Volume 04 Issue 06-2024
54
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
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.
Volume 04 Issue 06-2024
55
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
on the skin is not clear. According to the international
histological class
ification 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
Volume 04 Issue 06-2024
56
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
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
Volume 04 Issue 06-2024
57
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
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
Volume 04 Issue 06-2024
58
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
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”. Currentl
y, 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
Volume 04 Issue 06-2024
59
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
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
Volume 04 Issue 06-2024
60
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
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
div. 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
Volume 04 Issue 06-2024
61
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
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
Volume 04 Issue 06-2024
62
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
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-
Volume 04 Issue 06-2024
63
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
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
Volume 04 Issue 06-2024
64
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
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
Volume 04 Issue 06-2024
65
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
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.
REFERENCES
1.
Кожные
и
венерические
болезни.
Справочник. Под ред. О.Л.Иванова. М:
Медицина 2007; 117—
118.
2.
Родионов А. Н., Заславский Д. В., Сыдиков А.
А. Клиническая дерматология. –
2019.
3.
Болезнь Кирле (кератоз фолликулярный и
парафолликулярный,
проникающий):
клинический
случай
В.В.
КАРПОВ1КЛИНИЧЕСКАЯ ДЕРМАТОЛОГИЯ И
ВЕНЕРОЛОГИЯ 5, 2011стр.25
-28).
4.
Huang J. et al. An epidemiological study on skin
tumors of the elderly in a community in
Shanghai, China //Scientific Reports.
–
2023.
–
Т.
13.
–
№. 1. –
С. 4441.
5.
Alapatt G. F., Sukumar D., Bhat M. R. A
clinicopathological
and
dermoscopic
correlation of seborrheic keratosis //Indian
Journal of Dermatology.
–
2016.
–
Т. 61. –
№. 6.
–
С. 622
-627.
6.
Kim H.S., Park E.J., Kwon I.H., Kim K.H., Kim K.J.
Clinical and histopathologic study of benign
lichenoid keratosis on the face. Am. J.
Dermatopathol. 2013; 35(7): 738
–
41.].
7.
Mohamed M., Amri M., Njim L., Jribi M.,
Zakhama A., Zili J. Pigmented keratosis on the
face. Ann. Dermatol. Venereol. 2013; 140(5):
390-2.
8.
Bruecks
A.K.,
Kalia
S.,
Trotter
M.J.
Overexpression of p27 KIP1 in seborrheic
keratosis. J. Cutan. Med. Surg. 2007; 11(5): 174
–
8.
9.
Hafner C., van Oers J.M., Hartmann A.,
Landthaler M., Stoehr R., Blaszyk H., et al. High
frequency of FGFR3 mutations in ad¬enoid
seborrheic keratoses. J. Invest. Dermatol.
2006; 126(11): 2404
–
7.,
10.
Ruas M., Gregory .F, Jones R., Poolman R.,
Starborg M., Rowe J., et al. CDK4 and CDK6
delay senescence by kinase-dependent and
p16INK4a-independent mechanisms. Mol. Cell
Biol. 2007; 27(12): 4273
–
82.
11.
Seargent J.M., Loadman P.M., Martin S.W.,
Naylor B., Bibby M.C., Gill J.H. Expression of
matrix metalloproteinase-10 in human bladder
transitional cell carcinoma. Urology. 2005;
65(4): 815-20.
Volume 04 Issue 06-2024
66
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
12.
Morgan D. Cell Cycle: Principals of Control.
London: New Sci¬ence Press Ltd.; 2007: 145
–
6.,
Mitrea D.M., Yoon M.K., Ou L., Kriwacki R.W.
Disorder-func¬tion relationships for the cell
cycle regulatory proteins p21 and p27. Biol.
Chem. 2012; 393(4): 259
–
74.
13.
Mitrea D.M., Yoon M.K., Ou L., Kriwacki R.W.
Disorder-func¬tion relationships for the cell
cycle regulatory proteins p21 and p27. Biol.
Chem. 2012; 393(4): 259
–
74.
14.
Pellegata
N.S.,
Quintanilla-Martinez
L.,
Siggelkow H., Sam¬son E., Bink K., Hofler H., et
al. Germ-line mutations in p27 Kip1 cause a
multiple endocrine neoplasia syndrome in rats
and humans. Proc. Natl. Acad. Sci. U.S.A. 2006;
103(42): 15558
–
63.
15.
Александрова
А.К.1,
Суколин
Г.И.2,
Смольянникова
В.А.ОСОБЕННОСТИ
ЭКСПРЕССИИ БЕЛКА p27 ПРИ РАЗНЫХ
ФОРМАХ
СЕБОРЕЙНОГО
КЕРАТОЗА
Российский журнал кожных и венерических
болезней 2016,19 (5) стр.283
-286.
16.
