Melanoma can metastasize to various atypical locations beyond skin and subcutaneous tissues, with uveal melanoma being the most common primary eye malignancy. Key mutations in gnaq and gna11 are involved in 80% of uveal melanoma cases, influencing treatment options such as ipilimumab and targeted therapies like mek and pak inhibitors. Clinical outcomes show that ipilimumab provides over 30% one-year survival in metastatic cases, highlighting the need for further exploration of these mutations in therapeutic strategies.

1. Uncommon locations for melanoma and
uveal melanoma
2014
Lorenzo Alonso
Medical Oncology
www.foro-osler.com

2. Sinus
gingiva
intracardiac
Bronchial mucosa
Small bowel metastases
Genital/anal
subungueal
Toes/ sole
Please, could you try to figure out
some melanoma locations beyond the
skin and subcutaneous area?

3. Cardiac metastases from melanoma
Right atrium is the
most common site.

4. Clinical scenario
• Melanoma, anemia, abdominal lump
Metastases to small bowel: usually can be resected

5. Uveal melanoma: pathophysiology
Location
Iris
% 5-year mts.
%10-year mts
4%
7%
Ciliary body
19%
33%
Choroides
15%
25%
Conjuntival melanoma is related more with its
cutaneous counterpart
Predrag Jovanovic et al.
Int J Clin Exp Pathol 2013;6(7):12301244

6. Ocular melanoma: pathophysiology
Liver: 93% mts
Lung: 24% mts.
WHY?
Bones: 16% mts

7. Local treatment
Radiotherapy (plaque) and surgery
(enucleation) achieve the same
outcome…but not without harm

8. Uveal melanoma prognosis
Monosomy of chromosome 3 is the
most frequent chromosome aberration
in uveal melanoma (50%)
Class 1: low grade tumors with low metastatic risk
Class 2: high grade tumors with metastatic risk
chracterized by down-regulation of genes on
chromosome 3 and up-regulation of genes on
chromosome 8q.

9. BAP1: BCRA-1 associated protein-1 and metastatic
development of uveal melanoma
The gene encoding BAP-1 is located on chromosome
3p21.1 and is mutated in 80% of metastatic uveal
melanoma. BAP-1 is a enzyme that forms part of a
tumor-suppressor complex. BAP-1 mutation is associated
to metastatic behaviour

10. Uveal melanoma
Treatment options
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•
•
•
Ipilimumab
Chemotherapy: nanoparticles(taxanes)
MAPK pathway: MEK
Protein kinase C (PKC)

11. Ipilimumab in metastatic uveal melanoma
Outcome after compassionate use (USA, Italy):
1-year overall survival over 30%.
More common dose: 3 mg/Kg
Median overall survival 6 months (Italian use)
Toxicity experience and response similar to cutaneous

12. Uveal melanoma: rational for treatment
GNAQ and GNA11 are mutated in a mutually exclusive pattern (83% uveal):
these mutations are implicated in the stimulus of MAPK pathway via MEK.
GNAQ/GNA11 signals also via PLC(phospholipase C) and PKC (protein
kinase C), enzymes implicated in proliferation, invasion,apoptosis via ERK
Cancer Letters 2006;235:1-10

13. Therapeutic targets
• MEK inhibitors: (no response in wild-type GNAQ/GNA11)
– Selumetinib compared with temozolamide; 9 weeks benefit for
selumetinib for PFS
– MEK162
• PAK inhibitors: sotrastaurin (AEB071)/ enzastaurin.
– G1 cell cycle arrest
– Inhibition of PKC in GNAQ-mutant resulted in the inhibition of the
MAPK pathway.
A combination of a MEK and proteinkinase inhibitor could be a
perfect therapeutic combination

14. Conclusions
• 1. Metastases from melanoma can spread to almost
•
•
•
•
every anatomical location.
2. Uveal melanoma is the most common primary
malignancy of the eye
3. GNAQ and GNA11 are mutated in 80% of uveal
melanoma in a mutually exclusive pattern
4. Ipilimumab achieves a 30% survival in the first year in
uveal melanoma
5. MEK inhibitors and PAK inhibitors are key for
developing targeted therapies.