Guias de manejo melanoma no operable 2026

A clinical practice guideline has been published that provides recommendations on the use of systemic therapy in patients with unresectable, metastatic cutaneous melanomas. These guidelines were published by Cancer Care Ontario.

The evidence-based recommendations apply to adults with unresectable nodal or distant metastatic cutaneous melanoma, defined as American Joint Committee on Cancer (AJCC) 8th edition stage IIIC/D or stage IV, who are candidates for systemic therapy. Intended users of the guideline include medical oncologists, dermatologists, and other clinicians involved in melanoma care. The recommendations reflect a decade-long therapeutic shift driven by immune checkpoint inhibitors — including anti-programmed cell death protein 1 (anti-PD-1) inhibitors, anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) inhibitors, and anti-lymphocyte-activation gene 3 (anti-LAG-3) agents — and BRAF/MEK-targeted therapies.

First-Line Therapy: BRAF Wild-Type Disease

For patients with BRAF wild-type melanoma, recommended first-line options include nivolumab plus ipilimumab, nivolumab plus relatlimab, nivolumab monotherapy, and pembrolizumab monotherapy.

Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg is to be administered intravenously once every 3 weeks for 4 total doses, followed by nivolumab 3 mg/kg every 4 weeks until progression, toxicity, or the need for other treatment considerations. Nivolumab 480 mg plus relatlimab 160 mg should be administered intravenously every 4 weeks until progression. Nivolumab monotherapy is to be administered intravenously in a dose of 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks, with either dose continued until progression, toxicity, or other considerations. Similarly, pembrolizumab is to be administered intravenously in a dose of 2 mg/kg every 3 weeks or 6 mg/kg every 4 weeks for a maximum of 2 years, with the potential for retreatment for 1 year.

Due to the evolving environment surrounding systematic therapy for unresectable, metastatic melanoma, indications and approvals are changing rapidly.

Evidence is anchored in a 2018 Cochrane review and multiple randomized controlled trials. Anti-PD-1 therapy (nivolumab or pembrolizumab) significantly improved overall survival (OS) and progression-free survival (PFS) compared with ipilimumab, with lower rates of grade 3-4 toxicity. Better PFS but higher rates of grade 3-4 treatment-related adverse events occurred with nivolumab combination therapy vs nivolumab monotherapy. Nivolumab plus relatlimab demonstrated improved PFS compared with nivolumab alone, with higher toxicity rates than nivolumab alone but lower than with nivolumab plus ipilimumab. While chemotherapy remains an option, immunotherapy is preferred due to superior survival outcomes.

First-Line Therapy: BRAF-Mutated Disease

For patients with BRAF-mutated melanoma, both immunotherapy and targeted therapy are recommended. In addition to the recommended treatment options for BRAF-wild type melanoma, patients with BRAF-mutated melanoma may also receive BRAF/MEK inhibitor combinations of dabrafenib plus trametinib, encorafenib plus binimetinib, or vemurafenib plus cobimetinib. However, immunotherapy is preferred as first-line treatment based on sequencing data.

Dosing for nivolumab plus relatlimab and nivolumab monotherapy are the same for patients with BRAF-mutated disease as patients with BRAF-wild type disease. Nivolumab plus ipilimumab is to be administered intravenously every 3 weeks for up to 4 doses, followed by nivolumab 6 mg/kg every 4 weeks until progression, toxicity, or other considerations. Pembrolizumab monotherapy is available intravenously for up to 2 years with a 1-year potential retreatment period in a dose of 2 mg/kg every 3 weeks, 4 mg/kg every 6 weeks, or 6 mg/kg every 4 weeks. Dabrafenib 150 mg should be taken twice daily and trametinib 2 mg should be taken once daily, both orally. Similarly, encorafenib 450 mg should be taken once daily while binimetinib 45 mg should be taken twice daily, both orally. Vemurafenib 960 mg should be taken twice daily with cobimetinib 60 mg once daily for 21 days with a 7-day rest period in each 28-day cycle.

