Acanthosis nigricans in the pediatric population: a narrative review of the current approach to management in primary care

Introduction

The skin often provides clues as to the health of an individual, showing outwardly visible manifestations of health or lack thereof. In particular, the now common skin condition, acanthosis nigricans (AN), was known for its association with malignancy in the adult population (1), and in 2000, the American Diabetes Association (ADA) established AN as a formal risk factor for the development of type 2 diabetes mellitus (2). Over the years, the prevalence of AN among the pediatric population has increased in parallel with the incidence of obesity (3). This review aims to provide readers with a comprehensive overview of the current literature of AN in the pediatric population. We discuss the best practices for identifying the condition, with a focus on the recommended management in the primary care setting to enable early and enhanced intervention. We present the following article in accordance with the Narrative Review reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-21-70/rc). The studies included in this review are listed in Table 1.

Methods

In this narrative review, a literature search in English language was conducted across multiple databases including PubMed, MEDLINE, and Cochrane. MeSH and non-MeSH terms such as “acanthosis nigricans”, “diagnosis”, “treatment”, “topical”, “systemic therapy”, “insulin resistance”, “obesity”, “metabolic syndrome”, “diabetes mellitus”, “lasers”, were considered. We identified cross-sectional and case studies, clinical trials, and literature reviews of pediatric AN for ages 0 to 18 years in the United States and internationally. Publications considered for background information were identified from the years 1994 to 2007, and we considered publications for the approach to management from years 2007 to 2020 (Table 2).

Dermatologic presentation

AN is characterized by symmetrical distribution of thickened, velvety, brown to black hyperpigmented plaques most seen on the body’s intertriginous sites, such as the neck, axillae, groin, and anogenital areas (1) (Figure 1). The inframammary, abdominal, antecubital and popliteal fossae, face, eyelids, nasal creases, and nipples are less frequently affected. The condition may occasionally involve mucosal surfaces; however, hyperpigmentation is less common in these areas (3,4). An acral form of AN is characterized by hyperpigmented plaques on the knuckles, elbows, knees, palms, and soles.

Figure 1 Acanthosis nigricans on the neck of a pediatric patient. Note the accentuation of skin lines and papillomatous surface change of the hyperpigmented plaque.

In the early stages, AN may reveal a “dirty” and dry appearance that may appear differently on different skin phototypes; those with lighter skin may notice a yellowish-tan to red appearance in early stages, while those with deeper skin tones notice a darker brown (4). However, as the lesions progress, the skin becomes thicker, demonstrating accentuation of skin lines with ill-defined margins, and may show papillomatous surface change (Figure 1). Acrochordons (skin tags) may also be present within or around the affected areas (Figure 2). The acrochordons are usually asymptomatic though rarely may be associated with pruritus and inflammation due to excessive friction of affected skin folds (1).

Figure 2 Acrochordon in affected area of acanthosis nigricans.

AN is thought to be caused by factors that stimulate epidermal keratinocyte and dermal fibroblast proliferation. At high concentrations, insulin may exert proliferative effects via insulin growth factor (IGF) and IGF-1 receptors on keratinocytes and fibroblasts, leading to proliferation and progressive pigmentation of the skin, and development of papillomatous plaques of AN (5). Other proposed mediators include epidermal growth factor receptor (EGFR) or fibroblast growth factor receptor (FGFR). The predilection for body folds, such as neck and axillae, suggests that perspiration or friction may play a contributory role (6,7).

There are many cutaneous disorders that may share features with AN. Careful attention should be paid to the location and pattern, the alleviating or aggravating factors, and the skin texture itself to help determine the underlying condition. Table 3 highlights the most common disorders that may be confused with AN.

Recommended workup

Several causes have been described for AN, resulting in various classifications. It may be divided into benign and paraneoplastic, or into benign, malignant, and syndromic AN (4). Several complex classifications have been proposed, further dividing AN into etiological criteria to better understand the underlying pathology (7,9) (Tables 4,5).

AN occurs frequently in adolescents, with prevalence ranging from 49.2% to 58.2% in studies involving children or adolescents with obesity (3). With rates of obesity and type 2 diabetes rapidly increasing in the pediatric population, it is imperative that pediatric providers utilize the primary care setting as an opportunity to identify those at risk for obesity and type 2 diabetes, and provide early intervention for this at-risk group.

