Melanocytic nevus: clinical guidelines

List of Abbreviations

J – joule

CGMN - congenital giant melanocytic nevi

CMN - congenital melanocytic nevi

PUVA – therapy with drugs from the groups: topical psoralens or systemic psoralens combined with ultraviolet A irradiation

LoE – level of evidence

LER — level of evidence and recommendation

UV – ultraviolet

UVI – ultraviolet irradiation

FAMMM syndrome – familial atypical multiple mole-melanoma syndrome

Terms and Definitions

Melanoma risk factors are genetically predetermined human characteristics or external exposures that increase the probability of developing primary melanoma.

Screening is a system of primary examination of clinically asymptomatic groups of individuals to detect cases of the disease.

Early diagnosis is the earliest possible detection of pathological conditions in patients who already have symptoms.

FAMMM syndrome is a condition in which two or more first-degree relatives have multiple dysplastic nevi and a history of melanoma (1).

Dysplastic nevus is a benign acquired melanocytic nevus with atypical clinical characteristics and histological features (structural abnormalities and cytologic atypia, always involving the junctional zone [dermo-epidermal junction]), associated with an increased risk of melanoma in the patient.

Dermoscopy is a non-invasive optical diagnostic method for neoplasms and diseases of the skin and its appendages.

Dermoscopic structural pattern is a variant of the distribution of dermoscopic structures within a skin neoplasm, determined during dermoscopy.

MRI — magnetic resonance imaging

LM — longitudinal melanonychia

Dysplastic nevus syndrome is a genetically determined condition characterized by multiple nevi, including clinically atypical ones with histological features of dysplastic nevi. This syndrome is associated with a high risk of cutaneous melanoma. Multiple dysplastic nevi can be a manifestation of FAMMM syndrome associated with germline mutations in the CDKN2A and CDK4 genes.

Melanoma-pancreatic cancer syndrome is a hereditary disorder characterized by multiple dysplastic nevi (10–100) 5–15 mm in diameter, early onset of melanoma (20–45 years), sometimes multiple primary melanomas, and a familial clustering of melanoma and pancreatic adenocarcinoma. This syndrome is a phenotypic variant of FAMMM syndrome and is associated with germline mutations in the CDKN2A gene.

Melanoma-astrocytoma syndrome is a hereditary disorder manifested by a predisposition to melanoma and/or CNS glial tumors, both benign and malignant (2). This syndrome is a phenotypic variant of FAMMM syndrome and is associated with germline mutations in the CDKN2A gene.

Tumor predisposition syndrome or BAP1-syndrome is a predisposition to a wide range of neoplasms associated with germline mutations in the BAP1 gene. Patients with this syndrome have a significantly increased risk of developing melanoma and basal cell skin carcinoma, as well as certain malignant neoplasms of internal organs—primarily uveal melanoma, pleural and peritoneal mesothelioma, and renal cell carcinoma. A characteristic feature of this syndrome is the presence of 5 or more specific nevi in the patient, termed BAPomas (nevi with BAP1 inactivation; previously classified among atypical spitzoid tumors). At the same time, isolated BAPomas do not indicate a hereditary predisposition! (3).

Xeroderma pigmentosa is a hereditary disorder associated with germline mutations in the XP gene family. These genes are responsible for DNA repair following damage caused, in particular, by ultraviolet radiation. Therefore, patients with this condition exhibit marked photosensitivity, with severe sunburns after minimal sun exposure, early freckling, lentigines, and other signs of poikiloderma at a young age. Xeroderma pigmentosa carries an exceptionally high risk of melanoma and squamous cell carcinoma of the skin—according to some estimates, it exceeds the population average risk by more than 1,000 times (4).

Oculocutaneous albinism type 2 is a hereditary pigmentation disorder characterized by hypopigmentation of the skin, hair, and eyes, associated with germline mutations in the OCA2 gene. This condition dramatically increases the risk of melanoma and cutaneous squamous cell carcinoma, including at a very young age—under 20 years (5).

PUVA is a combined therapy using a photosensitizing agent from the groups: topical psoralens or systemic psoralens and long-wave ultraviolet radiation (UVA band, wavelength 320–400 nm)

Shave biopsy (tangential excision biopsy) is the removal of a thin slice of superficial tissue using a blade

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Melanocytic nevus is a benign melanocytic proliferation clinically presenting as a brown, pink, or blue symmetrically pigmented macula or a soft papule with a smooth surface. Benign acquired melanocytic nevi are typically less than 6 mm in diameter.

Acquired melanocytic nevi generally do not require treatment, but a high number of them, a clinically atypical appearance, histological confirmation of dysplasia within the nevus, or the presence of other clinical or anamnestic risk factors (Appendix A2) may indicate an increased risk of melanoma.

Melanoma risk factors are genetically predetermined human characteristics or external exposures that increase the probability of developing primary melanoma.

Cutaneous melanoma risk group refers to patients who possess risk factors for cutaneous melanoma.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Aetiological risk factors for melanoma are divided into endogenous (carrying melanoma-associated genes; human phenotypic characteristics) and exogenous (exposure to natural or artificial ultraviolet radiation, immunosuppression).

Ultraviolet radiation causes signature mutations in DNA. When mutations occur in genes associated with melanoma development, proliferation of malignant melanocytes is observed.

Genes associated with an increased risk of cutaneous melanoma determine human phenotypic characteristics (skin phototype, nevus count), which in turn indicate an increased risk of melanoma during clinical examination. The dependence of nevus count on genetic predisposition is confirmed in 60–70% of cases according to twin studies (6).

The risk of melanoma is highest in a number of genetic syndromes associated with melanoma. These primarily include FAMMM syndrome, melanoma-pancreatic cancer syndrome, melanoma-astrocytoma syndrome, tumor predisposition syndrome or BAP1-syndrome, xeroderma pigmentosa, oculocutaneous albinism (especially type 2), and hereditary retinoblastoma, as well as certain multisystem hereditary disorders, notably Cowden syndrome. The probability of developing melanoma is highest in individuals with xeroderma pigmentosa and oculocutaneous albinism; according to various authors, the risk in these patients is increased by 1,000 to 2,000 times compared to the general population level. In these two syndromes, the high risk of melanoma and other skin malignancies manifests starting from adolescence; in the other hereditary disorders listed above, the risk increases starting at approximately age 30.

An increased risk of cutaneous melanoma associated with specific genetic disorders can be suspected in the following cases:

1) Clinical presentation:

A) A significant number of atypical skin nevi in the patient — more than 20 dysplastic nevi OR more than 5 BAPomas OR more than 5 blue nevi — OR a large congenital nevus in the spine area OR symmetric upper and lower eyelid nevi ("kissing naevi");

B) Signs of a non-inherited genetic disorder associated with aberrant melanocytic proliferation — giant congenital nevus OR clinical picture of port-wine stain syndrome;

C) Clinical picture of a hereditary disorder manifested, among other things, by an increased risk of skin malignancies — hypersensitivity to ultraviolet radiation (xeroderma pigmentosa, Bloom syndrome, Nijmegen breakage syndrome) OR oculocutaneous albinism OR signs of a multisystem hereditary disorder accompanied by a large number of skin nevi.

2) Personal history:

A) History of two or more multiple primary cutaneous melanomas (especially if at least one was diagnosed before age 40);

B) History of cutaneous melanoma and brain glial tumor;

C) History of cutaneous melanoma and pancreatic adenocarcinoma;

D) History of retinoblastoma with a verified germline mutation or bilateral involvement;

E) History of uveal melanoma with a verified germline mutation or bilateral involvement.

3) Family history:

A) Diagnosis of cutaneous melanoma in three or more blood relatives of the patient;

B) Diagnosis of uveal melanoma in two or more blood relatives of the patient;

C) Diagnosis of multiple primary cutaneous melanomas in at least one of the patient's blood relatives;

D) Diagnosis of multiple primary tumors, specifically cutaneous melanoma and brain glial tumor, in at least one of the patient's blood relatives;

E) Diagnosis of multiple primary tumors, specifically cutaneous melanoma and pancreatic adenocarcinoma, in at least one of the patient's blood relatives.

In all of the above cases, the option of regular dermatological examination at least once a year can be considered and discussed with the patient.

In all of the above cases, except for item 1B, the patient may be offered a consultation with a geneticist followed by a decision on DNA diagnostics for a hereditary disease.

In the cases described in item 1B, i.e., in the presence of a giant congenital nevus or the clinical presentation of port-wine stain syndrome, the patient may be offered a consultation with a neurologist to rule out a more severe variant of the disease – neurocutaneous melanosis or Sturge-Weber syndrome, respectively (7-13).

1.3 Epidemiology of the Disease or Condition

Benign melanocytic skin neoplasms undergo certain changes throughout life. Thus, at birth, only congenital melanocytic nevus may be detected, while melanocytic neoplasms arising during the first three years of life are called "late congenital nevi" due to their histological similarity to congenital nevi (14). In subsequent years, the appearance of acquired nevi is noted in the child, which have a globular structure upon dermoscopy. The most active appearance and growth of new melanocytic neoplasms is observed during puberty, when dermatosocopic structural patterns of nevi also become more diverse. Clinically, nevi also acquire diverse characteristics, which is most noticeable in adulthood, when some nevi remain as pigmented macules, while others evolve into an elevated papule. In old age, flat nevi regress, and elevated nevi gradually lose pigment and persist as a fibrous papule in senility.

Of particular interest is the prevalence of melanocytic neoplasms associated with an increased risk of cutaneous melanoma (dysplastic nevi, congenital melanocytic nevi). Depending on whether the diagnosis of dysplastic nevus is made clinically or histologically, the reported incidence rate ranges from 2% to 53% (15). The prevalence of congenital melanocytic nevi ranges from 0.5 to 31.7%, and giant congenital melanocytic nevi develop in 1 in 20,000 to 500,000 newborns (16).

