Beyond the Scalpel: Advancing Strategic Approaches and Targeted Therapies in Nonexcisable Melanomas

Melanoma in challenging anatomical locations such as the face, acral surfaces, and mucosal areas presents unique hurdles for surgical excision. This review examines alternative nonsurgical treatment modalities in the context of these complexities, addressing the gaps in current guidelines and the varied efficacy of existing therapies. A comprehensive literature search was conducted using PubMed, Embase, and Web of Science databases. The review focuses on peer-reviewed articles discussing nonsurgical treatment options for melanoma in complex anatomical locations. Articles were screened by three independent researchers, ensuring a broad analysis of topical agents, immunotherapies, radiotherapies, and targeted therapies. The review highlights significant advancements in localized treatments such as imiquimod and intralesional therapy with talimogene laherparepvec (T-VEC), which show promise in managing nonexcisable melanomas. BRAF and MEK inhibitors, as well as checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1 pathways, demonstrate improved survival rates but pose challenges with resistance and systemic side effects. Radiotherapy serves as an adjunctive strategy due to melanoma's inherent radioresistant properties. Despite advancements, there is a notable absence of comprehensive, evidence-based protocols to guide the treatment of melanoma in these critical areas. This paper underscores the need for standardized treatment guidelines that account for the efficacy, side effects, and psychosocial impacts of therapies. Future research should focus on refining existing treatments and exploring innovative modalities to enhance patient outcomes in the management of nonexcisable melanomas. Comprehensive guidelines and long-term efficacy studies are essential to optimize care and improve the quality of life for patients afflicted with melanoma in challenging anatomical locations.


Introduction
Anatomic locations such as the face, acral surfaces, and mucosal areas pose unique challenges in devising efective therapeutic strategies for melanoma excision, necessitating an exhaustive examination of alternative medical modalities.Melanomas of the head and neck account for nearly 20% of all malignant melanomas, with 65% of those presenting in the facial region [1].Tough common in frequency, these melanomas pose signifcant challenges in terms of treatment due to the intricate anatomy of the face.Other locations, including acral surfaces and the mucosa, are not nearly as common but pose even greater challenges due to the progressive stage at diagnosis [1].Acral melanomas only make up 4-6% of all melanomas in Caucasians but are the most common subtype seen in Asians and African Americans [2].Even rarer are mucosal melanomas which contribute to 0.8-3.7% of all melanoma cases in Caucasians [2].Despite its infrequent occurrence, this anatomical location serves as one of the most aggressive melanomas with a signifcantly worse prognosis.Each of these locations varies in frequency among patients, but all pose unique challenges in terms of treatment decisions.
Current studies have begun to unravel promising avenues, exploring the application of topical agents, immunotherapies, and radiotherapies in addressing melanomas nestled within challenging anatomical contexts.However, despite the emergence of these alternative approaches, a critical gap persists in the lack of comprehensive guidelines and evidence-based protocols to systematically guide clinicians in managing nonexcisable melanomas.As such, this review seeks to critically analyze the existing literature, scrutinizing both the successes and limitations of these alternative modalities and expanding upon the associated challenges in refning and standardizing treatment approaches.
In envisioning the future trajectory of melanoma therapeutics, the discourse extends towards a proactive call for research endeavors aimed at refning existing modalities, evaluating their long-term efcacy, and discerning potential side efects.Furthermore, the exploration of innovative strategies, including targeted therapies and nanotechnologybased interventions, emerges as a focal point in this academic pursuit.Tis literature review is structured to present the current nonsurgical treatment modalities for nonexcisable melanomas, examine the anatomical challenges to surgical excision, identify existing limitations, and outline promising future research directions that aim to transform the nuances of melanoma therapeutics.

