
DIG. 23.7. Colorless melanoma. Amelanoti.
Types of melanoma
There are four main types of melanoma (clinical and histological forms) depending on the changes from which they arise and the way the neoplasm spreads.
1) LMM (lentigo maligna melanoma) – is a melanoma that originates from a malignant lentil stain (Fig. 23.1). The first symptom of the transformation of lentigo maligna into lentigo maligna melanoma is the formation of small, palpable nodules and the appearance of a slight infiltration. LMM occurs in 5-20% of cases. It is characterized by a relatively mild and chronic course and a poor growth dynamics. This type of melanoma most often occurs in elderly people, after the age of 70 (especially in women). It is located almost exclusively on the face, sometimes on the neck. Occasionally, it may appear in other exposed areas, such as the backs of the hands and shins. LMM appears to be associated with chronic sun exposure.
2) SSM (superfi cial spreading melanoma) – this in turn is a superficial spreading melanoma (Fig. 23.2). The most common form of melanoma, it accounts for 60-70% of all melanoma malignum cases. It originates from pigmented marks (mostly atypical). The enlargement of the nevus, its discoloration and the occurrence of an inflammatory rim with a tendency to decay suggest the beginning of the development of a melanoma on the basis of a pigmented lesion. SSM occurs mainly in young and middle-aged people (most often in women). It is mainly located on the lower limbs of women and the torso of men. In the clinical picture, the SSM is presented as a slightly raised, sometimes flat lesion extending peripherally. There may be small nodules on the surface. SSM is characterized by uneven color, from black through various shades of brown to gray-blue. There may be discoloration within the lesion, indicative of spontaneous regression of the tumor, which confirms its immunogenic nature. The development of the SSM is relatively slow – several months or several years. SSM, like LMM and ALM, is initially spread mostly superficially. As long as it shows only a horizontal growth phase, the prognosis is good.
3) NM (nodular melanoma) – this is nodular melanoma (Fig. 23.3-23.5). It occurs in 10-30% of cases. It develops on the basis of pigmented moles or anew from unchanged skin. Up to 20% of NM cases can arise de novo. It can appear at any age, with peak incidence in the 40’s-60’s. year These are dark lumps 1-2 cm in diameter and larger, rapidly growing in size, and may ulcerate or bleed. It is the most severe form of melanoma, with a rapid course ranging from several months to 2 years. NM does not have a horizontal growth phase, it shows vertical growth from the very beginning, which results in its worst prognosis among melanomas (it infiltrates the deep layers of the skin very quickly). Even in very early lesions – according to Clark, the degree of invasion is at least third. It often metastasizes to regional lymph nodes. This figure is twice as common in men. Fires are mainly located on:
• head,
• nape,
• the torso.
Nodular lesions are most often black, but can also be purple or reddish-brown. In about 5% of cases, NM may occur as the so-called melanoma amelanoticum– colorless form.
4) ALM (melanoma acrolentiginosum, acrolentiginous melanoma) – this in turn is melanoma located on the limbs, originating from lentil spots. The acral form is rare in Caucasians, accounting for only 5% of melanoma cases. It is the most common form among Middle Eastern and African Americans (up to 90%). It often occurs among older people, around 70 years of age. The course is faster than LMM and SSM, ranges from several months to several years (average 1-3 years), and earlier it may also metastasize. These are most often lesions over 3 cm in diameter, often with a hyperkeratotic, ulcerated surface. The traumatic factor plays an important role in the development of ALM. This type of melanoma occurs mainly on the soles of the feet and the palms. It can affect the periungual and subungual areas of the feet and hands – it is a special, rare subtype of ALM, the so-called subungual melanoma – subungual melanoma (Fig. 23.6). 3/4 of the cases are located under the fingernail or thumb nail plate. Brown or black discoloration of the nail bed, mainly in the proximal part, is particularly noteworthy, and then goes to the periphery and locates around the nail. When broken down, subungual melanoma destroys the nail plate.
In addition to the four basic types of melanoma, there are other, less common:
1) ALMM (acral lentiginous mucosal melanoma) – mucosal melanoma. It is most commonly found on the mucous membranes of the mouth, the labia, under the tongue and in the esophagus. It can also be found on the external genitalia, anus and the urethra. The worst prognosis is changes in the area of the anus and vulva – five-year survival rates are less than 10%.
