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Atypical Squamous Cells of Undetermined Significance
Introduction
Atypical squamous cells of undetermined significance (ASC-US) is a term used to report a category of cervical epithelial cell abnormalities described by the Bethesda system for reporting cervical cytology. It refers to abnormal cytologic changes that are suggestive of the squamous intraepithelial lesion (SIL) but are qualitatively and quantitatively less than those of a definitive SIL diagnosis.[1] The clinical significance of ASC-US is based on the fact that this cytology finding is suggestive of a varying degree of SIL. Nearly 10% to 20% of patients with ASC-US prove to have a varying degree of cervical intraepithelial neoplasia (CIN), which are distinctive precursor lesions of cervical squamous cell carcinoma.[2]
About a decade ago, cervical cancer was the third most common cancer in women worldwide, and it was ranked as the first most common cancer in women in 42 low-resourced countries.[3] However, the explained link between persistent infection with carcinogenic human papillomavirus (HPV) and the development of cervical cancer has paved the way for the advancement of primary and secondary prevention of this type of cancer. The currently used preventive measures include primary prevention by HPV vaccination and secondary prevention through cervical screening programs, patient's follow-up, and treatment of precursor lesions.[4]
In developed countries such as United States, United Kingdom, and Canada, widespread availability and access to cervical cancer screening have led to a significant reduction in both incidence and mortality from cervical cancer.[5][6][7][8] In the United States, the incidence of cervical cancer cases has dropped to 7.4 per 100,000, while deaths from invasive cervical cancer have dropped to 2.8 per 100,000 women.[9][10][11] A late diagnosis of invasive cervical cancer has a 100 percent mortality rate. The importance of screening in the prevention of cervical cancer is that precancerous stages are slow-growing and amenable to treatment.[12][13] Active screening and treatment of women for precancerous lesions, particularly in developing countries, have a very high chance of total elimination of deaths from cervical cancer.[14][5] A more recent study estimated the worldwide age-standardized incidence rate of cervical cancer to be 13·1 (6.4 for Northern America) per 100,000 women-years and an age-standardized mortality rate of 6·9 (1.9 for Northern America) per 100,000. In the same study, cervical cancer was ranked as the worldwide fourth most common cancer among women after breast cancer, colorectal cancer, and lung cancer.[15]
Though it has been previously theorized that alpha-1 antitrypsin deficiency may be a genetic predisposition, this is not yet confirmed.[16] Rather, ample scientific evidence suggests that certain high-risk Human papillomaviruses (hrHPV) cause over 90% of cervical cancers, with 50 to 73.8% attributed to HPV 16 strain and 12 to 16.4 % attributed to HPV 18.[17][18] The long-standing model of diagnosis has been by cytology using the Papanicolaou smear (Pap test) and biopsy, and most recently by liquid-based cytology (LBC).[19][20] Other methods of diagnosis include HPV DNA test and colposcopy.[21][22]
Women that have ever been sexually active are at risk of developing cervical cancer; however, there are women with a greater risk profile than others. Risk factors commonly associated with the development of cervical cancer include younger age at sexual debut, multiple concurrent sexual partners, chronic intense smoking, HIV infection, and persistent infection with high-risk HPV. Though the Pap test dates back to the late 1940s, it has not been fully adopted and utilized in resource-limited settings for several reasons, including high cost and delay in getting results. Very low rates of Pap smear have been reported in resource-limited countries, including Jamaica at 15% and Nicaragua at 20% national coverage. In some Asian and African countries, Pap testing rates are even lower, or it does not even exist, compared to Jamaica.[23] In other countries, at the time when cervical screening programs were not implemented, opportunistic Pap smear screening tests were used instead, but the rate was also remarkably low.[24]
