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Pigmentation disorders. Pathology of the melanocytic system of the epidermis. Melanocytic tumors

Melanocytes are located in the basal layer of the epidermis. Their number varies in different parts of the skin. Melanocytes synthesize melanin in specialized organelles - melanosomes; tyrosinase is involved in this process. This enzyme catalyzes the conversion of tyrosine to dioxyphenylalanine (DOPA), which is converted into melanin during other biochemical reactions. Melanosomes that release melanin into the extracellular space are distributed along them. There, melanin is captured by keratinocytes, where it is broken down by the action of lysosomal enzymes. Its main purpose is to protect the underlying tissues from ultraviolet radiation. Skin color (including the intensity of tanning in people of the European race) is associated not so much with the number of melanocytes, as with their activity.

Vitiligo. This is a violation of skin pigmentation, which is expressed in the appearance of depigmented maculae of various sizes and shapes, having a milky-white color and a fringing in the form of a narrow zone of moderate hyperpigmentation. Vitiligo occurs in all races, but is most pronounced in people with dark skin. In individuals of the European race, skin changes may be completely invisible until the surrounding normal skin is covered in tan. From a clinical point of view, vitiligo is usually an asymptomatic disease. The size of the macules varies from a few centimeters to several centimeters; usually affects the skin of the wrists and armpits, the skin around the mouth and orbit, as well as the integument of the genital organs and around the anus.

For foci of vitiligo is characterized by loss of melanocytes. This is convincingly proven by electron microscopy. Thus, vitiligo is radically different from another diffuse pigmentary disease - albinism, in which there are melanocytes, but due to the cessation or violation of the synthesis of tyrosine they do not produce melanin. Both diseases can be distinguished from other forms of hypopigmentation (unrelated to the absence of melanocytes or tyrosinase) by means of histochemical determination of the activity of melanocyte tyrosinase. Progressive violation of melanin formation is explained by the influence of autoimmune and neurohumoral factors, toxic intermediates of melanin synthesis, leading to the self-destruction of melanocytes. The greatest amount of evidence collected in favor of the first mechanism. We are talking about the presence of circulating antibodies to melanocytes in patients and the association of vitiligo with diseases that can stimulate autoimmune mechanisms: pernicious anemia (see chapter 12), Addison's disease and autoimmune thyroiditis (see chapter 23). In addition, abnormalities of Langerhans cells of the epidermis and T-lymphocytes of peripheral blood have recently been discovered, which indicate the possibility of participating in the pathogenesis of vitiligo abnormalities in cell-mediated immunity.

Freckles. These are the most common skin pigment changes in childhood in people of the European race with fair skin. Freckles are small (1–10 mm in diameter) red or light brown macules that first appear in early childhood after sun exposure. Once having arisen, freckles disappear in the winter and appear again in the spring in a kind of cyclical mode. Hyperpigmentation, which appears in the elements of freckles, is caused by an increased amount of melanin in the keratinocytes of the basal layer of the epidermis. At the same time, the number of melanocytes does not exceed the normal values, although some of these cells may be increased in size. It remains unclear whether the freckles reflect a focal anomaly of melanin synthesis or the delivery of an increased amount of this pigment to the adjacent keratinocytes of the basal layer or both.

Melasma (skin melanosis). Melanosis - excessive deposition of melanin in the skin, but more pronounced than in the elements of freckles. Usually, melasma is a mask-like area of ​​hyperpigmentation on the face, which often occurs during pregnancy. We are talking about barely visible maculae appearing on the cheeks, temples and forehead on both sides. Sunlight can enhance this pigmentation, which often passes spontaneously (especially after the end of the pregnancy).

There are two histological types of melanoderma: epidermal, which produces an increased amount of melanin in the cells of the basal layer of the epidermis, and dermal, characterized by accumulation of macrophages in the papillary dermis, which phagocytes melanin from the epidermis (this process is called melanin incontinence). It is very important to recognize both types, since the skin during epidermal melasma can react to hydroquinone, which has a local bleaching effect (hydroquinone is an intermediate product in the production of dyes, a polymerization inhibitor, an antioxidant, a reagent in photography). The pathogenesis of melanoderma is associated with functional changes in melanocytes, which lead to enhanced pigment transfer to basal keratinocytes or dermal macrophages. Besides the fact that melasma is associated with pregnancy, it can occur when using oral contraceptive drugs and may be of unclear origin.

