Smartphone-Based Visual Inspection with Acetic Acid

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1		Emilien Jeannot	--	2165	2023-07-17 03:14:59	\|
2	layout	Jessie Wu	+ 4 word(s)	2169	2023-07-17 05:53:35	\|

This entry is adapted from the peer-reviewed paper 10.3390/healthcare10020391

Visual inspection with acetic acid (VIA) is recommended by the World Health Organization for primary cervical cancer screening or triage of human papillomavirus-positive women living in low-resource settings. Nonetheless, traditional VIA with the naked-eye is associated with large variabilities in the detection of pre-cancer and with a lack of quality control. Digital-VIA (D-VIA), using high definition cameras, allows magnification and zooming on transformation zones and suspicious cervical regions, as well as simultaneously compare native and post-VIA images in real-time. The available results to date show that the quality of D-VIA images is satisfactory and enables CIN1/CIN2+ diagnosis, and that a smartphone is a promising tool for cervical cancer screening monitoring and for on- and off-site supervision, and training. The use of artificial intelligence algorithms could soon allow automated and accurate cervical lesion detection.

cervical cancer smartphone-based

1. Introduction

Cervical cancer (CC) is one of the most common cancers in women and one of the leading causes of cancer death in women in developing countries, although it is almost a totally preventable cancer. In 2020, more than 600,000 new cases of cervical cancer were reported worldwide ^[1]. To reduce the burden of disease, the World Health Organization (WHO) has launched a global program to eliminate cervical cancer, with the following targets: (i) all countries have to achieve 90% vaccination coverage, (ii) 70% of screening coverage, and (iii) 90% access to treatment for cervical pre-cancer or cancer ^[2].

To reach the second and third WHO targets, towards cervical cancer elimination, women should be screened using high-performance tests between the ages of 5 to 45 years old, coupled with treatment, if required ^[3]. Visual assessment of the cervix with acetic acid (VIA) has been adopted by the WHO in primary screenings or in the triage of HPV-positive women as an affordable and adapted method in low-resource settings ^[3]. However, “naked-eye” VIA assessment remains a highly subjective test with low performance and limited quality control ^[4].

To provide easier recognition of cervical intraepithelial neoplasia (CIN) by screeners, digital cervical pictures taken during VIA (D-VIA) with a camera have progressively developed and are being adopted by many with encouraging results ^[5]^[6]. However, picture acquisition has not been so easy to perform; in particular, good image quality, managing difficulties (e.g., focusing), and adequate light sources have been challenging.

To effectively evaluate the cervix before and after acetic acid application, light and magnification are needed, which can be easily and adequately obtained with a smartphone device. Smartphones can assist screeners in determining morphology, localization, and the type of transitional zone, and distribution of aceto-whitening features. Implementing smartphone D-VIA has opened up a new dimension to VIA and may be a major improvement in cervical cancer prevention. Furthermore, the increasing prevalence of smartphone-use in low-resource settings makes it an ideal low cost device. Research teams and engineers have developed programs to increase accuracy of D-VIA diagnosis from smartphone pictures.

2. Visual Inspection with Acetic Acid (VIA): Strengths and Limitations

VIA is a procedure in which a healthcare provider applies a solution of 3 to 5% acetic acid with the aim of highlighting and identifying CIN. The procedure requires an experienced screener able to conduct a naked-eye examination and interpret the cervical change before and after application of acetic acid. VIA interpretation is crucial for determining if the screen is positive or negative and to decide the strategy of treatment, if positive. The decision to treat relies on the provider’s evaluation and experience; false positive cases may lead to overtreatment while false negatives will lead to misdiagnosis. If the screen is positive and if treatment is required, the provider must decide if the condition is eligible for ablative treatment (thermal ablation or cryotherapy) or excisional treatment (i.e., large loop excision of the transformation zone (LLETZ)) or referral to multimodal therapy in case of suspicion of invasive cancer. The main strength of the VIA approach is that it is affordable and offers the possibility of immediate results and treatment in a single visit.

Since the end of the 1990s, some countries have endorsed VIA instead of cytology as a primary screening in their national cervical cancer control programs, linking in the same visit screenings and treatments ^[7]. However, the technique is considered by some as a low standard of care, with critical weaknesses, such as its subjectivity, which leads to high variability in the provider’s performance as well as a lack of validated quality assurance ^[8].

Mustafa et al. conducted a systematic review to compare the accuracy of an HPV test, cytology (cervical smear), unaided VIA, and a colposcopy for cervical cancer screening in high-income countries. Results showed a pooled sensitivity of 69% (CI 95% 54–81) for VIA compared to 95% (CI 95% 84–98) for HPV testing; and a specificity of 87% (CI 95% 79–92) for VIA compared to 84% (CI 95% 72–91) for HPV. When compared to cervical smear accuracy, VIA caused a significant increase in overtreatment with 58 more false positives for 1000 women ^[9]. These weaknesses might explain the absence of implementation of VIA-based screening programs more than 20 years after publication of the WHO guidelines ^[10]. Despite the existence of recommendations and important investments made by private and public organizations in the field, difficulties have occurred with implementation of the Sub-Saharan cervical screening program ^[11]. This is of great concern, as the likelihood of reducing the incidence of cervical cancer relies on an effective and inexpensive screening method and a well-organized program.