1.4 Features of Coding the Disease or Condition

Melanocytic nevus (D22)

D22.0 — Melanocytic nevus of lip

D22.1 — Melanocytic nevus of eyelid, including canthus

D22.2 — Melanocytic nevus of ear and external acoustic meatus

D22.3 — Melanocytic nevus of other and unspecified parts of face

D22.4 — Melanocytic nevus of scalp and neck

D22.5 — Melanocytic nevus of trunk

D22.6 — Melanocytic nevus of upper limb, including shoulder region

D22.7 — Melanocytic nevus of lower limb, including hip region

D22.9 — Melanocytic nevus, unspecified

1.5 Classification of the disease or condition

According to the histological classification proposed by the WHO in 2018, the following are distinguished:

Melanocytic tumors of skin periodically exposed to solar radiation

- Simple lentigo and lentiginous melanocytic nevus

- Junctional, compound, and intradermal nevus

- Dysplastic nevus

- Spotted nevus (Spitz nevus, nevus spilus)

- Nevi in special anatomical sites (breast, axillae, scalp, ear)

- Halo nevus

- Meyerson nevus

- Recurrent nevus

- Deep penetrating nevus and melanocytoma

- Pigmented epithelioid melanocytoma

- Combined nevus, including combination of BAP1-inactivated nevus and melanocytoma

Spitzoid tumors

- Spitz nevus

- Reed nevus

Melanocytic tumors on acral skin

- Acral nevus

Melanocytic tumors of mucous membranes and genitalia

- Genital nevus

Melanocytic tumors arising from blue nevus

- Blue nevus and cellular blue nevus

- Mongolian spot

- Ito nevus and Ota nevus

Melanocytic tumors arising from congenital nevus

- Congenital melanocytic nevus

- Proliferative nodules within congenital melanocytic nevus

Melanocytic tumors of the eye

- Conjunctival primary acquired melanosis with atypia / primary acquired melanosis

1.6 Clinical presentation of the disease or condition

Benign melanocytic neoplasms have independent clinical significance in the case of few (less than 50) lesions. Multiple melanocytic nevi are characteristic of a number of syndromes. A description of benign melanocytic neoplasms included in the WHO histological classification (2018) and associated syndromes is presented below.

Simple lentigo and lentiginous melanocytic nevus

An intensely pigmented round or oval macule with clear borders, usually less than 5 mm in diameter. Since an increase in the number of epidermal melanocytes is determined histologically in lentigo, in the histological classification of neoplasms (WHO, 2018), simple lentigo is classified among melanocytic neoplasms and is considered as an early stage in the formation of so-called simple nevi.

Junctional, compound, and intradermal melanocytic nevus (simple acquired nevi)

These are pigmented macules or papules with regular round outlines and uniform pigmentation, consisting of benign proliferates of nevus cells in the skin. Simple acquired nevi make up the bulk of melanocytic lesions detected upon naked-eye examination.

Junctional nevus (syn.: junctional nevus, transitional nevus)

Appears as a well-demarcated, uniformly pigmented brown macule (flat on palpation) or papule (slightly elevated on palpation) with round outlines and preserved skin markings on the surface. They appear in early childhood and evolve into intradermal nevi in subsequent years, and may acquire features of dysplastic nevi.

Intradermal nevus

Clinically defined as an elevated flesh-colored papule or nodule with a smooth surface and round or oval outlines. It is detected predominantly at 10-30 years of age. Unna nevus (papillomatous nevus, clinically resembling a blackberry, skin-colored to dark brown, most commonly located on the trunk skin) and Miescher nevus (dome-shaped papule with a smooth surface, pale brown or skin-colored, most commonly located on the facial skin) are distinguished.

Compound nevus (syn.: mixed nevus)

Clinically usually defined as an elevated, intensely pigmented nodule with preserved skin markings on the surface, typically less than 1 cm in size. Over the years, it may evolve into an intradermal nevus.

Dysplastic nevus

Dysplastic nevi are defined as nevi with atypical clinical characteristics (atypical melanocytic nevi) and histological features (structural abnormalities and cytological atypia always involving the junctional zone).

The generally accepted clinical criteria for diagnosing dysplastic nevi are those proposed by the International Agency for Research on Cancer (IARC, 1990). At least one area of the lesion must have a macular structure, and at least three of the following features must be present:

- indistinct borders,

- diameter of 5 mm or more,

- color variation,

- irregular outlines,

- erythema

Nevus spilus (Speckled lentiginous nevus)

Nevus spilus presents as a light brown, usually oval patch with distinct borders, within which multiple darker brown macules or papules (melanocytic nevi) are identified. Typically, nevus spilus is not associated with other diseases or developmental anomalies, nor is it a marker of an increased risk of cutaneous melanoma, although isolated case reports of melanoma developing within a nevus spilus exist.

Nevi in special anatomical sites

These are melanocytic nevi on the skin of the breast, axillae, scalp, ear, umbilical region, genitalia, and acral areas. These lesions are benign, but present with atypical or unusual clinical, dermoscopic, and histological features, which complicates differentiation from melanoma, leading to overdiagnosis and excessively frequent repeat excisions.

Clinically, nevi in special anatomical sites appear as benign melanocytic nevi (uniformly or nonuniformly pigmented macules or papules) distinguished by a larger size (>6 mm) and irregular outlines.

Halo nevus (Sutton nevus)

Clinically, a brown nodule or macule is identified, sometimes with a red tint, surrounded by a peripheral zone of hypopigmentation. Halo nevi most commonly occur without association with any underlying pathology, but may be associated with vitiligo, poliosis, pernicious anemia, Vogt-Koyanagi-Harada syndrome (poliosis, uveitis, vitiligo, alopecia, deafness), dysplastic nevus syndrome, and melanoma. As a rule, halo nevi occur in children and adolescents. Following the formation of the depigmented rim, a slow immune-mediated regression of the nevus is observed, followed by gradual repigmentation of the skin.

Meyerson nevus

This is a benign melanocytic nevus (of any histological structure) overlain by eczematous inflammation (Meyerson phenomenon). The Meyerson phenomenon is characterized by the development of an inflammatory reaction around a pre-existing nevus or another lesion: a sebaceous nevus, seborrheic keratosis, or even melanoma.

Recurrent nevus (synonyms: persistent nevus, pseudomelanoma)

This is a nevus that reappears within a scar following incomplete removal, biopsy, or trauma. Examination reveals pigmentation in the area of the scar: when removal is insufficiently deep, the pigment is located in the central part; when insufficiently wide, it is at the periphery. Recurrent nevi are distinguished from melanoma by two main criteria:

1) Timing of development (nevi recur within the first two years after removal, the majority within the first 6 months; melanoma may recur later than 6 months after removal).

2) Zone of pigment spread (recurrent nevi do not extend beyond the borders of the scar, whereas melanoma typically spreads into the tissues adjacent to the scar).

Deep penetrating nevus

This is an acquired melanocytic neoplasm consisting of pigmented spindle-shaped and/or epithelioid melanocytes with a characteristic deep-portion architecture. These neoplasms frequently mimic melanoma.

Pigmented epithelioid melanocytoma

Upon examination, it appears as a slowly growing, heavily pigmented nodule or papule. It may occur as a sporadic lesion or as part of Carney complex.

Combined nevus, including combined BAP1-inactivated nevus/melanocytoma

This melanocytic neoplasm contains two or more components of different melanocytic nevi within a single lesion. Most commonly, a combination of a common nevus and a blue nevus, deep penetrating nevus, or Spitz nevus is identified.

Spitz nevus

Belongs to the spectrum of spitzoid neoplasms along with atypical spitzoid tumor and malignant Spitz tumor. Most commonly encountered in childhood. Clinically, it usually appears as a pink or light brown, oval or round macule or papule with distinct borders and a smooth surface, less than 6 mm in diameter.

Reed nevus (pigmented spindle cell nevus)

This is a subtype of Spitz nevus (synonym: pigmented spindle cell nevus), frequently mimicking melanoma clinically and dermoscopically. Most commonly occurs in children and young adults (mean age 25 years) as a well-circumscribed, symmetric flat papule or nodule ranging from 1.5 to 10 mm in diameter. It is characterized by uniform dark brown, blue-black, or black pigmentation and a staged clinical course with periods of growth, stabilization, and subsequent spontaneous regression, which is observed in the majority of cases.

Blue nevus and cellular blue nevus

Clinically, a blue nevus is identified as a blue-gray macule or papule with round outlines, a smooth surface, and usually small size (up to 5 mm). Cellular blue nevus typically appears as a pigmented nodule elevated by several millimeters or even centimeters.

Blue nevus occurs at any age, most commonly sporadically, and occasionally forms as part of Carney complex (cardiac myxoma, lentigines, endocrine neoplasia). It is not associated with an increased risk of malignancy.

Mongolian spot

This is a dermal melanocytosis occurring in the lower trunk or gluteal region. More common in Asian and African populations, with the typical localization being the coccygeal region. Most commonly, the lesion fades as the child grows, but it may be associated with cleft lip, polydactyly, lysosomal storage disease, inborn errors of metabolism, Sjögren-Larsson syndrome, phacomatosis pigmentovascularis (association of widespread atypical persistent Mongolian spot with vascular developmental anomalies, such as capillary malformation).

Nevus of Ota

This is a dermal melanocytosis located within the innervation zone of the 1st and 2nd branches of the trigeminal nerve. Nevus of Ota develops during adolescence or is present at birth (50%) as a bluish macule within the innervation zone of the 1st and 2nd branches of the trigeminal nerve, with pigmentation intensifying after puberty. Association with deafness, intraocular melanocytosis, or cerebral melanocytosis is possible. There are case reports of orbital melanoma and brain melanoma associated with nevus of Ota.

Nevus of Ito

This is a dermal melanocytosis occurring in the lateral neck, supraclavicular, scapular, and deltoid regions.

It occurs at any age, most commonly sporadically, and occasionally forms as part of Carney complex (cardiac myxoma, lentigines, endocrine neoplasia). It is not associated with an increased risk of malignancy.

Congenital melanocytic nevus

This is a benign melanocytic neoplasm present at birth or appearing during the first three years of life (late congenital melanocytic nevi). They can occur in any anatomical site. Small (<1.5 cm), medium (1.5–20 cm), and giant (>20 cm) late congenital melanocytic nevi are distinguished. The size of a congenital melanocytic nevus is directly proportional to the risk of developing melanoma. Some blue nevi may also be congenital.

Large late congenital melanocytic nevi of the scalp and back, as well as late congenital melanocytic nevi with multiple satellite nevi, may be accompanied by neurocutaneous melanosis.

Proliferative nodules within a congenital melanocytic nevus

These are considered nevi arising within the dermal component of a congenital melanocytic nevus. Clinical manifestations may be detectable at birth or develop in subsequent years. In the second half of life, they decrease in size and regress; transformation of proliferative nodules into melanoma has not been proven.

Conjunctival primary acquired melanosis (with or without atypia)

This is a diffuse pigmented patch on the conjunctiva formed by a melanocytic proliferation, but not representing a melanocytic nevus.

Clinically, primary acquired melanosis with atypia is indistinguishable from primary acquired melanosis without atypia, and is characterized by a large size, irregular outlines, and frequently a multifocal nature. Junctional nevus of the conjunctiva differs from primary acquired melanosis by having distinct borders. The listed benign melanocytic neoplasms may have independent clinical significance or form as part of the syndromes indicated below.

