Desmoplastic Melanoma Research Articles

Genomic landscape of superficial malignant peripheral nerve sheath tumor

Superficial malignant peripheral nerve sheath tumors (SF-MPNSTs) are rare cancers and can be difficult to distinguish from spindle cell (SCM) or desmoplastic (DM) melanomas. Their biology is poorly understood. We performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) on SF-MPNST (n=8) and compared these to cases of SCM (n=7), DM (n=8), and deep MPNST (D-MPNST, n=8). Immunohistochemical staining for H3K27me3 and PRAME was also performed. SF-MPNST demonstrated intermediate features between D-MPNST and melanoma. Patients were younger than those with melanoma, and older than those with D-MPNST; outcome was worse and better respectively. SF-MPNST tumor mutational burden (TMB) was higher than D-MPNST and lower than melanoma; differences were significant only between SF-MPNST and SCM (p = 0.0454) and between D-MPNST and SCM (p = 0.001, Dunn's Kruskal-Wallis post-hoc test). Despite having an overlapping mutational profile in some common cancer-associated genes, the COSMIC mutational signatures clustered DM and SCM together with ultraviolet light exposure signatures (SBS7a, 7b), and SF- and D-MPNST together with defective DNA base excision repair (SBS30, 36). RNA-seq revealed differentially expressed genes between SF-MPNST and SCM (1670 genes), DM (831 genes), and D-MPNST (614 genes), some of which hold promise for development as immunohistochemical markers (SOX8, PLCH1) or aids (MLPH, CALB2, SOX11, TBX4). H3K27me3 immunoreactivity was diffusely lost in most D-MPNSTs (7/8, 88%), but showed variable and patchy loss in SF-MPNSTs (2/8, 25%). PRAME was entirely negative in the majority (0+ in 20/31, 65%), including 11/15 melanomas, and showed no significant difference between groups (p=0.105, Kruskal-Wallis test). Expression of immune cell transcripts was upregulated in melanomas relative to MPNSTs. Next-generation sequencing revealed multiple differential features between SF- MPNST, D-MPNST, SCM, and DM, including tumor mutation burden, mutational signatures, and differentially expressed genes. These findings help advance our understanding of disease pathogenesis and improve diagnostic modalities.

Neurofibroma-like Desmoplastic Melanoma: A Series of Five Cases Exploring the Role of Molecular Testing as a Diagnostic Adjunct and Highlighting the Differential Diagnosis With Diffuse-type Neurofibroma.

A subset of desmoplastic melanomas (DMs) can show extensive morphologic and immunohistochemical overlap with cutaneous diffuse-type neurofibroma. Neurofibroma-like desmoplastic melanoma (NFLDM) thus poses a significant diagnostic pitfall because the clinical implications of these 2 entities differ dramatically. A series of 17 DMs, including 5 cases of NFLDM, were compared with a cohort of 53 cutaneous diffuse-type neurofibromas to explore the utility of molecular testing in the differential diagnosis between NFLDM and neurofibroma and to determine potentially useful morphologic features in this differential diagnosis. Unlike NFLDM, cutaneous diffuse-type neurofibromas: (1) rarely feature intratumoral or peritumoral lymphoid aggregates, (2) consistently harbor an intrinsic stromal support vasculature composed of evenly spaced capillary-sized vessels, and (3) infiltrate adjacent adipose tissue in a dermatofibrosarcoma protuberans-like manner with a complete lack of chronic inflammation or fat necrosis at the leading edge of the tumor. Conversely, DMs, including NFLDM: (1) do not contain Wagner-Meissner bodies, (2) often induce fat necrosis and/or chronic inflammation at the interface with adjacent fibroadipose tissue, (3) lack the intrinsic capillary-sized stromal vasculature observed in most neurofibromas, and (4) may harbor foci of perineuriomatous differentiation, mimicking a hybrid nerve sheath tumor. Any deviation from the expected clinical or morphologic features of cutaneous diffuse-type neurofibroma should raise suspicion for NFLDM. Although not entirely sensitive or specific, molecular testing can help to support the diagnosis of NFLDM by demonstrating genetic abnormalities associated with melanoma, including a UV-light-induced mutational signature, high tumor mutational burden, and/or chromosomal copy number alterations typical of melanoma.

