Keywords
aging health - cytology - papanicolaou test - screening - uterine cervical neoplasms
Palavras-chave
saúde do idoso - citologia - teste de papanicolau - programas de rastreamento - neoplasias
do colo do útero
Introduction
Despite national guidelines for screening and treatment,[1] cervical cancer (CC) is the fourth most deadly cancer in Brazilian women.[2] Worldwide, the incidence of CC in 2020 was 13.3 per 100,000 women, and the mortality
was 7.3 per 100,000.[3] In Brazil, the mortality was 6.12 deaths per 100,000 women in 2022,[2] and among women > 65 years old (screened or not), it was 22.1% between 1996 and
2015.[4]
The Brazilian CC screening program targets women aged 25 to 64 years old based on
conventional cytology.[1] The first two tests should be performed yearly, and if both results are negative,
the tests should be performed every 3 years. However, almost half of the tests occur
within a year,[1]
[5] that is, some women were overscreened. In contrast, others are unscreened because
all cytological tests are spontaneous; thus, only women who seek health services undergo
cytologic examinations.[5]
In this context, there are various explanations for the high incidence and mortality
rates, including the low coverage rate of cytology, the opportunistic nature of the
program, and the fact that there are no testing intervals or age group restrictions.[5]
[6] Also, there is almost no control over the amount or quality of the latest tests
performed on older women who reach 64 years old when screening stops.[7]
[8] According to the guidelines, a patient should not reach the age limit without considering
her screening history; it is critical to have at least two negative tests in the previous
5 years and no prior history of preinvasive neoplastic disease before ceasing cytological
collections.[1] In this context, the present study compared the follow-up of cytological results
from women > 64 years old and biopsied patients who did or did not adhere to the Brazilian
national CC screening guidelines.
Methods
The present observational, retrospective and analytical study compared the prevalence
of abnormal cervical smears in women > 64 years old who did or did not follow the
screening protocol. Our cohort came from Araçatuba, a mid-sized city in the southeastern
countryside of the state of São Paulo, Brazil, and its region. The sample consisted
of conventional cervical smears obtained from the records of the Instituto de Patologia
de Araçatuba from January 1, 2002, to December 31, 2015 (14 years). This laboratory
receives tests collected for CC screening from patients of the Brazilian Unified Health
System (SUS, in the Portuguese acronym). Smears were collected from private clinics
in Araçatuba and surrounding areas.
The results were reported according to the Bethesda System: atypical squamous cells
of undetermined significance (ASC-US); atypical squamous cells cannot exclude high-grade
squamous intraepithelial lesion (ASC-H); low-grade squamous intraepithelial lesion
(LSIL); high-grade squamous intraepithelial lesion (HSIL); squamous cell carcinoma
(SCC); atypical glandular cells of undetermined significance (AGC-US); atypical glandular
cells favor neoplastic (AGC); endocervical carcinoma in situ; invasive cervical adenocarcinoma;
invasive endometrial adenocarcinoma; and adenocarcinoma not otherwise specified.[9] There are additional categories in the Brazilian national guidelines: atypical undetermined
cells of undetermined significance and atypical undetermined cells, which cannot exclude
high-grade intraepithelial lesions. Both refer to results in which it is impossible
to determine if the atypical cells are glandular or squamous.[1]
Patients with abnormal results were compared in a subsequent step: repeat cytology
in 6 months or go to colposcopy and biopsy, depending on the first abnormal cytology
result. Then, those who were biopsied were divided into two groups: those who had
at least two consecutive negative cytopathological tests in the previous 5 years (that
is, those who followed the national CC screening guidelines and those who did not).[1] The magnitude of association was analyzed using the odds ratio (OR) with a 95% confidence
interval (CI). Data were expressed as absolute (n) and relative (%) frequencies to assess the association between diagnostic categories.
The significance level was set at 5%. Our research ethics committee approved the study
under protocol CAAE: 83847517.10000.5379.
Results
Over these 14 years, there were 207 abnormal cytological results among women > 64
years old. Of these, 120 (58.0%) were classified as ASC-US and 8 (3.9%) were LSIL.
According to the national screening program,[1] these patients should undergo repeat cytology in 6 months: 112 (87.5%) repeated
the cytology and only 33 (25.7%) showed an abnormal result in the second exam. Finally,
33 (25.7%) biopsies were performed in this group, of which 7 (5.5%) demonstrated some
abnormality: 1 cervical intraepithelial neoplasia (CIN) I, 3 CIN II, 1 CIN III, 1
SCC and 1 endometrial carcinosarcoma. The other 79 (38.1%) patients with abnormal
results should have been referred to colposcopy and biopsy; however, 43 (54.4%) repeated
the cytology, with 22 abnormal results (1 ASC-US, 3 AGUS, 9 ASC-H, 1 AGCH, 1 LSIL,
5 HSIL, 1 SCC and 1 atypical undetermined cells that cannot exclude high-grade intraepithelial
lesions). Biopsy was performed in 41 (51.9%) of the women in this group, and 23 (29.1%)
were positive (2 endometrial adenocarcinomas, 9 SCC, 5 CIN II, 5 CIN III and 2 adenocarcinomas).