Combination BRAF/MEK inhibitors vs BRAF monotherapy consistently demonstrated improved outcomes with a reduced mortality risk without increased toxicity in pooled analyses. Improved PFS and OS were observed with encorafenib plus binimetinib vs vemurafenib. Other trials similarly supported dabrafenib plus trametinib.

Triplet regimens (BRAF/MEK plus anti-PD-1/PD-L1) yielded mixed results. Some analyses demonstrated PFS improvements but triple-therapy regimens did not consistently improve OS and were associated with higher grade 3-4 toxicity than double-therapy regimens.

Sequencing trials provide key guidance. Superior 2-year OS and PFS were observed when patients received nivolumab plus ipilimumab first, followed by targeted therapy at progression. Sustained superiority of immunotherapy-first strategies was confirmed at 5 years. Initial immunotherapy, with or without short targeted therapy, was preferred over targeted therapy-first approaches. Continuous BRAF/MEK dosing was superior to intermittent dosing.

PD-1-Refractory Disease

For patients with BRAF wild-type melanoma who are refractory to PD-1 monotherapy (including both primary and acquired resistance), recommended options include nivolumab plus ipilimumab or pembrolizumab plus ipilimumab. Nivolumab plus ipilimumab improved PFS compared with ipilimumab alone.

For PD-1-refractory BRAF-mutant melanoma, options include combination immunotherapy with nivolumab plus ipilimumab, nivolumab plus relatlimab, or pembrolizumab plus ipilimumab, as well as BRAF/MEK inhibitors. Subgroup analyses showed PFS benefits for pembrolizumab in certain previously treated BRAF-mutant populations.

Dosing schedules for all regimens are consistent among patients who are and are not refractory to PD-1 monotherapy.

Molecular and Clinical Subtypes

For NRAS-mutant melanoma, binimetinib may be considered with or without immunotherapy. Binimetinib improved PFS compared with dacarbazine, although responses were modest.

For KIT-mutant melanoma, evidence is limited to single-arm studies. Due to low-quality evidence and absence of randomized controlled trials, no specific recommendation is made beyond following general systemic therapy guidance.

For brain metastases, nivolumab plus ipilimumab is recommended. In trials evaluating patients with asymptomatic brain metastases, greater rates of intracranial response were observed with combination therapy vs nivolumab alone. Combination immunotherapy was also favored over chemotherapy-based approaches based on 7-year OS data. Further, BRAF/MEK inhibitors demonstrated promising intracranial response rates in BRAF V600-mutant brain metastases, although responses were less durable than in extracranial disease. Radiation therapy, particularly stereotactic approaches, remains an important component of multidisciplinary care.

Implementation and Evidence Limitations

For all patients, clinical trial participation is encouraged when standard options fail or are not acceptable.

The guideline emphasizes shared decision-making, balancing OS/PFS benefits against toxicity, patient comorbidities, and preferences. Toxicity profiles vary significantly, particularly with combination immunotherapy.

Key limitations include the lack of direct head-to-head randomized controlled trial comparisons between immunotherapy and targeted therapy, limited predictive biomarkers beyond BRAF mutation status, and reliance on subgroup analyses for brain metastases and refractory populations. Heterogeneity across trials precluded meta-analysis. Cost-effectiveness was outside the scope of these recommendations.

Future Directions

Further biomarker-driven research is needed to personalize therapy, optimize sequencing, and refine treatment duration strategies. Ongoing trials in NRAS-mutant disease and novel combinations may further evolve the therapeutic landscape.

Overall, the guideline reflects a paradigm in which immunotherapy, particularly in blocking combination immune checkpoints, provides durable survival benefit and is generally favored as first-line therapy, with targeted therapy integrated strategically based on mutation status, disease progression, and clinical circumstances.

