The role of reflectance confocal microscopy in the diagnosis and management of pigmentary disorders: A review

Abstract

Background

Reflectance confocal microscopy (RCM) has quickly transitioned from a research tool to an adjunct diagnostic bedside tool, providing the opportunity for noninvasive evaluation of skin lesions with histologic resolution. RCM is an optical imaging technique that uses near‐infrared excitation wavelengths and safe low‐power lasers. En‐face images of different skin layers (up to the superficial dermis) are acquired in grayscale based on the reflective indices of tissue components. Melanin has the highest reflective index (contrast) and appears bright on RCM.

Aims

We present a review of the current literature on the use of RCM in the diagnosis and management of pigmentary disorders.

Methods

We reviewed PubMed and Ovid Medline databases from January 2000 to June 2021, using MeSH key terms: “reflectance confocal microscopy, confocal laser scanning microscopy, pigmentary disorders, treatment, melasma, vitiligo, freckles, solar lentigo, lentigo, tattoo, complications, melanoma, skin cancers, pigmented lesions, post inflammatory, melanin, photoaging” to identify studies and review articles discussing the use of RCM in the diagnosis and management of pigmentary disorders.

Results

RCM findings of pigmentary disorders were divided into the following categories: (1) disorders of increased pigmentation (post‐inflammatory hyperpigmentation, melasma, Riehl's melanosis, solar lentigines, ephelides, hori nevus, naevus of Ota, café‐au‐lait macules, melanocytic nevus, melanoma, nevus spilus, labial mucosal melanosis, and mucosal melanoma), (2) disorders of decreased pigmentation or depigmentation (post‐inflammatory hypopigmentation, vitiligo, nevus depigmentosus, halo nevus), and (3) exogenous pigmentation (tattoo, ochronosis).

Conclusion

RCM has been explored and proven valuable for the evaluation and management of pigmentary disorders including melasma, vitiligo, solar lentigines, tattoo, and tattoo‐related complications.

INTRODUCTION

Reflectance confocal microscopy (RCM) is a non-invasive imaging technique that allows for the evaluation of skin lesions at the cellular level. Highly reflective tissue structures such as melanin, collagen, hemoglobin, and keratin appear bright in confocal images. Due to its ability to detect melanin, RCM has become a valuable adjunct bedside tool for the diagnosis and monitoring of pigmentary disorders.

Herein, we review the current understanding of RCM features seen in pigmentary disorders and critically evaluate the utility of RCM in monitoring treatment efficacy in these diseases. We have classified RCM findings into the following categories: (1) disorders of increased pigmentation (post-inflammatory hyperpigmentation, melasma, Riehl's melanosis, solar lentigines, ephelides, ephelides, hori nevus, naevus of Ota, café-au-lait macules, melanocytic nevus, melanoma, nevus spilus, labial mucosal melanosis, and mucosal melanoma), (2) disorders of decreased pigmentation or depigmentation (post-inflammatory hypopigmentation, vitiligo, nevus depigmentosus, and halo nevus), and (3) exogenous pigmentation (tattoo, ochronosis).

MATERIALS AND METHODS

We reviewed the medical literature (PubMed and Ovid Medline databases) from January 2000 to June 2021, using MeSH key terms: “reflectance confocal microscopy, confocal laser scanning microscopy, pigmentary disorders, treatment, melasma, vitiligo, ephelides, solar lentigo, lentigo, tattoo, nevus, nevus of ota, nevus spilus, nevus depigmentosus, halo nevus, melanoma, skin cancers, pigmented lesions, post inflammatory, melanin, photoaging” to identify studies and review articles discussing RCM and its use in the diagnosis and management of pigmentary disorders. Further papers were identified from the reference lists of the above-retrieved papers. Our search included English-language articles published between 2000 and 2021. The selection consisted of an initial screening of titles and abstracts, followed by the evaluation of full-text articles.

RESULTS

Table  outlines RCM features of pigmentary disorders that have been discussed in this paper. RCM images of pigmentary disorders are included with informed consent from patients for the publishing of images.

TABLE 1 RCM features of pigmentary disorders.