Literature Review
2.1.Materials and Methods.Tis narrative review was designed to comprehensively analyze and synthesize the current state of research concerning nonexcisable melanomas in anatomically challenging locations, highlighting alternative therapeutic strategies beyond surgical excision.Te focus was primarily on evaluating nonsurgical interventions such as topical therapies, immunotherapies, radiotherapies, and emerging nanotechnology-based interventions, emphasizing their efcacy, limitations, and clinical outcomes.A literature search was formulated to gather peer-reviewed articles from PubMed, Embase, and Web of Science databases.Search terms used were "melanoma" and any of the following: "non-excisional," "non-surgical," "immunotherapy," "radiotherapy," "nanotechnology," "anatomic challenge," OR "topical."Te search strings were adapted for each database to enhance the efciency and comprehensiveness of the search process.Te results of the search were independently screened by three researchers to ensure a thorough and unbiased selection process.Data were synthesized qualitatively to highlight key fndings, diferences in treatment approaches, and consensus or discrepancies among the studies.Te review particularly focused on the efectiveness of each treatment modality, challenges in treatments, and any reported long-term outcomes or adverse efects for nonexcisable melanomas.

Topical and Intralesional Terapy
2.2.1.Imiquimod.Topical therapies ofer a localized approach to melanoma treatment by targeting the immune system directly at the tumor site.Among topical agents, imiquimod has been the most extensively studied, though the evidence largely stems from case studies and a limited number of randomized clinical trials, with a notable absence of high-quality evidence supporting its use as a primary therapy in nonselected cases of melanoma in situ [3].Imiquimod stimulates toll-like receptor 7 (TLR7) and triggers a cascade of cytokine releases, such as interferonalpha [4].Tis process initiates both innate and adaptive immune responses against tumor cells, showcasing its potential in combating melanoma.Despite the potential of topical treatments, the research landscape reveals a paucity of comprehensive data on their efcacy against the invasive nature of melanoma.
Nonetheless, practice guidelines have evolved to consider topical imiquimod as a viable alternative in specifc scenarios where surgery or radiotherapy is not suitable [5].A systematic review by Mora et al. highlighted that imiquimod treatment for lentigo maligna (LM), a subtype of melanoma, yielded histologic and clinical clearance rates of 76.2% and 78.3%, respectively, underscoring its potential in certain cases [6].Supporting this, Tio et al. found that 84.2% of LM patients treated with imiquimod experienced complete clearance, reinforcing the therapeutic benefts of imiquimod [7].
Further evidence from two randomized control trials corroborates the efcacy of imiquimod in LM treatment, with one trial reporting a 64% complete response rate among patients and another observing a signifcant reduction in the overall LM score one month after treatment compared to controls [8,9].A prospective study illuminated the longterm outcomes of imiquimod treatment, reporting overall survival rates of 85.5% at fve years and 70.4% at ten years for LM patients [10].Moreover, the study identifed the localization of LM in the nasal region as a prognostic factor for disease-free survival.Tese fndings collectively highlight imiquimod's potential as a promising targeted therapy for nonexcisable melanoma, underscoring the need for more extensive research to conclusively validate its efcacy.
Clinical trials have underscored T-VEC's efcacy, particularly in patients with stage IIIB, IIIC, or IVM1a melanoma and those who have not received prior treatment [11,14].Tese trials documented not only improved overall 2 Journal of Skin Cancer survival but also enhanced quality of life among participants, leading to the approval of T-VEC in 2015 in the United States for local management of unresectable cutaneous, subcutaneous, and nodal lesions after initial surgery and in Europe for similar indications in regionally or distantly metastatic melanoma (stages IIIB-IVM1a) [15,16].Tis treatment achieves disease control through both the locoregional lytic efects of the virus and its systemic immune-mediated actions, ofering a strategy for managing melanoma in areas where surgical options are limited.Importantly, T-VEC is capable of inducing responses in visceral lesions via systemic immune efects and has the potential for activating T-cells that target metastases in anatomically similar sites when injected into dermal, subcutaneous, and nodal metastases [17].For melanomas located in the head and neck regions, where surgical intervention is not feasible, T-VEC monotherapy has demonstrated an impressive overall response rate (ORR) of 80% in a study by Franke et al. [18].Further research indicates T-VEC's role not just in treating locoregionally advanced melanoma but also as an option for patients with stable or regressive systemic metastases who have developed resistance to immune checkpoint inhibitors or targeted therapies [19,20].

