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

Abstract

Background: 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. Objectives: This study aimed to clarify the longitudinal clinical characteristics of subjects with MMPH. Methods: 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. Results: 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 (p < 0.05). Conclusions: 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.

Pulmonary manifestations in tuberous sclerosis complex

“…However, it is difficult to ascertain the exact prevalence of MMPH in TSC, as the differential diagnosis of nodules is broad, and most TSC patients with nodules are given a presumptive diagnosis of MMPH without undergoing histopathological confirmation. The presence of MMPH has no known physiological or prognostic consequences, with available literature suggesting an overall stable disease course (Konno et al, 2018). …”

Serum SP-A and KL-6 levels can predict the improvement and deterioration of patients with interstitial pneumonia with autoimmune features

“…In Japan, serum SP-A and KL-6 levels are widely used as biomarkers for the diagnosis, severity assessment and prognosis prediction of ILD patients [9]. These ndings collectively indicate that serum SP-A and KL-6 can act as a surrogate markers for the active process of disease progression [26,27]. However, it is not known whether changes in SP-A and KL-6 levels, especially in the serum of patients with IPAF, can re ect the correlation between the changes in and the progression of IPAF patients.…”

Familial multifocal micronodular pneumocyte hyperplasia with a novel splicing mutation in TSC1: Three cases in one family

“…MMPH is a mild disease [2, 31] and cannot be diagnosed unless CT is performed. Thus, familial aggregation may have been overlooked.…”

“…TSC patients require lifelong follow-up for potentially life-threatening complications, such as AML, LAM, and subependymal giant cell astrocytoma [35, 36], although MMPH itself has a limited effect on respiratory symptoms and respiratory function [2, 31]. Thus, early detection of TSC is crucial for all patients.…”