The results of the first cytology and their follow-up are shown in [Table 1].
Table 1
The frequency of abnormal cytology and follow-up among women over 64 years old compared
with following national guidelines
|
Cytologic results
|
First cytology
|
Repeated cytology
|
Abnormal results in second cytology
|
Biopsies
|
Abnormal biopsies
|
|
ASC-US
|
120 (58.3%)
|
105 (87.5%)
|
23 ASC-US
9 ASC-H
1 LSIL
|
29 (24.2%)
|
8 (6.6%)
|
|
ASC-H
|
28 (13.6%)
|
12 (42.8%)
|
6 ASC-H
2 HSIL
|
14 (50.0%)
|
8 (28.6%)
|
|
Atypical undetermined cells of undetermined significance
|
16 (7.8%)
|
12 (75%)
|
1ASCUC
1 AGUS
1 Atypical undetermined cells cannot exclude high-grade intraepithelial lesions
|
7 (43.7%)
|
2 (12.5%)
|
|
AGUS
|
9 (4.4%)
|
7 (7,8%)
|
1 AGCH
1 AGUS
|
3 (33.3%)
|
2 (22.2%)
|
|
LSIL
|
8 (3.9%)
|
7 (87.5%)
|
3 ASC-US
|
6 (75%)
|
1 (12.5%)
|
|
HSIL
|
8 (3.9%)
|
6 (75%)
|
2 ASC-H
3 HSIL
|
5 (62.5%)
|
2 (25%)
|
|
SCC
|
7 (3.4%)
|
2 (28.6%)
|
1 SCC
1 ASC-H
|
7 (100%)
|
6 (85.7%)
|
|
Atypical undetermined cells cannot exclude high-grade intraepithelial lesions
|
5 (2.4%)
|
3 (60%)
|
1 HSIL
|
3 (60%)
|
1 (20%)
|
|
AGC
|
3 (1.5%)
|
1 (33.3%)
|
1 AGUS
|
2 (66,7%)
|
1 (33.3%)
|
|
Adenocarcinoma not otherwise specified
|
1 (0.5%)
|
–
|
–
|
1 (100%)
|
1 (100%)
|
|
Invasive endometrial adenocarcinoma
|
1 (0.5%)
|
–
|
–
|
1 (100%)
|
1 (100%)
|
|
Invasive cervical adenocarcinoma
|
1 (0.5%)
|
–
|
–
|
–
|
–
|
|
Total
|
207 (100%)
|
155 (75.2%)
|
56 (27.1%)
|
78 (37.7%)
|
33 (15.9%)
|
Abbreviations: AGC: atypical glandular cells favor neoplastic; AGC-US: atypical glandular
cells of undetermined significance; ASC-H: atypical squamous cells cannot exclude
HSIL; ASC-US: atypical squamous cells of undetermined significance; CI: confidence
interval; HSIL: high-grade squamous intraepithelial lesion; SCC: squamous cell carcinomas;
LSIL: low-grade squamous intraepithelial lesion.
*All frequencies are relative to the total of the first cytology
Over the entire period, 78 (37.7% of the first abnormal results) biopsies were performed.
Of these, 40 (51.3%) had at least 2 negative tests consecutively in the previous 5
years, following the national protocol: 31 (77.5%) negative biopsies and 9 (22.5%)
positive results (1 endometrial adenocarcinoma, 1 SCC, 2 CIN I, 2 CIN II, 3 CIN III).
Among the 38 (48.8%) women who did not follow the guidelines, 14 (36.8%) biopsies
were negative and 24 (63.1%) were positive (1 endometrial carcinosarcoma, 1 endometrial
carcinoma, 9 squamous cell carcinomas, 2 cervical adenocarcinomas, 5 CIN II, and 6
CIN III). The biopsy results are shown in [Table 2]. Then, women who did not follow the guidelines demonstrated higher chances of cancer
and precursor lesions (OR: 5.904; 95%CI: 2.188–15.932;
p = 0.0002).
Table 2
Frequency of abnormal biopsies among women over 64 years old compared with following
national guidelines
|
Histological subtypes
|
Followed guideline
|
Not followed guideline
|
OR
(95% CI)
|
Total
|
|
Negative
|
31 (77.5%)
|
14 (36.8%)
|
1
|
45
(57.7%)
|
|
Premalignant lesions
(CIN I, II, and III)
|
7 (17.5%)
|
11 (28.9%)
|
3.479
(1.114–10.864)
|
18 (23.1%)
|
|
SCC
|
1 (2.5%)
|
9 (23.7%)
|
NA
|
10 (12.8%)
|
|
Cervical adenocarcinoma
|
–
|
2 (5.3%)
|
NA
|
2 (2.6%)
|
|
Others
|
1 (2.5%, endometrial adenocarcinoma)
|
2 (5.3%, endometrial carcinosarcoma and endometrial adenocarcinoma)
|
NA
|
3 (3.8%)
|
|
Total
|
40
|
38
|
5.904 (2.188–15.932)
p = 0.0002
|
78 (100%)
|
Abbreviations: CI: confidence interval; CIN: cervical intraepithelial neoplasia; OR:
odds ratio; SCC: squamous cell carcinoma.