3. Visual Inspection with Acetic Acid-Enhanced with Digital Imaging

The advent of digital cervical photography after acetic application (D-VIA), taken by on-site healthcare providers with cameras in order to assist the CIN identification was an important step in cervical cancer screenings ^[12]. A study evaluating cervical digital photography and colposcopy by different observers reported an agreement in 89.9% of the cases (kappa (k) = 0.588), a higher sensitivity (52.5%), and positive predictive value (PPV) (60%) as compared to colposcopy (35% and 48.28%, respectively). Specificity (91.8% vs. 91.2%), negative predictive value (NPV) (89.3% vs. 85.8%), and diagnostic accuracy (84.4% vs. 80.7%) were quite similar. In Zambia and Kenya, cervix digital images were taken by a camera and it was reported difficult to capture images and retain details without distortion (fluctuation in color, not enough light intensity, loss of resolution) ^[13]^[14]. Ensuring image quality (color accuracy, focus) with a camera is a challenging issue.

Alternatively, smartphones, which are often combined with auxiliary lenses (i.e., MobileODT), allowing the acquisition of high-resolution cervical images, enable visualization of morphological features, which may be difficult to see with naked-eye alone ^[15]. Advantages of a smartphone over a traditional camera is its ease of use, it does not need an external light source, and it allows easy zooming and comparisons of different pictures taken during an exam (native, VIA). D-VIA seems to have a higher discriminative power when compared to a naked-eye examination in detecting precancerous lesions; thus, making it an additive value to traditional VIAs to improve the diagnosis of cervical precancerous lesions.

4. Performance for CIN2+ Diagnosis

Image quality for cervical intraepithelial neoplasia (CIN) detection relies on the quality of the digital technology used, as well as on image classification and registration. Currently, there is no standard specific recommendation similar to what exists in other medical specialties (i.e., digital imaging and communication in medicine (DICOM)).

In Madagascar, Gallay et al. evaluated the quality of smartphone images to assess feasibility and usability of a mobile application in low-resource settings. Women aged 30–65 years old were recruited in a cervical cancer screening campaign and HPV-positive ones underwent VIA assessment ^[16]. Pictures were taken using a Samsung Galaxy S5 and a phone application called “Exam” was used to classify images. A total of 208 consecutive pictures were assessed by observers and quality was judged as adequate for diagnoses in 93.3% of cases.

Tran et al. reported a sensitivity of 71.3% (95% CI 67–75.7) and a specificity of 62.4% (95% CI 57.5–67.4) for CIN2+ detection from D-VIA images taken by smartphones—a Samsung Galaxy S4 and S5—in Madagascar and evaluated by off-site gynecologists ^[17].

Studies that evaluated these issues, with or without image management applications, support that the quality of the image was, most of the time, considered sufficient for diagnosis and the decision of treatment. However, current evidence regarding the use and benefits regarding implementation of digital-VIA for CIN2+ diagnosis is still weak, as there are no randomized controlled trials (VIA versus D-VIA) or large prospective studies that have evaluated this issue. Results show overall good specificity for D-VIA; sensitivity values are however heterogeneous (Table 1).

Table 1. Studies evaluating the performance of a digital colposcopy using a smartphone for cervical cancer screening in LMIC.