Reflectance confocal microscopy findings of pigmentary disorders
1- Disorders of increased pigmentation
Disease	Epidermal features	DEJ features	Dermal features
Post-inflammatory hyperpigmentation	-Small bright and large bright cells in the epidermis	-Bright edged papillae	-Small bright and large bright cells in the superficial dermis
Melasma	-Hyper refractile cobblestone pattern at the suprabasal layer -Dendritic cells	-Bright edged papillae	-Plump bright cells
Riehl's melanosis	-Regular honeycomb pattern	-Basal keratinocyte liquefactive degeneration	-Melanophages
Solar lentigines	-Supra papillary cobblestone pattern	-Polycyclic papillary contours and bulbous projections	-Crumbled coarse bright collagen in solar lentigo
Ephelides, Hori nevus, and naevus of ota	-Ephelides: pigmentation only in the epidermal basal layer	-Ephelides: Bright edged papillae	-Nevus fusco-caeruleus zygomaticus (Hori nevus) and naevus of ota: scattered cord-like highly reflective pigment masses between collagen in the dermis.
Café-au-lait macules	-Regular honeycomb pattern	-Enlarged papillae and hyperreflective peri-papillary rings	-Bright elongated fibrillar collagen structures/bundles with no cellular component
Melanocytic nevus	-Regular honeycomb epidermal pattern	-Meshwork pattern indicative of junctional nests	-Clod pattern indicative of dermal nests
Melanoma	-The presence of cytologic atypia and -Roundish and dendritic cells in the superficial layers spreading upward in a pagetoid fashion -Pagetoid cells widespread throughout the epidermis	-Disarray of the DEJ -Non-edged papillae at the basal layer	-Cerebriform clusters in the papillary dermis -Nucleated cells within the dermal papilla
Nevus spilus	-Regular honeycomb pattern	-Bright edged papillae -Uniformly distributed dermal papillae -Shiny plump cells without nuclei	-Bright elongated fibrillar collagen structures/bundles with no cellular component
Labial mucosal melanosis	-Regular honeycomb pattern and homogeneously distributed round or polycyclic ringed pattern	-Homogeneously distributed round or polycyclic ringed pattern -Hyperreflective basal layer -Sparse bright dendritic cells	-Dilated blood vessels within bright rings at the DEJ
Mucosal melanoma	-Irregular honeycomb pattern -Pagetoid cells and irregularly distributed intraepithelial atypical dendritic cells	-Roundish bright cells -High density of atypical dendritic cells -Continuous proliferation of atypical enlarged bright roundish, fusiform, and triangular/stellate cells	-Bright, round to triangular, nonnucleated cells corresponding to melanophages
2- Disorders of decreased pigmentation or depigmentation
Post-inflammatory hypopigmentation	-Regular honeycomb pattern	-Loss of DEJ signaling and bright rings	-Few melanophages and clumped collagen
Vitiligo	-Regular honeycomb pattern	-Total or partial disappearance of dermal bright papillary rings	-Small bright inflammatory cell infiltrate
Nevus depigmentosus	-Regular honeycomb	-Loss of dermal papillary rings compared to surrounding skin -Preserved dermal papillary integrity	-Bright elongated fibrillar collagen structures/bundles with no cellular component
Halo nevus	-Pagetoid cells -Atypical honeycomb pattern, reactive dendritic cells -Roundish pagetoid cells	-Non-edged dermal papillae -Junctional thickening -Dense nests in the periphery	-Nucleated cells -Plump bright cells -Multiple dilated blood vessels -Nonhomogeneous nests
3- Exogenous pigmentation
Tattoo	-Densely packed hyper-reflective granules up to 1–3 mm at the level of the epidermis	-Bright edged papillae	-Clustered bright particles in 1-3 mm in diameter in the papillary dermis
Ochronosis	None	None	-Well-defined round-to-oval and banana-shaped, non-reflective material deposition in the dermis -Bright-plump cells throughout the upper dermis corresponding to melanophages

DISCUSSION

Disorders of increased pigmentation

Postinflammatory hyperpigmentation

Histologically, hyperpigmentation presents with patchy epidermal or dermal pigmentation and the presence of melanophages in the superficial dermis. RCM shows small bright and large bright cells in the epidermis and superficial dermis.

Melasma

Melasma is characterized by light brown patches on the facial prominences and forehead. Histologically, there is increased melanin deposition in the epidermis, especially the basal layer. Melanocytes are slightly enlarged and increased in number with prominent dendritic processes. An increased number of melanophages can be visualized in the papillary dermis.

