福嶋 敬宜

Cancer-stromal interactions play important roles in the biology of various cancers, including lung adenocarcinoma. We aimed to comprehensively analyze the lung cancer interactome and identify the key ligand-receptor pairs involved in the aggressiveness of lung adenocarcinoma. Transcriptome data were obtained from xenografts of 11 lung cancer cell lines that represented the major driver mutations in lung adenocarcinomas. A quantitative dataset was constructed in both stroma-to-cancer and cancer-to-stroma directions using the cancer-stromal interactome analysis method. The prognostic value of each factor was evaluated using multiple datasets. Analysis of 24,250 stroma-derived mouse transcripts and 26,289 human cancer-derived transcripts identified 1150 cancer-stromal interactions, from which we selected 117 interactions based on the intensity score of ligand-stromal transcript levels. Further prognostic analysis using public databases led us to identify 21 ligand-receptor pairs, including well-known as well as less well-characterized ligand-receptor pairs. Therefore, we selected tumor necrosis factor superfamily member 12/tumor necrosis factor receptor superfamily member 12A as possible factors contributing to the aggressiveness of lung adenocarcinoma via cancer-stromal interactions; immunohistochemical analysis confirmed that these factors were expressed mainly in the stroma and cancer cells, respectively, in both xenografts and primary lung adenocarcinoma. In human clinical specimens, high tumor necrosis factor receptor superfamily member 12A expression significantly correlated with tumor size, invasive diameter, and stage. Thus, tumor necrosis factor superfamily member 12 and its receptor tumor necrosis factor receptor superfamily member 12A signaling axis may be potential candidates for therapeutic intervention for lung adenocarcinoma.

BACKGROUND/AIMS: Although endoscopic diagnosis of primary small intestinal lymphoma (PSIL) is important, the association between endoscopic findings and histologic types remains unclear. This study aimed to evaluate the diagnostic accuracy of endoscopic classifications and biopsies in PSIL. METHODS: We retrospectively reviewed 100 lesions from 49 patients with PSIL who underwent double-balloon enteroscopy between 2005 and 2020. Endoscopic findings were classified into six macroscopic types: polypoid, ulcerative, multiple nodules, diffuse, concentric stenosis, or unclassified. RESULTS: Of the 100 lesions, 47 were multiple nodules, 32 were ulcerative, 8 were polypoid, 7 were diffuse, 4 were concentric stenosis, and 2 were unclassified. Diffuse large B-cell lymphoma (DLBCL) was mainly ulcerative (72%) or polypoid (75%), whereas follicular lymphoma appeared as multiple nodules (98%) or concentric stenosis (100%) (p<0.001, Cramér's V=0.41). The ulcerative type was associated with DLBCL (sensitivity, 0.74; specificity, 0.87), and multiple-nodule type were associated with follicular lymphoma (sensitivity, 0.75; specificity, 0.97). The overall diagnostic yield of the biopsy was 95%. Interobserver agreement was substantial (κ=0.69; agreement, 78%). CONCLUSIONS: Endoscopic findings were significantly associated with histologic types. Endoscopic findings and biopsies provide a high diagnostic yield, supporting their central role in the diagnostic management of PSIL.

