Logo

To offer you a better experience, this site uses cookies, including those of third parties. To find out more and manage your preferences, consult the cookie policy

Get updates

When you see uveal melanoma, think
differently

Histologically, uveal melanoma (UM) and cutaneous melanoma (CM) may look similar, but they are actually unique diseases.

Courtesy of Prof Sarah Coupland, George Holt Chair in Pathology, Honorary Consultant Histopathologist, University of Liverpool, UK. While UM and CM both arise from melanocytes, they have distinct mechanisms of disease and require different therapeutic approaches.1-4

At all stages of disease, UM and CM are intrinsically different:

ink drop sequence
and especially in the number of FDA-approved systemic treatment options for metastatic disease1,6,9-11:
No therapy
has demonstrated a substantial benefit specifically for patients with metastatic UM.1,6
Numerous therapies
have demonstrated a benefit for patients with metastatic CM.9,10

While treatment options for UM are limited, patients should be referred to a multidisciplinary team for consideration of available systemic options.1,12,13

Watch Marlana Orloff, MD, discuss additional distinctions between UM and CM

Distinct genotypes and phenotypes3

The differences in oncogenic drivers and immunogenicity between UM and CM result in distinct mechanisms of disease.

Oncogenic drivers of UM and CM3

UM CM
GNAQ/GNA11 BRAF
SF3B1 NRAS
EIF1AX MEK1/2
CYSTLR2 PIK3CA
PLCβ4 PIK3CG
AKT1/AKT3
RAC1
KIT
CM, cutaneous melanoma; UM, uveal melanoma.

Rationale for targeted therapies3

Because CM has a high incidence of BRAF mutations, effective treatment options for CM include anti-BRAF and anti-MEK therapies.

Because UM lacks BRAF mutations, there is little support for the use of anti-BRAF therapies in the treatment of UM.3

Rationale for checkpoint inhibitors

Immunotherapy has increasingly become the latest pillar of systemic therapy in oncology, and the recent approvals of checkpoint inhibitors for CM have served as breakthrough options for many patients.3 Unfortunately, these therapies have not demonstrated the same efficacy in the treatment of UM.3,12,14

In addition to having different oncogenic drivers, UM and CM have distinct mutation burdens.3,15

ink drop sequence
In a study of more than
100 tumor types,
CM
is among those with the
highest
tumor mutation burden,
while UM
is among those with the
lowest.15

Tumor mutation burden varies by tumor type15

Disease Mutations/Mb
Skin squamous cell carcinoma
Skin melanoma
Lung squamous cell carcinoma
Brain glioblastoma
Eye intraocular melanoma
Bone marrow myelodysplastic syndrome
  0 10 100

UM tumor immunogenicity

The immune tumor microenvironment factors into the distinction between UM and CM. While CM contains adequate numbers of effector T cells and is inflamed (“hot”), the effector T cells surrounding UM are limited to the tumor periphery (immunologically “cold”).14-18

mUM
mCM
From Immunotherapy (2017) 9(16), 1323–1330. Reproduced with permission.14

PD-L1 expression differs significantly between metastases of UM and those of CM. Only 5.1% (4 of 78) of metastatic UM specimens expressed PD-L1 in comparison to 26.1% (77 of 295) of metastatic CM specimens.14

mCM, metastatic cutaneous melanoma; mUM, metastatic uveal melanoma; PD-L1, programmed death ligand 1.

Patient experiences differ greatly, as well

Not an actual image of this patient with UM.

“After 3 months of appointments with my optometrist, I was finally referred to a retina specialist.”

I was diagnosed with ocular cancer 4 years ago; I can remember the exact day like it was just yesterday. I went in for my annual eye exam feeling like there was a hair in my eye. Then I started seeing a light in my left eye and it was to the left, diagonal, coming at me from the top.

My optometrist didn’t see anything out of the norm. He just said it would work its way out. Over the next 3 months, the sensation continued to get worse. He finally referred me to a retina specialist—who dilated my eye and immediately noticed a “mole” on the back of it.

About a week later I started radiation, and then six and a half weeks later they said it didn’t work. On December 3rd, my eye was removed.

I am grateful for the care that I have received over the past several years. I just wished there was more information about this rare disease. More people need to be aware of the symptoms and what to do about it.

— Patient with UM

Not an actual image of this patient with CM.

“I had it checked out, it came back melanoma, and was quickly removed.”

In 2010 I had what looked like a pencil eraser on top of my head. I didn’t really think much of it—and just continued to shave around it. My wife was the one that encouraged me to get it looked at.

I was familiar with skin cancer but mine didn’t look like anything on the Internet. It came back positive as melanoma and I quickly had it surgically removed.

Within 6 months, I learned the cancer metastasized to my liver. Fortunately, I qualified for a clinical study and I have a wonderful treatment team that cared for me.

It’s one of those things; you never think it can happen to you. But I feel fortunate that there are new treatments that are helping people like me live longer.

— Patient with CM

Differences in clinical trial access

Click below to see the differences in the number of clinical trials.

  • 8
  • 115
  • 32
  • 2
  • 1
  • 1
  • 4
  • 163
  • 1,577
  • 15
  • 62
  • 634
  • 25
  • 77
  • 56
  • 5
  • 120
  • 14
  • 165
  • 37

Number of available clinical trials as of August 2019.