Dysplastic nevus syndrome

Diagnostic criteria for dysplastic nevus syndrome are still under discussion (Table 2). However, despite the variety of approaches to diagnosing dysplastic nevus syndrome, the need to monitor a group of patients with a confirmed diagnosis of dysplastic nevus syndrome according to any of the listed criteria is unquestionable.

Table 2. Diagnostic criteria for dysplastic nevus syndrome.

FAMMM syndrome (familial atypical multiple mole-melanoma syndrome) is diagnosed when two or more first-degree relatives (i.e., parents, siblings, or children) have multiple dysplastic nevi and a history of melanoma (17). This syndrome is associated with germline mutations in the CDKN2A and CDK4 genes, characterized by autosomal dominant inheritance with incomplete penetrance. Melanomas in these patients occur at a younger age than usual (18).

2. Diagnostics, medical indications and contraindications for diagnostic methods

2.1 Complaints and Anamnesis

Diagnostic criteria:

1) anamnesis data;

2) physical examination data;

3) dermoscopic examination data (skin inspection under magnification using a dermatoscope (dermoscopy));

4) confirmation using laboratory diagnostic methods;

5) if necessary, data from lifetime pathomorphological examination of skin biopsy (surgical) material.

When collecting complaints and medical history, a dermato-venereologist and/or oncologist/pediatric oncologist assesses risk factors for melanoma development and factors that may influence the choice of diagnostic methods, treatment tactics, and secondary prevention. The patient may report verbally or provide relevant documentation indicating information on the time of appearance or duration of the lesion, regular trauma, location of the nevus protruding above the skin surface subject to friction, and the subjective perception of the nevus as a cosmetic defect [7,11,12,15,19-22].

Risk factors for cutaneous melanoma identified during medical history collection:

• family history: history of melanoma and/or non-melanoma skin cancer (basal cell carcinoma, squamous cell carcinoma); history of mycosis fungoides; melanoma and/or non-melanoma skin cancer (basal cell carcinoma, squamous cell carcinoma) in relatives;

• familial atypical multiple mole-melanoma syndrome (FAMMM syndrome);

• excessive UV exposure, including past use of artificial UV radiation;

• history of burns;

• occupational hazards;

• chronic immunosuppression (malignancies, AIDS, organ transplantation);

• carriers of mutations in the CDKN2A and CDK4 genes, including first-degree relatives;

• Others: age and gender – men over 50 years old; history of suspicious skin lesion removal; childhood malignancy (mainly treated with radiotherapy), new, changing nevi, or nevi accompanied by symptoms (e.g., subjective sensations); regularly traumatized nevi.

2.2 Physical Examination

During the initial presentation of a patient complaining of a skin lesion, a physical examination is performed by a dermato-venereologist and/or oncologist/pediatric oncologist to evaluate the clinical presentation with simultaneous inspection of all skin integuments, skin appendages, and visible mucous membranes. When assessing skin lesions, it is necessary to determine their number (single/few (less than 50)) / multiple (more than 50)), and the primary morphological element or combination thereof (macule/macule-node/node). During the examination, clinical signs of skin lesions suspicious for melanoma must be identified or excluded [7,11,12,15,19-24].

Visual inspection is a fundamental component of skin lesion evaluation, especially for detecting melanoma-susicious features. However, evidence indicates that using visual inspection as a standalone and sole method of clinical evaluation leads to a high rate of false-negative results. Therefore, to ensure accurate diagnosis, other methods, particularly dermoscopy, must be used in combination with visual inspection.

It is necessary to correctly interpret certain clinical features of special types of nevi that may be misdiagnosed as clinical signs of melanoma. These include a hypopigmented rim around a halo nevus, the presence of erythema with fine-lamellar desquamation at the periphery of a Meyerson nevus (which regresses with dermatological glucocorticoids), the appearance of pigment within 1-2 months in the center of a scar after prior nevus removal in a recurrent nevus, the presence of all morphological elements varying in color and shape against the background of a hyperpigmented patch in a speckled nevus, and the appearance of erythema around and within the nevus upon trauma confirmation.

During the initial presentation of a patient complaining of a skin lesion, the presence of melanoma risk factors is assessed during the physical examination [20-24].

Risk factors for cutaneous melanoma identified during physical examination:

• nevus count: more than 20 acquired nevi on one upper extremity; >60 acquired nevi; >40 acquired nevi and at least 2 atypical nevi; >40 acquired nevi and a history of melanoma or BCC/SCC; >40 acquired nevi and red hair; >40 acquired nevi and a history of sunburns or artificial UV exposure; >40 acquired nevi and genetic mutations; >40 acquired nevi and a history of organ transplantation;

• Fitzpatrick skin phototypes I-II;

• signs of skin photodamage (actinic lentigo/seborrheic keratoses, actinic keratosis, simple lentigo, lichenoid keratosis, solar elastosis);

• high density of ephelides;

• "ugly duckling" sign (one lesion differs from all others);

• large and giant congenital nevi.

2.3 Laboratory Diagnostics

Laboratory diagnostics are not performed prior to morphological confirmation of the diagnosis, unless intercurrent pathology or the patient's general condition requires it for the safe execution of a skin biopsy. The treatment and evaluation plan should not be formulated before receiving the pathomorphological examination results of the biopsy (surgical) material [25].

Comment: High 24-hour urinary dopamine concentration in children with giant congenital melanocytic nevi, particularly in those with neurocutaneous melanosis, may help predict prognosis in patients with a more severe neurological course of the disease.

2.4 Instrumental Diagnostics

The examination of a patient presenting with skin lesions must be performed by a physician skilled in the early diagnosis of malignant skin tumors using dermoscopy (skin inspection under magnification using a dermatoscope) [23, 24, 28-35].

Comment: Dermoscopy of simple lentigo and lentiginous melanocytic nevus reveals a reticular pattern. Specific dermoscopic features of a junctional nevus include a typical pigment network, a structureless area, dots, round dark brown or black globules, or a combination of these structures, with mandatory preservation of the symmetry of the dermoscopic picture.

The dermoscopic picture of an intradermal nevus is characterized by the following typical structures: a globular pattern (more often at a young age), grey-brown polygonal cobblestone-like globules (often in Unna nevi), hypo- and hyperpigmented structureless areas (grey-blue or "blue-white veil") (in Miescher nevi), hairpin vessels, curved vessels, or a combination of these structures, with mandatory preservation of the symmetry of the dermoscopic picture.

In a compound nevus, the dermoscopic picture is characterized by a combination of structures typical of junctional and intradermal nevi.

A pigmented atypical nevus is characterized by a multi-component (pigment network, dots, round and polygonal globules, structureless area) yet symmetrical dermoscopic picture, and includes features of both compound and intradermal components. An amelanotic or minimally pigmented atypical nevus is characterized by a comma-like or serpentine vessel pattern. Dermoscopy of a dysplastic nevus may reveal any patterns characteristic of benign melanocytic nevi according to pattern analysis, but dysplastic nevi may differ from nevi without dysplasia by an imprecise match to these structural patterns.

A dermoscopic feature of a halo nevus is the presence of a peripheral white structureless area around any nevus.

In Meyerson's nevus, dermoscopy reveals a pink structureless area with a dotted vessel pattern forming around the nevus.

A characteristic dermoscopic feature of a recurrent nevus is the presence of a star-shaped grey-brown structureless area in the center of the scar following prior removal.

When dermoscopically examining a spot nevus (nevus spilus), areas of various dermoscopic structures corresponding to the surface nevus type (junctional, intradermal, Spitz nevus, blue nevus, etc.) are determined against the background of a light brown structureless area.

On dermoscopy, acral nevi present with one of three patterns: parallel furrows (along dermatoglyphic sulci), a lattice pattern (in lesions on the skin of the instep), or a fibrillar pattern (in lesions on the weight-bearing skin of the sole). Differentiation between benign melanocytic neoplasms and melanoma in acral regions is performed using the BRAAFF algorithm (see section "Additional information, including factors influencing the outcome of the disease or condition"). The most frequent dermoscopic feature of a benign acral nevus is the presence of parallel furrows along dermatoglyphic sulci. The most significant feature suspicious for acral melanoma is parallel ridges along dermatoglyphic crests.

Upon dermoscopy, benign mucosal melanocytic lesions more often exhibit a single organized pattern, whereas melanomas more frequently demonstrate a disorganized multicomponent structure with blue, grey, and/or white zones.

Subungual nevi also possess specific dermoscopic features. These include the sign of typical parallel thin brown lines, identical in color and thickness; sometimes, in heavily pigmented structures, the pseudo-Hutchinson sign may form due to subungual pigment translucent through the cuticle, creating a false impression of its pigmentation. Subungual melanoma is distinguished by the presence of parallel lines in the nail plate that vary in color and thickness and are located at varying distances from each other. An extremely suspicious sign for subungual melanoma is pigmentation of the adjacent skin (Hutchinson's sign).

Dermoscopy of a halo nevus (Sutton's nevus) reveals a hypopigmented zone at the periphery, with dermoscopic structures characteristic of a benign melanocytic neoplasm located in the center. As regression progresses, the nevus pattern becomes homogeneous, pigmentation decreases, and in the final stages of nevus regression, a milky-red veil and a peripheral red rim may form around the regressing nevus.

Dermoscopy of Meyerson's nevus reveals features characteristic of eczema at the periphery (orange round structureless areas corresponding to serous crusts, dotted vessels, erythema), while the center shows a nevus that undergoes marked changes under the influence of Meyerson's phenomenon, becoming pale, acquiring a greyish color and a homogeneous structure.

Upon dermoscopy, recurrent nevi exhibit the following dermoscopic features: asymmetry, distinct borders, a homogeneous or multicomponent pattern, an atypical pigment network, atypical streaks, black dots, globules, and a bluish-grey or reddish color.

Dermoscopy of pigmented epithelioid melanocytomas may reveal homogeneous blue pigmentation. In some cases, a combination of blue and black colors, white streaks, and less commonly, a brown color and comedo-like openings are detected.

Dermoscopy of a combined nevus reveals features characteristic of the types of nevi that are combined within the neoplasm.

Dermoscopic examination of an amelanotic Spitz nevus typically reveals a pattern with dotted vessels (in a flat neoplasm) or globular and/or serpentine vessels, a white network, or white streaks (in a nodular lesion) [42].

