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IMPROVING THE EARLY DIAGNOSIS OF PRECANCEROUS DISEASES
OF THE CERVIX IN PREMENOPAUSAL WOMEN
Amanboeva F.B.
Adizova Z.O.
Dsc An A.V.
Tashkent Medical Academy, Tashkent, Uzbekistan
https://doi.org/10.5281/zenodo.14065468
Cervical cancer is the fourth most common cancer among women globally,
with an estimated 604,000 new cases and 342,000 deaths worldwide. Few
diseases reflect global inequities as much as cancer of the cervix. Nearly 90% of
the deaths in 2020 occurred in low- and middle-income countries, which lag in
vaccination, screening, and treatment.
According to the World Health Organization (WHO), the average annual
increase in human papillomavirus infection exceeds 2.5-3 million, the frequency
of asymptomatic virus carriage in the world is high and amounts to 15.5% in
Russia; in the USA - 28.6%; in Europe - 2-12%. HPV-associated cervical cancer is
the third most common cancer among women in the world, with -70% of cases
due to infection with HPV types 16 and 18. Compared to other gynecological
diseases, cervical cancer is more common in young women, with an average age
of about 49 years. Over the past 50 years, the introduction of "... Pap smear
testing and HPV vaccination in developed countries has reduced morbidity and
mortality by 75% ...". Despite widely implemented prevention programs, the
prevalence of cervical cancer continues to remain high. Thus, despite the
widespread implementation of preventive measures, the development and
implementation of new methods for early diagnosis and treatment of cervical
intraepithelial neoplasia (CIN) is relevant.
Classification of HPV depending on oncogenicity (IARC, 2003)
The degree of oncogenicity of HPV
Highly oncogenic
Low-oncogenic
Medium oncogenic
Type of HPV
Highly oncogenic
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59,
68, 73,
82
Low-oncogenic
6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81
Medium oncogenic
26, 53, 66
In 2012, the IARC identified 3 groups of oncogenic HPV: group 1 - high
carcinogenic risk, group 2 A - probable carcinogenic risk, group 2B - possible
carcinogenic risk.
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Table 2
Carcinogenic risk groups depending on the type of HPV (IARC, 2012)
Carcinogenic risk
group
Type of HPV
1
HPV 16, HPV 18, HPV 31, HPV 33, PO 35, HPV 39, HPV 45, HPV
51, HPV 52, HPV 56, HPV 58 and HPV 59
2А
HPV 68
2В
P 26, PCH 30, PCH 34, PCH 53, PCH 66, PCH 67, PCH 69, PCH 70,
PCH 73, PCH 82, HPV 85, HPV 97
In August 2020, the World Health Assembly adopted the Global Strategy for
cervical cancer elimination. The WHO has set up global 90-70-90 targets to be
reached by 2030: 90% of girls fully vaccinated with the human papillomavirus
(HPV) vaccine by age 15; 70% of women are screened by 35, and again by 45
years of age; and 90% of women identified with cervical disease receive
treatment.
It is known that 96% of cases of cervical cancer are caused by HPV groups 1 and
2A (high and probable carcinogenic risk). HPV group 2B (possible carcinogenic
risk) is detected in 2.6% of women with breast cancer [13].
The process of carcinogenesis, starting with cellular changes caused by HPV
infection and ending with breast cancer, can take from 10 to 40 years, but in rare
cases, breast cancer can develop in 1-2 years [6]. Therefore, early diagnosis of
both cervical cancer and precancerous conditions - cervical intraepithelial
neoplasia of varying severity is of interest.
Diagnostic methods such as cytological examination, extended colposcopy,
molecular genetic methods (genotyping of twenty-one HPV types with
determination of viral load by Real-Time PCR, determination of the expression
level of viral oncoproteins E6, E7), cervical biopsy with histological examination
of biopsy material are widely used in the detection of cancerous and
precancerous
diseases
of
the
cervix,
immunocytochemical
and
immunohistochemical studies (p16 and Ki67), the use of optoelectronic signals
to assess the epithelium of the cervix (TruScreen apparatus) .
