Uncommon locations for melanoma and
Small bowel metastases
Please, could you try to figure out
some melanoma locations beyond the
skin and subcutaneous area?
Cardiac metastases from melanoma
Right atrium is the
most common site.
• Melanoma, anemia, abdominal lump
Metastases to small bowel: usually can be resected
Uveal melanoma: pathophysiology
% 5-year mts.
Conjuntival melanoma is related more with its
Predrag Jovanovic et al.
Int J Clin Exp Pathol 2013;6(7):12301244
Radiotherapy (plaque) and surgery
(enucleation) achieve the same
outcome…but not without harm
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
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
MAPK pathway: MEK
Protein kinase C (PKC)
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
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
• MEK inhibitors: (no response in wild-type GNAQ/GNA11)
– Selumetinib compared with temozolamide; 9 weeks benefit for
selumetinib for PFS
• PAK inhibitors: sotrastaurin (AEB071)/ enzastaurin.
– G1 cell cycle arrest
– Inhibition of PKC in GNAQ-mutant resulted in the inhibition of the
A combination of a MEK and proteinkinase inhibitor could be a
perfect therapeutic combination
• 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
5. MEK inhibitors and PAK inhibitors are key for
developing targeted therapies.