Many factors contribute to the development of metabolic abnormalities, including family history and obesity (8). Literature identifies race and ethnicity as risk factors, however this categorization may be a simplification (8). In an analysis of food insecurity trends from 2001 to 2016, both non-Hispanic black and Hispanic households were two times as likely to have food insecurity than that of non-Hispanic white households (15). Furthermore, recent studies demonstrate that regions with racial inequalities in poverty and employment are positively correlated with higher obesity rates (16). Independent of obesity, several studies suggest AN is associated with hyperinsulinemia and development of insulin resistance, and may be an early marker for such chronic illness (8). Given this independent association, only evaluating children who are already overweight may in fact overlook some cases of hyperinsulinemia.

When a pediatric patient is noted to have AN, physicians must utilize this warning sign to search for underlying associated disease and metabolic abnormalities. It is important to recognize that apart from the metabolic association, the skin lesions have a profound impact on the quality of life of patients. During a phase where physical changes and appearance occupy an important part of the development of an individual’s self-image, visible skin conditions and obesity may lead to psychosocial consequences. Studies have indicated that obese adolescents with AN may experience increased social anxiety and low self-esteem than the general population (17). Therefore, early intervention, and early identification of modifiable risk factors, not only for metabolic syndrome and AN, but for low-self-esteem in adolescents, is important to help prevent cardiovascular and psychosocial consequences and allow for a positive transition to adulthood. The following section highlights the recommended workup for such cases.

Fasting insulin levels and homeostasis model of insulin resistance

Most patients with AN have either clinical or sub-clinical insulin resistance, with higher levels of insulin than patients without AN (18). However, insulin resistance does not develop concurrently with development of AN, and in fact, may not be present until many years after the initial onset of the dermatosis. Insulin is most often implicated as the cause of AN, stimulating fibroblast proliferation through IGF-1 receptors as described previously (5). As such, the presence of AN can serve as a proxy physical marker for biochemical elevation in insulin.

In a sample of United States (US) middle school students, AN was found to be an independent predictor of hyperinsulinemia in adolescents; its presence increased the likelihood of hyperinsulinemia to four times the baseline, after adjusting for variables including body mass index (BMI) and pubertal development (19). The researchers found that the positive predictive value for hyperinsulinemia using AN alone was 39.4%, compared to 34.1% for obesity alone (19). Similarly, in a sample of US children aged 8 to 14 years, those with AN had more severe insulin resistance than age, sex, puberty, and BMI score matched controls without AN (20).

These findings are replicated in multiple studies across the age spectrum, all of which lend support to the theory that AN is an independent variable associated with hyperinsulinemia. In a sample of children 3–19 years of age from the Winnebago/Omaha tribe in Nebraska, subjects who exhibited AN had two-fold higher fasting insulin concentration compared to weight-matched subjects without AN. The authors concluded that AN prevalence among American Indians increases risk of insulin resistance and type 2 diabetes (21). In a comparable study of adolescents of Cherokee Indian background, after adjusting for weight, sex, and pubertal development, the mean insulin level was greater in those with AN than subjects without (22). Similar findings were reported by several other studies (18,23).

Although most studies report that AN is a clinical indicator of underlying insulin resistance, some researchers believe that AN is not an independent marker and as such all children with a BMI standard deviation score above or equal to 3 should be screened for hyperinsulinemia (24,25). Numerous studies have suggested that in children with both AN and obesity, the incidence and positive predictive value of insulin resistance increases compared to either factor alone (19,26,27).

In clinical practice, no single laboratory test is used to diagnose insulin resistance or measure insulin sensitivity. The Endocrine Society appointed Pediatric Task Force recommends against these routine measurements due to lack of standardized assays and poor reproducibility (28,29). However, in early stages of insulin resistance, the body releases more insulin in a compensatory manner, to maintain glucose homeostasis (8,20). At this stage, diabetes remains undiagnosed due to euglycemia while hyperinsulinemia may predominate. We suggest that testing for both impaired glucose tolerance and abnormal insulin levels together should therefore be included in the recommended screening for individuals at risk so that early diagnoses are not missed. The ADA has organized a task force to standardize assays in order to establish measures of insulin sensitivity and draft guidelines for their use in the clinical setting (30).