Targeted Terapy.
Te introduction of BRAF inhibitors marked a signifcant advancement in the management of advanced melanoma, highlighting the critical role of the BRAF and MEK proteins in melanoma pathogenesis through their involvement in the mitogen-activated protein kinase (MAPK) pathway [21].In approximately 50% of cutaneous melanomas, a mutation involving the substitution of valine with glutamic acid at position 600 (V600E) within the BRAF gene occurs, resulting in the uncontrolled proliferation and survival of melanoma cells [22,23].BRAF inhibitors, such as vemurafenib and dabrafenib, have demonstrated signifcant efcacy in treating patients with BRAF-mutant melanoma.In addition, MEK inhibitors such as trametinib and cobimetinib target downstream elements of the MAPK pathway, ofering a broader impact by afecting both tumor and normal cells, unlike BRAF inhibitors which only target mutated tumor cells [24,25].
However, the use of BRAF inhibitor monotherapy is often limited by the development of resistance within about seven months, leading to the strategic implementation of combination therapy [26].Combining BRAF inhibitors with MEK inhibitors helps to block multiple downstream points, mitigating the risk of resistance and enhancing treatment efcacy [27].Despite the benefts, the dual function of MEK inhibitors necessitates careful dosing to minimize toxicity risks, as they suppress function in normal cells as well [24].Given these considerations, the National Comprehensive Cancer Network (NCCN) recommends combination therapy as a preferred regimen for treating unresectable BRAF V600E melanoma, underscoring the efcacy of these therapies while also acknowledging the potential for increased toxicity and the challenges associated with resistance [28].

Immunotherapy.
Te treatment landscape for melanoma has been revolutionized with the introduction of immunotherapies, particularly checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1 pathways.Tis shift from direct tumor targeting to immune system modulation allows for the recognition and destruction of melanoma cells, offering a nonsurgical approach for managing melanoma in locations where surgical intervention is not feasible or carries signifcant risk.Te systemic nature of these therapies is especially advantageous for melanomas in anatomically challenging locations, providing an efective treatment option without the need for direct tumor access.

Anti-CTLA-4
Agents.CTLA-4, exclusively expressed in T-cells, plays a critical role in regulating early T-cell activation.It acts by competing with CD28 for binding to B7 molecules, thereby inhibiting the costimulatory signal essential for T-cell proliferation, and contributes to the downregulation of T helper cells and the stimulation of regulatory T-cells, which have immunosuppressive functions [29,30].By blocking this checkpoint, anti-CTLA-4 therapies such as ipilimumab amplify T-cell activation and proliferation, signifcantly enhancing the immune system's ability to target and destroy melanoma cells.Tis blockade leads to an increased production of interleukin 2 (IL-2) and creates an environment conducive to immune-mediated tumor destruction [30,31].
Ipilimumab, the frst FDA-approved immune checkpoint inhibitor, has shown signifcant efcacy in treating unresectable stage III or stage IV melanoma.A phase III clinical trial revealed that ipilimumab extended median survival to 10.1 months compared to 6.4 months with gp100 [32].In a separate study, it was shown that 20% of patients treated with ipilimumab survived at least two years following the conclusion of therapy, marking the frst therapy to demonstrate a survival beneft in metastatic melanoma patients [33].