Visual inspection of the ectocervix is the new way of screening, with immediate results and successful treatment of most of the identified precancerous lesions.[25] Negative cervical cytology is reported as "negative for intraepithelial lesion or malignancy" (Negative/NILM). Squamous cell abnormalities that can be detected by cervical cytology include ASC-US, atypical squamous cells-high-grade cannot be excluded (ASC-H), low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial session (HSIL), and invasive squamous cancer. Glandular cell abnormalities include atypical glandular cells (AGC), including endocervical and endometrial cells (not otherwise specified or favor neoplastic), endocervical adenocarcinoma in situ (AIS), and adenocarcinoma. This activity will improve the understanding of what ASC-US is and the implications and management of ASC-US diagnosis.[26][27][21][28]
Etiology
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Etiology
Cervical cancer is not a sexually transmitted infection, but it develops from precursor lesions (CIN) that are predisposed by a persistent infection with a common sexually transmitted pathogen, the HPV. There are over 200 species of human papillomavirus. Researchers have identified 13 hrHPV viral strains that cause human cancers, of which HPV 16 and HPV 18 cause about 70 percent of cervical cancers, and more so in HIV-infected women.[29][30] The atypical squamous cells seen in cervical cytology may be related to HPV infection and neoplasia. They are just cytologic mimics caused by inflammation, air drying, atrophy with degeneration, and other artifacts. One study of the U.S. cervical screening programs showed about 50% of women with atypical squamous cells are infected with HrHPV. In contrast, the other noninfected women are not at increased cancer risk.[2]
Other studies have demonstrated a high prevalence of hrHPV in patients with ASC-US; one study in Brazil analyzed 1,340 liquid-based cytology specimens and found out that 64% of ASC-US specimens harbored hrHPV.[31] In two separate studies, Mai Nishimura reported identifying hrHPV in 81 % of patients with ASC-US. In contrast, Ming Guo and colleagues reported a hrHPV 16/18 incidence rate of 37% in their ASC-US patient cohort, while one Mexican study found an incidence rate of 11.2 percent.[32][33][34] In another study in Turkey, 129 women with abnormal Pap smears were screened for hrHPV positivity, 94 had ASC-US diagnosis, and 94% of those had a hrHPV.[35]
Epidemiology
Cervical precancer lesions are slow-growing and are commonest between the ages of 35 and 45 years but can be seen more frequently in HIV-positive women between the ages of 25 and 35. With the persistence of hrHPV infection over the years or decades, actual cancer peaks after the age of 50 years.[36] We call ASC-US today originally described by Papanicolaou as atypical pathology, and it is a cytological nomenclature.[19] The original laboratory technicians who worked on smears reported them simply as normal, atypical, or suspicious/malignant.[19] ASC-US, therefore, represents a mix of squamous epithelial cells at different stages of transitioning from the lowest risk atypia to the worst form of precancer, with some harboring the potential to revert to normalcy.[32]
The histological classification known as cervical intraepithelial neoplasia or CIN is a three-tier grading of CIN that corresponds to the number of layers of epithelial cells affected by atypia.[36][37] The CIN classification replaces the dysplasia terminology, with CIN 1, CIN 2, and CIN 3 being equivalent to mild dysplasia, moderate dysplasia, and severe dysplasia, respectively. The dysplasia descriptions are, however, no longer in use. There modified Bethesda system of cytological classification divides atypical squamous cells (ASC) into atypical squamous cells of undetermined significance (ASC-US), and atypical squamous cells-high-grade cannot be excluded (ASC-H).[38][39]
ASC-US is a common diagnostic category considered to be a difficult and grey zone diagnosis between negative and a confirmed SIL.[36][39] Follow-up and further analyses of ASC-US results have not only identified LSIL cells but HSIL also.[40] By the Bethesda system, ASC-US/ASC-H taken together is of lesser risk compared to LSIL, which is the equivalent of CIN1 by histology and HSIL (CIN 2/3).[41][36][42][43] Different studies have reported the incidence of ASC-US to be as low as 2.5% in one Japanese study, 4.1% in one US study, 5.8% in another U.S. study, 7.4% in Bosnia, and as high as 19.1% in another Japanese study.[32][42][44][45][46]
Pathophysiology
