naling protein that impacts the mTOR, E-cadherin, LKBP1, and AMPK signaling pathways [124–127]. A proposed mechanisms of cyst formation is decreased structural integrity along the alveolar septal junctions due to dysregulation of key intercellular adhesion pathways, which renders them susceptible to mechanical damage during the respiratory cycle [124, 125].

Pathological and Radiographic Characteristics

Cysts in BHD are typically thin-walled, often with elliptical or oblong shape, and are predominantly located within the basilar segments (Fig. 20.3) [128]. Cysts tend to abut the pleura and pulmonary vessels [128]. In a study of 229 cysts from 50 patients with BHD, 88% involved interlobular septa and 14% contained intra-cystic structures [125]. On histological evaluation, the cysts are lined by pneumocytes, and surrounded by normal lung parenchyma, without evidence for cellular in l- tration or infammation [125], which distinguishes them from LAM and PLCH, but not from the air-­ lled, histologically bland structures that are characteristic of emphysema.

Diagnostic Approach

A spontaneous pneumothorax in a young patient should raise the suspicion of BHD. A thorough skin examination is important, as many (but not all) patients with BHD will have characteristic papular, waxy skin lesions of the face, neck, or upper trunk. Skin biopsy can be useful in patients with skin lesions and a spontaneous pneumothorax, as the nding of the characteristic hair follicle tumors, brofolliculomas or trichodiscomas, is diagnostic for BHD in the right clinical context [122].

HRCT is highly useful in the initial evaluation of a patient with suspected pulmonary BHD. Approximately 80–100%

of patients with BHD have pulmonary cysts [121, 122, 124], and their characteristic features and distribution can strongly suggest the diagnosis. A de nitive diagnosis typically requires a family history of a con rmed case, tissue con r- mation from kidney or skin biopsy, or genetic testing.

Abdominal imaging of the kidneys is useful for identifying BHD-associated renal masses and tracking their growth trajectory. The most common renal neoplasms in BHD are chromophobe adenomas and oncocytomas, and they are bilateral and multifocal in more than half of patients [129]. Approximately 20–30% of patients with BHD will develop renal cell carcinoma [121, 130, 131] at a mean age of 46 years (range 20–83 years) [132]. Other renal malignancies such as clear cell, papillary, and mixed pattern carcinomas can also occur [129, 133, 134]. In patients who develop early onset (<50 years old) multifocal or bilateral renal cancer, the diagnosis of BHD should be strongly considered [130].

Not all patients with pulmonary manifestations of BHD will have a positive family history or classical skin or renalndings [117, 135, 136]. Genetic counseling and testing for FLCN mutations should be recommended to patients suspected to have BHD to con rm the diagnosis and to facilitate screening of family members.

Prognosis andManagement

BHD does not commonly progress to respiratory failure. In a study of patients with BHD, pulmonary function tests revealed a mild reduction in diffusion capacity for carbon monoxide, but there was little evidence of lung function decline over time [137]. Due to frequent recurrences, pleurodesis after the rst pneumothorax should be considered [121]. Air travel is generally safe [138], although reports of delayed pneumothorax have emerged [139], and patients with a prior pneumothorax, extensive cystic changes, or new/ worsening chest symptoms should be evaluated by a pulmonologist prior to travel [140].

Patients with a diagnosis of BHD should be screened for the presence of renal tumors beginning at 20 years of age [130, 141]. Ultrasonography is not recommended for screening as it lacks sensitivity for detecting small lesions [142]. MRI is superior to CT for serial screening to avoid the cumulative radiation from CT scans [141]. If there are no abnormalities on the initial scan, imaging should be repeated within 3 years [141]. Renal cancer associated with BHD is indolent and with proper screening and early diagnosis, development of metastases is rare [130]. Resection is recommended for tumors >3 cm as the risk of metastasis increases with tumor size [130, 141].

