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American Journal Of Biomedical Science & Pharmaceutical Innovation    
(ISSN – 2771-2753) 
VOLUME 04 ISSUE 06 PAGES: 54-69 

OCLC – 1121105677     

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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ABSTRACT 

Studying the morphological and genetic different types of keratoses is key for correct diagnosis and choice of 

treatment. The association between metabolic disorders and skin diseases highlights the need for an integrated 

approach to the management of patients with chronic diseases, including diabetes mellitus. Further research is 

needed to better understand the pathogenesis and develop effective treatments. 

KEYWORDS 

Morphology, skin, keratoderma, diabetes mellitus. 

INTRODUCTION

In our country, data on the epidemiology of 

keratoderma is extremely scarce, which is due to a 

number of reasons. Firstly, the analysis of statistical 

data and publications in the scientific literature is 

complicated by the presence of many synonyms for the 

disease: seborrheic wart, seborrheic keratoma, senile 

wart, basal cell papilloma, pigmented epithelioma, 

pigmented papilloma, seborrheic acanthoma, 

pigmented basal cell epithelioma, senile papilloma, etc. 

Secondly, despite the fact that this benign tumor was 

first mentioned by S. Pollitzer at the end of the 19th 

century (1890) (1,4,7), its detailed description by D.I. 

Golovin did it relatively recently - in 1958 (2,3). And 

thirdly, to date the etiology of this proliferative process 

  Research Article 

 

MORPHOGENETIC CHARACTERISTICS OF KERATODERMA IN 

METABOLIC DISORDERS 
 

Submission Date: June 20, 2024, Accepted Date:  June 25, 2024,  

Published Date: June 30, 2024  

Crossref doi: https://doi.org/10.37547/ajbspi/Volume04Issue06-09 

 

 

Khamidova Farida Muinovna 
Samarkand State Medical University, Uzbekistan 

 

Nurullayev Javohir Asqar O’gli 
Samarkand State Medical University, Uzbekistan 

Journal Website: 

https://theusajournals.

com/index.php/ajbspi 

Copyright: Original 

content from this work 

may be used under the 

terms of the creative 

commons attributes 

4.0 licence. 

 

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Volume 04 Issue 06-2024 55 

                 

 
 

   
  
 

American Journal Of Biomedical Science & Pharmaceutical Innovation    
(ISSN – 2771-2753) 
VOLUME 04 ISSUE 06 PAGES: 54-69 

OCLC – 1121105677     

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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on the skin is not clear. According to the international 

histological classification of skin tumors “Pathology 

and Genetics of Skin Tumors”, published under the 

auspices of the International Agency for Research on 

Cancer (5,6,7), seborrheic keratosis is a benign 

epithelial tumor and is a type of acanthoma. The 

disease affects men and women almost equally, 

predominantly over 40 years of age (17). A clear 

correlation of its debut with age has been established. 

Thus, in the cohort of 24–49 year olds, the prevalence 

of seborrheic keratosis was 38%, in 50–59 year olds – 

69%, in 60–69 year olds – 86%, and among 70–79 year 

olds – more than 90% (34). The disease is extremely 

common in countries with high levels of insolation, for 

example, in Australia, where it occurs in 100% of cases 

in the population over 50 years of age. (35). 

European studies indicate a slightly lower incidence of 

this epithelial tumor: 82% among men and 62% among 

women aged over 70 years (8,9,10,37,39). Russian 

researchers point out that closed areas of the skin 

exposed to mechanical stress (friction, pressure) are 

most affected. In patients with numerous elements of 

seborrheic keratosis, a positive family history is often 

recorded (11,12,13,42,49). Seborrheic keratosis is 

represented by multiple foci of proliferative growth 

(14,16,21,45). Dermatoscopic and histological 

examination is mandatory to verify the diagnosis 

(15,16,23,28,29). 