Fasting glucose levels, oral glucose tolerance test (OGTT), hemoglobin A1C (HbA1C)

The ADA recommends that a child who is overweight and has any 2 of the following risk factors be screened for diabetes every two years beginning at the age of 10 or at pubertal onset: (I) 1^st or 2^nd degree relative with type 2 diabetes, (II) belonging to certain race/ethnic group at higher risk (Native American, African-America, Asian/South Pacific, Hispanic) and (III) signs of insulin resistance including AN, hypertension, dyslipidemia, and polycystic ovarian syndrome (2).

AN has been found in 56% to 92% of children and adolescents with type 2 diabetes mellitus. Not all children with AN develop type 2 diabetes, but are likely to have multiple risk factors for the disease (31). It is therefore important to identify these at-risk individuals as a part of healthcare maintenance.

A retrospective comparative study of obese Japanese children found that subjects with AN showed significantly more glucose intolerance, as measured by OGTT, or preexisting diagnosis of type 2 diabetes, compared to children without the dermatosis (23). This finding is supported by several other studies conducted in the United States (19,22,32), India (33) and Australia (34).

In a sample of US eighth grade students with a high proportion of overweight/obese adolescents (BMI >95^th percentile), AN was found to double the likelihood of dysglycemia after adjustment for BMI and pubertal development, suggesting AN imposes an additional risk for dysglycemia over that from obesity alone (35). Authors concluded AN is an easily identifiable marker for impaired glucose tolerance and elevations in hemoglobin A1C (35).

In a sample of Italian obese children, researchers found that presence of AN was significantly associated with a higher risk of metabolic syndrome and abnormal glucose control (36). Fasting blood glucose was not different between children with and without metabolic syndrome, however insulin and glucose levels after OGTT were significantly higher (36). The observation seen by several studies (20,36) reflects the increased insulin resistance of these children prior to development of fasting glucose derangements, highlighting the false negatives for type 2 diabetes and insulin sensitivity that can occur when relying on fasting glucose levels alone.

BMI and waist-to-hip ratio (WHR)

As a part of health maintenance, BMI is checked indirectly with weight and height measurements. Increased BMI and in particular increased WHR is correlated with increased likelihood of metabolic alterations in both children and adults (18). The increase in adipose tissue in childhood is the most probable initial event that leads to changes in glucose metabolism and later insulin resistance, contributing to metabolic syndrome and development of AN (37). For example, in a prospective study of kindergarten through 12^th grade students, the prevalence of AN in the context of other risk factors for diabetes was evaluated, showing that children with a higher BMI at baseline were at increased risk for having AN in the follow-up year (38). Children with AN were six times more likely to be obese, and four times more likely to be overweight, compared to normal weight children (38).

Several studies suggest that despite normal BMI, increased waist to hip circumference and abnormal distribution of body fat is associated with increased risk of metabolic abnormalities (18,37,39). In a study of US children in the Pacific Islands, the prevalence of AN among all healthy weight children was 2.2%, compared to 7.8% among all obese children (40). Similar data has been reported among adolescents in New Mexico, where the prevalence of AN was 49.2% in obese adolescents compared to 7.7% among normal weight subjects (19), and in regions of the Southwest US, where among 500 children sampled, only 3% of normal weight individuals had AN (32).

The first screenings that can help with initial management and prevention of metabolic abnormalities are the calculation of BMI and WHR. When presenting with AN, calculation of these factors enables the clinician to target at-risk individuals and initiate early interventions.

Total cholesterol panel [high-density lipoprotein (HDL), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), triglycerides]

Metabolic syndrome is believed to play a central role in the development of cardiovascular disease and type 2 diabetes. The third National Cholesterol Education Program Adult Treatment Panel defines metabolic syndrome as the presence of three of the following risk factors: central/abdominal obesity, hypertension, high fasting glucose levels, hypertriglyceridemia, and low HDL cholesterol (41). In addition, high triglyceride levels and IR are considered factors for vasculature thickness, providing a noninvasive measurement of subclinical atherosclerosis in children (2). The presence of dyslipidemia in children and adolescents tends to track into adult life, thus identifying the at-risk individuals at an early age may help prevent potential cardiometabolic complications.