Atypical squamous cells that are related to an underlying SIL are associated with HPV infection. Following the initial acquisition of hrHPV, there is an inflammatory response that resolves after a short time. The chronic cases progress to more severe persistent infection associated with nuclear and cytoplasmic changes. In the presence of hrHPV 16 and 18, the viral genes E6 and E7 are thought to encode viral proteins in the infected squamous cells that promote the degradation of tumor suppressor gene proteins p53 and Rb respectively, resulting in malignant transformation.[26][47] Mahira Jahic and Elmir Jahic did a prospective analysis of 1,784 Pap smears and found that, out of 254 abnormal smears, overall, 74% persisted, 8% regressed, and 18% progressed to the worse stage.[46] Studies using immunohistochemistry have associated the loss of certain capsid proteins in ASC-US specimens with progression to a more severe form of precancer. Eun Young Ki and colleagues showed that detection of HPV serotypes 16 and 18 in the absence of HPV L1 capsid expression predicted worsening of precancer.[48] HIV positivity has also been known to promote HPV persistence and associated with a higher incidence of ASC-US.[25][49] Furthermore, a low CD4 count and not being on antiretroviral therapy were associated with the persistence of HPV infection.[50][49][31][51][46][47][12]
Histopathology
ASC-US is a cytopathology term that implies cervical epithelial cell abnormalities described by the Bethesda system for reporting cervical cytology. It refers to abnormal cytologic changes that are suggestive of SIL but are qualitatively and quantitatively less than those of a definitive SIL diagnosis.[1] The morphologic criteria of ASC-US include cells that have the shape and size of superficial or intermediate squamous cells with enlarged nuclei 2.5 to 3 times the area of those of normal intermediate squamous cells, slightly increased nucleo-cytoplasmic ratio, with minimum hyperchromatism and irregular chromatin. The cytoplasm may show halo and atypical parakeratosis (dense orangeophilic). These criteria may vary slightly among different laboratories due to differences in slide preparation and staining techniques.[52][53][54] The distinction between a true premalignant lesion and a neoplastic one is based on the number, type, and severity of change both in the nucleus and cytoplasm. An ASC-US smear may also show mitosis, blurring of cytoplasmic borders, binucleation, and corneal pearls. Other histologic changes include squamous epithelial giant cells and parakeratosis.[55] Hyperchromasia and enlargement of nucleoli suggest a progression from a ‘mere’ ASC-US to LSIL/CIN 1 plus.[56][57] Histologically and as described earlier, the CIN histological classification is a three-tier grading of CIN that corresponds to the number of layers of epithelial cells affected by atypia.
History and Physical
ASC-US is not a clinical diagnosis. A woman receiving an ASC-US report from Pap test is most often asymptomatic and is most likely identified through a population-based screening. Alternatively, she may present with bloody, offensive, and or watery vaginal discharge, lower backache, or signs of urinary tract infection and be diagnosed opportunistically.[27] The physical examination evaluates the general health of the patient and checks for possible signs related to pathologies that may underlie the cytologic changes of ASC-US.
Considering that a late diagnosis or advanced invasive cervical cancer has no remedy, it is important to consider the risk factors that predispose women to develop this cancer and use that as a guide to determine the screening status of women in their care.[58] Risk factors for cervical cancer include lower age at sexual debut, multiple sexual partners, and sexually transmitted infections, including hrHPV and HIV. Also, women who have never had an initial Pap test were observed to present with a more severe form of a precancerous lesion or full-blown cancer.[58] Prolonged and intense smoking has also been linked to an increased risk of developing cervical cancer.[59]
Evaluation
Cervical cancer screening in women between the age of 21 and 65 years is supported by the American College of Obstetricians and Gynecologists (ACOG), American Cancer Society (ACS), U.S Preventive Services Task Force (USPSTF), and the U.S. Food and Drug Administration (FDA).[6][14] Studies have shown that regular and consistent screening of women for cervical cancer reduces invasive cervical cancer incidence and deaths.[7] Any sexually active woman presenting in the outpatient department with gynecologic or perianal symptoms, including abnormal vaginal bleeding, vaginal discharge, dysuria, or vaginal itching, should undergo triage testing.[44][34] Immunocompetent and asymptomatic women between the ages of 21 and 29 are to be screened once every three years by cytology alone. In the older age groups of 30 to 65 years, where HPV persistence may spell problems, HrHPV testing alone or co-testing (HrHPV and cytology) is also recommended every 5 years in addition to the option of screening by cytology alone every 3 years.[8][6][60] Screening is not recommended for women below age 21 because most HPV infections are transient or clear completely. Women older than 65 years can cease surveillance screening if they have consistently been previously negative.