Lymphoproliferative Disorders

Fig. 20.3  Patient with Birt-Hogg-Dubé. CT imaging showing discrete cysts that are located in the middle and lower lung zones

Lymphocytic Interstitial Pneumonia/Follicular

Bronchiolitis

Lymphocytic interstitial pneumonia (LIP) is characterized by lymphocytic in ltration of the lung parenchyma, airways, vessels, and other structures [143]. Follicular bronchiolitis (FB) is a form of LIP in which there is lymphoid follicular hyperplasia that is centered on airways, vessels, and interlobular septa in a lymphatic distribution [144]. LIP can be idiopathic or associated with an underlying condition. Autoimmune/rheumatological disorders, such as Sjögren syndrome (SjS), rheumatoid arthritis (RA), or systemic lupus erythematosus (SLE), viral infections due to human immunode ciency virus (HIV) or Epstein-Barr virus, or immunode ciencies, such as common variable immune de ciency (CVID), are the most common conditions associated with LIP [145]. Among rheumatological disorders, SjS has the highest association with both LIP and FB.

Pathogenesis

FB and LIP represent a spectrum of lymphocytic in ltration from a concentration in bronchus-associated lymphoid compartments to extensive cellular expansion of the interstitium withbrosis. The factors that lead to recruitment and targeting of lymphocytes to the lung are unknown, as are those that lead to destructive lung remodeling. Post-obstructive bronchiolar ectasia, ischemia from vascular obstruction, and bronchiolar compression by lymphoid tissues resulting in subsegmental infation due to ball valve physiology have all been suggested as the mechanisms for the cystic changes found in LIP and FB [146].

Pathological and Radiographic Characteristics

LIP is characterized by expansion of all pulmonary structures with lymphocytes (both T and B cells) mixed with variable numbers of plasma cells, while the de ning histological feature in FB is peribronchial and peribronchiolar lymphoid follicles with reactive germinal centers [147]. Classically, LIP presents as a diffuse interstitial lung disease, with or without FB and cystic changes. This review is focused on the diffuse cystic changes that occur with little or no interstitial change in LIP and FB. Pathologically the cysts associated with FB are of varying size, contain internal septations, and can be associated with eccentric vessels [148].

Radiographically, the cysts in both LIP and FB are randomly distributed, variable in size, and often contain internal structures [149]. The internal cystic structures can assume the appearance of disappearing lung [150] and can be useful for distinguishing LIP and FB from other forms of DCLD. In addition to cysts, it is not uncommon to nd ground-glass opacities, reticular changes, and centrilobular nodules on HRCT (Fig. 20.4) [151].

Diagnostic Approach

Patients with LIP and FB can be asymptomatic but typically present with nonspeci c symptoms, such as cough, dyspnea,

Fig. 20.4  Patient with Sjogren syndrome and follicular bronchiolitis. CT imaging showing multiple cysts, some with internal structures and associated ground-glass opacities

weight loss, fever, and fatigue. Pulmonary function tests in LIP that presents as diffuse ILD commonly show a restrictive defect with a reduced DLCO [145], while the PFT pattern in FB with diffuse cystic change is characterized by an obstructive pattern with a reduced DLCO [152].

Characteristic diffuse cystic change on CT in nonsmoking patients with a known rheumatologic disease, such as RA, SLE, or SjS (or even in patients who do not meet strict criteria for these diseases but who have convincing sicca complex or positive serologic studies), is considered to be diagnostic for FB, and biopsy is not recommended. To establish the diagnosis of LIP/FB in patients who do not have the features required for a con dent clinical diagnosis, a biopsy may be required. Transbronchial biopsy in LIP/FB has a low yield and surgical lung biopsy is typically required [145]. Bronchoscopic cryobiopsy is an emerging technique that has future promise as a nonsurgical approach to diagnosis in diseases that have a bronchovascular distribution, like FB. Evaluation of the specimen by an expert pathologist is required to rule out malignant lymphoproliferative disorders [146].

Prognosis andManagement

Improvement or stabilization of nodules and ground-glass opacities with corticosteroid treatment and/or immunosuppressive medications has been reported in patients with LIP; however, the effect of these treatments on progressive cystic change is less clear [145, 153]. In patients with HIV, ­treatment with anti-retroviral medications has resulted in clinical and radiological resolution in some cases of LIP [153].

Cystic lung disease in the presence of SjS may be associated with low grade malignancies such as MALT lymphoma [154]. In general, malignant transformation to lymphoma