Anti-PD-1/PDL-1 Agents.
Te PD-1 pathway plays a pivotal role in regulating T-cell activation through its ligands PD-L1 and PD-L2, inhibiting T-cell proliferation and IL-2 production, thereby reducing T-cell survival [30].In contrast to CTLA-4's specifc expression on T-cells, PD-1 is found on T-cells, B-cells, and myeloid cells; this pathway limits T-cell activity in peripheral tissues during infammatory responses [29,34].Inhibiting the PD-1/PD-L1 pathway plays a vital role in reinstating the immune system's natural function, which activates cytotoxic T-cells and enhances their infltration into the tumor microenvironment, resulting in the regression of melanoma [35,36].
Several agents targeting the PD-1/PD-L1 pathway, including nivolumab, pembrolizumab, and atezolizumab, have been approved for melanoma treatment.Studies have shown pembrolizumab to achieve a 24-month survival rate of 55%, which is signifcantly higher than ipilimumab's 43% [37].Moreover, nivolumab demonstrated a one-year overall survival rate of 72.9% in untreated melanoma patients, outperforming the 42.1% survival rate in the dacarbazine control Journal of Skin Cancer group [38].Notably, the CheckMate 067 trial marked a pivotal moment in the treatment of advanced melanoma, revealing a substantial increase in overall survival with the combined use of nivolumab and ipilimumab, in contrast to nivolumab and ipilimumab monotherapies [39].
According to the NCCN guidelines, the recommended initial approach for treating stage IB (T2a) or II (T2b or higher) melanoma involves wide excision followed by adjuvant therapy, with pembrolizumab or nivolumab being notable adjuvant options [28].Based on clinical trial results, the guidelines highlight anti-PD-1 monotherapy with pembrolizumab or nivolumab, or combination therapy with nivolumab and ipilimumab, as preferred regimens with the highest level of evidence to support their efcacy.

Radiotherapy.
Radiotherapy is a therapeutic approach that destroys cancer cell DNA leading to slowed growth or death of cancerous cells that the body can remove [40].Various types of radiotherapy and dosages can be implemented depending on the etiology, disease advancement, patient, and location.On a broad scope, the type of radiation can be thought of as external radiation versus brachytherapy, with external radiation being the most commonly used in melanoma [41].
Although advances have been made in radiotherapy technology, its use in melanoma treatment is often limited by data suggesting melanoma's radioresistant properties [42].Tus, its role as a defnitive treatment option for melanoma is limited, and it is more often implemented as an adjunctive strategy.Defnitive radiotherapy may be considered in cases of LM, desmoplastic melanoma limited by unobtainable surgical margins, difcult reresection, mucosal melanoma, ocular melanoma, and palliation [43,44].In LM, the typical radiotherapy dose is 50-56 Gy in 2 Gy fractions to a depth of 5 mm [45].For unresectable head and neck mucosal melanomas, the use of defnitive radiotherapy at 50-55 Gy has been reported in various case studies with the complete response obtained.
However, defnitive radiotherapy is advantageous in that it can be utilized in managing melanomas located in areas where surgical access is challenging, thereby limiting the use of Mohs micrographic surgery or wide excision.Tis ofers an alternative when the size of the tumor risks damage to vital structures [45].Te advantages of defnitive radiotherapy are further understood when candidacy evaluation for surgery is investigated.Defnitive radiotherapy is a viable option for patients who have ocular melanoma, are not good surgery candidates, or have medical interoperability [44].Tis encompasses a range of comorbid medical conditions, such as diabetes mellitus, which complicates wound healing, as well as bleeding disorders or the use of blood-thinning medications that increase the risk of bleeding during surgery.In addition, age plays a signifcant role in these considerations.
Apart from the radioresistant nature of melanoma limiting the efectiveness of defnitive radiotherapy, the adverse efects associated with radiotherapy also pose signifcant drawbacks.Radiotherapy is typically directed at the primary lesion site, yet it frequently results in damage to surrounding structures.Given that skin cancer often manifests in the head and neck regions, it poses a signifcant risk to the numerous critical structures located in these areas.A study by Souza et al. recognizes this risk by reporting damage to the arterial baroreceptors from radiation therapy causing or worsening hypertension [46].Hypopigmentation from targeting melanocytes, sunburn-like reactions, hair loss, nausea, and fatigue may also result from radiotherapy, impacting the patient's psychosocial well-being and quality of life [41].Considering the positive outcomes of the aforementioned nonsurgical treatments, it becomes evident that radiotherapy, immunotherapy, and topical and injected agents ofer innovative treatment approaches and further evolution towards patient-centered regimens.
2.6.Anatomic Challenges to Surgical Excision.Te surgical management of melanoma in anatomically sensitive areas demands a nuanced approach due to the inherent challenges these locations present.Te NCCN recommendations for peripheral surgical margins based on tumor thickness are outlined in Table 1 [28].However, they also acknowledge the necessity of modifying these margins to account for each patient's anatomical and functional considerations on a case-by-case basis.Te complexity of treating melanoma in these regions lies not only in the surgical procedure itself but also in the broader implications for patient outcomes, including functional integrity, aesthetic considerations, and overall quality of life.
2.6.1.Head and Neck.Head and neck melanoma treatment exemplifes the intricacies of balancing oncological efcacy with cosmetic outcomes, particularly in facial surgeries where the goal is to minimize disfgurement while ensuring thorough cancer removal.Adding to the complexity, the proximity of melanomas in the head and neck areas to vital structures such as nerves and blood vessels signifcantly complicates the surgical approach, and the extensive lymphatics of the head and neck result in the rapid progression of these tumors [47].
Carrera et al. presented a case illustrating these challenges, where initial attempts at wide-margin excision led to recurrence, rendering the patient a nonsurgical candidate [48].Te recurrence featured extensive invasion, including peri-and intraneural infltration, afecting the infraorbital nerve canal and the surrounding soft tissue, and bone erosion.Treatment with ipilimumab in this patient led to the stabilization of the patient's stage IIIC melanoma without evidence of distant disease over 43 months of follow-up.Moreover, Buck et al. explored aesthetic outcomes from patients' perspectives following wide local excision in the head and neck areas, assessing appearance alteration, satisfaction, and emotional impact via a visual analogue scale (VAS) [49].Te fndings indicated that skin grafts were associated with signifcantly less favorable VAS scores compared to other reconstructive options.Melanomas located on the eyelids and nose were associated with a greater emotional burden, refecting the intricate challenges in these areas.4 Journal of Skin Cancer Te management of melanoma on the nose and eyelids remains particularly challenging due to the anatomical complexities of the nasal pyramid and limited eyelid surface area, often resulting in narrower excision margins to spare functionality [47].Tis decision, though at the cost of higher rates of treatment failure, ultimately improves the quality of life of the patient.In regions such as the perioral, perinasal, and periorbital areas, primary skin closure may lead to distortion and skin grafts for larger defects often result in suboptimal aesthetic outcomes due to mismatches in color and texture.In addition, fap failure due to ischemia, though rare, can lead to signifcant ocular complications [50].

