- 109 例肺类癌：AE1/AE3 高度可变（均 H 分 127/300）；17% 低表达（H<50），其中 3 例阴性；CAM5.2 类似，但 OSCAR / CK18 在所有 AE1/AE3 低/阴性例中仍明确阳性。
- 35% 弥漫 sustentacular（S100/SOX10）；15/18 例 AE1/AE3 低表达者伴 sustentacular——合计 14%（15/109）同时「低角蛋白 + sustentacular」，肠胰 NET 仅 2%。
- 这些病例均 GATA3/PHOX2B 阴性，而 TTF1、OTP 和/或 ASCL1 阳性；NGS 无副神经节瘤典型突变、多见肺类癌改变。
- 低 AE1/AE3 与 sustentacular、梭形细胞、外周部位及 ASCL1+/TTF1+/OTP+/HNF4A−「proneuronal」表型相关。鉴别副神经节瘤时：加做其他角蛋白 + OTP/GATA3 等器官特异性转录因子。
收录范围：PubMed 英文摘要及中文翻译（abstract-only）。原文为 Modern Pathology / ScienceDirect；Unpaywall 标 hybrid，但本站出口未见可用 PDF，未采集全文与图表。
摘要
支持细胞（sustentacular cell）的存在与角蛋白表达缺如，历来被视为区分副神经节瘤与神经内分泌肿瘤/类癌的诊断标志。然而文献与日常实践提示，肺类癌也可同时具备这两项特征。本研究评估该现象的发生率及其生物学相关。对 109 例肺类癌检测多种常用角蛋白（含 AE1/AE3）、sustentacular 标志（S100、SOX10）、肺类癌核标志（OTP、TTF1、ASCL1）与副神经节瘤标志（GATA3、PHOX2B），并行 505 基因二代测序。AE1/AE3 差异显著（均 H 分 127/300；SD 80），18 例（17%）低标记（H 分 <50），其中 3 例 AE1/AE3 阴性。CAM5.2 同样可变（均 H 分 105；SD 94），在 18 例 AE1/AE3 低表达中有 16 例呈低/阴性。相反，广谱角蛋白 OSCAR 与 CK18 总体更高（均 H 分分别为 253 与 264），且在所有 AE1/AE3 低/阴性例中均明确阳性。35% 的类癌可见弥漫 sustentacular 细胞；18 例 AE1/AE3 低表达类癌中 15 例含 sustentacular 细胞。总体 15/109（14%）肺类癌同时为 AE1/AE3 低表达且 sustentacular 阳性；肠胰神经内分泌肿瘤中仅 4/188（2%）见此组合。所有 AE1/AE3 低表达肺类癌均 GATA3、PHOX2B 阴性，而 TTF1、OTP 和/或 ASCL1 阳性。NGS 显示均无副神经节瘤典型突变，且多数携带肺类癌常见改变。值得注意的是，较低 AE1/AE3 与 sustentacular 细胞存在（S100：P=0.003；SOX10：P=0.005）、梭形形态、外周部位以及 ASCL1+/TTF1+/OTP+/HNF4A− 免疫表型相关——这一组合反映新兴的「proneuronal」类癌概念。结论：肺类癌并非「角蛋白阴性」，而是角蛋白可变，部分病例可因抗体选择而看似阴性；再叠加常见 sustentacular 细胞，可形成与副神经节瘤重叠的表型。建议在此鉴别诊断中加做其他角蛋白及肿瘤特异性转录因子（如 OTP、GATA3）。文中并讨论了肺类癌「副神经节瘤样」特征的潜在生物学含义。
- 109 lung carcinoids: AE1/AE3 highly variable (mean H-score 127/300); 17% low (H<50), including 3 negative; CAM5.2 similar, but OSCAR/CK18 unequivocally positive in all AE1/AE3-low/negative cases.
- Diffuse sustentacular cells in 35%; 15/18 AE1/AE3-low cases had sustentaculars — 14% (15/109) were both AE1/AE3-low and sustentacular+, vs 2% of enteropancreatic NETs.
- All AE1/AE3-low cases GATA3/PHOX2B− and TTF1/OTP and/or ASCL1+; NGS lacked paraganglioma-typical mutations and often showed lung-carcinoid alterations.
- Lower AE1/AE3 associated with sustentaculars, spindle morphology, peripheral location, and ASCL1+/TTF1+/OTP+/HNF4A− “proneuronal” phenotype. For the paraganglioma differential: add other keratins + OTP/GATA3.
Scope: PubMed abstract only. Modern Pathology / ScienceDirect; Unpaywall lists hybrid OA, but no usable PDF was obtained from this egress — full text and figures not collected.
Abstract
Sustentacular cell presence and the absence of keratin expression represent diagnostic hallmarks for distinguishing paragangliomas from neuroendocrine tumors/carcinoids. However, based on the literature and our practice, pulmonary carcinoids can exhibit both features. Here, we examined the prevalence and biological correlates of this phenomenon. Lung carcinoids (N = 109) were analyzed with several common keratins, including AE1/AE3, sustentacular cell markers (S100 and SOX10), nuclear markers of lung carcinoids (OTP, TTF1, and ASCL1) and paragangliomas (GATA3 and PHOX2B), and 505-gene next-generation sequencing. AE1/AE3 was strikingly variable (mean H score, 127 of 300; SD, 80), with 18 cases (17%) exhibiting low labeling (H score, <50), including 3 AE1/AE3-negative cases. CAM5.2 was similarly variable (mean H score, 105; SD, 94) and was low/negative in 16 of 18 AE1/AE3-low cases. Conversely, pan-keratin OSCAR and CK18 were higher overall (mean H scores, 253 and 264, respectively) and showed unequivocal positivity in all AE1/AE3-low/negative cases. Sustentacular cells were present diffusely in 35% of carcinoids, with 15 of 18 AE1/AE3-low carcinoids containing sustentacular cells. Overall, 15 of 109 lung carcinoids (14%) were AE1/AE3 low and sustentacular cell positive. In contrast, such features were seen in only 4 of 188 enteropancreatic neuroendocrine tumors (2%). All AE1/AE3-low lung carcinoids were GATA3 and PHOX2B negative, while TTF1, OTP, and/or ASCL1 positive. By next-generation sequencing, all cases lacked mutations typical of paragangliomas, and many harbored alterations typical of lung carcinoids. Notably, lower AE1/AE3 was associated with the presence of sustentacular cells (S100: P = .003; SOX10: P = .005), spindle morphology, peripheral location, and ASCL1+/TTF1+/OTP+/HNF4A- immunophenotype-the constellation reflecting the emerging concept of "proneuronal" carcinoids. We conclude that lung carcinoids are not keratin negative but instead keratin variable, and some may appear as negative in an antibody-dependent manner. Together with the common presence of sustentacular cells, this may yield a profile overlapping with paragangliomas. We suggest using additional keratins and tumor-specific transcription factors (eg, OTP and GATA3) as the updated approach for this differential diagnosis. Potential biological implications of paraganglioma-like features in lung carcinoids are discussed.