Kang et al. describe RCM features of melasma including hyper-refractile cobblestone pattern at the suprabasal layer (identified in all patients) that corresponded to basal keratinocyte hyperpigmentation in histopathologic sections. Dendritic cells that corresponded to activated melanocytes in the epidermis (identified in 6/26 patients) were identified as well as plump bright and large cells (identified in 9/26 patients) that corresponded to melanophages in the superficial dermis. Significant solar elastosis and increased blood vessels in the dermis were noted compared to the adjacent normal skin.

Liu et al. evaluated a cohort of 210 Asian melasma patients with RCM. In 10 patients, they defined melasma features on RCM compared with the corresponding histopathology. Then, they used these RCM features to classify melasma in the remaining 200 patients. Reported RCM features of melasma included a cobblestone pattern in the suprapapillary layer. A flattened basal cell layer was also noted. Increased epidermal pigmentation in the spinous layer, strongly visible papillary rings at the dermo-epidermal junction (DEJ), and in some cases, the presence of round and polygonal refractile structures within dermal collagen bundles were also noted. The highly refractile dermal papillary rings were found in the lesional and perilesional forehead and upper lip skin, where an abrupt transition from stratum spinosum to papillary dermis was seen that corresponded to flattened rete ridges. H&E sections showed a significant increase in the density of melanin in all epidermal layers that corresponded to the cobblestone pattern on RCM. Polygonal refractile cells in the papillary dermis corresponded to dermal melanophages on H&E. Melasma was classified into “epidermal” type where increased melanin was seen only in the epidermis, observed in 71.5% of the patients and “mixed” type where increased melanin was seen in both epidermis and the dermis, in 28.5%. Figure  shows the RCM features of melasma. Bright-edged papillae at the DEJ and hyper-reflective cobblestone pattern at the suprabasal layer are seen. The angulated, bright-edged papillae at the DEJ correspond to the dermatoscopic thin pigment network. Large oval bright structures in dermal papillae represent melanophages.

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RCM has been used to assess the efficacy of topical treatments in melasma. Ardigo et al. evaluated the use of topical pyruvic acid and hydroquinone in 15 melasma patients. RCM was useful in identifying the extent of skin involvement and the amount of melanin pigment.

Similarly, Agozzino et al. reported RCM features of 20 melasma patients 12 weeks after treatment with a depigmenting agent. RCM showed a reduction of pigmented keratinocytes in the epidermis and around the DEJ with slightly decreased peri-adnexal brightness. The complete disappearance of pigment in the epidermal layer (33.3%) and the absence of pigmentation at the DEJ (22.2%) was also noted. Complete disappearance of pigmentation in the upper dermal layer was observed in only 5.6% of the patients, and all patients had reduced pigmentation in all epidermal layers and at the level of DEJ compared to baseline images.

Tsilika et al. used RCM to follow the treatment course in 10 patients with melasma 4 months after topical non-hydroquinone depigmenting agent. Decreased reflectivity of cobblestone pattern in the basal layer was noted, however, melanophages stayed persistent in the upper dermis after treatment and the presence of dendritic cells did not correlate with the treatment response.

RCM is also used for the therapeutic monitoring of various laser treatments in melasma. Jo et al. used RCM to visualize in-vivo melanolysis after picosecond, alexandrite, and Q-switched Nd: YAG lasers. Baseline images showed hyper-reflective rings (50%), irregular melanin distribution, higher melanin content compared to normal skin, densely aggregated epidermal melanosomes at the spinous layer, and dendritic melanocytes at the basal layer. Prominent dendritic basal melanocytes were detected in 37.5% of patients. Polygonal refractile structures in the dermis, likely corresponding to superficial dermal melanophages were also observed. One hour after treatment, 37.5% of the patients demonstrated melanocyte activation in the basal layer visualized as the accentuation of reflectance in the perifollicular space. Long-term follow-up was not performed.

Longo et al. evaluated the efficacy of low-dose Nd: YAG laser treatment in melasma patients with RCM. Four of the eight cases revealed dendritic cells on RCM, and the disease relapsed in these patients. Longo et. al concluded that the presence of dendritic cells may be associated with disease relapse after treatment and RCM may allow for the prediction of prognosis while helping to avoid adverse effects and overtreatment. RCM can also determine the prognosis and the risk of relapse in patients by showing melanin content and transepidermal water loss (TEWL). Patients who had higher TEWL had an increased rate of relapse following the 1064 nm Q-switch Nd: YAG laser.