Acral Surfaces.
Acral melanomas, found on the palms, soles, and under the nails, are not only notable for their distinctive location but also for their aggressive nature and tendency to be diagnosed at an advanced stage.Te fve-year survival rate for acral melanoma sits at 80.3% compared to the 91.3% seen in other cutaneous melanomas [2].While the majority of acral melanomas are present on the feet, those on the hands tend to be thicker and more prone to ulceration [51].Furthermore, a prospective cohort study over a 21-year period showed increased mortality in melanomas presenting on the nail [51].In contrast, Wei et al. analyzed 1157 Chinese patients with acral melanoma and found that those with melanomas on the soles of their feet had worse prognoses than patients with primary lesions on the palms or under the nails [52].
Te treatment of acral melanomas often requires either extensive plastic surgery reconstruction or amputation in severe cases [2].In a retrospective study by Chakera and Tompson, it was found that distal amputation was necessary in 91% of the cases [53].Te decision to amputate carries profound implications for the patient.It has been proposed that wide local excision could be an alternative to amputation for low-risk primary lesions; however, this approach can risk incomplete tumor removal due to the nail bed's immediate proximity to the periosteum [54].Te postsurgical loss of mobility or sensation markedly afects the patient's quality of life, emphasizing the urgent need for adjunct or alternative therapies to surgery.In addition, longer recovery times prove increasingly detrimental to older patients, who may sufer from poor circulation in the hands and feet, further complicating their recovery and management of acral melanoma [2].

