Impact of Next-generation Sequencing on Interobserver Agreement and Diagnosis of Spitzoid Neoplasms

Abstract

Atypical Spitzoid melanocytic tumors are diagnostically challenging. Many studies have suggested various genomic markers to improve classification and prognostication. We aimed to assess whether next-generation sequencing studies using the Tempus xO assay assessing mutations in 1711 cancer-related genes and performing whole transcriptome mRNA sequencing for structural alterations could improve diagnostic agreement and accuracy in assessing neoplasms with Spitzoid histologic features. Twenty expert pathologists were asked to review 70 consultation level cases with Spitzoid features, once with limited clinical information and again with additional genomic information. There was an improvement in overall agreement with additional genomic information. Most significantly, there was increase in agreement of the diagnosis of conventional melanoma from moderate (κ=0.470, SE=0.0105) to substantial (κ=0.645, SE=0.0143) as measured by an average Cohen κ. Clinical follow-up was available in all 70 cases which substantiated that the improved agreement was clinically significant. Among 3 patients with distant metastatic disease, there was a highly significant increase in diagnostic recognition of the cases as conventional melanoma with genomics (P<0.005). In one case, none of 20 pathologists recognized a tumor with BRAF and TERT promoter mutations associated with fatal outcome as a conventional melanoma when only limited clinical information was provided, whereas 60% of pathologists correctly diagnosed this case when genomic information was also available. There was also a significant improvement in agreement of which lesions should be classified in the Spitz category/WHO Pathway from an average Cohen κ of 0.360 (SE=0.00921) to 0.607 (SE=0.0232) with genomics.

Next‐generation sequencing improves agreement and accuracy in the diagnosis of Spitz and spitzoid melanocytic lesions

“…Of the total 70 cases, there were three (Cases 6, 11, and 47) in which the clinical follow‐up was that of either distant metastasis (Cases 11 and 47) or clinically bulky local metastasis (Case 6), indicating an unequivocally malignant tumor. The details of these cases are described in another study 3 . The genomic information provided in Survey 2 helped in the identification of these cases as being malignant melanomas (Figure 2).…”

“…A set of 70 previously sequenced cases composed of melanocytic neoplasms with spitzoid morphologic features was used. All cases were sequenced for research purposes and were the same set of cases as those evaluated by the melanoma experts in the study referenced previously 3 . Of note, 52 of the 70 cases contained a canonical structural variant including a Spitz‐associated genomic fusion ( n = 50) or HRAS mutation ( n = 2) as defined by the fourth edition of the WHO Classification of Skin Tumors 1 .…”

“…A recent study obtained diagnoses for a group of 70 spitzoid melanocytic neoplasms from 20 pathologists considered experts in melanoma pathology before and then again after having access to NGS studies with genomic data on the tumors 3 . In that study, there was improved inter‐rater agreement and accuracy following addition of the NGS data 3 .…”

“…A recent study obtained diagnoses for a group of 70 spitzoid melanocytic neoplasms from 20 pathologists considered experts in melanoma pathology before and then again after having access to NGS studies with genomic data on the tumors 3 . In that study, there was improved inter‐rater agreement and accuracy following addition of the NGS data 3 . The purpose of this current study was to test this same hypothesis in a broader group of dermatopathologists and general pathologists using participants in the Dermpedia (http://www.dermpedia.org) dermatopathology online CME course.…”

Conceptual Evolution and Current Approach to Spitz Tumors

“…Many studies are currently in progress. Next-generation-sequencing assays may be beneficial in improving interobserver agreement of challenging Spitz neoplasms and improve diagnosis and prognostication of these tumors [ 47 , 48 ]. Hopefully, future investigations will provide better understanding of Spitz tumors, suggesting new, more efficient approaches for this category of controversial tumors.…”