Large cell neuroendocrine carcinoma (LCNEC) is a neuroendocrine carcinoma (NEC) of the lung that is characterized by its heterogeneous morphology, diverse immunophenotypes, and complex genomic profiles. Among LCNECs, a subset expressing the transcription factor POU2F3 (LCNEC-P) has been suggested to share similarities with small cell lung carcinoma (SCLC)-P, a subtype of SCLC defined by POU2F3 expression. However, the specific characteristics of LCNEC-P have not been fully elucidated. Therefore, the aim of the present study is to clarify the clinicopathological, immunohistochemical, and genetic characteristics of LCNEC-P. Fifty-six LCNEC cases were analyzed, including 12 LCNEC-P and 44 LCNEC-non-P cases. Morphologically, LCNEC-P exhibited significantly lower cytomorphology scores, indicating a resemblance to SCLC. Immunohistochemically, LCNEC-P showed the lower expression of neuroendocrine markers (SYP, CHGA, and INSM1), but the higher expression of C-MYC than LCNEC-non-P. A strong mutually exclusive expression pattern was observed between POU2F3 and ASCL1/NEUROD1. Whole-genome sequencing of 20 cases revealed that LCNEC-P harbored RB1 mutations in 100 % of cases, which was significantly higher than in LCNEC-non-P (40 %). FGFR1 amplification was observed in 60 % of LCNEC-P cases, representing a higher prevalence than previously reported for LCNEC. In addition, LCNEC-P showed a distinct copy number alteration profile, including frequent 20q13 amplification, compared with LCNEC-non-P. These results demonstrate that LCNEC-P represents a distinct subgroup of LCNEC that is characterized by a specific morphological, immunohistochemical, and genetic profile, closely resembling SCLC-P. This study provides insights into the biology of LCNEC-P and supports its classification as a unique entity within LCNEC.

Acquired cystic kidney disease-associated renal cell carcinoma (ACKD-RCC) can develop in the kidneys of patients with chronic kidney disease, particularly those on long-term dialysis, and displays morphologic diversity. We present a 70-year-old man with acquired cystic disease who developed 3 discrete tumors, each with different morphology. The patient had been on hemodialysis for 22 years and underwent right nephrectomy for a newly detected kidney mass. Histopathology and immunohistochemistry revealed 3 discrete tumors: a superior polar tumor displaying classic ACKD-RCC architecture with PAX8, AMACR, and KRT7 expression; an inferior polar tumor displaying ACKD-RCC morphology combined with a high-grade sarcomatoid component with PAX8 expression without AMACR and KRT7, consistent with dedifferentiation; and a midkidney tumor consisting mainly of bland spindle cells in fascicles with PAX8 and focal KRT7 expression confirming its epithelial origin, and negative mesenchymal and melanocytic markers excluding mimics, leading to a diagnosis of renal cell carcinoma (RCC), not otherwise specified (NOS). The patient developed pulmonary and bone metastases postoperatively and died of the disease 3 months later. The synchronous occurrence of conventional ACKD-RCC, a dedifferentiated sarcomatoid form, and a spindle cell RCC, NOS demonstrate the marked morphological heterogeneity of neoplasia in ACKD. The presence of both sarcomatoid and spindle cell histologic patterns is associated with an aggressive clinical course, highlighting the importance of intensive surveillance and thorough pathological evaluation of kidney masses in patients on long-term dialysis.

Pathologic potassium (K+) deficiency causes kidney inflammation and injury, known as hypokalemic nephropathy (HN), the underlying pathogenesis of which is obscure. NLR family pyrin domain-containing 3 (NLRP3) inflammasomes are platforms that sense the reduction of intracellular K+, engaging inflammation and tissue injury. The present study investigated whether or not systemic K+ deficiency induces NLRP3 inflammasome activation in HN. Clinically diagnosed HN in humans manifested up-regulation of NLRP3 and apoptosis-associated speck-like protein-containing a CARD (ASC) in the kidney epithelia. A K+ depletion model in mice demonstrated that kidney-resident NLRP3 and ASC play key roles in triggering early inflammation in HN kidneys. Unexpectedly, the K+ depletion-induced kidney inflammation was not dependent on inflammasome activation. A single-cell RNA-sequencing analysis revealed ASC up-regulation, NF-κB activation, and an increased level of tumor necrosis factor-like weak inducer of apoptosis receptor fibroblast growth factor-inducible 14 (FN14) in the HN kidneys, primarily in the distal nephron/collecting duct epithelial cells. Although kidney epithelial cells did not drive NLRP3 inflammasomes, NLRP3 and ASC alternatively enhanced with-no-lysine kinase-dependent NF-κB signaling in response to tumor necrosis factor-like weak inducer of apoptosis under a low-K+ milieu. These findings indicate a unique proinflammatory cascade mediated by NLRP3 and ASC beyond the framework of inflammasomes, which broadens the understanding of electrolyte-associated immunity in the kidney.