Mucosal Sites.
Mucosal melanomas, with their hidden presentation within the oral and nasal cavities, gastrointestinal tract, and genitourinary system, pose signifcant challenges in early detection and efective management, culminating in a fve-year overall survival rate of only 14% [2].Te invasiveness required for surgical access in these regions often leads to considerable postoperative functional and aesthetic consequences.Specifcally, treating mucosal melanomas in the craniofacial area frequently involves accessing the sinonasal tract and intradural space, where two important goals are achieving a complete tumor resection and meticulous closure of anterior skull base defects, which are crucial to prevent complications such as infections, cerebrospinal fuid leakage, and brain prolapse [55].
Mucosal melanomas tend to present in older populations, with more aggressive forms occurring in women, particularly impacting the genital tract [56].Vulvovaginal melanomas, often found on the labia majora and the lower one-third of the anterior vaginal wall, present a surgical dilemma [57].Te spectrum of interventions ranges from conservative wide local excision to radical procedures such as vulvectomy/vaginectomy and pelvic exenteration [57].Te dilemma lies in the absence of a clear survival beneft and signifcant long-term consequences of radical surgery, such as morbidity, sexual dysfunction, and psychological distress.Concurrently, the absence of clear guidelines for conservative surgical margins leads to an elevated metastasis risk, exacerbated by the dense vascular and lymphatic network in the urogenital tract mucosa [57].
Similarly, in addressing localized anogenital melanoma, the debate between radical abdominoperineal resection and conservative wide local excision underscores the controversy in identifying the most efective surgical strategy [57].Although abdominoperineal resection historically ofered better local control, its efects on overall survival remain unclear.Tus, there has been a shift in emphasis towards achieving negative margins with conservative treatment while preserving sphincter function.Nevertheless, many patients ultimately develop metastatic disease despite locoregional control with surgery [57].Given these complexities, mucosal melanomas frequently necessitate adjunctive neoadjuvant or adjuvant therapies, which introduce varying degrees of toxicity risks, particularly in older patients [2].Te high recurrence rate further emphasizes the need for innovative treatment modalities, such as targeted radiation and immunotherapy, to enhance patient outcomes.

Evaluation and Summary of Existing Approaches.
Strategic approaches and targeted therapies ofer therapeutic variation in nonexcisable melanoma in anatomically challenging surgical locations.Advancements in these therapeutics, combined with a deeper understanding of their efcacy, have greatly improved both their application and efectiveness.Sas-Korczynska et al. analyzed cases of sinonasal mucosa melanoma treated with radiotherapy alone and reported complete remission and in some cases fve-year disease-free survival [58].Tis is very reassuring, especially in the case of location-limited mucosal melanoma, for the use of alternative therapy including defnitive radiotherapy.However, larger studies are needed for broader evaluation.Further evidence for the use of radiotherapy in Table 1: Wide excision surgical margins for primary cutaneous melanoma.