AN has been identified as a marker for increased risk of hypertriglyceridemia and decreased HDL cholesterol (2). When AN and high WHR are seen simultaneously, the odds of dyslipidemia are raised further (41). In a sample of 543 overweight/obese children, significantly higher mean values for fasting triglycerides and lower HDL levels were found in children with AN than in those without (42). Authors concluded that the presence of AN, high triglycerides, and low HDL levels were independent variables that predicted the presence of IR and metabolic syndrome in children and adolescents (42). This finding is supported by several other studies conducted in the US (20), India (33), and Iran (43) where subjects with AN had higher levels of triglycerides and decreased HDL cholesterol, known factors for metabolic syndrome (20).

These findings delineate the importance of early metabolic screenings to evaluate triglycerides (both fasting and non-fasting) and HDL levels in particular in the initial workup of a patient with AN. Early identification of abnormal cholesterol levels may then allow for interventions to protect future cardiovascular health.

Blood pressure (BP)

Elevated BP is a criterion included in the definition of metabolic syndrome in both adults and children. Although the BP cut-off for diagnosis of hypertension in adults (130/85 mmHg) is high for the pediatric population, several studies have reported increased systolic BP (SBP) and diastolic BP (DBP) readings in individuals with AN compared to the general population (37). BP levels greater than or equal to 95^th percentile for age, gender, and height were considered high. These findings are supported by several studies in Japan (23) and the US (20,22,39). Furthermore, it was demonstrated that for each 14 mmHg increase in SBP, the likelihood of having hyperinsulinemia increased approximately 1.3 times (22).

After controlling for obesity, a significant positive association was found between presence of AN and elevated SBP in young male subjects from India (33). In addition, increased severity of AN, as measured by thickness and distribution, were associated with higher SBP levels (44).

In a longitudinal study of kindergarten through 12^th grade students who were part of the Northern Plains American Indian population, students with AN were more than two times as likely to have elevated BP (39). The study team followed subjects for 1 year and showed a 2.34 relative risk of incident AN for children who had abnormal BP measures at baseline compared to those with normal BP (39).

Liver function tests (LFT)

Although thought of as predominately a disease in adulthood, with the increased prevalence of obesity and insulin resistance in children, non-alcoholic fatty liver disease (NAFLD) may arise in childhood and adolescence (42).

In a retrospective study of 543 overweight/obese children and adolescents, researchers evaluated the degree of liver dysfunction, finding significantly higher levels of alanine aminotransferase (ALT) among subjects with AN (42). Of those subjects, ultrasound scans revealed a high proportion of fatty liver (42). These findings are supported by several other studies (43,45,46), where higher ALT levels were found among patients with AN. Sayarifard et al. found elevations in both aspartate aminotransferase (AST) and ALT in subjects with AN (43).

In a similar sample of obese adolescents, approximately 30% diagnosed with NAFLD had AN (47). Authors determined that AN was an independent risk factor for NAFLD in children with obesity (47).

Recent studies suggest fatty liver is likely present in most pediatric obesity regardless of LFT elevation, and high ALT levels suggest a more advanced stage of NAFLD, hepatitis, or fibrotic changes (28,48,49). Sonography has been found to be an adequate screening method in fatty liver evaluation (28,49). In patients with AN, prevalence of ALT elevation and fatty liver is increased. With increase in adiposity, the level of liver function disturbance and severity of AN is increased further (47,49). The Endocrine Society Pediatric Task Force recommends obtaining screening ALT levels when assessing patients with AN or overweight children. A subsequent liver scan or ultrasound may be performed as a reflex test after abnormal laboratory results (28).

High risk acanthosis nigricans (AN)

AN can be graded on a standardized scale of 0–4, from not visible to severe, including grading of texture, and extending beyond the neck or beyond the axilla, originally classified by Burke et al. (Table 6) (50). A higher score may predict higher likelihood of insulin resistance (sensitivity 56.8%, specificity 83.9%) (51,52). Although the neck is the most common area affected by AN, appearance on the knuckles, dorsal hands, and dorsal feet, is commonly found in patients of normal or slightly overweight BMI (51). The presence in these non-classical and often ignored locations may occur earlier in the clinical course, with AN progressing to the neck in parallel with the rise in both BMI and insulin resistance (8,51). Therefore, AN on these areas in a patient, regardless of BMI, may indicate early clinical manifestations of insulin resistance (51,53), a finding that further establishes the import of a thorough dermatologic assessment in the primary care setting.