Triage testing involves cytology with Pap test or LBC, visual inspection with acetic acid (VIA) plus colposcopy, HPV DNA, or any combination as recommended in the setting where one works.[34][61][34] Triage testing is specifically relevant to a patient with an ASC-US diagnosis because it enables further delineation of an ASC-US result into a true NILM, LSIL, or HSIL.[62][44][32][47]
Initially, a bimanual and speculum vaginal examination is done. Either Pap test is done alone or together with hrHPV DNA assay, or VIA is done alone or in combination with hrHPV DNA, or hrHPV DNA is done alone (primary HPV testing).[60][63] The combination of cytology and HPV DNA testing is advocated for because HPV DNA testing is more sensitive than cytological analysis alone. At the same time, however, the very infrequent occurrence of HPV negative/cytology-positive cancers has highlighted the importance of co-testing.[64][44][32][60]
Visual inspection with acetic acid involves the application of 3% to 5% dilutes acetic acid for one minute on the ectocervix.[25] Aceto-whitening of ectocervical lesions is caused by the high absorption of acetic acid by protein-rich precancer cells.[65] Good visualization of the post-application cervix is achieved with a handheld bright light or colposcope. VIA studies are reported as VIA-negative, VIA-positive, or suspicious for cancer. Colposcopy-guided cervical biopsies are usually done for VIA positive and suspicious for cancer patients.[66][67][25]
Treatment / Management
The variable progression following the diagnosis of ASC-US poses a management challenge. There is a possibility of overtreatment, and at the same time, also the risk of progression to higher grade precancerous lesions or even invasive cancer with conservative treatment, especially if close follow-up is not carried out.[32] J Melnikow and colleagues found, in a meta-analysis, that 68% of ASC-US regressed to normal by 24 months, while 7.13 % of ASC-US progressed to a worse grade SIL in the same period.[68](A1)
The diagnosis of ASC-US begins to gain clinical significance when it is associated with a positive hrHPV diagnosis. Both reflex HPV DNA testing and co-testing have reported a high incidence of hrHPV in ASC-US specimens.[60][34] The 'U' in ASC-US stands for 'undetermined' significance because it is unclear how much of the ASC-US may resolve to become negative and how much would persist and progress to become low- or high-grade squamous intraepithelial lesion.[68] Also, the main factors responsible for persistence are not fully understood, though hrHPV infection is known to persist more in HIV positive patients compared to HIV negative patients, resulting in a higher incidence of invasive cervical cancer in HIV positive patients.[69][25](A1)
An initial ASC-US may warrant no further management except to repeat Pap cytology alone or do an acetic acid-guided visual inspection (VIA) with colposcopy or in combination with HPV genotyping (DNA or mRNA) where feasible.[70][25] Persistent ASC-US, including ASC-H, calls for a thorough analysis (triaging) and intervention, including referral for colposcopy.[40][10] Eun Young Ki and colleagues define ASC-US persistence at 12-month repeat cytology or serial ASC-US reports.[48] Studies have shown that HPV DNA testing prior to colposcopy in women with persistent ASC-US provided improved diagnostic sensitivity compared to a CIN 2+ diagnosis.[71](B2)
The American Society for Colposcopy and Cervical Pathology (ASCCP) has recently published (in April 2020) the 2019 ASCCP risk-based management guidelines for abnormal cervical cancer screening tests and cancer precursors. One of the essential changes from prior management guidelines is that patient's risk of CIN3+, determined by current test results and past history (including unknown history), has become a key factor on which recommendations of colposcopy, treatment, or surveillance are based.[28] (B3)
In patients younger than 25 years with LSIL, ASC-US HPV-positive, or ASC-US without HPV testing, repeat cytology at 1 year is preferred, and if the result is NILM/ASC-US/LSIL, another repeat cytology is needed in 1 year, after that if the result is negative, then routine age-based screening is resumed. If HPV testing was first done for a patient with ASC-US, and the test was negative, there would be no need for the repeat cytology described above, and routine age-based screening could be directly resumed. Colposcopy is indicated if the first one-year repeat cytology shows HSIL/ASC-H/AGC/AIS, and also when the second one-year repeat cytology shows ASC-US or more severe lesions.[28](B3)