Seborrheic keratosis (SK) is a common benign tumor of 

the epidermis in men and women, occurring more 

often after 45-50 years. KS elements appear as distinct 

brown spots and/or plaques widely distributed along 

the edges of the skin (17,18,19,25,26). There is no 

unified morphological classification of this disease, 

since the histological manifestations of KS are varied - 

symptoms of several histological types may be present 

in the same lesion (20,25,28,29). 

In foreign literature they are divided into acanthous, 

hyperkeratotic, adenoid, irritated, clonal type and 

melanoacanthomas. The diagnosis of KS in most cases 

is not in doubt, but the tumor can mimic other skin 

neoplasms: common warts, lentigines, melanocytic 

nevi, actinic keratosis, Bowen's disease, squamous cell 

carcinoma both clinically and during pathological 

examination (21,22,32,38). The etiology of KS is 

unknown, although genetics, increased sun exposure, 

somatic mutations in fibroblast growth factor receptor 

3 (FGFR3), and human papillomavirus have been 

identified as risk factors (23,24,31,35). Currently, the 

theory of keratinocyte aging and impaired apoptosis in 

KS is widely accepted.   Studies are rare, and the 

reasons for changes in the proliferative properties of 

cells in KS are unclear (25,26,27). In addition, MK is of 

interest for studying cell cycle disorders, since 

according to modern histological criteria it is classified 

as a benign tumor (28,29,30). However, many 

immunohistochemical features of malignant 

neoplasms and clinical cases of malignant 

transformation within MC foci make it necessary to 

continue the targeted study of the pathogenesis of the 

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(ISSN – 2771-2753) 
VOLUME 04 ISSUE 06 PAGES: 54-69 

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neoplasm. The main mechanism of proliferation 

impairment is a defect in the function of suppressor 

genes. In addition to high proliferation, tumor growth 

is associated with impaired cell ability to regulate 

apoptosis.  

The most studied cell cycle markers that are involved in 

the control of the proliferative potential of any cell are 

p53, p21, p27 and p16. Determination of their 

expression level using immunohistochemical methods 

allows us to identify the degree of proliferation 

disorder, which is invariably accompanied by tumor 

growth, the ability of the tumor to invade and 

metastasize (10,12,13,14). p27 (Kip1) is an inhibitor of 

cyclin-dependent kinase 1B, a product of the human 

CDKN1B suppressor gene, a member of the Cip/Kip 

protein family. This protein regulates the course of the 

cell cycle, is responsible for its arrest in the G1 phase by 

suppressing the activity of the cyclin A/cyclin-

dependent kinase 2 and cyclin E/cyclin-dependent 

kinase 2 complexes. p27 is a nuclear-cytoplasmic 

protein, its intracellular localization is regulated post-

translational modifications. It performs its inhibitory 

functions in the nucleus; after its movement into the 

cytoplasm, further advancement of the cell through 

the cycle becomes possible (10,11,15). Overexpression 

of p27 has been studied in malignant neoplasms of 

internal organs and is an unfavorable prognostic factor 

for tumor progression (24,27,28). There are few studies 

on benign neoplasms, and they contain conflicting 

data. Thus, in a study of 10 irritated and acanthotic SCs, 

A. Brueks et al. (8) overexpression of only p27 was 

detected along with the absence of expression of p53, 

p16 and a low proliferative index, which allowed the 

authors to talk about the leading role of p27 in the 

control of cell proliferation. However, it seems to us 

appropriate to study p27 in all types of KS, taking into 

account their morphological diversity. As a result of the 

study, a violation of p27 protein expression was 

revealed in all histological types of KS, which indicates 

its significant role in the pathogenesis of the disease. 

Increased expression of p27, normally found in the 

greatest quantity in cells in the G1 phase (19,20), was 

found in the authors’ studies in irritable, adenoid and 

some cases of clonal types. Considering that p27 is a 

“reserve brake” of cell division (12,13), its significant 

increase in KS may indicate the absence or insufficient 

response of the first link of cell cycle regulators - p53 

and p16 to an increase in the proliferative activity of 

cells. The staining of nuclear membranes and adjacent 

areas of the cytoplasm was considered as a decrease in 

the nuclear content of p27 and its release into the 

cytoplasm. An imbalance between the amounts of 

nuclear and cytoplasmic p27 is a poor prognostic sign 

and is found mainly in malignant skin tumors. 

