From 1990 to 2017, incidence of all diagnosed skin cancers has steadily increased, with approximately 320,000 cases of malignant melanoma diagnosed in 2020, specifically in fair-skinned populations of European descent (Urban et al., 2021; Arnold et al., 2022). In the United States, skin cancer represents 5% of all diagnosed cancers in 2023, with an average annual increase in incidence of 1.2% from 2010 to 2019 (National Cancer Institute, 2023). Cutaneous melanoma, hereafter referred to as melanoma, is a malignancy arising from the preexisting pigment-producing cells located in the skin of individuals known as melanocytes, originating from the neural crest during development (Saginala et al., 2021; Strashilov and Yordanov, 2021).

Several risk factors for melanoma have been explored in literature. The most significant contributor to melanoma formation is ultraviolet (UV) radiation, with 95% of diagnosed cases linked to UV exposure. (Gandini et al., 2005a; Islami et al., 2018). The entire UV spectrum is classified as a carcinogen due to its association with melanoma; hence, limiting UV exposure and using sunscreen is highly recommended as primary prevention (Autier and Doré, 2020; Dzwierzynski, 2021). Additionally, the risk of developing melanoma is notably higher in fair-skinned races when compared to darker skin tones (Lopes et al., 2021). Lastly, 8%–12% of melanoma cases are associated with a positive family history or specific genetic mutations, such as the CDKN2A mutation (Manson et al., 2000; Gandini et al., 2005b; Rossi et al., 2019).

The current diagnostic process for melanoma begins with identification of a suspicious lesion, often incidentally or through self-skin examination. Dermatologist then apply specific criteria and visual inspection techniques with the naked eye or dermoscopy (Kato et al., 2019). Dermoscopy is a technique that uses cross-polarized light and a magnifier placed on skin covered with liquid to see structures in the epidermis and superficial dermis that are not visible to the naked eye, thus allowing for better recognition of the signs of melanoma (Ankad et al., 2020). If the lesion requires additional investigation, an incisional (partial) or excisional (complete) biopsy is performed for histology, with excisional biopsy being the standard of care (Shellenberger et al., 2020).

Visual inspection by dermatologist shows high sensitivity (96.6%) and low specificity (32.3%), resulting in more frequent invasive biopsies with, an average, of 15.6 biopsies to diagnose one case of melanoma (Nelson et al., 2019; MacLellan et al., 2021). Additionally, an excisional biopsy can leave a large scar, require surgical fixation with a skin flap or can be difficult to perform in challenging areas, where an incisional biopsy is performed instead (Restrepo et al., 2019; Naik, 2021). Additionally, dermoscopy results in a limited diagnostic accuracy due to low resolution and lack of optical sectioning capabilities (Wang and Evans, 2016). Finally, a crucial prognostic indicator for treatment in melanoma is the early detection and treatment of the cancer, yet there is no approved screening recommended by the US Preventative Services Task Force (Mohammadpour et al., 2019; O'Neill and Scoggins, 2019; Arnold et al., 2022). However, in some populations, diagnosis is delayed by as long as 9 months, potentially due to inadequate education or irregular skin exams by physicians (Naik, 2021). Overall, our current diagnostic schema for early detection and diagnosis of melanoma is nonspecific and involves invasive procedures.

As advancements in precision medicine become clinically more apparent, medicine shifts towards a more individualized approach such as utilizing liquid biopsy to characterize the molecular features of a patient’s tumor to monitor therapeutic outcomes, recurrence, predict prognosis, and diagnose various cancers (El-Deiry et al., 2019; Ho et al., 2020; Tsimberidou et al., 2020; Alix-Panabières and Pantel, 2021). Liquid biopsy remains less invasive than excisional biopsy or other test requiring intravenous contrast by requiring only access to a peripheral vein for a blood draw (Perakis and Speicher, 2017; Lianidou and Pantel, 2019; Underwood et al., 2020).

Liquid biopsy utilizes various genetic material from cells that circulate in the blood, specifically the microRNAs (miRNAs), a small non-coding genetic material responsible for epigenetic regulation and maintains a pivotal role in oncogenesis (Tengda et al., 2018; Buscail et al., 2019; Sabato et al., 2022). The expression of miRNAs is altered due to mutations in the genetic code caused by the tumor, leading to the overexpression of oncogenic miRNAs or the under-expression of tumor-suppressing miRNAs (Gajos-Michniewicz and Czyz, 2019). The altered expression of miRNA levels have been established as a prognostic indicator correlating with survival time or relapse in patients (Lu et al., 2019; Dika et al., 2020). Furthermore, miRNA levels impact medical management because their levels can be used to gauge treatment effectiveness (Svedman et al., 2018; Kamińska et al., 2021). However, the clinical efficacy of using altered expression of miRNA in the diagnosis of melanoma is not established.