The dermoscopic picture of a pigmented Spitz nevus (Reed nevus) is represented by a grey-black structureless area with a symmetrical peripheral arrangement of pseudopods or lines ("radiated" or the so-called "starburst" sign), or a globular pattern with reticular depigmentation (negative network) [42]. Homogeneous (hyperpigmented structureless area), reticular, globular, and multicomponent patterns may occur less frequently. The pattern reflects the stage of nevus development: a radiating or globular pattern is determined during the growth phase, areas of homogeneous or reticulated structure may form during the stabilization period, and during lesion regression, characteristic features of regression are noted, often asymmetrically distributed (grey dots and grey structureless areas).

Dermoscopy of a blue nevus typically reveals a structureless blue zone across the entire area, gradually transitioning into healthy skin at the periphery.

Dermoscopy of a Mongolian spot, Ota nevus, and Ito nevus is characterized by a grey-blue structureless area of varying color intensity, occasionally with small white structureless areas or white lines.

Congenital melanocytic nevi are most commonly characterized by a dermoscopic picture of compound nevi with a combination of diverse dermoscopic structures and their symmetrical distribution. An additional sign of congenital nevi with acral localization (thick skin of the palms and soles) is the presence of globules against the background of pigmented sulci or the "lattice" pattern.

Proliferative nodules within a congenital melanocytic nevus on dermoscopy either have a pattern characteristic of the surrounding nevus areas or exhibit features typical of intradermal nevi. Multiple proliferative nodules often share a similar pattern. Dermoscopic features of cutaneous melanoma and erosions are characteristically absent.

When performing dermoscopic examination of skin neoplasms, it is necessary to examine all skin lesions present in the patient while assessing for features indicating an increased risk of melanoma development [43].

Features indicating an increased risk of cutaneous melanoma detected upon dermoscopy include:

• variability of nevus dermoscopic patterns in a single individual (e.g., black nevi with a globular structure + pink nevi with a homogeneous structure + brown nevi with a reticular-globular structure);

• non-conformity of the dermoscopic pattern of a single lesion to the structure of the majority of other lesions (the "ugly duckling" sign);

• non-conformity of the nevus structure to the expected pattern (according to age group and phototype);

• multicomponent dermoscopic pattern of most nevi, which is 3 times more common in patients with melanoma.

In the multicomponent (complex) dermoscopic structural pattern, dermoscopic algorithms for melanoma diagnosis are used (see the section "Additional information (including factors influencing the outcome of the disease or condition)"), which provide relative objectification of the assessment. The main dermoscopic patterns that can prompt skin biopsy are asymmetrically distributed peripheral globules and/or pseudopodia after puberty, atypical pigment network, polymorphic vessels, featureless grayish-blue area, or the "veil-like white-blue" sign or another color located peripherally, atypical dots and globules located asymmetrically, negative pigment network, regression areas.

2.5 Other Procedures

Comment. Based on the analysis of complaints, medical history, and physical examination of the patient using dermoscopic algorithms, and upon identification of dermoscopic criteria for a questionable ("grey zone") or melanoma-suspicious skin neoplasm, the need for a biopsy is determined.

If clinically atypical melanocytic neoplasms are identified that do not have clinical signs of melanoma according to the ABCDE rule, but reveal suspicious clinical or dermoscopic features, the patient must be referred for an excisional skin biopsy with pathological-anatomical examination of the skin biopsy (surgical) material using immunohistochemical methods (as indicated) for pathomorphological verification of the diagnosis and determination of further management. Suspicious clinical and dermoscopic features include:

• appearance and growth of a single melanocytic neoplasm that differs from the rest of the existing ones in clinical and/or dermoscopic features in patients over 50 years of age.

• appearance of a melanocytic neoplasm with clinical and dermoscopic features of a Spitz nevus or Reed nevus in patients over 12 years of age;

• features listed in dermoscopic algorithms for melanoma diagnosis (pattern analysis, chaos and clues algorithm, Argenziano algorithm, Menzies algorithm, BRAAFF algorithm) (see the section "Additional information (including factors influencing the outcome of the disease or condition));

• recording of changes in a melanocytic neoplasm in a patient at high risk of cutaneous melanoma, if comparison of serial dermoscopic images over time shows the emergence of features characteristic of cutaneous melanoma;

• identification of unclear skin neoplasms that are elevated or palpable, have a somewhat dense consistency on palpation, and increase in size;

• development of pronounced changes in dermoscopic features during dynamic monitoring;

• identification of pigmented skin neoplasms with asymmetrically distributed peripheral globules and/or pseudopodia after puberty, atypical pigment network, polymorphic vessels, featureless grayish-blue area, or the "veil-like white-blue" sign or another color located peripherally, atypical dots and globules located asymmetrically, negative pigment network, regression areas determined by dermoscopy;

• presence of cutaneous melanocytic neoplasms with a peripheral globule ring, if dynamic monitoring reveals asymmetric structural changes in addition to an increase in area;

• detection of non-pigmented or partially pigmented lesions with milky-red globules or areas of polymorphic vessels;

• presence of a solitary pigmented, non-pigmented, or atypical seborrheic keratosis lesion;

• identification of atypical blue nevi characterized by additional white dermoscopic structures in addition to a gray or grayish-blue featureless area;

• presence of an atypical acral neoplasm dermoscopically characterized by at least one atypical dermoscopic feature (parallel ridge pattern, nonspecific feature) or assessed using the BRAAFF algorithm;

• presence of dermatofibromas with atypical dermoscopic features;

• presence of neoplasms whose diagnosis remains unclear upon clinical and dermoscopic examination;

• emergence of a non-pigmented lesion or one identical to the initial lesion at the site of neoplasm destruction (laser, radiofrequency, cryodestruction, electrodesiccation).

When performing an excisional skin biopsy to confirm the diagnosis of a questionable or melanoma-suspected skin neoplasm, a 0.5 cm margin is observed (an acceptable margin is 0.1-0.3 cm). In cases of large and giant melanocytic neoplasms, especially in aesthetically significant areas, performing this may be associated with significant difficulties and unjustified surgical trauma for the patient. In these clinical situations, it is justified to perform a full-thickness incisional skin biopsy (or punch biopsy) of one of the representative areas on the surface of the questionable skin neoplasm, which does not negatively affect the prognosis.

When performing an excisional skin biopsy of a melanoma-suspected area, one should orient along a longitudinal skin incision in patients parallel to the lymphatic vessels toward regional lymphatic collectors using local infiltration anesthesia.

Comment: In other clinical cases with longitudinal melanonychia up to 6 mm in width, depending on the affected area of the nail matrix, it is advisable to use appropriate incisional biopsy techniques:

Comment: According to the classification of melanocytic pathology and its grading for MPATH-DX, five categories are distinguished: I - nevus/mild atypia, II - moderate atypia, III - severe atypia/melanoma in situ, IV - invasive melanoma T1a, V - ≥ invasive melanoma T1b. The most frequent cause of discrepancies among pathologists was differences in diagnostic thresholds associated with subjective evaluation. Reaching a consensus required a number of approaches, and the proposed classification can help objectify pathological reports.

Histological examination of simple lentigo and lentiginous melanocytic nevus reveals a somewhat increased number of epidermal melanocytes.

In a junctional nevus, histological examination reveals clusters of nevus cells in the lower part of the epidermis, at the dermo-epidermal junction. Mitoses are typically absent.

In an intradermal nevus, histological examination shows nevus cells forming clusters within the dermis. Unna nevus is more frequently characterized than Miescher nevus by: nests in the junctional zone above the intradermal component, radial growth of intradermal nests, vascular-like clefts lined by nevus cells, and maturation of deep compartments. Miescher nevus is more frequently characterized than Unna nevus by: sebaceous follicles, folliculitis beneath the nevus, large isolated melanocytes along the basal layer of the epidermis, multinucleated nevocytes, and adipocytes. In a compound nevus, histological examination shows nevus cells located at the dermo-epidermal junction and in the upper part of the dermis.

Histological diagnostic criteria for dysplastic nevus are defined in accordance with the histological classification (WHO, 2018) and include architectural and cytologic atypia. The term "architectural atypia" denotes a deviation from the stereotyped structure of junctional and lentiginous nevi (in which uniform nests of melanocytes are evenly distributed throughout the lesion at the tips of epidermal rete ridges), as well as an increase in the size of the lesion compared to simple acquired nevi. Features of architectural atypia include the presence of junctional "shoulders" (lateral extension of melanocytes) adjacent to the dermal component (or the lesion may be entirely junctional), fusion of adjacent epidermal rete ridges, slight suprabasal spread of melanocytes restricted to the lower level of the epidermis (usually less pronounced than in melanoma), concentric and lamellar fibroplasia around elongated epidermal rete ridges, and a focal lymphocytic infiltrate. Cytologic atypia is characterized by enlarged nuclei (with varying degrees of pleomorphism), chromatin clumping and hyperchromasia, and nucleoli of varying prominence. Melanocytes with the same cytologic characteristics as in a junctional nevus are identified in a dysplastic nevus. Mitoses are extremely rare.

In some cases, a specialist may describe the histological pattern of a melanocytic neoplasm as:

1) Superficial atypical melanocytic proliferation of uncertain significance (SAMPUS). Atypical melanocytic proliferation in the epidermis and superficial dermis with insufficient features to establish a definitive diagnosis, but not allowing the exclusion of melanoma in the horizontal growth phase, characterized by the absence of features of the vertical growth phase of the tumor.

2) Intraepidermal atypical melanocytic proliferation of uncertain significance (IAMPUS). The term IAMPUS is used to describe lesions that require differentiation from melanoma in situ. The terms SAMPUS and IAMPUS are applied to describe diagnostically challenging lesions that require differentiation from melanoma without metastatic potential, but with potential for local persistence, recurrence, and progression upon incomplete excision. These lesions have a very excellent prognosis after excision. In this context, "uncertain significance" denotes the risk of local regrowth and further progression.

3) Melanocytic tumor of uncertain malignant potential (MELTUMP). An atypical melanocytic infiltrate in the dermis that is neoplastic but lacks the specific features required to differentiate between benign and malignant proliferations. This term is used to describe neoplastic proliferations that require differentiation from melanoma in the vertical growth phase. Malignant potential refers to the risk of metastasis and death from the disease even after complete excision.

In a spot nevus (nevus spilus), histological examination within the hyperpigmented macule reveals elongated epidermal rete ridges with a slight increase in the number of melanocytes. Spots within the spot nevus may histologically have the structure of a lentiginous junctional nevus, compound and intradermal nevi, compound or intradermal nevi with features of congenital nevi, Spitz nevi, blue nevi, and dysplastic nevi (nevi with cytologic atypia).