Tumor thickness
Recommended peripheral surgical margins (cm) In situ 0.5-1 ≤1.0 mm 1 >1.0-2 mm 1-2 >2.0-4.0 mm 2 >4.0 mm 2 nonexcisional sinonasal melanoma is reported by Garousi et al. in which a total dose of 64 Gy in 32 fractions resulted in a decreased volume of the tumor and improvement in symptoms and signs with no progression at three months [59].Te use of alternative treatment in nonexcisable melanoma is further understood through implementation in LM and lentigo maligna melanoma (LMM).Hendrickx et al. performed a systematic literature review to examine the use of radiotherapy for LM and LMM and reported a recurrence rate of 0-31% with "good" to "excellent" cosmetic outcomes [60].Furthermore, this study provided evidence that the recurrence rate is comparable to surgical resection for LM and LMM.
Support for the use of radiotherapy in palliation is further reinforced by Olivier et al., who demonstrated efective palliation of non-CNS metastasis from malignant melanoma, particularly with the use of higher-dose radiotherapy [61].Notably, 9% of lesions had complete resolution of symptoms.Terefore, incorporating palliative care into treatment plans for melanoma, especially in cases of nonexcisable malignant melanoma, should be considered, as it often ofers patients symptom relief, including pain management.
Topical therapies ofer successful alternatives to surgical excision.Verga et al. report the case of a 77-year-old female with malleolar malignant melanoma treated with 5% topical imiquimod that resulted in complete resolution both histologically and clinically [62].Immunotherapies have shown to be advantageous to nonexcisable melanoma through immune system regulation and providing treatment at a systemic level.Furthermore, Addeo et al. documented a case of metastatic malignant melanoma that was completely responsive to four cycles of ipilimumab, resulting in sustained remission in a 65-year-old male who had shown progression on primary treatment with the chemotherapy agent dacarbazine [63].Te outcomes of complete remission not only highlight the immune aspect of melanoma but also underscore the necessity for additional data and the broader application of immunotherapies, especially in cases of nonexcisable melanoma.
Currently, available treatment modalities vary in efcacy.Treatments may not only consist of the traditional modalities used for progressive cutaneous melanomas but may also involve the addition of other modalities based on melanoma location.In mucosal melanomas, where wide excision is difcult due to anatomical challenges, radiotherapy has shown success in tumor shrinkage.Similarly, in nonexcisable LMM, radiotherapy has been promising in terms of recurrence rate, with results that resemble excisable melanomas.Tough the locations difer, radiotherapy's success opens discussions for its use in other nonexcisable melanomas.Furthermore, the use of topical therapies ofers a second approach in these challenging melanoma cases.
Te promising results of complete remission in progressive cases of metastatic melanoma warrant further exploration into the use of systemic therapy for nonexcisable melanoma.Several retrospective studies and prior clinical trials have shown improved survival in acral melanoma with the usage of immune checkpoint inhibitors such as pembrolizumab [2].While there is an overall improvement in survival rates, it is important to consider the slightly reduced survival observed in Asian populations [2].In those with mucosal melanomas, studies have indicated the increased clinical beneft of combined immunotherapies, such as the ipilimumab and nivolumab combination [2].Treatment decisions ultimately are patient-driven, as many neoadjuvant and adjuvant therapies present toxicities.

2.7.
Limitations and Future Research.Our comprehensive review of existing literature highlights a pressing concern; despite advancements in the treatment of nonexcisable skin cancers such as melanoma, there is a scarcity of guidelines and protocols on best practices for treatment options.As signifcant strides are made in treating nonexcisable melanomas and other skin cancers, our review highlights the imperative of developing comprehensive guidelines to ensure optimal patient treatment.
Consequently, the absence of centralized guidelines for treating nonexcisable melanomas imposes constraints on the current management of such cases.Certain therapies may exhibit greater potential for enhancing prognoses, while others might ofer more preventive advantages, and the diferent intended purposes and evidence-based outcomes of certain therapies ought to be considered when healthcare professionals are deliberating between varying nonsurgical therapies.
A notable gap exists in the scientifc literature regarding the long-term efcacy of treatments for nonexcisable melanomas.Tere is a pressing need for comprehensive, longterm studies to ascertain the efcacy of therapeutic interventions.Tis is imperative, as insufcient data hamper clinicians' ability to make informed treatment decisions for patients, especially in cases of nonexcisable melanomas where it is more challenging to monitor cancer growth and intervene to slow progression.Expanding research eforts, particularly through longitudinal investigations, is imperative to enhance our understanding and optimize the management of these challenging malignancies.
An encompassing understanding of potential long-term side efects across diverse skin cancer and melanoma therapies, spanning topical and intralesional treatments, targeted therapies, immunotherapies, radiotherapy, and surgery, is essential for informed clinical decision-making.Topical and intralesional therapies, often utilized for superfcial lesions, may result in adverse efects such as skin irritation, hyperpigmentation, and scarring.Targeted therapies, while efective against specifc molecular targets, can lead to systemic issues including fatigue, nausea, and liver toxicity.Immunotherapies, lauded for their ability to engage the immune system against cancer, may induce autoimmune reactions and endocrine dysfunction.Radiotherapy, a cornerstone in cancer treatment, carries risks of radiation dermatitis, fbrosis, and secondary malignancies.Surgical interventions, although crucial for tumor removal, may entail complications such as scarring, nerve damage, and lymphedema.An awareness of these potential long-term efects is vital for holistic patient care and the optimization of treatment strategies.