Discussion
There is a significant frequency of CC precursor lesions and neoplasm in Brazilian
women > 64 years old. A recent screening history influences the frequency and severity
of the abnormal diagnosis. Many women in this age group with abnormal cytology did
not correctly follow the screening protocols to confirm or treat the abnormality.
When women had indications to repeat the cytology because of their low-grade characteristics,
87.5% of the women did so. Under the Bethesda System, ASC-US suggests LSIL (CINI);
however, with a 10 to 20% possibility of HSIL (CIN II or CIN III).[9] The Brazilian guidelines assume this degree of benign behavior of the alteration
and make conservative recommendations; thus, women with ASC-US and LSIL cytology results
should undergo repeat cytology in 6 months.[1]
It is essential to highlight that some degree of neoplasia or premalignant lesions
was found in 5.5% of biopsied patients. Other studies showed that conventional cytology
had an overall sensitivity of 50 to 75% for detecting low-grade lesions and of 55
to 90% for high-grade lesions (CIN II/III).[8]
[10]
[11]
Considering women whose cytological results have high-grade characteristics with indications
to proceed directly to colposcopy and possible biopsy, 54.4% underwent a second cytological
test, not following the current guidelines. Of this group, 29.1% had some type of
neoplasm in a later biopsy. This finding suggests an underestimated number of CC diagnoses
and a higher accumulated risk of CC in women who did not undergo screening as recommended,
primarily among those with a high-grade lesion possibility.[12]
[13] In India, the frequency of abnormal biopsies in women > 65 years old was also high
(47.3%), demonstrating a higher frequency of cervical alterations among older women
who continue the screening, corroborating the present study.[14]
When analyzing biopsies from 15 women with premalignant lesions, only 18.7% had followed
the guidelines; among 10 cases of SCC, only 1 had followed the protocols, although
all cases of adenocarcinomas had improper screening history. For glandular lesions,
the difficulty in representing endocervical cells, especially among older women with
some grade of retraction, may explain the screening not being performed appropriately.[1]
[8]
[9] The Brazilian guidelines consider any atypical glandular cell high-risk and associated
with CIN II/III or cancer.[1]
Inadequate cervical screening in older women is a possible reason for delayed diagnosis
and poor prognosis.[15] On the other hand, adequate screening can reduce the incidence of cervical cancer
by 75%, as well as mortality.[16] Therefore, in agreement with the present study, women > 64 years old with inadequate
screening had a higher risk of CC and worse outcomes.[17]
[18]
Other studies showed that few women who reached the age of exiting screening programs
had been adequately screened during the preceding years.[19]
[20] Indeed, among women in the target group, there was poor follow-up, low frequency,
and precarious cellular representation in samples, which may lead to underestimation
of the prevalence of CC and premalignant lesions during screening of women at the
target age.[21] In the context of inadequate cervical screening program performance, the frequency
of cervical cancer could be more significant than expected.
In countries that implemented screening using DNA testing, high-risk human papillomavirus
was present in smears of women > 70 years old, and there were premalignant lesions
in 45% of them even after their exit from screening.[22] This finding indicates the importance of screening these women later in life, especially
if they had an abnormal screening history or were not screened. These findings reinforce
the relevance of reassessing the age of exit of the protocol, the quality of smears
and the frequency of previous screening.
We identified (63.1%) severe abnormalities in older women who did not follow the guidelines
(endometrial carcinosarcoma, SCC, adenocarcinomas, CIN II and CIN III). This finding
is similar to the American scenario, where lesions in advanced stages may be explained
by irregular screening history despite the guidelines.[23] The decreasing interest in screening with advancing age also explains why older
women have higher incidences of CC, especially where screening programs have an opportunistic
character, as is the case in Brazil.[24]
[25] These explanations were also advanced in Australia[26] and Finland[27] to explain the frequency of abnormal tests in older women with a history of inadequate
screening.
The suboptimal screening performance among this group can be explained by the level
of patient education regarding the disease and limited access to the test.[28] The lack of knowledge of health professionals in Brazil (and worldwide) about the
target ages and subsequent steps in national protocols for diagnosing, monitoring,
and treating precursor lesions and neoplasm can also explain the results.[29]
[30]
A limitation of the present study is that we analyzed data from a medium-sized city,
which might not represent all Brazilian populations. Nevertheless, the present study
illustrates the prevalence of abnormal cervical smear results in our community since
our laboratory is the only pathology laboratory in the city.
Conclusion
Because CC mortality in Brazil is high, the frequency of abnormal cytological results
among women > 64 years old is not insignificant. The present study demonstrated that
women who did not follow the national guidelines had higher rates of true precursor
lesions (CIN II/III) and invasive neoplasms (SCC, adenocarcinomas, and others) than
those who followed the guidelines. These findings suggest revising the screening exit
age in Brazil to reduce the incidence of CC.