According to the literature (12,13,40,41,46), more than 

70% of metastatic melanomas contain p27 in the 

cytoplasm, while melanomas without metastases 

contain p27 in the nucleus. The appearance of a 

significant number of cells with nuclear membrane 

staining, predominantly in the irritated and adenoid 

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Volume 04 Issue 06-2024 57 

                 

 
 

   
  
 

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(ISSN – 2771-2753) 
VOLUME 04 ISSUE 06 PAGES: 54-69 

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type of KS, indicates a greater risk of malignancy than 

in other histological types of tumors, where there is no 

membrane staining. A negative reaction during an IHC 

study or the detection of single positive nuclei of tumor 

cells in hyperkeratotic, acanthotic and clonal (in some 

cases) MC can be regarded, on the one hand, as the 

absence of significant proliferative activity of cells and 

the lack of inclusion of a “reserve” mechanism" in the 

form of p27, on the other hand, indicate a defect in 

apoptosis, given the slow, steady growth of elements. 

In none of these cases, specific staining of nuclear 

membranes was detected, which indicates different 

mechanisms of cell cycle disorders in different 

histological types of keratomas. Thus, morphological 

variants of MC have different prognosis for 

development, growth and risk of malignant 

transformation. The identified features of p27 protein 

expression indicate the presence of disturbances in the 

regulation of the cell cycle and proliferative activity of 

tumor cells, characteristic of each histological type of 

KS, which must be taken into account in a 

comprehensive assessment of the expression of other 

cell cycle markers in KS (13,45). 

The role of insulin resistance in the pathogenesis of KS 

brings us closer to the theory of keratinocyte aging. In 

a study by A. Saraiya et al. in 2013, a case was described 

in which the appearance of multiple MCs in the 

absence of a genetic predisposition was associated in 

patients with insulin resistance and type 2 diabetes 

mellitus (type 2 diabetes). Thus, a major role for high 

insulin concentrations was suggested in stimulating 

DNA synthesis and cell proliferation. Also, M. Blomberg 

et al., based on their observations, recommended that 

when FGFR mutations are found and concomitant skin 

pathology in the form of papillary pigmentary 

dystrophy of the skin or multiple MCs, insulin studies 

are carried out in order to detect hyperinsulinemia 2. It 

should be taken into account that type 2 diabetes is 

one of the most common diseases; every 20 

inhabitants of the planet suffer from it after 35–40 

years. In addition, it is included in the so-called group 

of “old age” diseases along with ischemic heart 

disease, stroke, and atherosclerosis. In a study by a 

number of authors of 150 patients with multiple KS, 

type 2 diabetes occurred in 65.3% of cases (98 

patients), and impaired glucose tolerance – in 24% of 

cases (36 patients). Such a high percentage of a 

combination of carbohydrate metabolism disorders 

and multiple KS can hardly be considered a mere 

coincidence, given that both diseases are genetically 

determined and develop in middle and old age. 

Interestingly, one of the possible factors in the 

development of type 2 diabetes is considered to be an 

increase in the level of p16 in the pancreas during 

aging, leading to inhibition of beta cell proliferation 

and a decrease in their ability to respond to damage, 

which subsequently leads to insulin resistance (50). 

Morphologically, 6 histological types are distinguished: 

acanthotic, adenoid (reticular), hyperkeratotic 

(papillomatous), clonal, melanoacanthoma and 

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irritated. In all histological types, hyperkeratosis, 

acanthosis, papillomatosis, horny and pseudohorny 

cysts are present to varying degrees of severity. The 

intensity of melanin pigment varies from almost 

completely absent to strong. In addition, 2 rare 

histological types of seborrheic keratosis have recently 

been described - with a large amount of mucin in the 

cells - adamantinoid and when basaloid keratinocytes 

are arranged like “pseudorosettes”. Currently, there is 

no consensus on the etiology and pathogenesis of KS. 