2) AMM (amelanotic malignant melanoma, melanoma amelanoticum) – is a pigment-free melanoma (Fig. 23.7). One of the most severe forms of melanoma; the lesion contains no or very little dye. The failure to produce the dye is due to the differentiation of the tumor cells, and thus their greater malignancy. These can be primary skin tumors or metastases.
3) DM (desmoplastic melanoma) – desmoplastic melanoma. Rare form, affects mainly people aged 40-60 years, with a predominance of women. Most often it is located on the head or neck. It is manifested by connective tissue overgrowth and infiltration of cancer cells along the nerves. Therefore, it is sometimes referred to as neurotropic melanoma. The clinical picture corresponds to SSM, LMM and ALM, the diagnosis is made on the basis of histopathological examination.
4) Intraepidermal malignant melanoma – intra-epidermal melanoma. A relatively recently separated clinical form. The lesion is limited to the epidermis. It differs from lentigo maligna in much younger people, the location is not limited to the face, and the development of this type of melanoma is not associated with sun damage to the skin and elastosis. It may resemble SSM clinically.
5) Melanoma developing in the eyeball – There is a significant difference in the immunogenicity of skin and eye melanoma cells. Melanoma of the eye is weakly immunogenic. Most often it affects the uvea (choroid, iris and ciliary body). Choroidal melanoma is the most common primary intraocular tumor in adults, occurring mainly in the 6th decade of life. Extremely rare among the black race. Unlike cutaneous melanoma, it grows slowly and metastasizes late. It can be pigmented or colorless (amelanocytic). Metastases can occur after many years, even after previous enucleation of the eyeball. Most tumors are characterized by slow growth. There is a genetic and family predisposition to skin melanoma in people with uveal melanoma. 2% of all neoplasms of the eyeball are conjunctival melanoma, and occasionally malignant transformation of the optic disc pigmentation nevus may occur.
6) MAR – melanoma associated retinopathy. It is an autoimmune disease with a sudden onset, manifested by night blindness and concentric visual field narrowing. A few months or years after the onset of cutaneous melanoma, autoantibodies against melanoma cells develop and cross-react with bipolar cells linked to the rod receptors of the retina.
Melanoma diagnosis
In the early diagnosis of melanoma, it is very important to know the symptoms that may accompany the neoplastic transformation of melanocytes. The American Cancer Society ABCDE rule applies to the diagnosis process:
A. Asymetry – asymmetry of shape,
B. Border – irregularity of the edge of the lesion,
C. Color – non-uniform color,
D. Diameter – diameter over 6 mm,
E. Elevation – elevation and unevenness of the surface.
The presence of all or some of the symptoms may suggest the development of melanoma.
Glasgow seven-point system (Scottish Melanoma Group): assessment of the following symptoms:
1) itching;
2) diameter over 1 cm;
3) enlargement of the birthmark;
4) irregular edge;
5) uneven color of the lesion;
6) inflammation;
7) bleeding or scab within the birthmark.
Each symptom is assigned 1 point. Change estimated at min. 3 and more points raise suspicion of melanoma.
The diagnosis is confirmed by:
• physical examination (epiluminescence microscopy, i.e. dermatoscopy, which makes it possible to visualize deep skin structures that are invisible to the unaided eye. Thanks to this examination, the doctor is able to magnify the image tenfold and analyze the distribution of the dye in the epidermis and on the border of the dermis;
• dermatoscopic examination can also be used in the differential diagnosis of vascular lesions, such as angioma capillare or granuloma telangiectodes, which in their clinical picture raise suspicion of melanoma malignum);
• histopathological examination supplemented by tests using monoclonal antibodies: S100 (always positive in melanoma cells, but not entirely specific) and more specific – HMB 45.
There is also the so-called Clark’s scale, i.e. the assessment of the depth of skin infiltration:
I – the changes concern only the epidermis,
II – lesions go to the upper parts of the papillary layer, III – lesions occupy the entire papillary layer of the skin (stratum papillare), IV – involvement of the reticulated layer of the skin (stratum reticulare), V – penetration into the subcutaneous tissue.
The greater the degree of skin infiltration, the worse the prognosis.
Melanoma and metastases
Melanoma can lead to local and distant metastases.
Local metastases are:
1) satellite metastases – occurring in the skin in the immediate vicinity of the tumor;
2) transit metastases – located intradermally or subcutaneously in the course of lymphatic outflow between the primary tumor and local lymph nodes;
3) local lymph node metastases – located according to the lymph drainage sites.