Despite impressive achievements in the field of molecular biology, which made it
possible to reveal the main mechanisms and stages of carcinogenesis and to
significantly improve the capabilities of instrumental diagnostics, every year
there is a disappointing trend in the world towards an increase in the number of
patients with oncological diseases.
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Cervical cancer is a dangerous disease, the second most common type of cancer
among women in Uzbekistan. In 2021, 1,827 new cases were identified, 997
women died. Morbidity and mortality are steadily increasing, and cervical
cancer is projected to cause 2,100 new cases and 1,300 deaths per year by 2030.
[1].
In Karakalpakstan, the incidence of cervical cancer ranks second after breast
cancer among the female population. A malignant tumor of the cervix in 2020
claimed the life of 71 women in Karakalpakstan.
Despite the widespread use in clinical practice of various destructive and
excisional methods of treatment of cervical intraepithelial neoplasia (CIN) and
carcinoma in situ, a number of patients subsequently revealed the persistence of
human papillomavirus (HPV) of high carcinogenic risk, which contributes to the
recurrence of the disease and repeated surgical interventions on the cervix [9;
90].
In order to accurately diagnose the severity of CIN, assess the prognosis of the
course of small forms of cervical lesions, and select the most optimal
management tactics for patients, it is necessary to search for effective
biomarkers with high diagnostic and prognostic significance.
Currently, the human genome and transcriptome are widely studied to search
for biomarkers of CIN and PCM [21; 30; 45; 92].
The purpose of the study
To develop differentiated approaches to the management of patients with
cervical intraepithelial neoplasia of varying severity based on the study of
clinical, morphological methods and special analysis of squamous cell
carcinoma antigen (SCC-Ag)
Research objectives
1. To conduct a retrospective analysis of the long-term results of destructive and
excisional treatment of patients with precancerous diseases and cervical cancer,
followed by simultaneous HPV genotyping.
2. To identify the correlation of histological diagnosis and lipidome of affected
tissues in HPV-associated cervical diseases, depending on the severity of the
lesion (LSIL, HSIL, RSM).
3. To improve the algorithm for the management of premenopausal patients
with HPV-associated cervical diseases, taking into account Squamous cell
carcinoma antigen (SCC-Ag)
Research methodology and methods
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According to the inclusion and exclusion criteria, 110 patients were recruited
into a single-stage prospective cohort study. Depending on the results of
histological examination of cervical biopsies, 4 groups were formed: chronic
cervicitis in combination with HPV infection (n=30), LSIL (n=30), HSIL (n=30)
and cervical cancer (n=20). General clinical and special methods were used to
examine women. Special methods included Squamous cell carcinoma antigen
(SCC-Ag) processes of the cervix.
A retrospective analysis of the long-term results of surgical treatment of 110
patients with HPV-associated cervical diseases (LSIL, HSIL, C-r in situ) for the
period 2020-2024 was also conducted. The average age of the patients and their
obstetric history after undergoing surgical treatment were evaluated. These
patients were called to the Tashkent City Cancer Center for simultaneous HPV
testing and cytological examination of cervical smears in order to identify the
persistence or reinfection of HPV and identify risk groups for the development
of relapses of CIN and cervical cancer.
According to the results of histological examination of cervical biopsies, 4 groups
of patients were formed : Group I - 30 (27%) patients with chronic cervicitis in
combination with HPV infection; group II - 30 (27%) patients with LSIL; Group
III - 30 (27%) patients with HSIL; Group IV consisted of 20 (19%) patients with
breast cancer (Figure 3).
Figure 1. Distribution of patients by groups
The average age of the patients in the 4 groups did not differ statistically
significantly and amounted to 33.4±7.0 years. Comparative analysis of
anthropometric data also revealed no significant differences between the groups
(p>0.05).