Study	Population	Intervention and Device	Outcome and Results	Strengths and Weaknesses
Mungo et al., 2021 ^[18]	Western Kenya 25–49 y HIV-positive n = 164 *	D-VIA images taken by nonphysicians. Samsung J8; three off-site expert colposcopists assessed images.	Outcome: performance to detect CIN2+ (off-site) and acceptability of D-VIA. Results: Se ranging from 21.4% (95% CI, 0.06 to 0.43) to 35.7% (95% CI, 0.26 to 0.46). Sp between 85.5% (95% CI, 0.81 to 0.90) to 94.9% (95% CI, 0.92 to 0.98). 99.4% of women were comfortable with the use of a smartphone.	Comment: low sensitivity, very good acceptability. Strengths: histology as reference standard. Limitations: HIV population.
Goldstein et al., 2019 ^[19]	China (rural Yunnan areas) 35–65 y n = 216 *	VIA and digital images. Samsung Galaxy J5 Pro (mobile ODT system).	Outcome: performance to detect CIN1 and CIN2+ Results: Se: NR, Sp: NR.	Comment: accuracy of D-VIA to differentiate between CIN1 and CIN2+ Strengths: histology as reference standard. Limitations: low observed prevalence of HPV (6%), small number of CIN2+ (n = 15).
Thay et al., 2019 ^[20]	Cambodia 30–49 y n= 250 HPV-positive = 56 **	VIA and digital images. Samsung Galaxy J5 Pro (mobile ODT system).	Outcome: differentiation between CIN1 and CIN2+. Results: Se: NR, Sp: NR.	Comment: accuracy of D-VIA to differentiate between CIN1 and CIN2+. Strengths: histology as reference standard (but only in case of CIN2+ suspicion). Limitations: study setting in an urban hospital, results might not be applicable to rural regions, few CIN2+ lesion (n = 4).
Tran et al., 2018 ^[17]	Madagascar 30–69 y n = 125 *	Forty-five gynecologists (different levels of expertise) assessed D-VIA images. Smartphone Galaxy S4/S5.	Outcome: performance to detect CIN2+. Results: Se 71.3% (95% CI 67–75.7); Sp 62.4% (95% CI 57.5–67.4)	Comment: visual assessment demonstrated relatively high Se. Strengths: histology as reference standard. Limitations: small sample size (19 CIN2+).
Gallay et al., 2017 ^[16]	Madagascar 30–65 y n= 56 *	Four clinicians assessed D-VIA images and classified them in an app called “Exam”. Smartphone Galaxy S4/S5.	Outcome: evaluation of image quality and inter-observer agreement. Results: adequate quality for visual assessment in 93.3% of cases. Moderate inter-observer agreement, with kappa value = 0.45 (0.23–0.56).	Comment: small study, designed only for quality of images. Limitations: no histology for diagnosis confirmation.
Urner et al., 2017 ^[21]	Madagascar 30–69 y n = 187 *	Fifteen clinician evaluated D-VIA images (off-site). Samsung Galaxy S4/S5.	Outcome: performance in the detection of CIN2+. Results: Se 94.1% (95%CI 81.6–98.3); Sp 50.4% (95%CI 35.9–64.8).	Comment: Se to detect CIN2+ lesion better than generally reported. Strengths: histology as reference. Limitations: small sample size and limited number of CIN2+ (n = 14).
Catarino et al., 2015 ^[22]	Madagascar 30–65 y n = 137 *	Comparison of VIA (on-site) and D-VIA (off-site). Samsung Galaxy S4/S5.	Outcome: performance to detect CIN2+ and inter-observer agreement. Results on-sites: Se 66.7% (95%CI 30–90.3); Sp 85.7% (95%CI 76.7–91.6). Results off-site: Se 66.7% (95%CI 30–90.3); Sp 82.3% (95%CI72.4–89.1). Moderate to poor inter-observer agreement: kappa 0.28.	Comment: higher Sp than generally reported, demonstration that off-site assessment is feasible. Strengths: histology as reference Limitations: 30.7% drop-out rate, small sample size
Ricard-Gauthier et al., 2015 ^[15]	Madagascar 30–65 y n = 122 *	Comparison of VIA and D-VIA (on-site) and D-VIA (off-site). Samsung Galaxy S4.	Outcome: performance to detect CIN 2+. Results on-site: Se 28.6% (95%CI 3.7–71%), Sp 87.2% (95%CI 77.7–93.7%). Results off-site: Se ranging from 42.9 (95%CI 9.9–81.6) to 85.7% (95%CI 42.1–99.6); Sp from 48.1 (95% CI 38.5–59.7) to 79.2% (95%CI 68.5–87.6).	Comment; Off-site assessment feasible, lower Se for on-site assessment than reported in literature. Strengths: histology as reference. Limitations: 27.9% drop-out rate, small sample size

Abbreviations: CIN (cervical intraepithelial neoplasia), DC (digital colposcopy), D-VIA (smartphone-based visual inspection with acetic acid), D-VILI (smartphone-based visual inspection with Lugol iodine), ECC (Endocervical curettage), HPV–Hr (human papilloma virus–high risk), HPV-positive (human papilloma virus positive), NR (not reported), Se (sensitivity), Sp (specificity), y (years old). * All HPV-positive; ** 56/250 women were HPV-positive.

5. On-Site Training and Supervision

Current understanding of a VIA-based approach supports that the method needs to be conducted with adequate training, supervision, and quality control to optimize the technique ^[8]. In a “screen and treat” strategy, frontline screeners play key roles and supervision is important, but it may not be available in healthcare centers located in remote areas ^[23]. Production of digital images allow to have records of the appearance of the cervix before and after acetic acid application, which permits screeners and supervisors to review the selected cases for quality control.

Asgary et al. explored the acceptability and feasibility of smartphone-based training of Ghanaian healthcare professionals using VIA and D-VIA. Community health nurses completed a two-week on-site introductory training, followed by ongoing, three-month text messaging, supported by a VIA reviewer. Smartphone-based training and mentorship were perceived by providers as important and essential complementary processes to further develop diagnostic and management competencies ^[24]. In semi-rural Tanzania, five providers were trained to perform smartphone-enhanced VIA with real-time trainees supported by regional experts. Images were sent through smartphone applications on the available mobile telephone networks. Within one month of training, the agreement rate between trainees and expert reviewers was 96.8% ^[25]. Maintaining competencies and accuracies of VIA are also major challenges as the standard short-term onsite VIA trainings may not guarantee skills retention. VIA web-based trainings appear to be tools that can be used for continuous education, to maintain frontline healthcare providers’ skills, which will eventually contribute to a higher diagnosis performance ^[26]^[27].

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