Clinical, morphologic, and genomic findings in ROS1 fusion Spitz neoplasms

Abstract

The presence of a characteristic chimeric fusion as the initiating genomic event is one defining feature of Spitz neoplasms. Characterization of specific subtypes of Spitz neoplasms allows for better recognition facilitating diagnosis. Data on clinical outcomes of the specific tumor types may help in predicting behavior. In this study we present the largest series to date on ROS1 fusion Spitz neoplasms. We present the clinical, morphologic and genomic features of 17 cases. We compared the morphologic features of these 17 cases to a cohort of 99 other non- ROS1 Spitz neoplasms to assess for features that may have high specificity for ROS1 fusions. These tumors consisted of 10 Spitz nevi and 7 Spitz tumors. None of the cases met criteria for a diagnosis of Spitz melanoma. Morphologically, the ROS1 fusion tumors of this series were characterized by a plaque-like or nodular silhouette, often densely cellular intraepidermal melanocyte proliferation, frequent pagetosis, tendency towards spindle cell cytomorphology, low grade nuclear atypia and floating nests with occasional transepidermal elimination. However, there was a significant range in microscopic appearances, including two cases with morphologic features of a desmoplastic Spitz nevus. Different binding partners to ROS1 were identified with PWWP2A and TPM3 being the most common. No case had a recurrence or metastasis. Our findings document that most ROS1 fusion Spitz neoplasms have some typical characteristic microscopic features, while a small proportion will have features overlapping with other genomic subtypes of Spitz neoplasms. Preliminary evidence suggests that they tend to be indolent or low grade neoplasms.

An Update on Molecular Genetic Aberrations in Spitz Melanocytic Proliferations: Correlation with Morphological Features and Biological Behavior

“…Nonetheless, large cells were described in 9 of 11 ROS1 fused Spitz neoplasms in a study by Wiesner et al (2), and up to 8 mitoses per square millimeter were reported in a study of such proliferations by Donati et al (65) Immunohistochemistry for ROS1 protein is a reliable surrogate for molecular testing (Figure 3c). Studies have confirmed that the vast majority (97.4%) of Spitz melanocytic proliferations harboring ROS1 fusions display ROS1 cytoplasmic positivity on immunohistochemistry (2,32). It is important to note, though, that immunohistochemical staining is often weak yet diffuse.…”

“…In addition to solitary lesions with typical desmoplastic Spitz nevus morphology, other melanocytic proliferations with HRAS mutations and/or 11p gain have also been described, including agminated Spitz nevi with or without associated nevus spilus (25)(26)(27)(28), recurrent Spitz nevi (30), melanocytic nevi with deep penetrating nevus-like morphology (21), pseudogranulomatous Spitz nevi (31) and a combination of syringocystadenoma papilliferum, tubular adenoma and a Spitz nevus (24). Moreover, the desmoplastic Spitz nevus phenotype is not restricted to HRAS mutated lesions since rare Spitz nevi harboring ROS1, ALK or even a BRAF fusion exhibiting a desmoplastic Spitz nevus morphology have been described (2,32).…”

“…ROS1 protooncogene resides on chromosome 6q22.1 and, like ALK, encodes a protein receptor tyrosine kinase that is part of the intracellular signaling pathways Ras-Raf-MEK-ERK, JAK3-STAT3, and PI3K-AKT-mTOR. (64) ROS1 fusions have been found in a variety of tumors, including non-small cell lung carcinomas, glioblastomas, pediatric gliomas, cholangiocarcinomas, inflamma- (2,32,65). The junctional melanocytic component is frequently prominent, with floating nests or trans-epidermal elimination of melanocytic nests, often colonizing the epithelium of skin adnexa (Figure 3) (32,65).…”

“…(64) ROS1 fusions have been found in a variety of tumors, including non-small cell lung carcinomas, glioblastomas, pediatric gliomas, cholangiocarcinomas, inflamma- (2,32,65). The junctional melanocytic component is frequently prominent, with floating nests or trans-epidermal elimination of melanocytic nests, often colonizing the epithelium of skin adnexa (Figure 3) (32,65). Kamino bodies seem to be more frequently present in ROS1 fused Spitz melanocytic proliferations, along with signs of maturation, lack of high-grade cytological atypia, lack of large cells, and fewer mitoses -all statistically significant features differing between ROS1 and non-ROS1 Spitz neoplasms in a study by Gerami et al (32).…”

“…The junctional melanocytic component is frequently prominent, with floating nests or trans-epidermal elimination of melanocytic nests, often colonizing the epithelium of skin adnexa (Figure 3) (32,65). Kamino bodies seem to be more frequently present in ROS1 fused Spitz melanocytic proliferations, along with signs of maturation, lack of high-grade cytological atypia, lack of large cells, and fewer mitoses -all statistically significant features differing between ROS1 and non-ROS1 Spitz neoplasms in a study by Gerami et al (32). Nonetheless, large cells were described in 9 of 11 ROS1 fused Spitz neoplasms in a study by Wiesner et al (2), and up to 8 mitoses per square millimeter were reported in a study of such proliferations by Donati et al (65) Immunohistochemistry for ROS1 protein is a reliable surrogate for molecular testing (Figure 3c).…”