The dermatosis is more common and clinically more severe in adolescents as compared to younger children, correlating with increased IR in older children (7). While examining various characteristics of AN in adolescents, rougher texture, higher degree of pigmentation, and increased width of pigmented area were shown to be significantly correlated with hyperinsulinemia, paralleling serum insulin levels (19). In African-American subjects with AN, a significant positive correlation was seen between epidermal thickness, fasting plasma insulin levels, and increasing WHR (54). High severity of AN, according to the degree of skin affected and epidermal thickness, correlates with higher triglyceride, VLDL, fasting glucose levels, and lower HDL levels (20,44).

As reported by various studies, not only does the presence or absence of AN correlate with metabolic changes, but the degree of AN may predict more severe laboratory abnormalities. Therefore, primary care physicians should be trained in identification of AN to be able to implement interventions at an early stage.

Dermatologic management for AN

Therapy for AN involves a multidisciplinary approach, targeting the underlying associated conditions, as well as topical/oral agents and cosmetic surgery (Table 7). Diminishing hyperkeratosis has been described in some patients following insulin, glucose, and obesity control, however, hyperpigmentation and thickness may remain (7,9,58). Improvement of the lesions is often the patient’s primary concern, and consulting with a dermatologist may be beneficial. While the goal of therapy may be to treat the underlying cause, cosmetic resolution of AN lesions is often important for patients’ quality of life.

Topical treatments

Topical treatments with keratolytics are considered first-line options and are generally well tolerated by children and adolescents (7,55). Topical tretinoin 0.25–0.1% is effective in reducing hyperkeratosis after consistent application, with mild improvement in skin pigmentation (10). However, maintenance with intermittent application may be necessary as relapse has been noted after discontinuation (58). Topical adapalene gel is found to be effective in reducing skin pigmentation in children with AN (56). It is available over-the-counter and causes less irritation than other retinoid derivatives (56). In a randomized comparative study between topical 0.01% adapalene gel and 0.025% tretinoin cream for childhood AN, no significant difference was seen between the two groups, and both achieved improvement in hyperpigmentation (55). Over-the-counter ammonium lactate cream with lactic acid can be applied to affected areas of the body. Combination therapy with topical tretinoin and 12% ammonium lactate has shown efficacy in treating AN (57). Further combinations, including triple therapy with tretinoin, depigmenting agent 4% hydroquinone, and 0.01% fluocinolone acetonide, may reduce the appearance of AN (62).

Vitamin D analogs are another option for the topical treatment of AN. Calcipotriol cream has been reported as safe, effective, and well-tolerated for AN, and hyperkeratosis of the nipple has shown good response to this agent (59).

Oral treatments

For treatment of more extensive AN, comorbid conditions, or in areas less conducive to topical application, oral therapy with various medications may be an option.

Extensive AN associated with obesity has been successfully treated with the oral retinoid isotretinoin, however may relapse upon cessation of treatment, requiring maintenance treatment with either topicals or alternative oral agents including metformin (58). The oral retinoid acitretin has been reported to induce successful clearance in several patients with AN (58). However, acitretin is not an option for adolescent females given the potential for long term teratogenicity up to 3 years after discontinuation of the medicine. Additionally, hypertriglyceridemia can be a side effect of retinoid therapy and thus should be monitored carefully.

Metformin, an antihyperglycemic agent used for the management of type II diabetes, is shown to improve both AN and insulin resistance (7). Metformin reduces glucose production by increasing insulin sensitivity, thereby reducing hyperinsulinemia, body weight, and fat mass (7,63). In a recent clinical trial, patients treated with metformin demonstrated significant improvement in AN of the neck and axilla, but not of the knuckles, fingers, or elbows (58). A case study of a patient with initial improvement of axillary AN on isotretinoin, recurred after tapering the dose; however, the lesions improved upon taking 1,000 mg of metformin twice daily (64). Combination treatment with metformin and thiazolidinediones have reported benefit in patients with AN, as thiazolidinediones work to further increase insulin sensitivity (7,12). Women with hyperandrogenemia, insulin resistance, and AN may also be treated with metformin and oral contraceptive pills (12,58).