Nevi in special anatomic sites show architectural features on histological examination that differ from those of simple acquired nevi and resemble those of dysplastic nevi and melanomas, including asymmetry, uneven distribution of melanocyte nests, cytologic atypia, pagetoid spread, dermal fibroplasia, and lymphocytic infiltrate.

In a halo nevus, histological examination reveals nevus cells in the dermis and epidermis, partially or completely obscured by a lymphocytic infiltrate.

Meyerson nevus is characterized histologically by features of a nevus combined with spongiotic dermatitis: parakeratosis and serous exudate are detected over epidermal acanthosis and spongiosis. A superficial perivascular lymphocytic infiltrate, predominantly CD4+, is identified. Eosinophils may be present. The infiltrate may overlie the nevus, which can be acquired or congenital.

Recurrent nevi can be histologically compound, junctional, or intradermal. Pagetoid spread of atypical melanocytes resembling melanoma may be detected, and solitary atypical cells may be found in the superficial part of the scar. Cytologic atypia is usually mild, but can occasionally reach moderate to severe grades. Mitoses may occasionally be observed. The presence of atypia does not appear to depend on the type of nevus initially removed. The histological landmark for differentiation from melanoma is the localization of melanocytes within the scar. In complex cases, revision of the initial biopsy is mandatory.

Deep penetrating nevi histologically appear as a well-circumscribed, symmetric intradermal melanocytic tumor composed of enlarged pigmented spindle and epithelioid cells, often forming a V-shaped configuration.

Pigmented epithelioid melanocytoma on pathomorphological examination represents a melanocytic neoplasm consisting of pigment-laden epithelioid and dendritic cells, capable of metastasizing to regional lymph nodes.

A combined nevus is histologically characterized by features typical of the nevus types combined within the neoplasm.

Spitz nevi histologically consist of large epithelioid and/or spindle cells and have a characteristic architectural organization.

Reed nevi are identified on histological examination by vertically oriented, convoluted, or concentric bundles of uniform, mildly pigmented spindle cells comprising the junctional component. Pagetoid spread of melanocytes is frequent, though restricted to the lower half of the epidermis.

A blue nevus pathomorphologically represents a dermal melanocytic tumor composed of dendritic, spindle, and/or ovoid cells laden with melanin, accompanied by stromal sclerosis.

Mongolian spot, Ota nevus, and Ito nevus reveal solitary pigmented dendritic melanocytes in the dermis upon histological examination.

Comment: Experts have proposed dividing ambiguous clinical cases into two diagnostic categories:

• SAMPUS (Superficial Atypical Melanocytic Proliferation of Unknown Significance) – superficial atypical melanocytic proliferation of unknown significance;

• MELTUMP (MELanocytic tumours of Uncertain Malignant Potential) – melanocytic tumour of uncertain malignant potential.

• According to the concept of melanoma progression through radial and vertical growth phases, it was appropriate to distinguish additional categories, such as:

• STUMP (Spitz Tumour with Uncertain Malignant Potential) – atypical Spitz tumour with uncertain malignant potential;

• THIM (THIn Melanoma) – thin melanoma;

• THIMUMP (THIn Melanoma of Uncertain Metastatic Potential) – thin melanoma of uncertain metastatic potential.

The SAMPUS category includes neoplasms with a Breslow thickness of ≤ 1 mm on the border between in situ/THIM and non-neoplastic epidermal, junctional, and/or dermal (papillary dermis) melanocytic proliferation (such as atypical actinic lentigo, junctional or superficial mixed dysplastic nevus, pigmented spindle cell nevus of Reed), with an absence of mitoses and tumor dermal growth. The prognosis for such neoplasms is favorable, but given the insufficient data, wide local excision of the skin neoplasm is preferred.

The MELTUMP category includes neoplasms with a Breslow thickness of > 1 mm with the presence of dermal melanocytic proliferation, exhibiting vague features of a malignant neoplasm, with a potential for metastatic events. This group includes neoplasms such as atypical Spitz nevus (STUMP), pigmented spindle cell nevus with dermal atypia with minimal difference from melanoma, pigmented epithelioid melanocytoma, atypical blue nevus, dysplastic nevus with dermal atypia, and certain deep penetrating nevi. In such clinical situations, it is advisable to seek a second expert opinion from a pathologist specializing in melanocytic pathology. When choosing a therapeutic strategy, wide local excision and sentinel lymph node biopsy (SLNB) followed by molecular genetic testing are preferred.

1. Non-metastatic THIM with a radial growth phase, Breslow thickness ≤ 1 mm, invasion into the papillary dermis, with absence of proliferation or formation of tumor nodules, mitoses, and regression zones. In such clinical cases, wide local excision without SLNB is preferred.

2. Metastatic THIM with a vertical growth phase, Breslow thickness ≤ 1 mm, associated with a statistical chance of distant metastases, presence of large tumor nests of 25–50 cells in the papillary dermis that are larger than in the epidermis, and presence of mitoses, which should be counted using the "hot spot" method. In this case, wide local excision and SLNB are indicated.

3. THIM with unknown metastatic potential, Breslow thickness ≤ 1 mm, with extensive regression zones (greater than 75%). Wide local excision and SLNB are preferred.

Comment: Molecular genetic testing in some cases allows for the clarification of the malignant potential of a melanocytic tumor classified in the "gray zone" based on purely histological criteria.

Molecular markers that allow a melanocytic tumor to be classified as malignant primarily include hotspot mutations in the TERT gene promoter region, homozygous deletion of the CDKN2A gene, RREB1 gene amplification, and PRAME gene expression. These markers can be assessed using methods based on PCR, sequencing, MLPA, and FISH technologies. In individual cases, additional tests, including immunohistochemistry, may be used.

These molecular markers possess high specificity and, consequently, a high positive predictive value. A negative result for these markers generally does not allow the tumor to be definitively classified as benign. An exception is spitzoid tumors, in which these markers—when used in combination with a number of additional molecular tests—allow for a fairly confident assessment of a specific neoplasm as benign (Spitz nevus), intermediate (atypical Spitz nevus), or malignant (spitzoid melanoma).

Special mention should be made of two groups of melanocytic tumors characterized by a specific set of molecular alterations. These are, firstly, blue nevi and blue nevus melanomas (as well as rarer tumors originating from dermal melanocytes, in particular nevus of Ota and nevus of Ito), and secondly, proliferating nodules and melanomas arising in giant congenital nevi. In both cases, molecular testing can be performed to clarify the malignant potential of a specific neoplasm. It requires a special panel of markers relevant only to these types of melanocytic tumors, but allows for the highly reliable detection of both benign neoplasms and melanomas.

The decision to use molecular genetic testing to clarify the malignant potential of a specific melanocytic neoplasm should be made on an individual and multidisciplinary basis through a collaborative discussion involving a dermatologist and/or oncologist/pediatric oncologist, a pathologist, and a geneticist specializing in melanocytic pathology.

NB! Not all molecular markers can be used for differential diagnosis. Testing for so-called driver molecular alterations, including mutations in BRAF, NRAS, HRAS, KRAS, KIT, GNAQ, GNA11 genes, molecular genetic testing for gene translocations of ALK, ROS1, RET, NTRK1, NTRK2, NTRK3, RAF1, BRAF, etc., allows for the identification of targets for targeted therapy, which is extremely important when planning drug treatment for cutaneous melanoma. However, these molecular alterations occur in melanomas and nevi with approximately the same frequency. Consequently, testing for these markers does not allow benign melanocytic lesions to be distinguished from malignant ones and, accordingly, cannot be used for the differential diagnosis of melanomas and nevi [64–88].

Comments: suspicious clinical and dermoscopic signs include the appearance and growth of a melanocytic neoplasm in patients over 50 years of age; the appearance of a melanocytic neoplasm with clinical and dermoscopic features of a Spitz nevus or Reed nevus in patients over 12 years of age; and signs listed in dermoscopic algorithms for melanoma diagnosis (pattern analysis, chaos and clues algorithm, Menzies method, Argenziano algorithm, BRAAFF algorithm) (see section "Additional Information (including factors influencing the outcome of the disease or condition)").

Comments: prophylactic removal of dysplastic nevi is considered inappropriate and excessively traumatic, since 70% of melanomas in patients with dysplastic nevi develop de novo (on initially "clean" skin) [46]. Therefore, the current consensus is that monitoring and selective removal of the lesions most suspicious for melanoma is the preferable approach.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Treatment of benign melanocytic nevi with a typical clinical and dermoscopic picture is not required. However, in case of physical or aesthetic discomfort, removal of benign skin lesions or destruction of benign melanocytic nevi with pathomorphological verification of the diagnosis is possible. Targeted therapy is considered as a "last resort" option for unresectable or recurrent large nevi causing significant symptoms. The literature describes at least two cases of targeted therapy for large and giant nevi not amenable to surgical treatment, after identifying a molecular target for therapy; in both cases, a very substantial antitumor effect was achieved[93-97].

Comment: unlike small and medium congenital melanocytic nevi (CMN), melanomas arising in large and giant CMN frequently develop deep within the dermis or subcutaneous tissue, making early detection difficult. Based on several large prospective and retrospective cohort studies, the risk of melanoma associated with a large or giant CMN is 5% or greater. Therefore, early and "complete" surgical removal is desirable for large and giant CMN to prevent the development of melanoma; however, this is often either impossible or extremely difficult, carrying high risks to the child's life and health. Pediatric oncology practice utilizes staged excision of CGMN using tissue expanders to create excess skin for subsequent defect closure. An alternative approach is meticulous active surveillance. Decision-making regarding the management of a child with a CGMN should be carried out by a multidisciplinary team at the federal center level.

The use of analgesia and dietary therapy for benign melanocytic nevi is not recommended.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Medical rehabilitation is not required for patients with benign melanocytic skin neoplasms.

5. Prevention and Dispensary Observation

Prophylactic removal of clinically typical lesions is not performed in patients with multiple melanocytic neoplasms.

Comments: patients with risk factors for melanoma are advised against using tanning beds. It is necessary to wear protective clothing and use sunscreens. Patients with risk factors for cutaneous melanoma should perform a monthly self-examination of the entire skin surface.