Most theories are contradictory and do not explain the 

essence of the pathological process and the variety of 

forms. 

Follicular keratoses represent a disorder of 

keratinization and differentiation of keratinocytes, 

leading to the formation of keratotic plugs and 

parakeratotic cones that penetrate the dermis, causing 

perforation of the epidermis. There is no uniform 

classification of keratoses pilaris. There are papular, 

atrophying and vegetative forms (4,29,30). The 

etiology and pathogenesis have not been fully studied. 

The previously assumed role of a viral or bacterial 

infection, a violation of vitamin A metabolism in the 

development of this dermatosis is only of historical 

interest. A certain significance in the development of 

the disease, in addition to impaired carbohydrate 

metabolism, is attributed to liver damage (chronic 

hepatitis) with the development of secondary vitamin 

A deficiency (4.14). A genetic predisposition to the 

development of Kirle disease (KD) has not been 

conclusively proven, although cases of the disease 

among relatives in the same family with consanguinity 

(first-degree relatives) have been described.  As 

originally defined by J. Kirle (30), it is a disease in which 

an atypical clone of keratinocytes penetrates through 

the epidermis into the dermis. It is believed that the 

basis of the pathological process is a violation of 

keratinization, differentiation and keratinization of 

keratinocytes (formation of dyskeratotic foci and 

acceleration of the keratinization process). This leads 

to the formation of keratotic plugs with areas of 

parakeratosis. Keratification begins already at the 

border of the epidermis and dermis. The rate of 

differentiation and keratinization exceeds the rate of 

cell proliferation, therefore the parakeratotic cone 

partially penetrates deeper into the damaged 

epidermis and causes its perforation into the dermis 

(4,5,43,49). 

There is no uniform classification of keratoses pilaris. 

Among the independent nosological forms, papular, 

atrophying and vegetative follicular keratoses are 

distinguished. Some authors note the similarity of Kirle 

disease (KD) with lenticular persistent hyperkeratosis 

of Flegel, considering the latter as a variant of KD, 

although the clinical manifestations differ. Other 

authors (5,7,18) classify CD as vegetative follicular 

keratoses, and Flegel's disease as papular. 

 There is a concept of reactive perforating 

keratinization disorder in kidney disease, liver disease 

and diabetes mellitus. The concept of perforating skin 

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diseases has emerged, in which the elimination of 

altered skin components occurs through the epidermis 

(transepidermal elimination). Some authors dispute 

the independence of CD as a nosological entity (45,47). 

In ICD-10, in class XII (diseases of the skin and 

subcutaneous tissue), CD has a subcategory L87.0 - 

transepidermal perforated changes. 

Pathomorphologically, there are depressions in the 

epidermis and dilated orifices of hair follicles filled with 

hyperkeratotic plugs. Under the plugs, the growth of 

the granular layer is pronounced, and in places without 

hypergranulosis there is parakeratosis, penetrating to 

the dermis. Next, the epidermis becomes thinner and 

horny masses penetrate into the dermis, and 

inflammatory infiltrates such as granulomas are 

formed from lymphocytes, leukocytes, histiocytes and 

giant cells. Death of the sebaceous glands, 

degeneration of collagen fibers, and hyperelastosis are 

observed (49). Clinically, the onset is gradual, new 

rashes appear as old ones disappear. Characteristic are 

follicular or parafollicular papules, first the color of 

healthy skin, then a grayish or brownish-red hue, up to 

1 cm in diameter. In the center of the elements there is 

a horny plug, when removed, a crater-shaped 

depression is formed. Papules tend to grow 

peripherally and coalesce, forming dry polycyclic 

plaques covered with scales and crusts. The 

consistency is dense, the surface is uneven, warty. 

Fresh rashes are accompanied by mild itching (more 

often in patients with diabetes) or do not bother. Old 

lesions are painful when pressed. Localization of 

rashes - extensor surfaces of the limbs, torso, buttocks. 