Desmoplastic Melanoma

Desmoplastic melanoma is a rare fibrosing variant of melanoma. It typically affects elderly patients but can occasionally affect young or middle-aged individuals. Desmoplastic melanoma is relevant as a diagnostic pitfall for pure tumor variants' distinct histopathologic and clinical features. The latter includes a lower regional lymph node involvement frequency and a more favorable prognosis among thick melanomas. Classic cases of desmoplastic melanoma tend to carry a high mutation burden. Patients with metastases from those tumors tend to respond favorably to novel immunotherapies.

A Case Series of Primary Cutaneous Sarcomatoid Carcinoma With Aberrant Smooth Muscle Actin Expression: A Clinicopathologic and Immunophenotypic Study.

Primary cutaneous sarcomatoid squamous cell carcinoma can show significant histologic overlap with other malignant spindle cell tumors, posing a diagnostic challenge. Even with a wide array of immunohistochemical markers, the exact line of differentiation can be a challenge to identify in some cases. The picture is further complicated by the aberrant expression of myofibroblastic markers [such as smooth muscle actin (SMA)] by these neoplasms, along with a concomitant loss of conventional epithelial markers. The histologic differential diagnoses of primary cutaneous sarcomatoid squamous cell carcinoma include desmoplastic melanoma, leiomyosarcoma, and spindle cell atypical fibroxanthoma/pleomorphic dermal sarcoma (AFX/PDS). A retrospective analysis of 16 cases of PCSSCCs with SMA expression, obtained from large academic institutions, was performed and is summarized below. The tumors were in the scalp (6 cases), arm (4 cases), leg (2 cases), face (2 cases), hand (1 case), and neck (1 case). Immunohistochemical studies were performed in all cases with the following antibodies: AE1/AE3, CAM 5.2, MNF-116, p63, p40, CK5/6, S-100, SOX10, SMA, desmin, calponin, H-caldesmon, CD10, CD68, CD163, and CD34. Histopathologically, all cases were classified as high-grade malignant poorly differentiated neoplasms. Tumors were characterized by an infiltrative neoplasm that involved the entire reticular dermis and, in 7 cases, the subcutaneous fat. Three cases were associated with a well-differentiated squamous cell component. The neoplasms were composed of atypical spindle and epithelioid cells arranged in long and intersecting fascicles. All neoplasms were positive for epithelial markers (at least 1 marker), and all cases were strongly positive for SMA. Our data emphasize the diagnostic utility of multiple epithelial markers as a first screening tool in the detection and workup of malignant cutaneous sarcomatoid neoplasms. Awareness of SMA expression in these tumors can complicate its diagnosis, and it is important to recognize this aberrant immunophenotype to facilitate definitive diagnosis and avoid misdiagnosis.

Clinical Characteristics and Special Considerations in the Management of Rare Melanoma Subtypes.

Rare histologic subtypes of melanoma, including acral, mucosal, uveal, and desmoplastic melanomas, only make up 5% of all diagnosed melanomas and are often underrepresented in large, randomized trials. Recent advancements in systemic therapy have shown marked improvement in pathologic response rates, improving progression-free and overall survival among cutaneous melanoma patients, but there are limited data to demonstrate improved survival among rarer subtypes of melanoma. Acral melanoma has a poor response to immunotherapy and is associated with worse survival. Mucosal melanoma has a large variability in its presentation, a poor prognosis, and a low mutational burden. Uveal melanoma is associated with a high rate of liver metastasis; recent adoption of infusion and perfusion therapies has demonstrated improved survival among these patients. Desmoplastic melanoma, a high-risk cutaneous melanoma, is associated with high locoregional recurrence rates and mutational burden, suggesting this melanoma may have enhanced response to immunotherapy. While these variants of melanoma represent distinct disease entities, this review highlights the clinicopathologic characteristics and treatment recommendations for each of these rare melanomas and highlights the utility of modern therapies for each of them.

In Situ Protein Expression Analysis of Melanocyte Differentiation Antigen TRP1 (Tyrosinase-Related Protein-1).