6
Journal of Skin Cancer Furthermore, it is crucial to acknowledge the enduring psychosocial ramifcations of the dermatological side efects resulting from cancer therapy.A recent systematic review conducted by Almeida et al. underscores this concern, highlighting that cancer treatments cause the most varied skin changes compared to the treatment of other diseases.As a result, this leads to diminished self-esteem, reduced quality of life, and distorted body image.Consequently, these factors often contribute to heightened levels of stress, anxiety, and depression among afected individuals [64].
As emphasized in this exhaustive review of the medical literature, targeted therapies have emerged as promising interventions for the treatment of nonexcisable melanomas, ofering a tailored approach to combating these challenging malignancies.Unlike conventional chemotherapy, which often lacks specifcity and can lead to widespread toxicity, targeted therapies selectively inhibit molecular pathways implicated in melanoma progression.By targeting specifc genetic mutations or aberrant signaling pathways driving tumor growth, these therapies hold the potential to achieve more precise and efective tumor control.Despite these promising attributes, challenges such as the development of resistance mechanisms and of-target efects underscore the need for ongoing research to optimize treatment strategies and enhance long-term outcomes [65].
2.7.1.Future Directions.Te advent of novel, nanotechnologybased approaches has been pivotal in advancing the treatment of melanoma.Nanoscale drug delivery systems ofer multiple advantages including enhanced drug solubility, improved drug stability, prolonged half-life, optimized bioavailability, targeted tumor delivery, and minimized side efects [66].In addition to targeted therapies, nanoscale liposomes have shown to be promising; Bedikian et al. found that liposomes have the potential to signifcantly increase the half-life of drugs in circulation and can even enhance drug efcacy in the treatment of melanoma, particularly in cases such as where drugs target the cell cycle [67].
Future research should prioritize the development of comprehensive guidelines and evidence-based protocols for standardized treatment of melanomas in challenging anatomical sites.Te current landscape of nonexcisional treatments, such as immunotherapy and targeted topical and intralesional therapies, has shown promise, but a lack of standardized protocols hampers their widespread implementation.Te development and implementation of standardized guidelines would both ensure consistency and optimize treatment outcomes.Standardized protocols should be evidence-based, considering long-term outcomes, recurrence rates, and side efects of various treatment modalities in nonexcisional melanomas classifed by location.Tough melanomas are currently classifed by growth pattern and tumor stage, future innovative research may incorporate a classifcation system based on specifc anatomical locations.Tis will enable the assessment of nonexcisional treatment modalities by their efcacy in various anatomical locations and aid in guiding personalized care for individual patient needs.
Furthermore, there exists a pressing need to identify areas for refnement within existing treatment modalities to enhance both efcacy and patient tolerability.Innovative targeted treatment modalities and nanotechnology approaches show promise in reducing mortality and improving outcomes for nonexcisional melanoma treatment, and research eforts should strive to refne these treatments.With goals of implementing standardized protocols and refning existing treatment approaches, future research can pave the way for more personalized and efective nonexcisional melanoma treatments.

Conclusions
Melanoma located in complex anatomical areas such as the head, neck, acral, and mucosal surfaces presents a signifcant challenge due to the impracticality of traditional wide excision.Tis review highlights important advances and reveals critical gaps in the treatment of nonexcisable melanomas.Standardized, evidence-based guidelines are needed to optimize therapeutic outcomes by balancing effcacy and side efects and by considering the psychosocial impacts on patients.Emerging therapies such as targeted topical agents, immunotherapies, radiotherapies, and nanotechnology-based interventions have shown promise in managing these challenging cases.Future research should focus on assessing the long-term efcacy of these treatments, refning therapeutic protocols, and exploring innovative treatment options.Enhanced focus on these areas will be the key to improving care and enhancing the overall outcomes for patients with nonexcisable melanomas.