Guideline authors concluded, “Due to the evolving environment surrounding systematic therapy for unresectable, metastatic melanoma, indications and approvals are changing rapidly.”

References:

Petrella T, Kellett S, Knight G, et al; Melanoma Disease Site Group. Systemic treatments for unresectable and metastatic cutaneous melanoma. Cancer Care Ontario. Published January 5, 2026. Accessed February 17, 2026. https://www.cancercareontario.ca/en/guidelines-advice/types-of-cancer/79966

Lisa Kuhns, PhD

Lisa Kuhns, PhD is an experienced medical writer specializing in news-focused content for healthcare professionals. With over 15 years in the life sciences and 5 years of freelance experience, she brings a keen editorial eye and scientific rigor to the development of timely, clinically relevant news articles and summaries. Lisa also has extensive experience supporting accredited continuing medical education (CME), including the development of needs assessments and expert-driven slide decks across multiple therapeutic areas. Her work supports evidence-based clinical decision-making and bridges science and medicine to keep clinicians informed and engaged. Website: www.lgkmedicalwriting.com LinkedIn: https://www.linkedin.com/in/lisakuhns/

Espectro de Lesiones de Spitz

Exploring Spitz nevi in the molecular era

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Dermatopathologists discuss how to approach spitzoid lesions and how molecular testing can aid in assessing their potential malignancy.

Feature

By Allison Evans, Assistant Managing Editor, April 1, 2026

Spitz nevi. Spitz tumor. Spitz melanoma. It has long been recognized that the histopathologic differential diagnosis between a Spitz nevus and melanoma — and the spectrum in between — can be challenging, with hazards related to under- and overtreatment. The advent of advanced molecular techniques like next generation sequencing (NGS), conventional or microarray comparative genomic hybridization (CGH), and fluorescence in situ hybridization (FISH), have provided new sophisticated tools to assist with this vexing differential diagnosis. 

Spitz nevus is named after Sophie Spitz, a pathologist who reported a case series of “melanomas of childhood” in 1948. Nearly all of Spitz’s original series of 13 cases are now regarded as representing Spitz nevi, with only one case having proved to be a melanoma resulting in metastasis and death. 

“This case series fundamentally changed our understanding of these lesions,” said Alina Bridges, DO, FAAD, director of cutaneous pathology at Northwell Health and director of dermatopathology at the Zucker School of Medicine at Hofstra/Northwell. 

Spitz refers to a family of melanocytic tumors that have commonalities, which include certain morphologic features under a microscope but also common genomic features, said Pedram Gerami, MD, FAAD, IDP Foundation professor of skin cancer research and professor of dermatology and dermatopathology, pathology, and pediatrics at Northwestern’s Feinberg School of Medicine.

“In 2013, the primary genomic drivers of Spitz were discovered,” he explained, “which allowed us to use genomics to more objectively and definitively determine if a lesion belongs to the Spitz family and to exclude mimickers of Spitz when the genomics do not match a Spitz profile.” 

To biopsy or not

According to Dr. Gerami, it is not necessary to biopsy all Spitz nevi. “However, prior to the biopsy, we don’t always know if we are dealing with a lesion in the Spitz family or a mimicker of Spitz. If the lesion is in the Spitz family we may not necessarily know if we are dealing with a Spitz nevus, atypical Spitz nevus, Spitz tumor (also called a melanocytoma), or Spitz melanoma.”

It’s a matter of risk management, he continued. “If you imagine the Spitz spectrum from Spitz nevus to atypical Spitz nevus to Spitz tumor to Spitz melanoma, in a prepubertal child the probability of being toward the benign end of this spectrum is significantly higher. In prepubertal children with symmetric macular lesions or even symmetric small papular lesions, observation is completely acceptable.” 

“Biopsies should be done any time the lesion exhibits atypical features such as a larger lesion — greater than 1 cm — exhibiting rapid growth or is ulcerating, if there’s any asymmetry, or if you have a patient who is older or post-pubertal,” Dr. Bridges said. 