As per the new 2019 ASCCP guidelines, practitioners should start using CIN3+ risk estimates (based on HPV testing/co-testing and past history) when a patient reaches the age of 25 years. Previously (before the recent guidelines update), patients aged 25 years and older with ASCUS have two management options, one option is to do HPV testing (preferred), and if the test is positive, colposcopy is indicated, while patients with negative HPV test will have repeat cytology in three years. The second option is to repeat the cytology in one year, and if an abnormality is detected, then colposcopy is indicated. If the one-year repeat cytology is negative, then the patient can return to routine age-based screening. But per the new guidelines, a colposcopy can be deferred for certain patients if they have only minor screening abnormalities indicating HPV infection, provided that the risk of having CIN3+ is low. For example, a patient who tested HPV positive with low-grade cytologic abnormalities (LSIL/ASC-US), and has a past history of documented negative screening HPV test or co-test, can now be managed by repeating HPV testing or co-testing at 1 year. Practitioners can start managing their patients based on these new 2019 ASCCP guidelines using the tables of Egemen et al. or by using an app or website that will be designed and made available at the ASCCP website.[28][72](B3)
SIL treatment options include ablation methods such as cryotherapy or thermocoagulation, while HSIL (CIN 2+) is best treated by large loop excision of the transformation zone/loop electrosurgical excision procedure (LLETZ/LEEP) or laser or cold knife conization in cases of adenocarcinoma in-situ (AIS).[73][74][75][76][77][12][78] During cryotherapy, pressurized gas, either carbon dioxide or nitrous oxide, is used to freeze acetowhite lesions that are 3 to 5 mm deep under normal light or colposcopic guidance.[13] Thermal coagulation is the burning of acetowhite areas depicting precancerous lesions. Both heat and cold coagulation cause tissue necrosis with minimal or no systemic complications.[13] Under certain circumstances, a test and treat or single visit approach with VIA and colposcopy showed to be preferred to Pap test, particularly in resource-limited settings.[79][80][70][77][66][74][67][12](A1)
Apart from surgical interventions, certain pharmacological approaches have been employed under various randomized controlled trials (RCTs), with some showing promising outcomes at phase II.[81][82][83][84] In one study done by G Laccetta and colleagues, 176 patients with ASC-US were treated with topical beta-glucan, and Pap test repeated after 6 months. Sixty-three percent reverted to a negative Pap test. No side effects were reported.[85] Cho et al. studied the effects of 1 to 1.5 g of oral poly-gamma-glutamic acid daily in 195 patients; and reported an HPV clearance rate of 44% in 85 patients with hrHPV.[82] In 1996, Manetta A and colleagues investigated the effects of a daily oral dose of beta carotenes in patients diagnosed with CIN 1 and 2. After 12 months of treatment, they reported as high as 60 percent regression of CIN1 in some of the patients.[86] Some other studies did not show positive effects on CIN lesions. Research conducted at the Medical College of Wisconsin explored the effects of 400 mg of daily oral celecoxib in 63 patients with CIN3. There was no positive change in the severity of the disease.[86](A1)
Differential Diagnosis
ASC-US could represent different pathologies NILM, LSIL/CIN 1, HSIL/CIN 2+, or even early invasive cervical carcinoma. On the other hand, ASC-US could be just a cytologic mimic caused by inflammation (cervicitis), air drying, atrophy with degeneration, and other artifacts. True differentiation is best achieved with HPV DNA testing, colposcopy, and biopsy, particularly in persistent ASC-US.[55][63]
Prognosis
In the presence of quality triage studies, most ASC-US diagnoses have a good prognosis.[87][88] Clearance of HPV infection returns the cervical tissues to normal. Still, progression to HSIL/CIN 2+ can be treated either by cryotherapy, LLETZ, or conization methods, and the patient stands a chance of complete lifetime elimination of the possibility of cancer.