Melanocyte differentiation antigens refer to molecules expressed in cells of melanocytic lineage such as gp100/PMEL, tyrosinase, and Melan-A. Corresponding antibodies such as HMB45, T311, and A103 have become key immunohistochemical tools in surgical pathology for the diagnosis of pigmented and related lesions. Little is known about tyrosinase-related protein 1 (TRP1), another melanocyte differentiation antigen, which is an enzymatic component of melanogenesis and known as the brown locus in mice. In this study, we tested several commercial reagents to TRP1 and identified one clone, EPR13063, which we further characterized by testing its specificity and usefulness for surgical pathology. Subsequently, we analyzed the expression of TRP1 in panels of normal tissues and tumors. TRP1 is regularly expressed in normal skin and in cutaneous nevi predominantly present in junctional and to a lesser extent in dermal nevocytes. In melanoma, TRP1 is present in 100% and 44% of primary and metastatic melanomas, respectively. TRP1 was absent in 5 desmoplastic melanomas but heterogeneously present in 9 of 11 PEComas/angiomyolipomas. No TRP1 was found in neoplasms of nonmelanocytic lineage. We demonstrate that EPR13063 is a valuable reagent for the analysis of TRP1 expression in archival surgical pathology material. The TRP1 expression pattern in melanocytic and related lesions appears to parallel other melanocyte differentiation antigens with a higher incidence in primary and a lower incidence in metastatic melanomas.

Randomized Trial of Postoperative Radiation Therapy After Wide Excision of Neurotropic Melanoma of the Head and Neck (RTN2 Trial 01.09)

BackgroundCutaneous neurotropic melanoma (NM) of the head and neck (H&N) is prone to local relapse, possibly due to difficulties widely excising the tumor. This trial assessed radiation therapy (RT) to the primary site after local excision.MethodsParticipants from 15 international centers were randomized to observation or RT. The participants were required to have microscopically negative excision margins 5 mm wide or wider and no evidence of disease elsewhere. The primary outcome was time to local relapse. The secondary outcomes included time to any recurrence, overall survival (OS), and toxicity.ResultsThe trial ceased prematurely due to slow recruitment and the COVID-19 pandemic. During 2009–2020, 50 participants were randomized: 23 to observation and 27 to RT. The most common NM subsites were scalp (32%), midface (22%), and lip (20%). The median depth of invasion was 5 mm, and desmoplasia observed in 69%. The median duration from randomization to last contact was 4.8 years. Four participants (8%) experienced local relapse as a first recurrence during the study period: 3 in the observation arm and 1 in the RT arm (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.03–2.76; p = 0.279). No statistically significant difference in time to any relapse or OS was observed. More than 6 months after randomization, grade 3 or greater toxicity was experienced by 10% of the participants in the observation arm and 12.5% of the participants in the RT arm of the study.ConclusionDue to low accrual, the role of adjuvant RT for cutaneous NM of the H&N excised with microscopically negative margins 5 mm wide or wider remains undefined. Its routine use cannot be recommended. Local relapse might be less common than previously anticipated based on retrospective reports.

Joinpoint regression analysis of recent trends in desmoplastic malignant melanoma incidence and mortality: 15-year multicentre retrospective study.

Recent data reveal a marked rise in the detection and mortality rates of Desmoplastic Malignant Melanoma (DMM). This trend underscores the imperative for an in-depth analysis of DMM's epidemiology, which is crucial for the formulation of precise medical and public health strategies. This investigation seeks to elucidate the variations in the incidence and mortality of DMM over a 15-year period (2005-2019). Data on DMM patients was sourced from the Surveillance, Epidemiology, and End Results (SEER) database. Both incidence and incidence-based mortality rates (IBM) were directly extracted from the SEER database. Joinpoint regression was used to analyze and calculate the average annual percent change (AAPC) and its 95% confidence interval (CI). Between 2005 and 2019, 3,384 DMM cases were identified, boasting an age-adjusted incidence rate of 36.3 cases per 1000,000 person-years (95% CI 3.51-3.76) and an IBM of 1.65cases per 1000,000 person-years (95% CI 1.57-1.74). Of these, 2,353 were males (69.53%) and 1,031 were females (30.47%). There were 1894 patients (55.97%) who were over 70years old. Predominantly, DMM lesions manifested in exposed areas: Limbs (955, 28.22%), Face (906, 26.77%), and Scalp and Neck (865, 25.56%). The incidence of DMM increased significantly at a rate of APC = 0.9% during 2005-2019, while the incidence-based mortality showed a significant upward trend (APC = 7%) during 2005-2012, and slowly increasing trend (APC = 0.6%) during 2012-2019. In contrast to the modest upward trajectory in female incidence and mortality, male incidence initially surged, later declining, while male mortality peaked and stabilized post-2012. The primary sites for incidence and mortality were chronically sun-exposed areas: Face, Scalp and Neck, and Limbs. In recent years, the incidence and incidence-based mortality of DMM have significantly increased. Each subgroup analysis has different trends, and these trends can provide better support for our exploration of DMM.