Riehl's melanosis (pigmented contact dermatitis)

Riehl's melanosis is an acquired pigmentary disorder that presents with brown-bluish pigmentation on the forehead, and temporal and zygomatic face. On histopathology, lesions show increased epidermal melanocyte density and marked dense inflammatory infiltrate admixed with melanophages in the superficial dermis. Xu et al. investigated RCM features and treatment monitoring (with glycyrrhizin and oral tranexamic acid) of Riehl's melanosis in 10 patients. Baseline images showed follicular infundibular infiltrate with dilated vessels and hyperreflective pigment granules, and dermal perivascular inflammation. Six months after treatment, pigmentation of the epidermis, pigment granules, and dilated vessels in the dermis reduced, with 7/10 patients showing marked improvement.

Solar lentigines

Lentigines are flat brown lesions with a well-demarcated edge. Solar lentigines show densely packed, bright cord-like rete ridges and branching tubular structures with bulbous endings at the level of DEJ on RCM. These findings correspond to lentiginous melanocytic hyperplasia at the basal layer of the epidermis on histopathology. Bulbous projections and polycyclic papillary contours at the DEJ are depicted in Figure . Corresponding dermoscopy and histopathology are also included (Figure ,). RCM can distinguish solar lentigines from other pigmented lesions arising on sun-damaged skin, such as pigmented actinic keratosis, lichen-planus-like-keratosis, and lentigo maligna.

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Richtig et al. treated 12 patients with solar lentigines with a Q-switched ruby laser (QSRL) and imaged the treated areas with RCM 30 minutes and 10 days after the treatment. Thirty minutes after treatment, RCM revealed disruption of the stratum corneum and the presence of multiple highly reflective round-to-polygonal areas, which corresponded clinically to white scaling on the lesions. The epidermal honeycomb pattern showed indistinct borders with weak intercellular connections. Dark structureless areas varying in size and shape were observed where the laser beam penetrated the skin throughout the epidermis and in the superficial dermis. Histopathology from treated areas on two patients showed epidermal and dermal edema with multiple cell-debris-filled vacuoles in different sizes and shapes at the level of DEJ and tips of the rete ridges. On day 10, RCM images showed aggregated granules, which corresponded to extracellular melanin deposits. Polycyclic papillary contours, a hallmark feature of solar lentigines, were no longer observed.

Ephelides, Hori nevus, and naevus of ota

Considering that biopsies are not easy or desirable to perform on the face, RCM can play a part in determining the etiology of facial pigmentation. In a 2020 study, melasma was visualized with hyperpigmentation in the basal layer and pigment particle deposition in the upper dermis, whereas freckles showed pigmentation only in the epidermal basal layer. Nevus fusco-caeruleus zygomaticus (Hori nevus) and naevus of Ota showed scattered cord-like highly reflective pigment masses between collagen in the dermis. However, one notable limitation of this study was the absence of a histopathological evaluation of the lesions involved.

Café au lait macules

Café-au-lait-macules (CALMs) are flat, light-brown colored patches that may be present at birth or early childhood, due to localized melanogenesis. Although CALMs may be sporadic, they can be seen in large numbers in genetic disorders such as Fanconi aplastic anemia, McCune-Albright syndrome, neurofibromatosis, and tuberous sclerosis complex. RCM can be helpful to diagnose and distinguish CALMs from other congenital nevi, including speckled lentiginous nevus and flat congenital nevus. Soenen et al. found that enlarged papillae and hyperreflective peripapillary rings were highly specific for CALMs, while the presence of melanocytic nests was found in congenital nevi. RCM features of CALM, depicted in Figure , show multiple enlarged regular-edged papillae and hyperreflective peri-papillary rings at the DEJ.

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Melanocytic nevus

Features of a melanocytic nevus on RCM include a regular epidermal honeycomb pattern as well as either a meshwork pattern indicative of junctional nests or a clod pattern indicative of dermal nests. Both patterns contain monomorphous cells. Figure  shows the RCM of a compound melanocytic nevus with junctional nests (red arrow) at the DEJ along with dermal nests (white arrow).