Surgical or procedural treatments

Newer treatment modalities for AN recalcitrant to first line treatments have shown promising results (61). These procedural and surgical treatments include chemical peels with alpha-hydroxy acids, microdermabrasion, cryotherapy, laser therapy, curettage, electrodessication, and simple surgical excision (61). Procedures are recommended primarily for older adolescents due to possible pain with treatment (7,65).

Superficial chemical peels with exfoliating agents such as trichloroacetic acid (TCA) are relatively safe and effective options. Zayed et al. reported improvement in hyperpigmentation, thickening, and overall appearance in female patients with TCA peels (60). In a comparative study between TCA and topical tretinoin, researchers concluded that TCA was less effective but better tolerated and should be considered an effective second line therapy in the management of AN (65).

The alexandrite laser with 755 mm wavelength can target melanin pigment in keratinocytes and lead to their destruction without damaging surrounding tissues. Its efficacy has been demonstrated for the treatment of axillary AN, resulting in greater than 95% clearance after 7 treatments at 4–8-week intervals (66). When compared to combination topical tretinoin and ammonium lactate, higher reduction in pigmentation was seen in the alexandrite laser treatment group (61).

Microdermabrasion is a minimally invasive procedure that is used to renew skin tone and texture, and may help reduce hyperkeratosis of AN in affected patients (7,58,67). Dermabrasion is used for smaller lesions and is limited by the cost and potential for post-inflammatory hyperpigmentation (58).

Cryotherapy is an alternative method for treatment of AN however the efficacy depends on various factors including the severity and depth of AN, the number of freezing cycles, and the vascularity of the lesions (61). In darker skin, cryotherapy may result in worsened hyperpigmentation and local recurrence is more common than other treatment modalities (61).

Multidisciplinary approach

While primary care physicians may be the first to diagnose and treat AN and associated conditions, a multidisciplinary approach is recommended. Patients may benefit from care from dieticians/nutritionists, endocrinologists, dermatologists, and behavioral health specialists. Furthermore, an important aspect of pediatric care is the involvement of the entire family, as interventions and subsequent improvement often start at home. Parents are encouraged to serve as role models, offering a healthy home environment and providing a strong support system. In a recent multicomponent randomized clinical trial, children and adolescents were included in the Children’s Healthy Living Program to study the effect of early intervention on obesity and AN (40). The authors concluded that comprehensive and sustainable methods including behaviors such as sleep, physical activity, and nutrient intake are needed to improve health, and interventions at an early age may reduce the prevalence of obesity as well as AN (40).

With the aid of health care professionals, school administration, and families, strategies such as setting small achievable goals, providing education about nutrition, and incorporating physical activity both after and during school hours can be employed to educate, treat, and prevent AN, insulin resistance, and its associated comorbidities.

Conclusions

The presence and severity of AN can be used as a clinical predictor of metabolic disorders and underlying nutritional status in normal, overweight, and obese children and adolescents. The rates of obesity and AN have been shown to increase with age, with a high prevalence of AN among adolescents that suggests impending high rates of diabetes, metabolic dysfunction, and cardiovascular disease that parallel the adult population (8).

The most effective first line treatment for AN is weight loss, through both dietary modification and physical activity, to improve underlying hyperinsulinemia and dyslipidemia, and in addition to weight and metabolic control, dermatologic treatment may be implemented. Health professionals should be trained to identify AN, whether on classical areas such as the posterior neck, or atypical areas such as the hands and feet. Appropriate screening, and identifying AN among children who are at risk for developing metabolic syndrome, will allow for earlier implementation of preventive measures to better control metabolic risk factors, decreasing the risk of cardiovascular complications. If diagnosed, further testing of insulin, glucose, lipids, and transaminases is recommended. As treatment of obesity, insulin resistance, and its associated comorbidities is often complex, early identification of individuals who would benefit from such treatment is a valuable part of clinical practice.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-21-70/rc

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-21-70/coif). The authors have no conflicts of interest to declare.

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