Ever since the first description of SN by Sophie Spitz in 1948 pathologists and dermatopathologists in particular have been struggling with the distinction between SN and SMM. To diagnose a young child with melanoma, which has devastating consequences, and subject the child to surgery and chemotherapy is not a simple matter. Imagine if you were the parent of that child?
Spitzoid neoplasms are melanocytic lesions that include a spectrum ranging from completely benign “typical” SN to malignant melanomas that show “Spitzoid” features –”Spitzoid” malignant melanomas (SMM). The gold standard for diagnosing SN and differentiating it from SMM is histopathologic examination applying well-established criteria. However, there are melanocytic lesions, which show conflicting histopathologic criteria and the distinction between a benign SN and SMM may be extremely difficult. These lesions are referred to as “Atypical SN” or “Atypical Spitzoid tumors/neoplasms”.1–4
There is a great interobserver variability and discordance even among expert dermatopathologists regarding Spitzoid neoplasms.2, 5–8
Ancillary techniques such as Comparative genomic hybridization (CGH) and Fluorescent in situ
hybridization (FISH) may be helpful. The majority of SN reveal no DNA copy number changes by CGH.9–11
Approximately 20% of SN show an isolated gain of chromosome11p.9
A subset of SN with 11p copy number increases has HRAS mutation; however, that is extremely uncommon in cutaneous melanoma.12, 13
In contrast, more than 95% of conventional melanomas show multiple chromosomal aberrations including gains and loses by CGH.14, 15
B-RAF mutations have been found only in a small subset of SN whereas the majority of conventional melanomas have B-RAF or N-RAS mutations.16
Furthermore, activating hotspot mutations in the B-RAF, N-RAS, and H-RAS genes were not identified in SMM or SN.17, 18
This data suggests that SMM might be a distinct form of melanoma with unknown genes and/or signaling pathways involved in its development.17, 19, 20
Matrix-assisted laser desorption ionization (MALDI) Imaging Mass Spectrometry (IMS) is a powerful method for analyzing metabolites, peptides and proteins, DNA segments, and lipids directly from tissue sections with spatial fidelity. Although gene expression is useful for distinguishing melanocytic nevi from melanomas, it does not always correlate with protein translation and does not account for post-translational modification (PMT). However, both protein expression level and PTM state have fundamental effect on cellular function or dysfunction, therefore, it is more meaningful to analyze proteins and peptides that are involved in the development and progression of diseases, especially cancer. IMS has the ability to discover molecular signatures of diseases and cancer. These molecular signatures are typically comprised of 5–20 different proteins that together result in robust diagnostic patterns.21, 22
IMS-based studies have been used to elucidate molecular signatures of different tumor types and grades including brain, oral, lung, breast, gastric, pancreatic, renal, ovarian and prostate cancer.23–26
The presence of a grey area, in which it is extremely difficult or utterly impossible to distinguish between SN and SMM, prompted this investigation. Since both SN and SMM are composed of large epithelioid cells with abundant cytoplasm containing ample amount of proteins, we hypothesized that there were proteomic differences, which might be able to differentiate between the two groups. We applied IMS to find specific proteomic markers to aid in the diagnosis of SN and SMM.