Koebner phenomenon and secondary infection are 

possible (30). The mucous membranes are not 

affected, and rashes on the palms, soles, genitals and 

mouth are rare. The course of Kirle disease (KD) is 

chronic and relapsing, treatment is difficult, and the 

prognosis depends on the underlying disease. 

Diagnosis is based on history, clinical and histological 

picture. Differential diagnosis includes Devergy's lichen 

pilaris, Darier's follicular dyskeratosis, Mibelli's 

porokeratosis, elastosis perforating creeping, reactive 

perforating collagenosis and Flegel's disease (31,32). 

Flegel's disease, like CD, a rare form of keratosis pilaris, 

is associated with impaired synthesis of keratin 55K. 

Histologically, thinning of the epidermis, follicular 

orthokeratosis with parakeratosis, spongiosis and 

lymphocytic infiltrate in the dermis are revealed. The 

previously assumed importance of Odland bodies in 

the pathogenesis of dermatosis is now doubtful. Unlike 

CD, this dermatosis appears in adolescence and middle 

age and is characterized by small horny papules that 

are not prone to plaque formation (27,29,31,32,33). 

Actinic keratosis is a skin disease characterized by 

limited, dense hyperkeratotic lesions in areas exposed 

to solar radiation. The probability of occurrence of 

squamous cell carcinoma in lesions of actinic keratosis, 

according to some data, is estimated from 0.85 to 10% 

per lesion per year [48,49,50]. As a rule, squamous cell 

carcinoma that develops in areas of actinic keratosis 

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has a favorable course, but in rare cases it can 

metastasize (15,16,17). 

Porokeratosis is a rare group of acquired or hereditary 

dermatoses characterized by linear or annular plaques 

with a keratotic border. 

Disseminated superficial actinic porokeratosis (DSAP) 

is a disease characterized by impaired keratinization. 

Disseminated superficial actinic porokeratosis is one of 

six types of porokeratosis. It has wider participation 

than most other options. These other variants include 

linear porokeratosis, Mibelli porokeratosis, punctate 

porokeratosis, palmar and plantar disseminated 

porokeratosis, and disseminated superficial 

porokeratosis. Other rare variants are ptychotropic 

porokeratosis, facial porokeratosis, giant 

porokeratosis, hypertrophic verrucous porokeratosis, 

reticular porokeratosis, and eruptive pruritic papular 

porokeratosis. The eruptive form of porokeratosis is 

associated with malignancy, immunosuppression, and 

a proinflammatory state. Rashes appear all over the 

body. A feature that is observed in all these variants is 

the horn-shaped plate. On histology, it appears as a 

column of parakeratotic cells and is characterized by a 

raised ridge bordering the porokeratotic lesions. Risk 

factors for porokeratosis include genetics, 

immunosuppression, and ultraviolet light. Lesions in 

disseminated superficial actinic porokeratosis begin as 

papules and pink to brown macules with a raised 

border on exposed skin that may be asymptomatic or 

mildly itchy. These lesions are considered 

precancerous. There is a risk of malignant 

transformation to squamous cell or basal cell 

carcinoma from 7.5 to 10% (12,22,23) 

Eruptive pruritic papular porokeratosis is a rare 

subtype of porokeratosis that manifests as an acute 

exacerbation of an annular papule with a distinct 

peripheral border of a hyperkeratotic ridge and intense 

itching. EPPP mainly occurs in older East Asian men. Its 

etiology and pathogenesis are unknown (24). 

The development of disseminated superficial 

porokeratosis is sometimes observed in association 

with renal transplantation, autoimmune diseases, and 

various hematologic disorders, suggesting that certain 

immunosuppression may cause widespread abnormal 

keratinization. It may also be associated with 

exacerbation of diabetes mellitus due to the formation 

of anti-insulin antibodies (32). 

Benign lichenoid keratosis (BLK, LPLK) is clinically 

often misdiagnosed as superficial basal cell carcinoma 

(BCC), especially when it occurs on the trunk. However, 

regression of the BCC may be associated with lichenoid 

interface dermatitis, which may be misinterpreted as 

BLK on histopathological sections (48). 