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Malignant melanoma

Melanoma has been studied extensively under RCM. Pellacani et. al note that the presence of at least one of the following major criteria and one of the following minor criteria is required for the diagnosis of melanoma. Major criteria include the presence of cytologic atypia and non-edged papillae at the basal layer. Minor criteria include the presence of roundish cells in the superficial layers spreading upward in a pagetoid fashion, pagetoid cells widespread throughout the lesion, cerebriform clusters in the papillary dermis, and nucleated cells within the dermal papilla. Figure  highlights an example of dermatoscopic and RCM images of invasive melanoma. Dermatoscopy shows an irregularly pigmented lesion with gray-brown circles and angulated lines on sun-damaged skin. RCM image at the level of DEJ shows epidermal disarray with hyperreflective large round and dendritic shaped cells around the follicles.

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Nevus spilus

RCM features of nevus spilus are similar to benign congenital melanocytic nevi, with a typical honeycomb pattern in the epidermis, bright-edged papillae at the DEJ, and uniformly distributed dermal papillae with shiny plump cells without nuclei (Figure ).

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Labial mucosal melanosis

Differential diagnosis of labial pigmented macules are labial mucosal melanosis (LMM) and mucosal melanoma. RCM features of LMM are regular epidermal honeycomb pattern and homogeneously distributed round or polycyclic ringed pattern, hyperreflective basal layer, and sparse bright dendritic cells at the basal layer. Mucosal melanoma presents with an irregular honeycomb pattern in the epidermis, pagetoid cells, and irregularly distributed atypical dendritic cells. An RCM lip scoring system was developed by Uribe et. al to distinguish labial mucosal melanosis from mucosal melanoma, proving 100% sensitive and 88% specific for diagnosing mucosal melanoma. Dermoscopic and RCM images of the labial melanotic macule are given in Figure .

Disorders of decreased pigmentation or depigmentation

Post-inflammatory hypopigmentation

Xiang et. al note that in post-inflammatory hypopigmentation, the content of melanin and dermal papillary rings “depends on the depth and site of the inflammation”. Melanophages were occasionally observed in post-inflammatory hypopigmentation, while not in other disorders of decreased pigmentation such as vitiligo and nevus depigmentosus. Melanophages may or may not be visualized. We report a case of post-inflammatory hypopigmentation which shows a loss of melanin reflectance signal at the DEJ and the presence of a few melanophages in the superficial dermis (Figure ).

Vitiligo

Vitiligo is the most common pigmentary disorder, affecting 0.5%–2% of the population worldwide, and presents as multiple achromic patches due to progressive loss of melanocytes at the DEJ. RCM has been utilized to diagnose, monitor disease progression, and monitor treatment outcomes in vitiligo patients in the last decade. Vitiligo is characterized by the total or partial disappearance of dermal bright papillary rings on RCM.

Ardigo et al described vitiligo on RCM as a complete loss of dermal papillae rings at the DEJ, whereas perilesional skin showed ‘half-ring’ structures corresponding to a partial loss of papillary rings. Conversely, Kang et al. observed the ‘half ring’ structures in normal skin, which suggests that these structures may be a physiological variation rather than a distinguishing trait of vitiligo on RCM. Additional studies have visualized melanocytes within the hair follicles, which have been described as the ‘follicular reservoir’ in vitiliginous skin. RCM was used to monitor treatment response in vitiliginous skin after UVB treatment, with re-pigmented areas showing large, bright dendritic melanocytes at the DEJ. Further studies have used RCM to assess the stage of vitiligo activity, which would lead to an improved selection of patients appropriate for grafting. Figure . shows RCM images of vitiliginous skin before and 3 weeks after microneedling.

Nevus depigmentosus

Nevus depigmentosus (ND) is a congenital non-progressive hypopigmented lesion, which shows less refractile melanin in dermal papillary rings, while the integrity of the rings is preserved. No melanophages are observed.