Melanoma malignum also metastasizes via the lymphatic vessels to distant lymph nodes and via the blood vessels to the lungs, liver, brain, bone and skin. Very rarely, MM metastases to the pancreas and trachea.
Melanoma – treatment
Any suspected melanoma lesion should be removed completely, partial biopsy or shave biopsy prevent pathomorphological assessment of tumor thickness and depth of infiltration. An important prognostic indicator, apart from the Clark and Breslow criteria, is also the mitotic index. Determination of all parameters (depth of infiltration, thickness of the lesion, mitotic index) enables an accurate prognosis of survival and the risk of metastasis. Treatment of melanoma malignum is started as early as possible in order to be successful.
The methods used to treat melanoma are listed below.
1. Surgery – the only effective treatment for melanoma is still the treatment of choice. Lesions are removed with an appropriate margin of intact tissue (both from the edge and from the bottom). The issues of contention in the field of melanoma surgery are: prophylactic excision of un enlarged local lymph nodes and the width of the margin of unchanged tissues.
It has been proven that prophylactic removal of lymph nodes does not improve prognosis and does not significantly increase survival rates. Careful observation of the patient is recommended (every 1-2 months), especially when the drainage of the lymph from the tumor area takes place in two or more directions.
Administration of dyes or radionuclides in place of the primary tumor can sometimes reveal a preferential area of lymphatic drainage. A diagnostic biopsy of local lymph nodes can also be performed to detect possible metastases early. Metastases can develop within a month to 20 years. Only when metastases to regional lymph nodes are found, radical surgery is performed. Nevertheless, the prognosis remains unfavorable. Only 67,7% of patients survive 3 years after removal of regional lymph node metastases, and 53,5% – 5 years.
Controversy among surgeons is also raised by the width of the healthy skin margin, which would protect against recurrence or metastasis. It is recommended: I – 2 mm margin of macroscopically unchanged skin around the lesion during diagnostic procedure; II – in therapeutic procedures, the margins of healthy skin are as follows: 1 cm for a lesion less than or equal to 2 mm thick (according to Breslow’s classification), 2 cm for a lesion greater than 2 mm and less than or equal to 4 mm, at least 2 cm margin or greater for lesions greater than 4 mm in thickness. In the case of subungual or periungual melanoma, the commonly used therapy is toe amputation.
2. Isolated perfusion – a method of treating inoperable melanomas on the limbs, used as an adjuvant treatment. It consists in excluding the limb from the bloodstream with the use of a tourniquet. This is followed by perfusion with a supraletal dose of cytostatic drug (melphalan, dacarbazine – DTIC). During perfusion, an oxygen pump is used and the system is leak-monitored to avoid poisoning. Isolated perfusion is effective in the case of numerous relapses or metastases within the limbs, especially in the case of axillary and inguinal lymph nodes.
3. Radiotherapy – under certain circumstances, it may be effective. It can be used as a treatment method in inoperable tumors, as a palliative or complementary method in case of incomplete surgical removal of the lesion. Irradiation should be used in large fractions (500-600 R twice a week), as opposed to radiotherapy in most cancers, for which lower and more frequent doses are administered.
4. Chemotherapy – combined immunosuppressive treatment with dacarbazine in combination with other drugs (bleomycin, vincristine, lomustine), aimed at influencing various development stages of the neoplastic cell, is used in very extensive lesions and with metastases. Due to the lack of significant differences in the statistics of long-term survival, aggressive polychemotherapy in many centers is replaced by a better tolerated monochemotherapy with dacarbazine in the treatment of metastases. Temozolamide is a drug of a new generation, chemically similar to dacarbazine and with comparable potency. It exceeds dacarbazine with the ability to penetrate the central nervous system and good absorption after oral administration. Treatment with TMZ in combination with interferons and other drugs is under consideration.
5. Treatment of metastases – single metastases in a distant lymph node or organ (brain, lung, liver) are removed surgically. Interferon alpha prolongs remission after resection of primary, advanced melanoma or after removal
6. Melanoma immunotherapy – the role of interferon and the effect of monoclonal antibodies directed against melanoma cell surface antigens are investigated. IL-2 – has no direct effect on melanoma cells. It works by stimulating T cells. IL-2 may also prolong metastatic survival. Rosenberg’s method – it is based on the activation of cytotoxic cells by means of IL-2 – NK cells and cytotoxic T lymphocytes. Patients’ lymphocytes are stimulated in vitro with IL-2 and then introduced into the patient’s system.