When studying the characteristics of the sexual life of the patients, it was
revealed that 35 (32%) women had a sexual debut before the age of 18. Earlier,
the onset of sexual activity (under 18 years of age) was observed in 10 (32.3%)
patients from group 1, in 6 (20%) patients from group 2, in 13 (43.3%) patients
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from group 3, in 6 (30%) patients from group 4. The average age of sexual
initiation was 18.6 ±
3.3 years (19.7 ± 5.3 years in group 1, 18.8 ± 2.1 years in group 2, 17.6 ± 1.0
years in group 3 and 18.3 ± 2.2 years in group 4). The average number of sexual
partners was 2.6 ± 1.8 in group 1, 2.4 ± 1.0 in group 2, 3.4 ± 1.0 in group 3, 3.5 ±
1.0 in group 4. 16 (51.6%) patients reported having more than 3 sexual partners
in group 1, and 12 in group 2 (40%) of patients, 25 (83.3%) patients in group 3,
17 (85%) patients in group 4. 75 (68%) of the patients began sexual activity
outside of an official marriage.
Statistically significant differences in the indicator "more than 3 sexual partners"
were revealed between 1 and 3 groups of patients (p=0.008; OR= 4.7 (1.4-15.4));
between 1 and 4 groups (p=0.015; OR = 5.3 (1.29-21.8)); between 2 and 3
groups (p=0.001; OR =7.5 (2.2-25.0); between 2 and 4 groups (p=0.002; OR=8.5
(2.0-35.4)). These results demonstrated that women with severe precancerous
and malignant diseases of the cervix have a significantly higher number of sexual
partners in the anamnesis, compared with women with benign and
precancerous diseases of the cervix of mild severity.
All 110 patients included in the study underwent cytological examination of
cervical smears (liquid cytology). The results of cytological examination by
groups are presented in Table 12.
The results of cytological examination
Cytogram
Group 1, n=30 Group 2, n=30 Group 3, n=30 Group 4, n=20
NILM
6 (20%)
3 (10%)
1 (3,3%)
1 (5%)
Cervitcits
11 (37%)
6 (20%)
1 (3,3%)
1 (5%)
ASCUS
7 (23%)
6 (20%)
2 (7%)
-
LSIL
4 (13,4%)
12 (40%)
4 (13,4%)
-
HSIL
1 (3,3%)
3 (10%)
22 (73%)
3 (15%)
Cervical canser 1 (3,3%)
-
-
15 (75%)
In our study, the specificity of the cytological method in patients with chronic
cervicitis was 90%, in patients with LSIL also 90%, in patients with HSIL - 81%,
in patients with cervical cancer - 99%.
Despite the high specificity, the sensitivity of the cytological examination
method, especially the traditional one, is no more than 60%. Thus, it is possible
to explain the presence of cytograms of LSIL (13.4%) and NILM (3.3%) in
patients with histologically confirmed diagnosis of HSIL, as well as the presence
of cytological findings of NILM (5%) and chronic cervicitis (5%) in patients with
breast cancer. Due to the low sensitivity of the cytological research method,
there is a danger of underestimating the severity of damage to the cervical
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epithelium in patients with HPV-associated diseases, which requires further
search for lipidomic markers for accurate early and differential diagnosis of the
severity of damage to the cervical epithelium.
From a cytological point of view, chronic cervicitis consists of cells of flat,
cylindrical and metaplastic epithelium, elements of chronic inflammation
(lymphocytes, histiocytes, cells of the plasma and fibroblastic series), non-
specific signs such as acanthosis, hyper- and parakeratosis were often noted
(Figure 2).
Figure 2. Cytological picture of chronic cervicitis in combination with HPV
infection
The cytological picture in ASCUS was characterized by the presence of single
squamous epithelial cells with signs of atypia, the interpretation of which caused
difficulty. Coilocytes were often found - cells of the intermediate layer with
enlarged nuclei, an uneven membrane and hyperchromia, with the presence of
an extensive perinuclear zone of enlightenment, clearly delimited from the
peripheral parts of the cytoplasm, which were stained more evenly and
intensively. The perinuclear zone of enlightenment is the result of degenerative
changes, necrosis of the cytoplasm, which begins with the nucleus with a gradual
spread to the periphery.
