Supplementary Material for: Clinical Course of Histologically Proven Multifocal Micronodular Pneumocyte Hyperplasia in Tuberous Sclerosis Complex: A Case Series and Comparison with Lymphangiomyomatosis

<b><i>Background:</i></b> Multifocal micronodular pneumocyte hyperplasia (MMPH) is a rare pulmonary manifestation of tuberous sclerosis complex (TSC). Because of its rarity, no previous study has described the detailed clinical course of this disease. <b><i>Objectives:</i></b> This study aimed to clarify the longitudinal clinical characteristics of subjects with MMPH. <b><i>Methods:</i></b> Nine patients with MMPH diagnosed at Hokkaido University Hospital were retrospectively analyzed. Changes in computed tomography findings and pulmonary function were compared during the follow-up period. Serum levels of KL-6, surfactant protein (SP)-A, and SP-D were measured to clarify their potentials as blood biomarkers of the disease. Fourteen cases of lymphangiomyomatosis (LAM) were also included to compare their clinical characteristics with those of subjects with MMPH. <b><i>Results:</i></b> Of the 9 patients, 7 were female and 2 were male. The median age at diagnosis was 43 years (range, 19–56), and all cases were diagnosed following incidental abnormal radiographic findings. During the follow-up, 1 patient died of lung cancer, but others were radiographically stable and had stable pulmonary function. Serum levels of SP-A in 5 patients (mean, 146.4 ng/mL) and SP-D in 6 patients (mean, 337.3 ng/mL) were elevated in subjects with MMPH, whereas KL-6 levels were within the reference range (mean, 230 U/mL) in all patients. Levels of SP-A and SP-D were significantly higher in subjects with MMPH than those with LAM (<i>p</i> &lt; 0.05). <b><i>Conclusions:</i></b> Radiographic findings and pulmonary function were stable in all cases of MMPH. Serum SP-A and SP-D, but not KL-6, may be useful markers for suspicion of the presence of MMPH in patients with TSC.

<b><i>背景：</i></b> 多发性灶性结节性肺泡上皮细胞增生（Multifocal micronodular pneumocyte hyperplasia，MMPH）是结节性硬化症（Tuberous sclerosis complex，TSC）的罕见肺部表现。由于该疾病发病率极低，此前尚无研究阐述其详细临床病程。
<b><i>目标：</i></b> 本研究旨在明确MMPH患者的纵向临床特征。
<b><i>方法：</i></b> 回顾性分析北海道大学医院确诊的9例MMPH患者。对比随访期间的计算机断层扫描（Computed Tomography，CT）结果与肺功能变化。检测KL-6、表面活性蛋白（Surfactant Protein，SP）-A及SP-D的血清水平，以明确其作为该疾病血液生物标志物的潜力。另纳入14例淋巴管平滑肌瘤病（Lymphangiomyomatosis，LAM）病例，用于对比其与MMPH患者的临床特征。
<b><i>结果：</i></b> 9例患者中7例为女性，2例为男性。确诊时中位年龄为43岁（范围19~56岁），所有病例均因影像学检查偶然发现异常而确诊。随访期间，1例患者因肺癌死亡，其余患者影像学表现及肺功能均保持稳定。5例患者的血清SP-A水平（均值146.4 ng/mL）及6例患者的SP-D水平（均值337.3 ng/mL）均升高，而所有患者的KL-6水平均处于参考范围内（均值230 U/mL）。MMPH患者的SP-A及SP-D水平显著高于LAM患者（p < 0.05）。
<b><i>结论：</i></b> 所有MMPH病例的影像学表现及肺功能均保持稳定。血清SP-A与SP-D（而非KL-6）或可作为疑似TSC患者合并MMPH的有效辅助诊断标志物。