In the ages between puberty and 40, the decision to biopsy is often made on a case-by-case basis, Dr. Gerami noted. “In a patient older than 40, the probability of malignancy in a lesion with a clinically spitzoid appearance becomes significant enough that I typically would biopsy these. The greatest threat is not a malignant Spitz melanoma but rather a conventional malignant melanoma mimicking a Spitz.”

“If the pigmented lesion in a child is a classic fit for a Spitz nevus, including the dermoscopy findings and the clinical evolution, then it can be safely monitored,” agreed Jeffrey North, MD, FAAD, professor of dermatology and pathology and managing director of UCSF Dermatopathology and Oral Pathology Service. 

“But it really needs to match all of those characteristics — symmetrical appearance, well circumscribed, no rapid growth, a uniform starburst pattern or globular pattern on dermoscopy.” He also noted the importance of ensuring the patient has the means to reliably follow up so the lesion can be monitored if a biopsy is not done.

Advances in dermatopathology

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Learn more about the latest trends and developments in dermpath.

Excision

According to the National Comprehensive Cancer Network (NCCN) Guidelines, the lesion should be removed in its entirety, Dr. Bridges said. “Dermatologists should do an excisional or complete biopsy, whether or not that’s a deep shave, a punch biopsy for smaller lesions, or an elliptical excision so that you can get around it with 1- to 3-millimeter margins.”

The ability to do molecular testing is mostly dependent on having adequate tumor DNA, Dr. Gerami agreed. “This can be compromised by doing small shaves of small lesions or small biopsies of large lesions, resulting in inadequate sampling. Regardless of the biopsy method, if the entire lesion is removed, this maximizes the likelihood that there will be enough tissue for immunostains and molecular testing.” 

“If I have just a small piece of tissue, then I have to sacrifice the number of immunostains that I’m going to do so that I have enough tissue left to do the molecular testing,” Dr. Bridges added.

This is particularly important when it comes to pediatric patients, she continued. “The parent and the child may not be too happy with you saying that you need to perform another excision to get a larger sample when we should have done it in the first place.”

Dr. North explained that he frequently sees Spitz tumors biopsied where they’re transected across the base, and oftentimes at the edges, and that really limits what the dermatopathologist can do in assessing the neoplasm. 

“We may be able to do molecular testing, but we can’t see if there’s good dermal maturation, if the lesion is well circumscribed — we can’t see what the bottom of the tumor looks like. Sometimes, a Spitz tumor may have an atypical part that’s not visible in the superficial part,” he added.

Diagnosing Spitz lesions: Case examples

Dr. Bridges highlighted one of her cases in which she received a specimen to rule out a dermatofibroma. “It may be challenging to clinically suspect Spitz nevi because they may not be pigmented. With immunostains and molecular testing, I rendered a diagnosis of Spitz melanoma as opposed to severely atypical Spitz nevus.”

“You can’t tell based solely on histomorphology, and I only did a few immunostains because I had very little tissue. I tried to see if there was any mitotic activity — there wasn’t. I sent this for a chromosomal microarray (similar to comparative genomic hybridization), which identified four copy number alterations; anything greater than three is considered suspicious for melanoma.”

In another of Dr. Bridge’s cases, a teenager presented with a history of a lesion on the ear. A superficial shave biopsy was performed, and it was diagnosed as a Spitz nevus. The lesion recurred and a deeper shave biopsy was performed. “The lesion was very atypical; it had three mitoses and was diagnosed as a Spitz melanoma based on the immunostains.”

“The first workup that was done came from haemotoxylin and eosin (H&E) and the second one came from immunostains. When I got the case, I did molecular testing and was able to downgrade the lesion to a severely atypical Spitz tumor rather than a Spitz melanoma,” she added.