The Impact of Next-generation Sequencing on Interobserver Agreement and Diagnostic Accuracy of Desmoplastic Melanocytic Neoplasms.

Next-generation sequencing (NGS) is increasingly being utilized as an ancillary tool for diagnostically challenging melanocytic neoplasms. It is incumbent upon the pathology community to perform studies assessing the benefits and limitations of these tools in specific diagnostic scenarios. One of the most challenging diagnostic scenarios faced by skin pathologists involves accurate diagnosis of desmoplastic melanocytic neoplasms (DMNs). In this study, 20 expert melanoma pathologists rendered a diagnosis on 47 DMNs based on hematoxylin and eosin sections with demographic information. After submitting their diagnosis, the experts were given the same cases, but this time with comprehensive genomic sequencing results, and asked to render a diagnosis again. Identification of desmoplastic melanoma (DM) improved by 7%, and this difference was statistically significant ( P <0.05). In addition, among the 15 melanoma cases, in the pregenomic assessment, only 12 were favored to be DM by the experts, while after genomics, this improved to 14 of the cases being favored to be DM. In fact, some cases resulting in metastatic disease had a substantial increase in the number of experts recognizing them as DM after genomics. The impact of the genomic findings was less dramatic among benign and intermediate-grade desmoplastic tumors (BIDTs). Interobserver agreement also improved, with the Fleiss multirater Kappa being 0.36 before genomics to 0.4 after genomics. NGS has the potential to improve diagnostic accuracy in the assessment of desmoplastic melanocytic tumors. The degree of improvement will be most substantial among pathologists with some background and experience in bioinformatics and melanoma genetics.

Digital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma

BackgroundDesmoplastic melanoma (DM) is a rare melanoma subtype characterized by dense fibrous stroma, a propensity for local recurrence, and a high response rate to programmed cell death protein 1 (PD-1)...

Perineural differentiation in neurotized nevi

BackgroundPerineuriomatous melanocytic nevi are rare and this may indicate the similar embryological source of melanocytes and peripheral nerves in the neural crest. Neurotized melanocytic nevi may resemble nerve sheath tumors histologically, and show schwannian differentiation. However, literature on whether neurotized nevi differentiate into perineural cells is controversial. We examined our cases of neurotized nevi for evidence of perineural differentiation. Materials and methodsA total of 100 benign nevi with large neurotized component (microscopically involved a low power field 4.2 mm in diameter) were prospectively evaluated in excisional biopsy samples. Immunohistochemical stainings for EMA, Claudin1, Glut1 and neurofilament were performed. ResultsPerineural differentiation was immunohistochemically detected in the neurotized component of the nevi in 61% of the cases with EMA and in all the cases with Glut1 and Claudin1. Axonal differentiation was not detected with neurofilament. The expression pattern, especially with Glut1, was usually in form of partial or complete staining surrounding the Meissner's corpuscle-like structure (MCLS). Also, a linear/curvilinear staining pattern was observed particularly with Claudin1. A diffuse staining pattern with EMA, Glut1 and Claudin1 was detected in a case with a microscopically distinct whorl structure, and in which spindle cells are separated from the superficial epithelioid melanocytes with an abrupt transition histologically. These findings of the case are compatible with previous reports of perineuromatous nevus. ConclusionPerineural differentiation is not uncommon and immunohistochemically observed in all nevi with a relatively large component of neurotization. To prevent misdiagnosing desmoplastic melanoma and overtreating patients, it is crucial to be aware of perineuromatous nevi.

Hidden beneath the surface: Atypical presentation of Desmoplastic Melanoma in the teledermatology era

Hidden beneath the surface: Atypical presentation of Desmoplastic Melanoma in the teledermatology era

Pure and Mixed Variants of Desmoplastic Melanoma: A Single-Center, Retrospective, Clinicopathologic Review.