7. TIL (tumor infiltrating lymphocytes), ie cells from the vicinity of the tumor cultured in the presence of IL-2, which exhibit 1000-fold greater activity than LAK, especially after the introduction of the TNF-alpha gene. This method is still in the experimental phase. IL-12 – another cytokine which, together with other cytokines or in combination with specific immunostimulation, may prove helpful in the treatment of melanoma.
8. Gene therapy – introduces the MHC class I gene into neoplastic cells, which increases the tumor’s immunogenicity. Clinical trials are underway on a genetic vaccine for melanoma – containing genes that code substances that stimulate the immune system to fight skin cancer cells (IL-6 and its soluble receptor).
In the case of cutaneous melanoma, early diagnosis plays the most important role, enabling the diagnosis of melanoma when it is fully cured. It is possible thanks to the wide-scale education of the society and proper education of health care workers. As 90% of non-melanoma skin cancers and most melanomas are caused by ultraviolet radiation, it is very important to avoid excessive sun exposure, especially for people with Fitzpatrick skin phototypes I and II.
Melanoma – prevention
• Avoid exposure to sunlight, especially in childhood, associated with sunbathing and sunburn.
• It is advisable to wear protective clothing, sunglasses, wide-brimmed hats and avoid the sun when it is at its strongest – between 11.00 a.m. and 15.00 p.m.
• It is recommended to use sunscreen creams on a regular basis.
Filters – are physical substances that reflect and chemical substances that absorb ultraviolet radiation, reducing the amount of it reaching the skin. Thus, they weaken the harmful effects of UV radiation on skin cells. It should be emphasized that the use of filters does not completely prevent tissue damage from the sun. Paradoxically, numerous studies indicate that the use of sunscreen is associated with a higher risk of melanoma and non-melanoma skin cancers. Filters delay the onset of redness and skin burn symptoms, encouraging prolonged and uncontrolled exposure to the sun. So they often give a false sense of security. Despite the skilful use of filters, even several times while in the sun, the time of exposure to UV should be limited as much as possible. It is the only effective way of preventing the development of melanoma to date.
The prognosis of melanoma
The prognosis for melanoma depends on:
• clinical variety,
• depth of skin infiltration,
• thickness of the lesion.
As the thickness of the lesion increases, the risk of metastases in the local lymph nodes increases (respectively for: T1 <1%; T2 10-25%; T3 20-40%; T4 50-65%) and the risk of death (T1 <1%; T2 5-20%; T3 25-50%; T4 55-70%).
The 5-year survival at stage T1 is almost 100%, in T2 – about 93%, T3 – 67%, and in T4 on average 37%. With metastases to internal organs, the fatal descent occurs within several months – several years. Lesions located on the trunk have the worst prognosis, melanomas are better in women than in men. The worst-prognostic clinical forms are: nodular and pigmented melanoma.
Patients with cutaneous melanoma and eye melanoma are more likely to develop a second primary tumor. While patients with cutaneous melanoma are at increased risk of developing chronic lymphocytic leukemia and CNS tumors, patients with ocular melanoma are at increased risk of developing liver cancer.
LITERATURE:
1. Cattaruzza M.S.: Th e relationship between melanoma and continuous or intermittent exposure to UV radiation, Arch Dermatol 2000, 136, 773-774.
2. Dooley T.P.: Recent advances in cutaneous melanoma oncogenesis research, Oncol Res 1991, 6 (1), 1-9.
3. Katsambas A., Nicolaidon E.: Cutaneous malignant melanoma and sun exposure. Recent developments in epidemiology, Arch Dermatol 1996, 132, 444-450.
4. Mallory SB, Bree A., Chern P .: Pediatric dermatology – diagnosis and treatment, ed. half. Kaszuba A, Czelej Publishing House, Lublin 2007.
5. Th omas L., Braun RP: Atlas of dermoscopy, ed. half. Kaszuba A., Elsevier Urban & Partner Publishing House, Wrocław 2008.
Source: A. Kaszub, Z. Adamski, Dermatology. Practitioner’s Guidebook; Czelej Publishing House