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New trends in cystic lung diseases

Presented by
Prof. Cormac McCarthy, University College Dublin, Ireland
ERS 2022

The progress of 3 common diffuse cystic lung diseases (DCLDs) was discussed, including lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis (PLCH), and Birt-Hogg-Dubé syndrome (BHD). LAM cells were found that could serve as a diagnostic marker and VEGF-D has proven to be a distinctive biomarker for LAM. BRAF mutations in patients seem an indicator for PLCH and smoking cessation is an important intervention. FLCN mutations may offer a lead into the pathogenic mechanisms to be targeted in BHD. Finally, future research should focus on the common pathogenesis in DCLDs.

“DCLDs are pathophysiologically distinct entities that share a common phenotypic manifestation of thin-walled cysts on chest radiology,” explained Prof. Cormac McCarthy (University College Dublin, Ireland) at the start of his presentation titled ‘New trends in cystic lung diseases’ [1]. The thin-walled cysts are usually less than 2 mm thick and are interfaced with normal lung tissue. In general, high-resolution CT imaging is needed to analyse the cyst characteristics [2]. “Recently, data that may improve prognostication and guidelines for patients with DCLD has become available,” said Prof. McCarthy. “Today I will be discussing the progress we have made in 3 of the more common DCLDs, namely LAM, PLCH, and BHD.”
Underlying causes of DCLDs

It is important to distinguish between the underlying causes of DCLDs, because of the different approach that is required for the different conditions; family screening is indicated for BHD, neoplastic monitoring is indicated for LAM and BHD, various lifestyle modifications are recommended for patients with LAM or PLCH, and the prognoses of the diseases are different. Prof. McCarthy added that measuring VEGF-D levels and detecting FLCN mutations are non-invasive lab tests to distinguish LAM and BHD, respectively, from other DCLDs. “The use of these lab tests may avoid invasive testing in our patients with DCLDs.”
How to handle pneumothorax

Spontaneous pneumothorax is common in patients with LAM (>50%), BHD (25–75%), and PLCH (15–30%). Importantly, after the first presentation of pneumothorax, the recurrence rate of spontaneous pneumothorax is >70% in patients with LAM and BHD, and approximately 60% in patients with PLCH. If pleurodesis is offered, the recurrence rates drop to 30‒35% in patients with LAM or BHD and to 15‒20% in patients with PLCH, resulting in a cost benefit and a mortality benefit [3–5]. “Therefore, it is crucial that pleurodesis is offered on the first presentation of spontaneous pneumothorax in patients with these conditions,” emphasised Prof. McCarthy. In addition, a study by Gupta et al. showed that screening for DCLDs in patients with spontaneous pneumothorax via high-resolution CT is a cost-effective approach to detect patients with DLCDs [6].

LAM involves systemic, low-grade metastasising neoplasm and may occur sporadic or in association with tuberous sclerosis complex (TSC-LAM). Furthermore, TSC mutations lead to mTOR activation, which drives clonal, neoplastic proliferation of smooth muscle-like cells [7]. Recently, it has been demonstrated that LAM cells, migrating to the lungs, are likely to come from the uterus [8]. “The uniquely identified LAM cells in this study may serve as a diagnostic marker and therapeutic target in the future,” added Prof. McCarthy.

An important development is the investigation of serum VEGF-D in women with TSC as a biomarker for the presence of LAM. On CT imaging, conditions like LAM, PLCH, and Sjögren’s syndrome may mimic each other, but VEGF-D is a distinctive biomarker for LAM, saving biopsies and other invasive tests in 70% of patients [9,10]. In addition, it has been demonstrated that LAM and angiomyolipomas occur more frequently in women with TSC and TSC2 mutations compared with those harbouring TSC1 mutations [11]. Furthermore, higher VEGF-D levels (>600 pg/mL), lower baseline diffusing capacity of the lungs for carbon monoxide (DLCO), and a pre-menopausal status have been associated with a faster disease progression [12,13]. Finally, regarding the treatment of this condition, sirolimus has been approved as the first therapy for patients with LAM, based on the results of the MILES trial (NCT00414648) [14]. Recently, it has been demonstrated that administration of this agent reduces the 5-year probability of pneumothorax recurrence with 80% [15].
Pulmonary Langerhans cell histiocytosis

“It has been shown that 50% of patients with the smoking-related disease PLCH harbour BRAF mutations in the myeloid/monocyte lineage,” continued Prof. McCarthy.” This finding is pathologically relevant for the molecular mechanisms behind the disease and may lead to treatment targets for this disease in the future. Also, smoking cessation is the most important intervention to treat this condition [16‒18]. Although a recent French study has demonstrated that the survival of patients with PLCH is comparable with that of the general French population, those with pulmonary hypertension and/or chronic respiratory failure had a worse prognosis [19]. “Therefore, screening for pulmonary hypertension is important in patients with PLCH,” argued Prof. McCarthy. Finally, a study showed that, like in patients with LAM, loss of heterozygosity for TSC2 was common in patients with PLCH, indicating that this may be a treatment target in the future [20].
Birt-Hogg-Dubé syndrome

BHD is a genetic syndrome, characterised by diffuse cystic lung disease and an increased risk for renal tumours. “Approximately 30% of patients will develop a renal tumour in their lifetime,” added Prof. McCarthy. Recently, several FLCN mutations have been associated with the risk of pneumothorax, offering a lead into pathogenic mechanisms that may be targeted in patients with BHD. Also, it has been reported that younger patients with a first spontaneous pneumothorax are at higher risk for recurrent pneumothorax than older patients [21].

Finally, constitutive activation of transcription factor EB (TFEB) by mTORC1 may be the missing link between BHD, TSC, and other DCLDs, a recent study in Nature displayed [22]. “Are TSC and the mTOR pathway the key in understanding the common pathogenesis in DCLDs?,” wondered Prof. McCarthy at the end of his presentation. Answering this question is an important target for future research and may lead the field to new heights.

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