Lentigo. This hyperplasia of melanocytes, which occurs at any age, but especially often in infancy and early childhood. Sexual and racial predisposition was not identified, and the cause and pathogenesis of lentigo are unclear. The disease can affect both mucous membranes and skin. It manifests itself in the form of small (5-10 mm in diameter) oval brown maculae. Unlike freckles lentigo does not darken when exposed to sunlight. Its main histological feature is linear hyperplasia of melanocytes (occurring in the plane of the epidermis), which results in the formation of a basal layer containing an excessive amount of pigment. When lentigo often marked thinning of the net layer of the dermis.

Non-cellular nevus (pigmented nevus, mole). The mole is one of the most diverse, dynamic and biologically significant skin tumors. The name "non-cellular nevus" is used in relation to any congenital or acquired tumor consisting of melanocytes. The most common (acquired) non-cellular nevus is a small reddish-brown, uniformly pigmented, dense papule, usually less than 6 mm in diameter and well-defined rounded borders. There are a large number of clinical and histological types of non-cellular nevus, the most important of which are listed in the table. 25.1. A non-cellular nevus is formed from melanocytes, which are transformed from single process cells scattered among basal keratinocytes, into round or oval cells, growing in groups or nests along the junction of the epidermis and dermis. The nuclei of nevus cells are rounded, relatively monomorphic and contain not very visible nucleoli. Their mitotic activity is insignificant.

The surface form of the tumor reflects the early stage of its development and is called the border nevus. Gradually, the majority of border nevi grows into the underlying dermis in the form of cellular nests and cords (complex nevi) (Fig. 25.2, A). In more mature tumors, these nests may already be completely isolated from the epidermis. This is a dermal (intradermal) nevus (Fig. 25.2, B). Complicated and dermal nevi are usually elevated above the surface of the skin, unlike their borderline analogues. Progressive growth of nevus cells from the zone of a dermatoepidermal junction to the underlying derma is accompanied by a process called maturation. Despite their full maturity, those nevus cells that are closer to the surface of the skin are larger, tend to produce melanin and form nests. More: relian nevus cells, which are located deeper, are smaller. They grow with cords and synthesize a small amount of melanin or

Table 25.1.

Characteristic morphological forms of non-cellular nevi

it does not produce it at all. The most mature nevus cells can be found in the very heart of the tumor, where they often acquire a spindle-shaped form and grow in bundles, resembling nerve tissue. In such non-synthesizing pigment, deep-lying nevus cells similar to nerve structures, changes in enzyme activity (progressive loss of tyrosinase activity and the emergence of cholinesterase activity) are noted.

More rare variants of non-cellular nevus compared to those described are blue nevus (Fig. 25.3, A, B) and halo-nevus (Fig. 25.3, C).

Dysplastic nevus. The connection of non-cellular nevus with the development of malignant melanoma was discovered more than 160 years ago.
However, the true predecessor of malignant melanoma was studied in detail only about 20 years ago. In 1978, WHClark et al. described in detail the lesions, which they called the moles of the VC (after the initial letters of the names of the first two families studied). Birthmarks of VK (dysplastic

Fig. 25.2.

Nevi of various types


And - a complex nevus, B - dsrmalny (ntradsmalny) nevus (negatives of TA, Novitskaya and I.N. Chuprova).

Fig, 25.3,

Nevi of a different structure



blue nevus

, general view, masses of melanin are located in the deep parts of the dermis; B - light cells lacking pigment in the so-called proliferative part of the blue nevus.

Fig. 25.3. Continued.

AT -

halonevus, foci of nevus cells in the papillary dermis

protruding into the epidermis (negatives by TA Novinka and I.N. Chuprova).

cue nevi) are larger than other acquired moles: often their diameter exceeds 5 mm. These are flat maculae, or plaques, slightly protruding above the surface of the skin and possessing an uneven surface. As a rule, the degree of their pigmentation varies, and the edges have uneven contours.

Unlike freckles, dysplastic nevi appear on the surface of the skin, both exposed to sunlight and closed clothing. These tumors are found in many family members who have a tendency to develop malignant melanomas (suffering from hereditary melanoma syndrome). Genetic analyzes that were carried out on such persons revealed an autosomal dominant type of inheritance of dysplastic nevi. It has been suggested to participate in the hereditary transmission of a sensitive gene, which is located on the short arm of chromosome 1 near the Rh locus [according to Cotran RS, Kumar V., Collins T., 1998]. Dysplastic nevi can also occur as independent tumors that are not associated with hereditary melanoma syndrome, in this case the risk of malignancy is low. With the help of a serial study of biopsy specimens, clinically and histologically, some ling traced the transformation of dysplastic nevus into an early form of melanoma. It turned out that it occurs within a few weeks. However, most of these nevi are still stable (benign) neoplasms.

