Pigmented Paraganglioid Carcinoid Tumors of the Lung: Spatial Transcriptomics Reveals Shared and Distinct Features with Typical Carcinoid Tumors and Extra-Adrenal Paragangliomas

Pigmented paraganglioid carcinoid tumors (PPCT) of the lung are a rare, underrecognized, and poorly characterized morphologic variant of pulmonary neuroendocrine tumors (NETs). While these tumors are usually diagnosed as typical carcinoid (TC) tumors, PPCT may represent a diagnostic challenge due to the histologic resemblance with extra-adrenal paraganglioma (PG). In this study, we aimed to comprehensively characterize the histomorphologic, immunophenotypic, and transcriptomic profiles of PPCT in comparison to TC and PG using spatially resolved transcriptomic analysis. Using a tissue microarray (TMA) composed of 38 tumors, including 20 TC, 16 PG, and 2 PPCT, we performed immunohistochemical (IHC) and digital spatial transcriptomic (GeoMx(R) DSP) profiling. The TMA included two punches and two regions of interest (ROIs) per case. Cellular transcriptomes were selected based on epithelial (PanCK+), sustentacular (S100+), and immune (CD45+) compartments. By IHC, PPCT retained neuroendocrine markers (synaptophysin, INSM1, chromogranin A) but showed decreased or absent pancytokeratin cocktail expression and increased number of sustentacular cells highlighted by strong expression of S100 and SOX-10, similar to PG. Expression of AE1/AE3 and CK8/18 confirmed their epithelial origin and helped distinguish them from PG. The transcriptome of PPCT clustered with that of TC but displayed distinct expression patterns in a small subset of genes. Although the sustentacular and immune compartments showed limited divergence, the epithelial compartment showed differentially expressed genes in PPCT including FABP5, MLPH, GPNMB, and SOX1, which indicate upregulation of melanocytic and neural crest markers. Gene set enrichment analysis (GSEA) revealed significant upregulation of pathways related to inflammation (e.g., TLR4-TRAF6-TAK1), PTEN trafficking, and inositol phosphate metabolism. PPCT show increased melanocytic pathway expression, which may explain the morphologic resemblance to PG.