Benign lichenoid keratosis is a skin lesion consisting of 

a non-pruritic papule or slightly indurated plaque, 

histologically characterized by a band-shaped 

inflammatory infiltrate involving the surface of the 

skin. 

The authors believe that benign lichenoid keratosis 

may be a specific disease rather than an inflammatory 

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stage of regressive solar lentigo, large cell acanthoma, 

or reticulate seborrheic keratosis (16,17,19). 

A study of palmoplantar keratoderma in eighty-two 

cases showed that the cause of palmoplantar 

keratoderma is twenty different diseases, both 

hereditary and acquired. The maximum number of 

cases occurs in the hereditary variety of palmoplantar 

keratoderma (Unna-Tost syndrome) (28.05%). While 

among acquired diseases the leading cause was 

psoriasis (17.07%). Two histopathological types of 

Unna-Tost syndrome and their correlation with clinical 

features have been reported (4,5) 

Keratoderma spinosa is a rare dermatosis consisting of 

multiple projections located on the palms and soles, 

with a distinct histopathological feature of a 

parakeratotic column over a hypogranular epidermis. 

Although there are some hereditary cases, most are 

acquired. The latter may be idiopathic or associated 

with neoplasms and chronic systemic diseases (15,25). 

In some literature sources, keratoderma spinosum is 

referred to as keratoderma spinosa. This condition is 

identified under several names, such as “music box 

spinal keratosis” and “palmoplantar filiform 

hyperkeratosis,” which creates ambiguity in the 

diagnostic and histopathological features of the 

disease. Because of its association with cancer, all 

patients with keratoderma spinosa should undergo 

baseline cancer screening based on age and then once 

or twice a year or as symptoms appear (3,4). 

The incidence of skin malignancies has been increasing 

over the years (46,47). Since 1960, their incidence 

worldwide has increased annually by 4–8% and 

amounts to about 3 million newly identified cases per 

year. One of the most significant etiological factors is 

considered to be excessive insolation - frequent 

exposure to the sun for a long time and repeated 

sunburn. In many cases, malignant epithelial skin 

tumors develop in the setting of preexisting 

dermatoses such as actinic keratosis and Bowen's 

disease (22). 

Bowen's disease is an intraepidermal form of 

squamous cell carcinoma (or squamous cell carcinoma 

in situ) in the form of a single, slowly growing plaque. 

Its development is most often associated with 

exposure to ultraviolet radiation, less often with skin 

trauma or contact with arsenic. In this regard, two 

forms of the disease are considered: one is localized in 

open areas of the skin (exposed to insolation), and the 

other is localized in closed areas. The course of 

Bowen's disease is steadily progressive, although in 

the vast majority of cases it remains cancer in situ 

throughout the patient's life. Invasive squamous cell 

skin cancer develops against the background of 

Bowen's disease with a frequency of 5% to 11% of cases 

of long-term existence of the pathology. As long as the 

disease remains in the intraepidermal stage, 

metastases do not occur. It is possible to differentiate 

actinic keratosis and Bowen's disease only on the basis 

of histological examination. Thus, with actinic 

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keratosis, dysplastic changes in the epidermis are 

observed, which occupy no more than ⅔ of its 

thickness, sometimes with penetration of epidermal 

strands into the upper parts of the dermis. However, 

atypical cells can spread throughout the entire 

thickness of the epidermis - in such cases they are 

called bowenoid actinic keratosis (22,24). Bowen's 

disease is characterized by a sharp thickening of the 

epidermis, consisting of enlarged cells, in places piling 

up on each other, with pronounced polymorphism and 

polychromasia, with acanthotic growths to the 

reticular layer of the dermis (23,26). Proliferation of 

atypical keratinocytes, as in bowenoid actinic 

keratosis, is observed throughout the entire thickness 

of the epidermis. Actinic keratosis with foci of 

Bowenization and Bowen's disease are distinguished 

by dysplastic changes in the keratinocytes of the 

follicular epithelium - a sign inherent in Bowen's 

disease. In addition, with bowenoid actinic keratosis, 

manifestations of solar elastosis are always observed 

in the dermis. However, according to some authors, 

the bowenoid type of solar keratosis is histologically 

indistinguishable from Bowen's disease and at this 

stage of development is regarded as carcinoma in situ 

(1,22,6,28). Despite the atypia of keratinocytes, 

characteristic of both actinic keratosis and Bowen's 

disease, there are no signs of true invasion - the 

boundary between the epidermis and dermis remains 

clear. 