Desmoplastic melanoma (DM) is a rare melanoma variant. Prognostic indicators and survival vary widely and are further confounded by the histopathologic distinction between pure DM (pDM) and mixed DM (mDM) subtypes. The utility of current treatment guidelines is limited by the lack of evidence-based recommendations. To compare the clinicopathologic characteristics of pure and mixed subtypes of DMs. All cases of DM were identified from the Washington University in St Louis institutional pathology database between January 2000 and September 2022. Fifty-two cases were identified and subsequently categorized as pure ( n = 26) or mixed ( n = 26). Clinical and histopathologic data were collected and compared. There were no differences in demographics or tumor location between pure and mixed subtypes. Patients with mDM were more likely to have mitoses present ( p = .03). There were no differences in Breslow depth, tumor diameter, level of invasion, ulceration, and lymphovascular or perineural invasion. The utilization of sentinel lymph node biopsy ( p = .17) and sentinel lymph node positivity ( p = .67) were also similar. Despite histopathologic distinction between pDM and mDM, these subtypes were found to have similar clinicopathologic characteristics, including similar rates of sentinel lymph node metastasis.

PRAME Expression Is a Useful Tool in the Diagnosis of Primary and Metastatic Dedifferentiated and Undifferentiated Melanoma.

Although mostly recognized in the metastatic setting dedifferentiated and undifferentiated melanomas are increasingly recognized as cutaneous and, less commonly, mucosal primary tumors. Their diagnosis is challenging and dependent on sampling and recognition of a conventional melanoma precursor and/or detection of a mutation in a conventional melanoma driver gene. PRAME immunohistochemistry has recently become an important ancillary tool in the separation of melanoma from benign nevi, but no comprehensive studies exist regarding its value in the detection of dedifferentiated and undifferentiated melanomas and their separation from atypical fibroxanthoma and pleomorphic dermal sarcoma, the main differential diagnoses on sun-damaged skin. After retrieval from archival files, we performed PRAME immunohistochemistry on 11 primary and 10 metastatic dedifferentiated and undifferentiated melanomas, 11 atypical fibroxanthomas, and 10 pleomorphic dermal sarcomas. Nuclear staining was assigned extent (ranging from 0 to 4 and reflecting the percentage of PRAME-positive tumor nuclei) and intensity scores (graded as absent, weak, moderate, and strong, with assigned scores ranging from 0 to 3) with combined scores ranging from 0 to 7. Both primary and metastatic dedifferentiated and undifferentiated melanomas showed strong and diffuse nuclear PRAME staining with median combined scores of 7. Strong and diffuse staining was also seen in all conventional melanoma precursors except for desmoplastic melanoma. In contrast, PRAME staining in atypical fibroxanthoma and pleomorphic dermal sarcoma was patchy and weak with median combined scores of 2. Our data emphasize the diagnostic utility of PRAME staining as a first screening tool in the detection and workup of dedifferentiated and undifferentiated melanomas, both in the primary and metastatic settings. PRAME immunohistochemistry is particularly helpful as it is also positive in tumors without a recognizable conventional melanoma precursor and in those associated with desmoplastic melanomas, where PRAME is typically found to be negative.

Refining the application of PRAME-a useful marker in high CSD and acral melanoma subtypes.

Pathologic discordance affecting patient management may approach 20% in melanocytic cases following specialist review. The diagnostic utility of PRAME has been highlighted in several studies but interpretative challenges exist including its use in severely dysplastic compound nevi showing progression to melanoma in situ, nevoid melanoma, and coexisting nevi with melanoma. We examine the PRAME status of a broad spectrum of melanocytic lesions including challenging, dysplastic nevi with severe atypia from a large Irish patient cohort. Retrospective review of the dermatopathology database was conducted to evaluate the PRAME staining characteristics of two hundred and twenty-one melanocytic lesions using a commercially available PRAME antibody (EPR20330). The proportion of nuclear labeling and intensity of staining was recorded. The sensitivity and specificity of PRAME for in situ and malignant melanocytic lesions was 77% and 100%, respectively. Virtually all of our melanoma in situ from high-cumulative sun damaged (CSD) skin (22/23) and all acral lentiginous melanoma (5/5) were PRAME positive while 80% (8/10) of our lentigo maligna melanoma showed diffuse expression. None of our benign subgroup showed diffuse immunoexpression (0/82), including thirty-seven moderate or severely dysplastic nevi. In all cases of melanoma in situ arising in association with a dysplastic compound nevus (0/10), no immunoexpression was observed in the nevic component while in five cases of melanoma in situ with coexistent, intradermal nevus immunostaining was confined to the in situ component. A total of 100% (2/2) of desmoplastic melanomas and 50% (4/8) of nodular melanomas were PRAME positive. PRAME is a sensitive and highly specific immunostain in the diagnosis of in situ and invasive melanoma and we emphasize its application in the evaluation of high CSD and acral melanoma subtypes as well as in challenging threshold cases.