Learn about presentation, symptoms, and management of UM Explore UM resources and clinical perspectives

Get the latest updates in your inbox

Sign up to receive e-mail updates about new content on this website, including information about UM, expert clinical perspectives, and patient resources.

Specialty
  • Ocular oncologist
  • Ophthalmologist
  • Optometrist
  • Retina specialist
  • Dermatologic oncologist
  • Medical oncologist
  • Other healthcare professional

Unsubscribe

You have requested to no longer receive e-mail communications from ThinkUvealMelanoma.com.

Please verify your e-mail address below to confirm.

    References:
  1. Yang J, Manson DK, Marr BP, Carvajal RD. Treatment of uveal melanoma: where are we now? Ther Adv Med Oncol. 2018;10:1-17. doi:10.1177/1758834018757175
  2. Rodrigues M, de Koning L, Coupland SE, et al; UM Cure 2020 Consortium. So close, yet so far: discrepancies between uveal and other melanomas. A position paper from UM Cure 2020. Cancers. 2019;11(7):E1032. doi:10.3390/cancers11071032
  3. Pandiani C, Béranger GE, Leclerc J, Ballotti R, Bertolotto C. Focus on cutaneous and uveal melanoma specificities. Genes Dev. 2017;31:724-743.
  4. Barker CA, Salama AK. New NCCN guidelines for uveal melanoma and treatment of recurrent or progressive distant metastatic melanoma. J Natl Compr Canc Netw. 2018;16(5.5):646-650.
  5. Zbytek B, Carlson JA, Granese J, Ross J, Mihm MC Jr, Slominski A. Current concepts of metastasis in melanoma [published online for public access]. Expert Rev Dermatol. 2008;3(5):569-585. doi:10.1586/17469872.3.5.569
  6. Khoja L, Atenafu EG, Suciu S, et al. Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study. Ann Oncol. 2019;30(8):1370-1380.
  7. Rantala ES, Hernberg M, Kivelä TT. Overall survival after treatment for metastatic uveal melanoma: a systematic review and meta-analysis [published online for public access]. Melanoma Res. In press. doi:10.1097/CMR.0000000000000575
  8. Leonardi GC, Falzone L, Salemi R, et al. Cutaneous melanoma: from pathogenesis to therapy (review). Int J Oncol. 2018;52(4):1071-1080.
  9. Pasquali S, Hadjinicolaou AV, Chiarion SV, Rossi CR, Mocellin S. Systemic treatments for metastatic cutaneous melanoma (review). Cochrane Library website. https://www.cochranelibrary.com​/cdsr​/doi​/10.1002​/14651858.CD011123.pub2​/epdf​/full. Accessed August 20, 2019.
  10. Drugs approved for skin cancer. National Cancer Institute website. https://www.cancer.gov​/about-cancer​/treatment​/drugs​/skin#3. Updated October 17, 2018. Accessed July 29, 2019.
  11. Violanti SS, Bononi I, Gallenga CE, Martini F, Tognon M, Perri P. New insights into molecular oncogenesis and therapy of uveal melanoma. Cancers. 2019;11(5):E694. doi:10.3390/cancers11050694
  12. Carvajal RD, Schwartz GK, Tezel T, Marr B, Francis JH, Nathan PD. Metastatic disease from uveal melanoma: treatment options and future prospects. Br J Ophthalmol. 2017;101(1):38-44.
  13. Weis E, Salopek TG, McKinnon JG, et al. Management of uveal melanoma: a consensus-based provincial clinical practice guideline. Curr Oncol. 2016;23(1):e57-e64.
  14. Javed A, Arguello D, Johnston C, et al. PD-L1 expression in tumor metastasis is different between uveal melanoma and cutaneous melanoma. Immunotherapy. 2017;9(16):1323 -1330.
  15. Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;19(1):34. doi:10.1186/s13073-017-0424-2
  16. Qin Y, de Macedo MP, Reuben A, et al. Parallel profiling of immune infiltrate subsets in uveal melanoma versus cutaneous melanoma unveils similarities and differences: a pilot study. Oncoimmunology. 2017;6(6):e1321187. doi:10.1080/2162402X.2017.1321187
  17. Krishna Y, McCarthy C, Kalirai H, Coupland SE. Inflammatory cell infiltrates in advanced metastatic uveal melanoma. Hum Pathol. 2017;66:159-166.
  18. Rothermel LD, Sabesan AC, Stephens DJ, et al. Identification of an immunogenic subset of metastatic uveal melanoma [published online for public access]. Clin Cancer Res. 2016;22(9):2237-2249. doi:10.1158/1078-0432.CCR-15-2294
  19. Search of uveal melanoma—Results on map [map]. ClinicalTrials.gov website. https://clinicaltrials.gov​/ct2​/results​/map?cond=uveal+melanoma&map=. Accessed August 19, 2019.
  20. Search of cutaneous melanoma—Results on map [map]. ClinicalTrials.gov website. https://clinicaltrials.gov​/ct2​/results​/map?cond=Cutaneous+Melanoma&map=. Accessed August 19, 2019.
The information and other content contained on this website are not intended to be, nor should they be, used as medical advice, diagnosis, or treatment. Each patient must be evaluated, diagnosed, and treated based upon that individual patient’s specific circumstances.