Exploring Spitz: A spectrum of Spitz melanocytic lesions

Spitz nevi - Definitively benign

Atypical Spitz nevi - Definitively benign but with atypical histologic features

Spitz tumors - Borderline morphologic features but with most cases having an indolent clinical course

Spitz melanoma - Malignant melanoma version of a Spitz

Molecular diagnostics

Advances in molecular techniques have revealed many genetic differences between benign nevi and melanomas. Next generation sequencing, chromosomal microarray and/or CGH, and FISH are all tests that can be useful in certain scenarios to assess Spitz neoplasms and determine where they lie on the Spitz spectrum.

“Over the years that I’ve practiced, I have a lot more satisfaction handling these lesions,” Dr. Bridges said. “Before it was very ambiguous. You could say that it’s benign or atypical, but you couldn’t definitively rule out malignancy. We used to use the phrase ‘uncertain malignant potential’ all the time for these lesions, but now because of advanced immunostains and molecular testing, I can not only diagnose, but I’m almost prognosticating as well.”

The most important thing to determine is whether you are really dealing with a Spitz or a Spitz mimicker, Dr. Gerami emphasized. “Melanocytic tumors with mutations in BRAF, NRAS, GNAQ, and GNA11, for example, are immediately excluded from the Spitz family and belong to other classes of melanocytic neoplasia. However, an HRAS mutation or a characteristic Spitz fusion is highly consistent with classification in the Spitz family.” 

Immunostains

One of the most important stains is BRAF because all Spitz lesions will be negative for BRAF, Dr. Bridges said. “Conventional nevi usually have a single driver mutation — most commonly BRAF and less frequently NRAS.”

Dr. Bridges also uses the p16 stain to determine whether that tumor suppressor has been disabled. “In order to determine whether the specific mutation (CDKN 2A/2B genes) associated with melanoma is found, we need to do further molecular testing.”

While PRAME can be used, it has pitfalls because melanomas can be PRAME positive or negative, and benign lesions can be PRAME positive. Dr. Bridges recalled her aforementioned case of the teenager with the ear lesion that was downgraded from a Spitz melanoma to a severely atypical Spitz tumor. “She was diagnosed with Spitz melanoma because her p16 was lost and her PRAME was positive.”

Immunostains can be helpful, noted Dr. North. “Some can identify mutations that would exclude a Spitz family tumor. However, immunostaining to confirm a Spitz family tumor is limited. ALK staining to detect an ALK gene fusion in the Spitz family is the most reliable. The remaining immunostains for Spitz genetic drivers (e.g., NTRK1, ROS1, etc.) can be challenging to interpret and can lead to misdiagnosis. Most pathologists try immunostains before molecular testing.”

You can’t interpret any of these tests in isolation, Dr. Bridges remarked. “If there is severe atypia or if we’re in the category of Spitz tumors or melanocytomas and they have mitoses, then we’re going to be doing next generation sequencing to classify the lesion.” 

NGS and CGH

Comparative genomic hybridization can be helpful by providing the chromosomal copy number information and, in some cases, can show features suggestive of a Spitz gene fusion, but it’s not as comprehensive as NGS. “We rarely do CGH now because our next generation sequencing panel gives us the same data,” said Dr. North. “It provides mutation and fusion information about whether the tumor has a Spitz family genetic driver as well as potential additional progression mutations in other oncogenes and tumor suppressor genes. It also provides chromosomal copy number information similar to CGH to give a comprehensive genetic analysis of the tumor.”

Next generation sequencing identifies the specific driver alteration, so it definitively classifies the lesions, Dr. Bridges said. “Classification is important because even atypical Spitz tumors have an excellent long-term prognosis, despite having worrisome histologic or immunohistochemical features. There have been very large studies that showed event-free survival of 98% and overall survival of 100%.”

Spitz melanomas typically have additional pathogenic mutations, such as a TERT promoter mutation, and copy number aberrations, Dr. Bridges said.