Of particular importance in all cases is the study of the 

expression of a number of cellular markers involved in 

the mechanisms of development of malignant skin 

tumors, such as oncoproteins associated with 

intercellular adhesion and proliferation. Several 

nuclear and membrane antigens are known, changes in 

expression of which are due to proliferative activity 

cells. One of the most studied molecular biomarkers is 

the indicator of proliferative activity Ki-67, whose 

antibodies react with proliferating cells. If the cell does 

not proliferate, this interaction does not occur. 

Normally, in healthy epidermis, Ki-67 expression is 

observed only in the basal layer, and the average 

proliferative index, according to various sources, varies 

from 0.8 to 11% (24,25,34,35,36). 

The architectural integrity of the epidermis is ensured 

by keratins and intercellular adhesion molecules - 

epithelial cadherins. E-cadherin is a calcium-dependent 

adhesion molecule characteristic of epithelial tissue 

cells. Its long extracellular sections form parallel 

dimers on the cell surface, which, when in contact with 

E-cadherin molecules of neighboring keratinocytes, 

form strong zipper-type bonds. A decrease in 

intercellular adhesion allows affected cells to split off 

from normal ones, which leads to destruction of 

histological structures. Normally, in the epidermis, E-

cadherin is detected in 100% of cells in the form of 

uniform membrane staining. Increased cell 

proliferative activity and impaired expression of E-

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cadherin indicate an increase in cell invasive capacity 

(26,27). 

Data from a number of authors indicate that actinic 

keratosis, bowenoid actinic keratosis and Bowen's 

disease represent different stages of the development 

of the same malignant process. The predominance of 

low proliferative activity, the expression of Ki-67 in the 

lower parts of the epidermis and the preservation of 

adhesive interactions between cells in actinic keratosis 

indicate the initial stages of the process and its low 

invasive potential (22,23). 

Epithelial skin tumors are common human neoplasms, 

accounting for from 20–24.9 to 55.4–61.7% of calls for 

skin neoplasms. One of the key factors contributing to 

the activation of proliferative processes in the skin with 

the subsequent development of neoplasms of various 

natures is the infection of skin cells with the human 

papillomavirus (HPV). Certain characteristic HPV 

fragments suppress the activity of the keratinocyte p53 

gene, which leads to uncontrolled proliferation of 

keratinocytes. The importance of certain types of HPV 

in the development of a number of skin tumors has 

been shown (27,47,49). 

The PCNA protein is recognized as a more accurate 

indicator of proliferation, identifying cells in the 

process of preparing for division in the S-phase of the 

cell cycle. The evidence that the S-phase in cells 

affected by HPV is longer (from 18 to 20 hours) than the 

S-phase in normal epidermal keratinocytes (16 hours) is 

confirmed by immunohistochemical studies. 

Seborrheic keratosis is the most common benign skin 

tumor in different regions of the world (47,49). 

It is known that the vast majority of proto-oncogenes 

and tumor suppressors are components of several 

common signaling pathways that control the cell cycle, 

apoptosis, genome integrity, morphogenetic reactions 

and cell differentiation. Changes in these signaling 

pathways ultimately lead to the development of 

tumors. To date, about a hundred potential oncogenes 

(cellular and viral) and about two dozen tumor 

suppressors are known. Changes characteristic of 

predominantly malignant human tumors have been 

identified, including highly specific anomalies used to 

make a diagnosis, while almost no attention has been 

paid to benign formations (16,22). 