The cytological picture in patients with LSIL was characterized by the presence
of cells with mild dyskariosis. Coilocytoatypy, binuclear cells, an indistinct
increase in the nuclear-cytoplasmic ratio and weak hyperchromia of the nuclei
were detected (Figure 3).
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Figure 3. Cytological picture of LSIL
All patients included in the study underwent extended colposcopy. Satisfactory
colposcopic picture (type 1 and type 2 CT) was found in 60% of patients,
unsatisfactory (type 3 CT) - in 40%. An abnormal colposcopic pattern was found
in the majority (87%) of women. Mild colposcopic changes (Figures 20-23) were
observed in 44% of patients and included the presence of a thin ABE with
delicate mosaic and punctuation, slow manifestation of acetobility.
An unsatisfactory colposcopic picture (type 3 transformation zone) was
observed in 13.3% of patients from the chronic cervicitis group, in 10% from the
LSIL group, in 3.3% of women with HSIL and in 5% of patients with breast
cancer. Mild colposcopic changes were most common in women with chronic
cervicitis (80%) and LSIL (66.7%), in the HSIL and breast cancer groups they
were less common - in 10% and 25% of cases, respectively. Pronounced
colposcopic changes were detected in the majority of patients with HSIL (86.7%)
and breast cancer (70%). However, 23.3% of cases of LSIL and 6.7% of cases of
chronic cervicitis were also accompanied by pronounced changes in colposcopy.
Cervical hypertrophy was most common in patients with breast cancer (30%), in
the groups of chronic cervicitis, LSIL and HSIL it was less common - in 16.7%,
6.7% and 6.7% of cases, respectively. Cervical deformity was detected in 23.3%
of patients with chronic cervicitis, in 13.3% in the LSIL group, in 16.7% of
patients with HSIL and in 20% of women with breast cancer. In patients with
chronic cervicitis, genital warts of the vulva occurred in 6.7% of cases, genital
warts of the cervix and perianal region occurred with the same frequency -
3.3%. In women with LSIL, genital warts of the vulva, vagina and cervix were
found with the same frequency - 3.3%, genital warts of the perianal region were
detected more often - in 6.7% of cases.
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Figures 4. Colposcopic changes in group II patients
A comparative analysis of the occurrence of various types of HPV by group
revealed that HPV group A9 was significantly more common (60%), and the
dominant type of HPV in all groups was type 16 (25.7% in the LSIL group, 43%
in the HSIL group and 39.3% in the breast cancer group). The presence of other
highly oncogenic HPV types also attracted attention: 18, 52, 56, 33, 31, 35, 58.
The results of the study showed that in the HSIL (p=0.001) and breast cancer
(p=0.001) groups, the presence of 2 or more types of HPV in one patient was
significantly more common than in group I (chronic cervicitis in combination
with HPV infection).
Thus, the vast majority of cases of HSIL (86%) and breast cancer (89.3%) were
due to the action of HPV group 1, a high carcinogenic risk, according to the IARC
classification. However, 6% of patients with HSIL were diagnosed with HPV
types 66 and 82, which, according to this classification, belong to a possible
carcinogenic risk. In patients with breast cancer, HPV of probable carcinogenic
risk from group 2A (type 68) was detected in 3.7% of cases, and in 7% of
possible carcinogenic risk from group 2B (types 53 and 66).
In 92% of the patients, the viral load was clinically significant - more than 3 Lg.
More than half (53%) of the patients had a high level of viral load (more than 5
Lg). The results of the analysis showed that HPV with a high viral load was
significantly more common in the groups with severe dysplasia and breast
cancer compared with the group with chronic cervicitis and LSIL.
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