Complications
Complications of ASC-US may arise from inadequate follow-up or the lack of it, or they may result from treatment in general. An ASC-US diagnosis may completely return to normal on repeat Pap test, but generally, an ASC-US diagnosis that is not followed up may worsen to HSIL/CIN 2+ or invasive cancer in underserved populations with limited or no access to comprehensive screening services.[23][68][23] In resource-limited settings, with unskilled staff, there is a risk of overtreatment of ASC-US/LSIL. All forms of treatment carry a very small risk of complications, ranging from mild pain during the procedure to bleeding, postoperative pain, and brownish vaginal discharge. Doing cryotherapy or LLETZ in the presence of cervicitis, bacterial vaginosis, or vaginal trichomoniasis may give rise to severe and malodorous vaginal discharge. Recurrence of the lesion may indicate poor quality treatment resulting from incomplete excision of lesion or transformation zone, though the presence of HPV is a stronger predictor of treatment failure. Preterm births have been reported to complicate the conization of the cervix in patients with CIN 2+ or AIS.[77] The persistence of lesions has also been reported to be more in HIV-infected patients compared to immunocompetent individuals.[89]
Postoperative and Rehabilitation Care
Patients treated with cryotherapy and LLETZ/LEEP are usually managed as day cases and are given mild oral analgesics such as ibuprofen. They are usually instructed to avoid sex for 4 to 6 weeks and to use condoms where abstinence fails. Patients are also advised not to insert tampons and not to douche. Those who develop malodorous discharge and or persistent vaginal discharge beyond 14 days are asked to return to the physician for reevaluation and treatment. Where signs of postoperative infection exist, endocervical or high vaginal swabs can be sent for culture, and the woman treated empirically with doxycycline 100 mg orally two times daily for seven days and metronidazole 400 mg orally three times a day for seven days.
Deterrence and Patient Education
Full-blown advanced cervical cancer, whether in HIV-positive or negative women, has 100 percent mortality. All women should be made aware of the importance of regular screening and the availability of the HPV vaccine. Patients with nonspecific cervical abnormalities like ASC-US must be educated and closely monitored, so they do not fall through the cracks and later appear with invasive cervical cancer. Weigh the costs of screening for hrHPV and treating invasive cancer with attendant grave consequences on human lives and families; versus prevention. We should choose prevention over cure because it is a less expensive choice. Combined prevention and lifestyle modification, including delay in sexual debut, reduction of sexual partners, consistent and correct use of condoms, male circumcision, and smoking cessation, would go a long way to reduce precancer and cancer.
Pearls and Other Issues
- The coverage for cervical cancer screening in most resource-limited settings is still below 35 percent of the population.
- Women can be screened and followed up for cervical pre-malignant diseases, usually by Pap test, and also by VIA with colposcopy, HPV DNA, and biopsy.
- It is possible to do at least one cervical cancer screening method in any country in the world where cervical screening programs are not available. In 1949, Papanicolaou and Traut began doing simple cytology, and today we have evolved to the more sophisticated molecular DNA testing for HPV. There should be no excuse for not doing cervical cancer screening.
- Prioritizing and integrating cervical cancer screening in the daily management of women in primary healthcare facilities would go a long way to reducing new cases of cancer and possible elimination of deaths from invasive cervical cancer.
- ASC-US diagnosis is an abnormal finding that requires a further evaluation from 6 months after the initial result but not later than 12 months.
- An ASC-US diagnosis may mean NILM or true precancer and hence poses a management challenge, which needs to be addressed by triaging with molecular testing and histology.
- VIA (visual inspection with acetic acid), together with same-day treatment, has been shown to reduce the incidence of invasive cervical cancers.
- All patients with HIV must be prioritized to have a visual inspection with acetic acid. This is a simple and cheap procedure delivered as a screening and treating procedure or single visit approach.
- Large-scale HPV vaccination before the onset of sexual activity may hold the key to the elimination of cervical cancer.
Enhancing Healthcare Team Outcomes
Most women who would receive an ASC-US diagnosis are asymptomatic. Healthcare workers at primary care facilities, maternities, general outpatient departments, gynecology, and sexually transmitted infection (STI) clinics, need to be proactive, engage women, create awareness, and screen all sexually active women for cervical precancer. Healthcare professionals need to understand the interplay of culture, behavior, and socioeconomic status and their relationship to cervical cancer incidence.[23] Community health workers, nurses at immunization clinics, and midwives must be engaged to inform patients and create awareness on the benefits of cervical cancer screening and the dangers of invasive cervical cancer. The diagnosis and treatment of cervical precancer must be done in collaboration with skilled cytopathologists, gynecologic oncologists, and doctors specifically trained in cryotherapy, LLETZ, and conization. Finally, prophylactic HPV vaccination in girls 9 to 15 years has been shown to have a huge decrease in new HPV infections.[90] Healthcare professions attending to female children and adolescent girls have ample opportunity to advocate for the scale-up of HPV vaccination across the globe.[90][91]
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