EDINBURGH –Kinase fusions have been well described in hematologic malignancies and are the newest genetic aberration to be identified in Spitz tumors.
Kinase fusions are actually quite common in Spitzoid neoplasms, with 51% of Spitzoid tumors and melanomas harboring a kinase fusion in a recent analysis of 140 tumors (Nat. Commun. 2014;5:3116. doi:10.1038/ncommons4116 ).
The fusions were identified across the entire biological spectrum of Spitzoid neoplasms, including 55% of Spitz nevi, 56% of atypical Spitz tumors, and 39% of Spitzoid melanomas. Therefore, kinase fusions are not useful to distinguish benign from malignant tumors, study author Dr. Thomas Wiesner said at the 15thWorld Congress on Cancers of the Skin.
However, the kinase fusions were mutually exclusive, meaning that only one fusion activates the oncogenic pathway in a tumor. Small molecule kinase inhibitors have become mainstays of modern oncologic therapy in recent years and thus may be useful in Spitz tumors, which typically affect the young.
“These genetic aberrations represent targets for therapeutic interventions and offer investigational treatment options for patients with metastatic disease,” said Dr. Wiesner, a research associate at Memorial Sloan-Kettering Cancer Center in New York City.
ROS1 (c-ros oncogene 1) fusions were the most frequent in the series at 17% and have been shown in mouse models to respond to crizotinib (Xalkori). ALK fusions, present in 10% of tumors, are also sensitive to this drug.
“I think Spitzoid melanoma that is metastatic should be stained for ROS1 or ALK fusions because crizotinib might help these patients,” he said. “We have good evidence that it helps, at least in lung cancer and lymphoma.”
Other drugs target NTRK1 (neurotrophic tyrosine kinase receptor type 1) fusions, which were identified in 16% of Spitzoid tumors, and are in preclinical trials.
The researchers have also published a description of the morphological features that point to the underlying genetic aberrations (Am. J. Surg. Pathol. Jul 2014;38:925-33)). The study, involving 17 patients, aged 2 to 35 years, indicates that BAP1 loss and BRAF mutations are common in epithelioid Spitz tumors, HRAS mutations and gains of 11p are seen in desmoplastic Spitz nevi, while ALK fusions usually point to plexiform Spitz tumors, Dr. Wiesner said.
Clinicians can use the morphological features along with basic immunohistochemistry to identify the distinct subsets of tumors with BAP1 loss or ALK, NTRK1, or ROS1 fusions.
BAP1 loss Spitz tumors are important to identify because they are associated with a hereditary tumor syndrome very similar to Peutz-Jeghers or Muir-Torre syndrome, Dr. Wiesner said.
“When we see multiple epithelioid Spitz tumors in one patient, we have to think about a hereditary tumor syndrome,” he said at the meeting, sponsored by the Skin Cancer Foundation.