NGS helps dermatopathologists classify the melanocytic pathway, Dr. North said. “This becomes really important because when you look at them under a microscope, they may look like a Spitz family tumor. But when you sequence them, they may not have the genetics of a Spitz tumor.”

“If there isn’t truly a Spitz genetic driver — if instead there is a BRAF mutation — that’s potentially a worse prognosis in an atypical tumor with spitzoid features. For the most part, even these very atypical Spitz tumors tend not to behave as aggressively. You can often only get this type of information with next generation sequencing,” he added.

PRAME sets its eyes on the road to fame

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Jason B. Lee, MD, FAAD, discusses preferentially expressed antigen in melanoma (PRAME) in evaluating melanocytic neoplasms.

FISH

There is a middle ground if there isn’t enough tissue, Dr. Bridges noted. “You could use FISH to detect chromosomal aberrations, which requires less tissue and has quicker turnaround time. However, 20% of melanomas will be FISH negative.” 

FISH is one of the oldest molecular tests used to assess Spitz tumors, said Dr. North. “Because it has the most studies published on it, it tends to be what’s most readily approved by insurance. With FISH you’re only able to look at four to eight segments of the genome, while NGS looks at a large amount of the genome with targeted panels looking at 300-600 of the most mutated genes in cancer.”

“We often see consults where physicians send specimens because the tumor looks very atypical. There may be loss of p16 expression and PRAME positivity, so it looks quite worrisome for a melanoma,” said Dr. North. “But in a 10-year-old child, you don’t want to make a melanoma diagnosis without having a full assessment of the tumor. We would get NGS on this, and sometimes it ends up being on the benign side even with the concerning features noticed in the initial workup.”

Sometimes more than one test is indicated, Dr. Gerami said. “NGS may be performed to identify the primary driver and some progression events. If the pathologist does not find anything and is still worried, then CGH or FISH may be added to look for other potential progression events.”

Next steps

With severely atypical Spitz tumors, dermatologists often want to know whether they should do a sentinel lymph node biopsy, Dr. Bridges said. “There’s no reason to do a sentinel lymph node biopsy because it has no prognostic benefit. Yes, they can have a positive sentinel lymph node biopsy, but it doesn’t predict a poor outcome in these patients, particularly pediatric patients.”

Everybody wants to know about margins, said Dr. Bridges. “If it’s anything that is atypical or severely atypical, then you have to excise it with 5-millimeter margins; you treat Spitz melanomas like any other melanoma.”

If a dermatologist receives a report in which NGS is done, if anything is not clear, call the dermatopathologist, advised Dr. North. “It’s not the same as a lab test in which there is a clear positive or negative result.” 

“It’s very easy to get confused when seeing all the next generation sequencing data. It can even confuse the molecular pathologists sometimes because there may be mutations listed in the reports that are not significant,” he continued.

“If you feel like there’s a disconnect between your clinical impression and the report, you should call the dermatopathologist to walk through everything and ask questions about whether the mutations are significant,” said Dr. North. “Don’t feel you like you have to have a grasp of everything molecular to make the call.”

“Perhaps there was not a definitive diagnosis in a biopsy without comprehensive testing,” continued Dr. North. “The call could simply be, ‘Could we do some additional testing to see if we could get a more definitive diagnosis?’ or ‘Could we get a second opinion consult with possible additional testing?’”

Dr. Gerami urges dermatologists to forge a good working relationship with their dermatopathologist and discuss cases that are concerning. “If the diagnosis is straightforward from the pathologist, then some of these molecular tests may not be needed. If they are needed, then it may be worthwhile to discuss the details of the case with the pathologist to understand the testing and what level of certainty the pathologist has of a benign or malignant diagnosis.”

Spitz pathology reports can be anxiety-inducing because of how atypical and yet how clinically unaggressive they can be, Dr. North said. “The goal should be proper treatment, not overtreatment, in these tumors that generally have a very excellent prognosis, even in that intermediate category of an atypical Spitz tumor.”