Dysplastic nevi are built from elements of a complex nevus that has architectural and cytological signs of abnormal growth. Intraepidermal nests of nevus cells have larger sizes and often merge with each other. Part of this process is that the individual nevus cells begin to replace keratinocytes of the basal layer, spreading along the dermatoepidermal junction. At the same time, there is atypia of nevus cells, manifested in the form of uneven, often angular contours and hyperchromasy of the nuclei. Changes affect the superficial regions of the dermis. Rare lymphoid infiltrates, loss of melanin from degraded nevus cells and its phagocytosis by dermal macrophages (melanin incontinence), as well as characteristic linear fibrosis of the reticular layer are found here. The probability of developing melanoma in people aged 60 years with dysplastic nevus syndrome is currently estimated at 56%.

Malignant melanoma. This is a relatively widespread disease, which was recently considered almost exclusively as fatal. In the vast majority of patients, melanoma occurs in the skin. At other localizations of this tumor, the mucous membranes are affected: oral cavity, genital organs, anus and esophagus. Especially often this tumor develops in the choroid (see below). Occasionally it is found in the membranes of the brain and mucous membranes of the urinary and biliary tract.

Sunlight plays an important role in the occurrence of malignant melanoma of the skin. For example, in men, it often develops on the upper back, and in women, on the back and legs. People with lighter skin are more at risk of developing melanoma than people with dark skin. Melanogenic factors include not only sunlight. The presence of preexisting nevus (especially dysplastic), hereditary factors or even the effect of certain carcinogens - all of this is important in the origin of tumors. The earliest clinical manifestation of a malignant melanoma of the skin is itching, and the most important symptom is a discoloration of the pigment lesion. Unlike the color of a benign (non-dysplastic) nevus, the pigmentation by melanomas varies considerably and is manifested in all sorts of shades of black, brown, red and gray. Sometimes there are zones of hypopigmentation of white or solid color. The boundaries of melanoma are indistinct, and the shape is non-circular, as with non-cellular nevus. They have the appearance of an irregular, convoluted and not everywhere clearly defined line.

Fig. 25.4.

Malignant lentigomelanom



superficial tumor spread

containing black pigment (melanin); B - detail of the structure, illustrating the malignant nature of growth (drugs A.S. Gordeladze),

Fig. 25.5.

Malignant melanoma


And - superficial type of distribution of a tumor; B - detail of the structure of the zone of surface distribution (approximate growth)

Fig. 25.5. Continued.

AT -

stage of tumor site formation

(drugs A.S. Gordeladz).

The concept of radial and vertical growth underlies the interpretation of the structure of malignant melanoma. Radial growth indicates the tendency of tumor cells to spread horizontally (growth) in the epidermal and superficial dermal layers. Such growth often takes a long period of time. In the course of his melanoma cells still do not show the ability to metastasize. There are three types of radial growth of melanoma: malignant lentigo (Fig. 25.4, A, B), surface spread (Fig. 25.5, A, B), lentiginous lesions of the mucous membranes and limbs. They are determined by the overall composition of growth and the structure of tumor elements in the epidermal layer, as well as by the biological behavior of melanoma. For example, a malignant lentigo in the radial growth phase usually occurs on the sun-damaged skin of the face of older people; it may exist for several decades before it suddenly metastases. Over time, the radial growth changes to vertical. In the form of an expansively increasing mass, the tissue of the melanoma rushes into the deeper layers of the dermis. In this mass, the cells remain at the stage of low differentiation and, as they spread into the net layer of the dermis, become smaller and smaller. At the same time, on the basis of the preceding flat and radial growth phase, a tumor site is visually (clinically) noted (Fig. 25.5, B). It is during this period that clones of tumor cells with metastatic potential are formed. The probability of metastasis can be predicted using a simple measurement (in millimeters) of the depth of invasion, which is determined by the thickness of the vertical growth zone, which begins just below the granular layer of the epidermis.

As a rule, melanoma cells are much larger than the elements of the nevus. They have large nuclei with irregular contours and marginally (under the nuclear membrane) located chromatin, as well as clearly defined eosinophilic nucleoli. These cells either form solid nests, or grow in small groups or alone. All this occurs in all layers of the epidermis or in the dermis. As with other malignant tumors, it is important to note not only the degree of histological differentiation of tumor nests and complexes, but also the presence of melanin and the depth of invasion. The number of mitosis figures determined among tumor cells, the level of lymphocytic infiltration of the stroma and parenchymal complexes of the neoplasm are considered to be important prognostic indicators.

As for melanoma of the eye, the incidence of this tumor is V5o from that for skin melanoma (for this tumor, see Chapter 26).

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Pigmentation disorders. Pathology of the melanocytic system of the epidermis. Melanocytic tumors

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