Comments: Sequential digital dermoscopy is the periodic recording and evaluation of dermoscopic images of the skin and skin neoplasms to detect new dermoscopic features of melanoma. Patients with very high-risk factors who undergo total body skin photography with dermoscopic image documentation of skin neoplasms are recommended to have their first follow-up visit with a physician in 1.5–4.5 months to rule out rapidly growing skin neoplasms. If the clinical and dermoscopic picture remains stable, subsequent follow-up examinations are recommended at intervals of 6–12 months [104]. Patients with solitary atypical melanocytic nevi are recommended to undergo short-term digital dermoscopy at intervals of 1.5–4.5 months. Long-term digital dermoscopy at intervals of 6–12 months is recommended for high-risk patients with or without multiple atypical nevi [105-114].

• changing or new lesions in patients older than 50 years;

• lesions causing concern to the patient;

• lesions corresponding to the "ugly duckling" clinical sign (differing from other lesions in the given anatomical area in the patient);

• lesions clinically similar to surrounding growths but dermoscopically distinct from them (exhibiting a positive "Little Red Riding Hood" sign)

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comments: patients with very high-risk factors need to remain under dispensary observation for life due to the persistent risk of developing cutaneous melanoma.

6. Organization of Medical Care

Primary specialized health care for patients with benign melanocytic neoplasms is provided by dermatovenerologists, surgeons, oncologists/pediatric oncologists on an outpatient basis.

Specialized medical care is provided to patients by dermatovenerologists, surgeons, oncologists/pediatric oncologists and includes the prevention, diagnosis, and treatment of benign melanocytic skin neoplasms requiring the use of special methods and complex medical technologies, as well as medical rehabilitation.

In severe cases of benign melanocytic neoplasms, when outpatient therapy is ineffective, and after clarifying the diagnosis, inpatient treatment in a 24-hour / day hospital is indicated.

Indications for hospitalization (day / 24-hour hospital):

• Presence of a benign melanocytic neoplasm requiring surgical treatment in a hospital setting.

Indication for patient discharge

• Achieving remission

7. Additional Information

Risk factors for cutaneous melanoma in patients with melaniform nevi

1) Personal history of melanoma

The risk of developing a second primary melanoma in patients with a history of melanoma is higher than in the general population. A second tumor is detected in 1–11% of patients, half of them within the first year [115, 116]. If the patient has a family history of melanoma, this figure increases to 19% [117]. In one-third of these patients, the second melanoma is detected simultaneously with the first, while the rest are diagnosed during follow-up [117].

2) Personal history of non-melanoma skin cancer (basal cell carcinoma, cutaneous squamous cell carcinoma, mycosis fungoides)

Since the development of malignant epithelial skin tumors (basal cell carcinoma, squamous cell carcinoma), as well as melanoma, correlates with cumulative lifetime ultraviolet exposure, the risk of developing melanoma in patients with a history of these malignant epithelial skin tumors is increased 17-fold. At the same time, 80% of lesions occur on sun-protected skin areas [118]. In patients with mycosis fungoides, the risk of cutaneous melanoma is increased 15-fold, likely due to immunosuppressive therapy [119].

3) Family history of melanoma (including familial atypical multiple mole-melanoma syndrome) and certain other malignancies and hereditary syndromes in relatives

Up to 12% of melanoma patients have a hereditary form of the disease [119-121]. A hereditary form of melanoma should be suspected in cases of multiple melanoma cases along a single family lineage, multiple primary malignancies in a single patient, and when melanoma is diagnosed at a young age (under 40 years). Furthermore, having a single relative with melanoma increases the patient's risk of developing it by 1.7-fold, while having two relatives with melanoma increases the risk by 9-fold.

4) FAMMM syndrome (familial atypical multiple mole-melanoma syndrome) is diagnosed when two or more first-degree relatives (i.e., parents, siblings, or children) have multiple dysplastic nevi and a history of melanoma [122]. Germline mutations in the CDKN2A gene, as well as in the CDK4 and ARF genes, accumulate in the population of these patients, with autosomal dominant inheritance and incomplete penetrance. Melanomas in these patients occur at a younger age than usual [123].

5) Age and gender — men over 50 years of age

Melanomas in this patient group often grow rapidly, have a thickness of ≥3 mm, and predominantly present as the nodular type [124].

6) New, changing nevi, or nevi accompanied by subjective symptoms

New or changing melanocytic neoplasms detected in adulthood and old age are particularly suspicious [124].

7) History of removal of pigmented lesions (removal of benign skin lesions) due to suspected melanoma (including those histologically verified as dysplastic nevi or melanoma)

It should be emphasized that the removal of dysplastic nevi does not eliminate the risk of cutaneous melanoma, as 70% of melanomas develop de novo. Therefore, the current consensus is that a strategy of active surveillance for patients with dysplastic nevi, with the removal of the most suspicious or significantly changing ones, is more appropriate [124].

8) Intense sun exposure

It is well established that sunburns in childhood double the risk of developing melanoma. Furthermore, the lifetime pattern of sun exposure influences the spectrum of subsequent neoplasms. Intense episodic sun exposure (e.g., during vacations) is associated with the highest risk of melanoma, particularly its superficial spreading form. Chronic continuous sun exposure leads to actinic keratosis, squamous cell carcinoma, and lentigo maligna melanoma [124].

9) Artificial ultraviolet radiation (tanning bed sessions, phototherapy, use of UV lamps for manicures)

Artificial UV radiation makes a significant contribution to the incidence of cutaneous melanoma. The UVA dose per unit of time during a typical tanning bed session is significantly higher than that from natural sunlight. Multiple tanning bed sessions are the primary driver of rising melanoma incidence among young women: in Australia, 76% of fair-skinned patients aged 18 to 29 developed melanoma linked to the use of tanning beds [125].

An increased risk of cutaneous melanoma may be observed in patients with dermatoses receiving prolonged, multi-course PUVA therapy. Evidence indicates that in patients with long-standing psoriasis who have received more than 250 PUVA sessions, the incidence of melanoma increases 5-fold 15 years after treatment, and 10-fold after 25 years [126].

10) Occupational hazards

Ultraviolet exposure related to occupational duties should also be considered a significant risk factor. Pilots and flight crew members serve as a prime example, as workplace studies have shown that during 56.6 minutes on duty, a pilot receives a UV dose equivalent to 20 minutes in a tanning bed [127].

11) Childhood malignancy (primarily treated with radiation therapy)

Radiation therapy is known to increase the risk of basal cell carcinomas, and the risk of melanoma is also increased, albeit to a lesser extent. Therefore, patients in this group require an annual dermatological examination [124].

12) Carriers of a CDKN2A gene mutation and first-degree relatives

Genetic predisposition to melanoma, confirmed by appropriate testing, is associated with a high risk of cutaneous melanoma and serves as an indication for regular follow-up at a specialized center for cutaneous melanoma diagnosis (Section 1.5).

13) Pigmentary phenotype

Fitzpatrick skin phototypes I and II are risk factors for melanoma. A very high number of freckles doubles the risk compared to having none or a few, particularly when located on the upper back [128].

It is important to note that patients with skin phototype I or II are more likely to develop amelanotic melanomas; therefore, physicians must maintain a high index of suspicion for non-pigmented neoplasms in these patients. Furthermore, these patients require monitoring regardless of other risk factors [124].

14) Signs of photodamage

Signs of photodamage include uneven skin pigmentation, solar lentigines and labial lentigines, solar elastosis, poikiloderma, cutis rhomboidalis nuchae, and actinic keratosis. The presence of these changes indicates a high cumulative lifetime UV dose and indirectly points to the development of corresponding mutations capable of driving skin cell malignant transformation. Therefore, the presence of these signs of photodamage indicates an increased risk of cutaneous melanoma (particularly lentigo maligna melanoma) and keratinocyte malignancies [125].

16) Multiple common nevi or more than 20 nevi on the arms with a diameter of 2 mm or more

Criteria for multiple nevi vary across countries. For instance, in Australia and New Zealand, more than 100 nevi are considered multiple (Cancer Council Australia Guidelines Working Party (2008)). In some countries (Canada, United Kingdom), more than 50 nevi are classified as high risk, and more than 100 as very high risk. In Scotland, even more than 10 nevi with a diameter of >2 mm are considered a high-risk factor.

In most European countries, more than 50 nevi are considered multiple. Naturally, counting the total number of nevi during an outpatient visit can present certain challenges. Therefore, the findings of a multicenter cross-sectional study of 2,175 patients evaluating the correlation between the number of nevi on the arms and the total body nevus count have proven very useful. The authors confirmed that finding 20 or more nevi with a diameter of >2 mm on the arms allows a patient to be placed in a risk group, as this count correlates with multiple nevi (more than 50) on the trunk [130]. It must be emphasized that this approach is applicable only to patients under the age of 50, as melanocytic neoplasms tend to regress in older age.

17) Atypical nevi

Clinical diagnostic criteria for atypical nevi include several parameters. At least one part of the lesion must show a macular component, and at least three of the following features must be present [131]: ill-defined borders, a diameter of 5 mm or more, color variation (darkening, lightening, or the appearance of new colors), irregular outlines, and the presence of erythema. It is now well established that the more dysplastic nevi a patient has, the higher their risk of developing melanoma: the presence of a single dysplastic nevus is associated with a 1.45-fold increase in risk, while the presence of five dysplastic nevi increases the risk 6-fold. Furthermore, the presence of dysplastic nevi increases the risk of multiple primary melanomas [124].

18) Congenital melanocytic nevi

Congenital nevi are defined as those present at birth or appearing within the first year of life [132]. Melanocytic nevi are classified as small (<1.5 cm), medium (1.5–20 cm), and large/giant (>20 cm) [4]. In turn, large and giant nevi are subdivided into three groups: G1 (21–30 cm), G2 (31–40 cm), and G3 (>40 cm).

As is well known, the risk of developing cutaneous melanoma is directly proportional to the size of the CMN. In patients with small or medium congenital melanocytic nevi, melanoma will develop during their lifetime in only 1% of cases [133]. At the same time, congenital melanocytic nevi are one of the most important risk factors associated with the development of melanoma in children: according to Bonifazi E. et al., in children under 12 years of age, a third of melanoma cases were associated with giant congenital melanocytic nevi [134]. Overall, the incidence of melanoma in patients with congenital melanocytic nevi ranges from 0.05% to 10.7%. In one study, during the follow-up of 6,571 patients with congenital melanocytic nevi for 3.4–23.7 years, only 0.7% of them developed melanoma. The risk of developing melanoma strongly depended on the size of the nevus, being highest in giant CMNs and peaking in childhood [135].

It should be noted that the risk is highest in patients with giant congenital melanocytic nevi located in the spine and cranial regions or with multiple satellite lesions, as such formations may be accompanied by neurocutaneous melanosis. Symptoms of neurocutaneous melanosis include increased intracranial pressure, spinal cord compression, or leptomeningeal melanoma. The manifestation of symptoms of neurocutaneous melanosis indicates a poor prognosis, as 50% of patients develop leptomeningeal melanoma. A fatal outcome in more than half of patients with symptomatic neurocutaneous melanosis occurs approximately within 3 years after the onset of symptoms (predominantly under the age of 10) [136].