Two families of proteins, inhibitors of cyclin-dependent 

kinases, have been identified: Ink4 and Cip/Kip. The 

first includes four members, including the tumor 

suppressors p15INK4b and p16INK4a. Ink4 proteins 

have a fairly narrow specificity: by binding the cyclin-

dependent kinase (Cdk) Cdk4 and Cdk6, they prevent 

the formation of their complexes with cyclins D. The 

Cip/Kip family consists of three members: 

p21WAF1/CIP1, p27KIP1a and p57KIP2. These proteins 

bind and inhibit already fully formed complexes of 

cyclin D – Cdk4(6), cyclin E – Cdk2 and cyclin A – Cdk2 

[5, 6]. Inhibition of the functions of cyclin-dependent 

kinases leads to hypophosphorylation of the pRB 

protein, which reduces the expression of E2F-

dependent genes, blocks the transition of the cell from 

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the G1 phase to the S phase, and controls cell division 

and proliferation. Many sources confirm that 

disturbances in the G1 phase and G1/S checkpoint lead 

to uncontrolled tumor growth. Thus, it has been 

experimentally proven that a decrease in p16 protein 

expression leads to hyperphosphorylation of pRB and 

subsequently leads to activation of the transcription of 

S-phase-specific genes. The p16 protein was discovered 

by researchers in 1993 and since its discovery has 

become one of the most sought-after markers in the 

field of cancer research [10]. It is encoded by the tumor 

suppressor gene CDKN2A, located on chromosome 9 

(9p21.3). The participation of this gene has been noted 

in the development of both sporadic and familial forms 

of melanoma, glioma, lung cancer, T-cell leukemia, and 

B-cell leukemia. In addition, p16 is currently used as a 

prognostic biomarker for patients with oropharyngeal 

squamous cell carcinoma and cervical cancer. The 

expression of this protein and its role in the 

pathogenesis of benign skin tumors, in particular 

seborrheic keratosis, have been little studied 

(22,24,44,45,49). 

Thus, Y. H. Wu et al. in 17 cases of seborrheic keratosis 

with signs of bowenoid transformation, he found 

increased expression of p16 and p21 in the cells, which 

is also characteristic of Bowen's disease and bowenoid 

papulosis. They were asked to study p16 in patients 

with seborrheic keratosis to identify possible 

malignancy of the elements. Other authors - S. 

Nakamura et al., having identified in skin samples from 

KS lesions (including in cultured keratinocytes from 

patients with KS) a pronounced expression of the p16 

protein in all tumor cells, associated this not with the 

possibility of malignancy, but with a violation of the cell 

cycle , blocking the entry into the S-phase of cells and 

their premature aging. In support of this hypothesis, in 

the 4 studied SC samples, genetic analysis revealed the 

absence of DNA fragmentation in tumor cells, whereas 

in normal epidermis fragmentation was present in the 

granular and stratum corneum. This indicates that 

apoptosis is inhibited in KS. Brueks et al., studying 

10 cases of seborrheic keratomas of exclusively 

acanthotic and irritable types, noted an average level 

of expression of the p16 protein and a pronounced, 

diffuse expression of another protein, the p27 kinase 

inhibitor, which, in his opinion, indicates the dominant 

influence of this protein on cell proliferative activity. 

Like p16, the p27 protein (Kip1) regulates the course of 

the cell cycle and is responsible for its arrest in the G1 

phase. It is the product of the human CDKN1B gene 

(22,43). 

So, today, ideas about the role of proteins - inhibitors 

of cyclin-dependent kinases in oncogenesis are not 

entirely clear; the data from most studies are 

contradictory. The possibility of using them in practice 

as prognostic biomarkers opens up prospects for an 

individual approach to the treatment of each patient, 

understanding the pathogenesis of many both 

malignant and benign human tumors, which 

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determines the relevance and need for their further 

study. 

CONCLUSIONS 

Studying the morphological and genetic different 

types of keratoses is key for correct diagnosis and 

choice of treatment. The association between 

metabolic disorders and skin diseases highlights the 

need for an integrated approach to the management 

of patients with chronic diseases, including diabetes 

mellitus. Further research is needed to better 

understand the pathogenesis and develop effective 

treatments. 

 

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