Definitive treatment with PD-1 blockade and radiation therapy of unresected primary desmoplastic melanoma of the nose.

Two patients with primary desmoplastic melanoma of the nose were treated with definitive anti-PD-1 checkpoint inhibitor (anti-PD1) and radiation therapy. Both patients were technically resectable with partial rhinectomy but both declined for cosmetic reasons. The melanoma multidisciplinary team recommended that the patients receive PD1 blockade. The initial response to PD-1 blockade was temporary in the first case and partial in the second one. With the addition of high-dose radiotherapy, complete responses were obtained in both patients, with recurrence-free and good functional and cosmetic outcomes at a six-year and 22-month follow-up. Despite surgery being the gold standard, both cases illustrated that PD-1 blockade and radiation therapy can be a safe alternative option for desmoplastic melanoma where surgery is morbidly disfiguring.

Use of NovoSorb Biodegradable Temporizing Matrix in the Management of Complex Scalp Defects

Summary: Dermal substitutes have emerged as a potential option in complex wound management. PolyNovo NovoSorb Biodegradable Temporizing Matrix has shown promise in managing partial and full-thickness wounds. We discuss here the successful use of this product in the management of a scalp defect complicated by exposed bone, following wide local excision of a desmoplastic melanoma of the scalp.

Dramatic response of face desmoplastic melanoma after two doses of immunotherapy.

Dramatic response of face desmoplastic melanoma after two doses of immunotherapy.

Identification of Novel Dermoscopic Patterns for "Featureless Melanoma": Clinical-Pathological Correlation.

Diagnosis of melanoma can be very difficult because of its phenotypic and histological heterogeneity. Difficult-to-diagnose melanoma can be represented by mucosal melanoma, pink lesions, amelanotic melanoma (amelanotic lentigo maligna, amelanotic acral melanoma, desmoplastic melanoma), melanoma arising on sun-damaged facial skin, and "featureless melanoma". The aim of the study was to improve the identification of featureless melanoma (scoring 0-2 according to the 7-point-checklist) describing the variegated dermoscopic features and their histopathological correlation. Study samples included all melanomas excised based on clinical and/or dermoscopic findings in the period between January 2017 and April 2021. Before excisional biopsy, all lesions were recorded by means of digital dermoscopy at the department of Dermatology. Only lesions with a diagnosis of melanoma and a high quality of dermoscopic images were included in this study. After clinical and dermoscopic evaluation of 7-point checklist score, single dermoscopic and histological features were considered for lesions with a score of 2 or lower and a diagnosis of melanoma (corresponding to dermoscopic featureless melanoma). A total of 691 melanomas fulfilled inclusion criteria and were retrieved from the database. The 7-point checklist evaluation identified 19 "negative-featureless" melanoma. The 100% of the lesions with score 1 showed a globular pattern. Dermoscopy is still the best diagnostic method for melanoma. The 7-point checklist provides a simplification of standard pattern analysis because of the algorithm based on a scoring system and the lower number of features to recognize. In the daily practice it is more comfortable for many clinicians to keep in mind a list of principles that may help in the decision.

Single-Agent PD-1 Blockade Is "Treatment of Choice" for Desmoplastic Melanoma.

Data from the phase II S1512 trial indicate that patients with inoperable metastatic desmoplastic melanoma are highly responsive to first-line pembrolizumab. As such, anti-PD-1 monotherapy, rather than current combinations such as nivolumab-relatlimab, should be considered for these patients.