19) Nevus changes detected during follow-up

It should be noted that all nevi appear, grow, change at a certain point in life, and then regress in the second half of life. During annual examinations, about 5% of nevi will show changes on dermoscopy. Therefore, the interpretation of detected changes should be carried out taking into account the following aspects:

1) characteristics of dermoscopic changes;

2) comparison with other skin neoplasms;

3) assessment of the patient's risk factors.

When describing dermoscopic changes, the appearance of dermoscopic features of cutaneous melanoma is evaluated. If there are none, attention is drawn to the appearance of asymmetric dermoscopic changes in the structure of the melanocytic neoplasm. Symmetric changes are usually considered benign, but in elderly patients, the appearance of symmetric signs of growth in a single melanocytic neoplasm (a peripheral rim of globules, a radial streaming pattern) may be a sign of cutaneous melanoma [137].

Comparison of one lesion with the rest of the foci is given special importance, since clinical or dermoscopic dissimilarity is a suspicious sign.

Among the listed risk factors for melanoma development, high and very high risk factors for melanoma development are distinguished (Table 3).

Table 3. High and very high risk factors (indication for mandatory follow-up) [28].

For the convenience of clinical examination, risk factors are conveniently grouped into those detected:

1) during history taking,

2) during physical examination,

3) during instrumental or laboratory studies.

Dermoscopic algorithms for the diagnosis of melanocytic lesions and melanoma

1. Short algorithm based on pattern analysis ("chaos and clues") (H. Kittler's algorithm)

A simple diagnostic algorithm aimed at identifying lesions that require removal, rather than determining a specific diagnosis.

To denote dermoscopic criteria, terminology is used that avoids metaphorical designations and reduces the description of features to five geometric elements: lines, pseudopods, circles, globules, and dots. These elements form all patterns considered in pattern analysis.

First, the presence of "chaos" is assessed, which is defined as asymmetry of structures or color. In the absence of such asymmetry, the lesion is considered benign and is not evaluated further.

However, there are three exceptions where excision with histological examination is required in the absence of asymmetry:

• facial skin lesions with gray or blue structures;

• acral lesions showing a parallel furrow pattern along the ridges of dermatoglyphics; and

• any steadily growing, elevated firm lesions.

Asymmetric lesions are examined to identify at least one of eight signs of malignancy. If one of these signs is present, excision of the lesion with pathomorphological examination of the skin biopsy (surgical) material is necessary.

The specificity of this simple method increases if asymmetric lesions that can be unambiguously classified as seborrheic keratoses are excluded.

The following eight criteria for pigmented malignant tumors (melanoma, pigmented basal cell carcinoma (BCC), pigmented Bowen's disease (PBD)) are used:

1. Atypical (non-central) structureless zone.

2. Gray or blue structures: gray dots can be observed in melanoma and pigmented basal cell carcinoma; gray rings are noted on facial skin in non-invasive melanoma; dense accumulation of melanin in the dermis causes the formation of blue globules or blue structureless areas in BCC or invasive melanoma.

3. Black dots or globules located at the periphery: usually observed in melanoma, formed by cells or clusters of cells respectively located close to or at the level of the stratum corneum as a result of pagetoid spread. Black structures are rarely observed in basal cell carcinoma (BCC) or pigmented basal cell carcinoma (PBCC).

4. Radial lines or pseudopods located segmentally (not along the entire perimeter of the lesion). Radial lines can be observed in any part of BCC. The arrangement of radial lines or pseudopods along the entire perimeter of the lesion is characteristic of Reed nevus, but the segmental arrangement of these structures is highly specific for melanoma.

5. Polymorphous vessels. Vessels are considered polymorphous if more than one vascular pattern is present. The polymorphous nature of the vascular pattern reflects chaotic growth in a malignant neoplasm and, possibly, increased metabolic demands in actively growing tumor tissue. In the presence of dotted vessels, melanoma is more likely than basal cell carcinoma.

6. White lines: for this feature to be established, it is necessary that the color of the lines is distinctly lighter than the color of the surrounding skin.

7. Reticular or branching lines, thickened. Lines are called thickened when they are wider than the spaces they surround. This pattern is formed by the proliferation of melanoma cells in the area of epidermal ridges and is absent in BCC and PBCC.

8. Parallel lines in the area of dermatoglyphic ridges (skin of the palms and soles). This sign indicates the presence of a malignant tumor even in the absence of "chaos". A similar picture can be observed with hemorrhages.

Pattern analysis of melanocytic neoplasms

The differential diagnosis of benign melanocytic nevi and melanoma begins with a general assessment of the color of the lesion, its symmetry, and its architecture.

1) In benign melanocytic neoplasms, THREE OR FEWER colors are identified; the following colors are usually identified:

• Light brown

• Dark brown

• Black

• Blue (in the absence of other colors)

2) Symmetry: when determining symmetry, the distribution of colors and structures on both sides of a drawn line is evaluated, rather than the outline of the lesion.

3) Architecture (pattern): this is the nature of the structures and their distribution within the neoplasm (with the formation of "benign" architectural variants)

Architectural variants (patterns) of melanocytic nevi

1. Reticular

2. Globular

3. Homogeneous

4. Reticular-homogeneous:

a) "Mottled" areas of the network with several structureless areas

b) Reticular with central homogeneous hypopigmentation

c) Reticular with central homogeneous hyperpigmentation

5. Reticular-globular:

a) Reticular, globules in the center

b) Reticular, globules at the periphery

c) Reticular, globules diffusely

6. Globular-homogeneous:

a) Homogeneous, globular

b) Homogeneous, globules at the periphery

Dermoscopic patterns of melanoma

1. Polychromatic

2. With atypical network at the periphery

3. With a focus of globules at the periphery

4. With gray dots

5. With foci of streaks at the periphery

6. With black blotches not in the center

7. With blue-white veil

8. With milky-red veil

9. With polymorphous vessels

10. With a focus of dotted vessels

11. With a white regression structure

12. With negative network

13. Without dermoscopic structures

14. With a combination of different structures

G. Argenziano's algorithm

Major criteria (2 points each)

Atypical pigment network

Blue-white veil

Atypical vessels

Minor criteria (1 point each)

Atypical streaks

Atypical dots/globules

Atypical blotches

Regression structures

A total score of 3 or more points indicates a diagnosis of melanoma

S. Menzies' algorithm

Negative features

Symmetry of the lesion

Monochromasia

Positive features

Blue-white veil

Multiple brown dots

Pseudopods (streaks)

Radial streaming (streaks)

Scar-like depigmentation

Peripheral black dots/globules

Multiple colors (5 or 6)

Multiple blue/gray dots

Network widening

In melanoma, negative features are absent and there is 1 or more positive feature.

5. BRAAFF checklist for acral melanoma (Lallas algorithm)

B – Atypical blotch (+1 point)

R – Parallel ridge pattern (+3 points)

A – Asymmetry of structures (+1 point)

A – Asymmetry of colors (+1 point)

F – Parallel furrow pattern (-1 point)

F – Fibrillar pattern (-1 point)

A diagnosis of melanoma is established with ≥1 point.

MPATH-Dx reporting schema for melanocytic neoplasms and melanoma

Stages of skin biopsy [145, 146]

Skin biopsy is considered a minor surgical procedure and therefore must be performed under strict sterility and adequate anesthesia. The procedure includes the following steps.

1. Obtaining informed consent. The patient should be informed about the nature of the procedure, potential complications, and necessary postoperative wound care. Ensure that the patient understands the explanation; consent must be documented in the medical record.

2. Clarifying indications. Prior to the procedure, specify the goal of the morphological examination and the list of differential diagnoses, as the biopsy site depends on these factors.

3. Checking for contraindications. Before the procedure, re-verify the absence of contraindications by interviewing and examining the patient.

4. Monitoring precautionary measures must be carried out at all stages of the biopsy by both the physician and nursing staff.

5. Preparation of materials and instruments. Non-sterile and sterile areas are prepared on the workspace, where appropriate instruments and consumables are placed.

6. Preparation for excision

If the set of sterile instruments is packaged in a box with sterile drapes, unpack it without compromising sterility: unfold the drapes by holding the corners without touching the inner surface.

A sterile scalpel, sterile suture material, and sterile gloves are removed from their packaging and placed onto the unfolded drape.

Wipe the cap of the vial with an alcohol wipe if the specimen is drawn from a multidose vial with a rubber stopper rather than an ampoule. Attach a needle to a sterile, two-piece single-use injection syringe with a needle, draw 1–2 ml of air into the syringe, insert the needle into the vial through the rubber stopper, expel the air, and draw the anesthetic. Then remove the needle and replace it with the needle that will be used for the injection.

All prepared materials and instruments should then be arranged conveniently to maintain the sterile field.

7. Preparation of the surgical site. Before administering the anesthetic, clean the skin with a wipe containing an antiseptic and disinfectant agent. If necessary, draw markings for subsequent incisions (with appropriate margins and along Langer's lines).

8. Administration of a local anesthetic. Before administration, verify the patient's history of anesthetic tolerance. If necessary, perform an anesthetic skin test.

The injection technique depends on the planned biopsy method and suspected diagnosis. In dermatology, the intradermal 'lemon peel' technique is most commonly used: the needle is inserted intradermally parallel to the skin surface; the plunger is then pulled back to ensure the needle is not in a blood vessel; the anesthetic is injected as the needle is withdrawn; the anesthetic is infiltrated throughout the entire area of the intended biopsy.

9. Excision. Performed according to the chosen biopsy technique. First, the skin biopsy site is treated with an antiseptic and disinfectant agent, a sterile drape is placed around the surgical field, and residual antiseptic and disinfectant agents are removed with a sterile wipe. After 4–6 minutes, test the anesthesia by pricking with the tip of the scalpel along the planned incision line. The physician then adopts a comfortable working position (sitting or standing) with relaxed shoulders and performs the skin biopsy according to the chosen technique. When grasping the biopsy specimen with forceps, avoid squeezing with the tips to prevent mechanical crush artifacts, which can negatively affect histological examination results. After excision, biopsy specimens obtained by incisional biopsy and needle biopsy should be spread flat on a piece of cardboard or heavy writing paper to prevent deformation before placing them in fixative. Until handed over to the dermatopathology laboratory, biopsy specimens in fixative are stored at room temperature. To avoid fixation defects, biopsy material must not be placed in a refrigerator.

