The new ESMO–EURACAN guideline on uveal melanoma offers an important and much-needed framework for a rare and biologically distinct disease. It clarifies current standards in diagnosis, local therapy, surveillance, prognostic assessment, and metastatic management, while reinforcing the central role of expert multidisciplinary care. But in a cancer like uveal melanoma, where many of the hardest questions remain unanswered, the publication of a guideline is not the end of the conversation. In many ways, it is the beginning of a more important one.
Two expert reflections add exactly that dimension. Rather than revisiting what is already established, they shift the focus toward what remains unresolved in biology, clinical decision-making, and evidence generation.
Uveal Melanoma 2026: What the Latest ESMO–EURACAN Guideline Tells Us
Bettina Ryll: The Biology We Still Do Not Understand
Bettina Ryll highlights how much of uveal melanoma biology remains unclear—particularly the timing of metastatic spread.
“UM seeds early—micromets have been found in patients who died of something else. And the liver somehow shields them.” — Bettina Ryll
This observation reframes the disease entirely. If dissemination occurs early, then the key question is not when metastases appear, but what controls their dormancy and what triggers progression. The liver, therefore, is not simply a metastatic site—it is a biologically active immune environment that may determine disease trajectory.
The Liver Is Not Just a Target Organ
Ryll emphasizes that uveal melanoma sits at the intersection of unique immune environments.
“UM is as immunologically fascinating as it is clinically devastating—the eye is an immune-protected environment, and the liver… there is just something that is different here.” — Bettina Ryll
This shifts the research focus toward liver immunobiology, particularly how hepatic immune cells—such as NK cells—may initially control micrometastatic disease and why that control eventually fails.
When Immunotherapy Challenges Conventional Thinking
Another key point is how immunotherapy should be interpreted in uveal melanoma.
“Immunos work—but just not how in [cutaneous melanoma]… Tebby is an IO drug as well, after all.” — Bettina Ryll
The success of tebentafusp challenges traditional assumptions. Despite modest radiographic responses, it improves overall survival—raising critical questions about whether commonly used endpoints like PFS truly capture clinical benefit in this disease.
Ryll warns against rigid reliance on conventional frameworks:
“People were so set on PFS overestimating OS that they didn’t even see the clinical data in UM.” — Bettina Ryll
This highlights a broader issue: whether established oncology paradigms may obscure meaningful advances in rare cancers like uveal melanoma.
The Surveillance Catch-22
One of the most striking insights is the structural barrier in evidence generation.
“Risk is not systematically assessed and liver surveillance is patchy… we will never get [evidence] if we don’t… conduct proper surveillance to intervene early.” — Bettina Ryll
This creates a self-perpetuating cycle: lack of evidence limits surveillance strategies, but without systematic surveillance, the evidence can never be generated. As she notes, the field must actively break this cycle rather than accept it.
Scott Walter: Why Biopsy Is Becoming Harder to Ignore
Scott Walter focuses on a different—but equally important—shift: the evolving role of biopsy.
“While many UMs are still diagnosed clinically, there’s an emerging shift… toward more routine use of tumor biopsy.” — Scott Walter
This reflects a transition away from purely clinical diagnosis toward a more integrated, biology-driven approach.
From Visual Diagnosis to Molecular Precision
Walter emphasizes that biopsy is no longer just about confirming diagnosis—it is about understanding tumor biology.
“Molecular confirmation… helps establish melanocytic origin… Detection of higher-order alterations… supports malignant transformation and informs us about the cancer cell fraction.” — Scott Walter
Genomic information—including GNAQ/GNA11 mutations, BAP1, SF3B1, EIF1AX, and chromosomal changes—now provides critical insight into tumor behavior, risk stratification, and even eligibility for clinical trials.
The Biggest Impact May Be in Small or Uncertain Lesions
Importantly, the value of biopsy may be greatest in early or ambiguous cases.
“Where biopsy is arguably most impactful… is in smaller or indeterminate lesions… genomic data provides immediate insight into tumor biology that we simply can’t ascertain clinically.” — Scott Walter
This allows earlier identification of aggressive disease and supports more tailored decision-making—ranging from early intervention to conservative management.
A Promising Shift That Still Needs Validation
Despite this progress, Walter acknowledges current limitations:
“This biology-driven approach… has not yet been prospectively validated.” — Scott Walter
Still, the direction is clear: uveal melanoma is moving toward integrated clinical and molecular decision-making, where biopsy plays a central role.
Beyond Recommendations, Toward the Next Standard
Taken together, these expert perspectives point toward a common conclusion. The future of uveal melanoma care will not be defined solely by guidelines, but by deeper biological understanding and more adaptive clinical strategies.
Bettina Ryll highlights unresolved questions in liver immunology, endpoint interpretation, and evidence generation. Scott Walter illustrates how diagnosis itself is evolving—shifting toward earlier and more precise molecular characterization.
What emerges is a field in transition.
Uveal melanoma is no longer defined by anatomy alone, nor can it rely on frameworks borrowed from cutaneous melanoma. The next phase will require:
- deeper understanding of liver immunobiology
- smarter, risk-adapted surveillance strategies
- more flexible interpretation of clinical endpoints
- and earlier integration of molecular profiling into routine care
The guideline defines today’s standard.
These expert voices help define what tomorrow’s standard must become.