Karadag A. S., Parish L. C. The status of the
seborrheic keratosis //Clinics in Dermatology.
–
2018.
–
Т. 36. –
№. 2. –
С. 275
-277.
17.
Jackson J. M. et al. Current understanding of
seborrheic keratosis: prevalence, etiology,
clinical
presentation,
diagnosis,
and
management
//Journal
of
drugs
in
dermatology: JDD.
–
2015.
–
Т. 14. –
№. 10. –
С.
1119-1125.
18.
Sanders M. G. H. et al. Prevalence and
determinants of seborrhoeic dermatitis in a
middle‐aged and elderly population: the
Rotterdam
Study
//British
Journal
of
Dermatology.
–
2018.
–
Т. 178. –
№. 1. –
С. 148
-
153.
19.
Squillace L. et al. Unusual dermoscopic
patterns
of
seborrheic
keratosis
//Dermatology.
–
2016.
–
Т. 232. –
№. 2. –
С. 198
-
202.
20.
Wollina U. Recent advances in managing and
understanding
seborrheic
keratosis
//F1000Research.
–
2019.
–
Т. 8.
21.
Del Rosso J. Q. A closer look at seborrheic
keratoses:
patient
perspectives,
clinical
relevance, medical necessity, and implications
for management //The Journal of clinical and
aesthetic dermatology.
–
2017.
–
Т. 10. –
№. 3. –
С. 16.
22.
Bagazgoitia L, Cuevas J, Juarranz A. Expression
of p53 and p16 in actinic keratosis, Bowenoid
actinic keratosis and Bowen's disease. J Eur
Acad Dermatol Venereol. 2010;24(2):228
–
30.
23.
Broers J. L. V., Ramaekers F. C. S. The role of the
nuclear lamina in cancer and apoptosis //Cancer
Biology and the Nuclear Envelope: Recent
Advances May Elucidate Past Paradoxes.
–
2014.
–
С. 27
-48.
Volume 04 Issue 06-2024
67
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
24.
Talghini S, Halimi M, Baybordi H. Expression of
p 27, Ki 67, p 53 in squamous cell carcinoma,
actinic keratosis and Bowen disease. Pakistan
Journal of Biological Sciences. 2009;12(12):929
–
33. doi: 10.3923/pjbs.2009.929.933.
25.
Ahlgrimm-Siess V. et al. Seborrheic keratosis:
reflectance confocal microscopy features and
correlation with dermoscopy //Journal of the
American Academy of Dermatology.
–
2013.
–
Т.
69.
–
№. 1. –
С. 120
-126.
26.
Papadavid E, Pignatelli M, Zakynthinos S,
Krausz T, Chu AC. Abnormal immunoreactivity
of the E-cadherin/catenin (alpha-, beta-, and
gamma-) complex in premalignant and
malignant non-melanocytic skin tumours. J
Pathol.2002;196(2):154
–
62.
27.
Fuller LC, Allen MH, Montesu M, Barker JN,
Macdonald DM. Expression of E-cadherin in
human epidermal non-melanoma cutaneous
tumours. Br J Dermatol. 1996;134(1):28
–
32.).
28.
Хлебникова А.Н., Гуревич Л.Е.,
Селезнева
Е.В., Обыденова К.В., Седова Т.Г.,Кунцевич
Ж.С.
Особенности
пролиферации
и
межклеточной адгезии в предраковых и
злокачественных эпителиальных опухолях
кожи. Альманах клинической медицины.
2016 Январь; 44 (1): 58–
63.
29.
Aljada A. et al. Altered Lamin A/C splice variant
expression as a possible diagnostic marker in
breast cancer //Cellular Oncology.
–
2016.
–
Т.
39.
–
С. 161
-174.
30.
Dubik N., Mai S. Lamin A/C: function in normal
and tumor cells //Cancers.
–
2020.
–
Т. 12. –
№.
12.
–
С. 3688.
31.
Blomberg M., Jeppesen E.M., Skovby F.,
Benfeldt E. "FGFR3 Mutations and the Skin:
Report of a Patient with a FGFR3 Gene
Mutation,
Acanthosis
Nigricans,
Hypochondroplasia and Hyperinsulinemia and
Review of the Literature." Dermatology 220.4
(2010):297
–
300. DOI: 10.1159/000297575.
32.
Kim Y. The impact of altered lamin B1 levels on
nuclear lamina structure and function in aging
and human diseases //Current Opinion in Cell
Biology.
–
2023.
–
Т. 85. –
С. 102257.
33.
Saraiya A., Al-Shoha A., Brodell R.T.
"Hyperinsulinemia Associated with Acanthosis
Nigricans, Finger Pebbles, Acrochordons, and
the Sign of Leser-Trélat." Endocr. Pract. 19.3
(2013): 522
–
555. DOI: 10.4158/EP12192.RA.
34.