10. Wound closure. Performed by suturing in incisional, excisional, or punch biopsies. For shave biopsies or snip excisions, the surface is treated with an antiseptic and disinfectant agent, sterile petroleum jelly is applied if necessary, and sutures are placed. After completing the suture, clean the skin around the wound and apply a dressing.

11. Dressing application, follow-up, and home care instructions. The postoperative wound area is treated with an antiseptic and disinfectant agent. Sterile adhesive strips can be placed over the suture. A small gauze pad may be placed over them to absorb drainage. A bandage is applied over the gauze; if a transparent dressing is used, the presence, nature, and amount of drainage can be assessed without removing the dressing.

In cases of secondary intention healing, a sterile hemostatic sponge may be applied under the dressing if necessary. Instruct the patient to leave the dressing in place until the next follow-up visit or to change it daily and clean the wound surface with an antiseptic and disinfectant agent.

It is important to explain to the patient that in case of any signs of infection, bleeding, or inflammation, they should consult a physician immediately.

12. Specimen fixation. The first stage of tissue processing—fixation—begins right in the operating room. For pathomorphological examination of skin biopsy (surgical) material, including the use of immunohistochemical methods and in situ hybridization, a special fixing solution is used as a fixative. The volume of the transport container must match the size of the biopsy or surgical specimen. The biopsy or surgical material must be completely immersed in the fixing solution, which should exceed the volume of the biopsy specimen by at least 10 times. It is recommended to completely fill the container with the fixative so that the biopsy specimen does not stick to its walls and lid.

Tissue fixation occurs at a rate of about 1 mm per hour at room temperature. When the temperature drops, the fixation rate slows down sharply, which can negatively affect its quality; therefore, placing the container with the biopsy specimen in a refrigerator is strictly prohibited. Material placed in the fixing solution can be stored at room temperature indefinitely. Large objects thicker than 1 cm should be delivered to the histological laboratory as soon as possible for histological grossing and to prevent autolytic changes. Biopsy specimens subject to immunofluorescence examination are placed in a container with transport medium and delivered to the pathomorphological laboratory within 2 hours. The use of fixing solutions and transport media not approved by the pathomorphological laboratory is prohibited!

13. Bio-specimen labeling. The container with the biopsy specimen must be labeled with the patient's full name, medical record number, date of material collection, and hermetically sealed. A referral form for pathomorphological examination of biopsy (surgical) material (Form 014U), filled out in a fully legible handwriting, must be attached to the biopsy material. The referral must indicate passport data, detailed information about the clinical picture, localization and nature of the rashes, as well as previously performed treatments and the results of prior histological examinations. Important: if a skin biopsy of several neoplasms is performed simultaneously, each biopsy specimen must be placed in a separate container, and the anatomical region from which this biopsy specimen was obtained must be added to the label.

14. Cleaning the workspace. Performed in gloves. First, make sure that the obtained biopsy specimen is placed in a container with a sufficient amount of fixing solution (the volume of the fixing solution must be ten times greater than the volume of the biopsy specimen), if a routine pathomorphological examination of the biopsy (surgical) material is planned. Next, clean the workspace. First, dispose of all sharp objects in a labeled sharps container. Then, dispose of all materials that have come into contact with the patient's biological fluids and other waste materials.

15. Documentation completed by the physician. Material sent for pathomorphological examination of biopsy (surgical) material must be accompanied by a detailed description of the clinical symptoms of the disease, anamnestic data relevant to the disease, and a brief summary of therapy administered over the last month. It is also important to provide a description of the local status and indicate from which element and using what technique the biopsy specimen was taken. An presumptive diagnosis is indicated, and if necessary, a list of nosologies for differential diagnosis is provided. At the end, provide the contact information of the attending physician for communication. If a joint examination with a pathologist (histologist) was not performed prior to the biopsy, clinical and/or dermoscopic photographs of the patient must be provided to the pathologist.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Potekaev N.N. – Doctor of Medical Sciences, Professor, President of the Association «National Alliance of Dermatovenerologists and Cosmetologists», member of the International Union against Sexually Transmitted Infections (IUSTI/WHO), Honorary President of the Euro-Asian Association of Dermatovenerologists (EAAD), Board Member of the European Academy of Dermatology and Venereology (EADV), Corresponding Member of the German Dermatological Society (DDG), Honored Doctor of the Russian Federation, Chief freelance specialist in dermatovenerology and cosmetology of the Russian Ministry of Health, Chief freelance specialist in dermatovenerology and cosmetology of the Moscow Healthcare Department, Director of the Moscow Scientific and Practical Center of Dermatovenerology and Cosmetology of the Moscow Healthcare Department, Head of the Department of Skin Diseases and Cosmetology at the Faculty of Continuing Professional Education of the Pirogov Russian National Research Medical University of the Russian Ministry of Health

2. Bobko S.I. – Candidate of Medical Sciences, member of the Association «National Alliance of Dermatovenerologists and Cosmetologists», Senior Researcher at the Moscow Scientific and Practical Center of Dermatovenerology and Cosmetology of the Moscow Healthcare Department

3. Bobrov M.A. – member of the Association «National Alliance of Dermatovenerologists and Cosmetologists», Head of the Pathomorphology Laboratory at the Moscow Scientific and Practical Center of Dermatovenerology and Cosmetology of the Moscow Healthcare Department

4. Volnukhin V.A. – Doctor of Medical Sciences, Professor, member of the Association «National Alliance of Dermatovenerologists and Cosmetologists», Chief Researcher at the Moscow Scientific and Practical Center of Dermatovenerology and Cosmetology of the Moscow Healthcare Department

5. Gadzhigoroeva A.G. – Doctor of Medical Sciences, member of the Association «National Alliance of Dermatovenerologists and Cosmetologists», Head of the Department of Clinical Dermatovenerology and Cosmetology at the Moscow Scientific and Practical Center of Dermatovenerology and Cosmetology of the Moscow Healthcare Department

6. Garanina O.E. – Candidate of Medical Sciences, Assistant at the Department of Skin and Venereal Diseases of the Privolzhsky Research Medical University of the Russian Ministry of Health, member of the Melanoma Experts Association

7. Demidov L.V. – Doctor of Medical Sciences, Head of the Department of Surgical Treatment Methods No. 12 (Oncodermatology) at the Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health; member of the All-Russian National Union «Association of Oncologists of Russia», Chairman of the Board of the Melanoma Experts Association

8. Dolya O.V. – Doctor of Medical Sciences, member of the Association «National Alliance of Dermatovenerologists and Cosmetologists», member of the International Union against Sexually Transmitted Infections (IUSTI/WHO), member of the European Academy of Dermatology and Venereology (EADV), member of the Guild of Sexually Transmitted Infection Specialists «YUSTI RU», Deputy Director for Science at the Moscow Scientific and Practical Center of Dermatovenerology and Cosmetology of the Moscow Healthcare Department

9. Zhukova, O.V. – Doctor of Medicine, Professor, Executive Director of the National Alliance of Dermatovenereologists and Cosmetologists, member of the European Sexually Transmitted Infections Union (IUSTI/WHO), member of the "YUSTI RU" Guild of Sexually Transmitted Infection Specialists, Chief Freelance Specialist in Dermatovenereology and Cosmetology for the Central Federal District of the Russian Ministry of Health, Chief Medical Officer of the Moscow Center for Dermatovenereology and Cosmetology of the Moscow Healthcare Department, Head of the Department of Dermatovenereology and Allergology with a Course in Immunology at the Medical Institute of the Peoples' Friendship University of Russia (RUDN University)

10. Zaretsky, A.R. – Head of the Oncology Division at the E.I. Shvarts Association of Specialists in Molecular Medicine, Laboratory and Clinical Genetics, Head of the Department of Molecular Oncology at Eurogen, Researcher at the Laboratory of Immunosequencing and Genomics of Antitumor Immunity at the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences

11. Katunina, O.R. – Doctor of Medicine, member of the National Alliance of Dermatovenereologists and Cosmetologists, pathomorphologist, Chief Researcher at the Moscow Center for Dermatovenereology and Cosmetology of the Moscow Healthcare Department

12. Kochetkov, M.A. – Candidate of Medical Sciences, member of the National Alliance of Dermatovenereologists and Cosmetologists, Leading Researcher at the Moscow Center for Dermatovenereology and Cosmetology of the Moscow Healthcare Department

13. Michenko, A.V. – Candidate of Medical Sciences, member of the National Alliance of Dermatovenereologists and Cosmetologists, Leading Researcher at the Moscow Center for Dermatovenereology and Cosmetology of the Moscow Healthcare Department

14. Rassokhina, O.I. – Candidate of Medical Sciences, member of the National Alliance of Dermatovenereologists and Cosmetologists, Head of the Training Department at the Moscow Center for Dermatovenereology and Cosmetology of the Moscow Healthcare Department, Associate Professor at the Department of Skin Diseases and Cosmetology, Faculty of Additional Professional Education, Pirogov Russian National Research Medical University of the Russian Ministry of Health

15. Samoylenko, I.V. – Candidate of Medical Sciences, Senior Researcher at the Department of Surgical Treatment Methods No. 12 (Oncodermatology), N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health; member of the All-Russian National Union "Association of Oncologists of Russia", Board Member of the Melanoma Association

16. Sinelnikov, I.E. – Candidate of Medical Sciences, Board Member of the Melanoma Association, Chief Oncologist at the Melanoma Unit, Israel Medical Research Center

17. Frigo, N.V. – Doctor of Medicine, member of the National Alliance of Dermatovenereologists and Cosmetologists, member of the Association of Specialists and Organizations of Laboratory Service "Federation of Laboratory Medicine", member of the European Sexually Transmitted Infections Union (IUSTI/WHO), member of the "YUSTI RU" Guild of Sexually Transmitted Infection Specialists, Head of the Department of Scientific and Applied Research Methods at the Moscow Center for Dermatovenereology and Cosmetology of the Moscow Healthcare Department

18. Shlivko, I.L. – Doctor of Medicine, Head of the Department of Skin and Venereal Diseases at the Privolzhsky Research Medical University of the Russian Ministry of Health, member of the Melanoma Association

Conflict of interest: None declared

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Oncologists;

2. Surgeons;

3. Geneticists;

4. Dermatovenereologists;

5. Pathologists;

6. Medical students, residents, and postgraduate students.

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Levels of Evidence (LE) grading scale for preventive, therapeutic, and rehabilitation methods (interventions)

Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnosis, treatment and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

No

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

none

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

none