This systematic review and meta-analysis aim to collect published data on upregulated miRNAs in melanoma patients. We seek to establish clinical viability of circulating miRNAs as a less invasive alternative for diagnosing melanoma, reducing reliance on excisional biopsies.

Melanoma is the most aggressive and lethal form of skin cancer, particularly in advanced stages. Melanoma can appear on skin not normally exposed to the sun, and if untreated, it swiftly escalates into a life-threatening condition within a mere 6 weeks.

The most misdiagnosed lesion is amelanotic melanoma. An aggressive subtype of melanoma that does not produce the pigment melanin, it can be easily misidentified as harmless scars or mole. Patients may miss the opportunity to be fully cured because amelanotic melanomas often spread faster than the more easy-to-recognize melanomas. Therefore, the combination of routine examination of the skin using dermoscopy, coupled with liquid biopsy, provides a realistic opportunity for the detection of malignant melanomas including amelanotic forms.

Early detection of melanoma can improve prognosis for patients significantly. Key to early detection is the identification of biomarkers, and this is facilitated via obtaining liquid biopsy samples that contain tumor-derived materials such as miRNA (Nonaka and Wong, 2023). miRNAs play an essential role in biological processes by regulating gene expression at the post-transcription level. miRNAs bind to messenger RNA (mRNA) in the cytoplasm, resulting in mRNA degradation or temporary inhibition of translation. miRNAs contribute to nearly all aspects of cancer biology, including proliferation, differentiation, angiogenesis, and metastasis. Their expression is frequently dysregulated in cancer, creating a distinct expression profile. Each cancer possesses a specific miRNA expression profile, either overexpressed miRNAs targeting tumor-suppressor genes or downregulated miRNAs targeting oncogenes (Sethi et al., 2014). This miRNA expression profile could potentially be used to establish biomarkers capable of identifying specific cancer types.

Circulating miRNAs are being considered as promising biomarkers for many human diseases since they fulfill several criteria for being preferable biomarkers. These circulating miRNAs are enriched in extracellular vesicles, and they are stable and protected from endogenous RNase activity (Valadi et al., 2007). Additionally, miRNAs demonstrate high specificity for tissue or cell types (Jung et al., 2012; Wang et al., 2012; Wu et al., 2012). Distinct miRNA profiles can be identified for different cancer types, which could then serve as phenotypic signatures (Ahmad et al., 2014).

This study aimed to evaluate the clinical utility of using liquid biopsy of upregulated circulating miRNAs to diagnose melanoma. This study has shown that using blood levels is a highly sensitive and specific test with pooled values of 0.89 and 0.85, respectively, highlighting the strengths of using miRNAs as a clinical test in diagnosing melanoma. The NLR or PLR, 0.13 and 5.98, respectively, have moderate effects on the shift from pre-test probability to post-test probability (Jaeschke et al., 1994). The AUC of the SROC curve was 0.93, indicating that using upregulated miRNA levels in the blood for diagnosing melanoma is an excellent test (Šimundić, 2009). Additionally, this study adds to a gap in the literature on using miRNA to diagnose melanoma and can lead to advances in precision oncology, proving that a less invasive liquid biopsy for upregulated miRNA could become the new gold standard for melanoma diagnosis instead of an invasive excisional biopsy.

Although our meta-analysis demonstrated the potential use of upregulated miRNAs in diagnosing melanoma, certain limitations persist in their application. First, significant heterogeneity was observed among the included studies. Second, specific patient characteristics that could affect circulating miRNA levels, such as other comorbidities or ongoing treatments of patients during the blood draw, were not consistency recorded across studies. Future studies should prioritize standardizing the method of miRNA collection, determine the specific strands for evaluating patients suspected of melanoma, and consider alternative participant selection methods, moving away from the case-control format to increase validity in larger, diverse populations.

A growing body of evidence implicates the clinical utility of circulating biomarkers extracted from multiple body fluids (e.g., blood, saliva, urine) for cancer patients, focusing on patient stratification and monitoring disease status (Nonaka and Wong, 2018). The use of circulating biomarkers for cancer detection, diagnosis, and disease monitoring is an exciting prospect (Nonaka and Wong, 2022). Indeed, our study illustrates a high diagnostic accuracy of circulating miRNAs in diagnosing melanoma. These findings further reinforce the notion that precision medicine in oncology is advancing and that less invasive testing can achieve similar or better results compared to the established paradigm for diagnosing melanoma.