Squillace L, Cappello M, Longo C, Moscarella E,
Alfano R, Argenziano G. Unusual dermoscopic
patterns of seborrheic keratosis. Dermatology.
2016;232(2): 198
–
202. doi:10.1159/000442439.
19.
35.
Roh NK, Hahn HJ, Lee YW, Choe YB, Ahn KJ.
Clinical and histopathological investigation of
seborrheic
keratosis.
Ann
Dermatol.
2016;28(2):152
–
8. doi: 10.5021/ad.2016.28.2.152.
Volume 04 Issue 06-2024
68
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
36.
Tardío J.C., Bancalari E., Moreno A., Martín-
Fragueiro L.M. "Genital Seborrheic Keratoses
Are Human Papillomavirus-related Lesions. A
Linear Array Genotyping Test Study." APMIS.
120.6 (2012): 477
–
483. DOI: 10.1111/j.1600-
0463.2011.02853.x.,
37.
Jackson JM, Alexis A, Berman B, Berson
DS,Taylor S, Weiss JS. Current understanding
of seborrheic keratosis: prevalence, etiology,
clinical
presentation,
diagnosis,
and
management.J Drugs Dermatol. 2015;14(10):
1119
–
25. 18.
38.
Squillace L, Cappello M, Longo C, Moscarella E,
Alfano R, Argenziano G. Unusual dermoscopic
patterns of seborrheic keratosis. Dermatology.
2016;232(2): 198
–
202. doi: 10.1159/000442439.
19.
39.
Roh NK, Hahn HJ, Lee YW, Choe YB, Ahn KJ.
Clinicaland histopathological investigation of
seborrheic
keratosis.
Ann
Dermatol.
2016;28(2): 152
–
8. doi: 10.5021/ad.2016.28.2.152.
40.
Martin B.C., Warram J.H., Krolewski A.S.,
Bergman R.N., Soeldner J.S., Kahn C.R. "Role of
Glucose and Insulin Resistance in Development
of Type 2 Diabetes Mellitus: Results of a 25-year
Follow-up Study." Lancet 340 (1992): 925
–
929.,
41.
Юсупова Л. А. и др. Патогенетические
механизмы, диагностика и клиническая
картина себорейного кератоза //Лечащий
врач. –
2018.
–
№. 10. –
С. 73.
42.
Saraiya A., Al-Shoha A., Brodell R.T.
"Hyperinsulinemia Associated with Acanthosis
Nigricans, Finger Pebbles, Acrochordons, and
the Sign of Leser-Trélat." Endocr. Pract. 19.3
(2013): 522
–
555.
43.
Elder D.E., Elenitsas R., Johnson B.L. Jr, Murphy
G.F., Xu X. Lever's Histopathology of the Skin.
Philadelphia: Lippincott-Raven, 2009. 795
–
798
44.
Пашинян А. Г., Джаваева Д. Г., Молчанова О.
В. Себорейный дерматит в практике врача
-
косметолога.
Клинические
проявления.
Диагностика. Лечение //Метаморфозы. –
2018.
–
№. 24. –
С. 12
-16..
45.
Alapatt GF, Sukumar D, Bhat MR. A
clinicopathological
and
dermoscopic
correlation of seborrheic keratosis. Indian J
Dermatol. 2016;61(6):622
–
7.
46.
Saraiya A., Al-Shoha A., Brodell R.T.
"Hyperinsulinemia Associated with Acanthosis
Nigricans, Finger Pebbles, Acrochordons, and
the Sign of Leser-Trélat." Endocr. Pract. 19.3
(2013): 522
–
555. DOI: 10.4158/EP12192.RA.
47.
Choi HJ, Lee JH. Multiple human papilloma
virus 16 infection presenting as various skin
lesions. J Craniofac Surg. 2016;27(4):e379
–
81.
48.
Wu YH, Hsiao PF, Chen CK. Seborrheic keratosis
with
bowenoid
transformation:
the
immunohistochemical
features
and
its
association
with
human
papillomavirus
Volume 04 Issue 06-2024
69
American Journal Of Biomedical Science & Pharmaceutical Innovation
(ISSN
–
2771-2753)
VOLUME
04
ISSUE
06
P
AGES
:
54-69
OCLC
–
1121105677
Publisher:
Oscar Publishing Services
Servi
infection. Am J Dermatopathol. 2015;37(6):
462
–
8.
49.
Писклакова Т.П., Костенко Е.И., Телешева
Л.Ф. Себорейный кератоз: клинические
особенности и ассоциация с вирусом
папилломы человека рода β Альманах
клинической медицины. 2017 Март
-
апрель;
45 (2): 118
–
126.
50.
Rayess H., Wang M. B., Srivatsan E. S. Cellular
senescence and tumor suppressor gene p16 //
Int. j. cancer
–
2012.
–
V. 130 (8).
–
P. 171
–
174.,