Halo nevus

Halo nevus (HN) is a benign melanocytic nevus seen in young adults, which presents as a lesion with a dark brown center surrounded by a white halo. HN occurs due to pigmentary loss of a previously typical nevus due to an immune reaction by CD8⁺ T lymphocytes and is associated with vitiligo. RCM features of HN were first described by Schwartz et al, who reported the presence of pagetoid cells, non-edged dermal papillae, junctional thickening, nucleated cells in the dermal papillae, and the presence of plump bright cells. HN had overlapping RCM features with other atypical nevi and melanoma. Pogorzelska-Antkowiak et al. reported HN had an atypical honeycomb pattern, dendritic cells in the epidermis, roundish pagetoid cells, non-edged papillae, multiple dilated blood vessels located on the peripheral white area, dense nests in the periphery, and nonhomogeneous nests. Both authors concluded that HN may show features consistent with melanoma on RCM, thus additional clinical findings should be considered while managing these lesions. An example of a halo nevus from a 16-year-old patient is given in Figure .

Exogenous pigmentation

Tattoo

Ogos'hi et al. reported RCM features of black, blue, and green tattoo pigment in two patients with multicolored tattoos. Black ink was observed as densely packed, hyper-reflective granules measuring 2–3 mm at the epidermis and DEJ. Blue ink showed smaller (~1 mm in size) diffuse pigmented granules in the epidermis and dermis without clustering. Green ink showed fine-pigmented granules at the lower epidermis. Pigment granules were seen around dermal papillae under the basal layer.

Complications due to decorative tattooing, as well as treatment outcomes can be assessed with RCM by revealing subtle inflammatory changes and pigment granules. Guichard et. al observed inflammatory changes in RCM that led to a diagnosis of tattoo rejection which was clinically and dermoscopically subtle. RCM showed epidermal spongiosis and an inflammatory cell infiltrate evidenced by the presence of small bright and large bright cells concentrated in the dermal papillae. Likewise, Maier et al. reported subepidermal pigmentation and granulomatous changes on RCM after permanent make-up of the lip. Granuloma formations were seen as clustered, roundish, bright structures, and pigment-loaded macrophages at the level of the superficial dermis. Moreover, 3 months after treatment with 5-FU and triamcinolone injection, follow-up RCM showed regression of the nodular lesions with scarce pigmented bright granules.

Due to the pigmentary alteration of the tattooed skin, the diagnosis of pigmented cancers can be especially challenging. Reilly et al. investigated 19 pigmented lesions in 15 patients occurring in or near tattooed skin with RCM. Tattoo pigment did not hinder the diagnosis of pigmented lesions on RCM. The authors observed round tattoo pigment deposits in 89.4% of the lesions, spindle-shaped tattoo pigment deposits in 36.8% of the lesions, and tattoo pigment-engulfed macrophages in 21% of the lesions. Ink deposits were visualized within both nevi and skin adjacent to nevi. Tattoo particles were differentiated from other reflective structures on RCM such as keratinocytes, melanocytes, melanophages, and inflammatory cells based on their size and morphology. Moreover, RCM showed an excellent correlation with tattoo pigment on clinical/dermoscopic images. Examples of dermatoscopic and RCM images of tattooed skin are presented in Figure .

Exogenous ochronosis

Gil et al. reported RCM features of exogenous ochronosis due to the application of hydroquinone. In this case, authors observed well-defined round-to-oval and banana-shaped, non-reflective material deposition in the dermis. Additionally, bright-plump cells throughout the upper dermis were seen that corresponded to melanophages.

CONCLUSION

Pigmentary disorders exhibit characteristic patterns on RCM. Without the need for a biopsy, RCM presents as a promising adjunct tool in the diagnosis and treatment monitoring of pigmentary disorders.

CONSENT

Patient gave consent for skin imaging and medical information to be published in print and online with the understanding that this information may be publicly available.

AUTHOR CONTRIBUTIONS

Banu Farabi, Marielle Jamgochian, Babar K. Rao designed the research study. Banu Farabi, Samavia Khan, Marielle Jamgochian, Mehmet Fatih Atak, Marielle Jamgochian, Babar K. Rao contributed to the study selection, analysis, and writing of the paper. All authors, Banu Farabi, Samavia Khan, Marielle Jamgochian, Mehmet Fatih Atak, Marielle Jamgochian, Babar K. Rao have all read and approved the final manuscript.

CONFLICT OF INTEREST STATEMENT

Babar Rao serves as a consultant for Caliber I.D. (Rochester, NY). Other authors have no conflicts of interest to disclose.

ETHICS STATEMENT

Patients consented to the inclusion of medical information and imaging in this publication. Study is IRB approved (CIRBI: Pro00035376, Expiry date: 1/17/2024).

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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