Table 20.3  Characteristic chest CT ndings of selected DCLDs

Several pathophysiologic mechanisms have been proposed to explain cyst formation within the lung, including ball valve obstruction with distal over-infation, ischemia, or remodeling secondary to matrix-degrading enzymes [1]. Unfortunately, there is a paucity of good animals models addressing this question and the quality of evidence supporting these pathogenic mechanisms is weak.

Common Difuse Cystic Lung Diseases

Lymphangioleiomyomatosis

LAM is a rare cystic lung disease that primarily affects females and is caused by in ltration of the lung by smooth muscle cells that contain growth-activating mutations in tuberous sclerosis genes. The origin of these neoplastic cells remains unclear, but it is apparent that they arise from an extrapulmonary source and spread to the lungs via the blood and lymphatics [2, 3]. Recent single-cell RNA sequencing data of LAM cells suggests a possible uterine primary [4], but other candidates include kidney, bone marrow, genitourinary tract, and lymphatic system.

LAM occurs in patients with tuberous sclerosis complex (TSC-LAM) and in a “sporadic” form in patients who do not have tuberous sclerosis (S-LAM) [5]. In TSC-LAM, tuberous sclerosis mutations are found in the germ line, while in S-LAM, tuberous sclerosis mutations are found only within

the neoplastic lesions [6, 7]. TSC-LAM occurs in >30% of women with TSC [8–10] and in 10–15% of men with TSC [11, 12]. S-LAM appears to be almost entirely restricted to women, with one possible exception in the literature, mentioned with the caveat that mutational analysis is not perfectly sensitive and low-level mosaicism for TSC mutations is dif cult to exclude [13].

The average age at diagnosis is about 35 years, but cases have been seen in teenagers [14] and octagenarians [15]. The prevalence is reported to be about 3.4–7.8 per million women in the US and Europe [16], but as with all rare diseases is likely underestimated [17].

Pathogenesis

To date, S-LAM has been associated with only TSC2 mutations, while TSC-LAM is caused by mutations within TSC1 or TSC2, with TSC1 disease being less common and less severe. In patients with TSC-LAM, mutations in TSC genes are present in all cells, and neoplasms and dysplasias arise in various organs when “second hit” somatic TSC mutations occur. In patients with S-LAM, mutations in both copies of the parental TSC2 alleles occur post-conception and within somatic tissues and tend to be con ned to lesions in the lung, kidney, and lymph nodes [6, 18]. In both cases, the cells that comprise the pulmonary lesions are thought to arise from extrapulmonary sources.

TSC1 and TSC2 encode for proteins called hamartin and tuberin, respectively, which form a complex that maintains mTOR in an inactive state. De ciency or dysfunction in either protein results in upregulated activity of mTOR, which increases protein translation and leads to inappropriate cellular proliferation, migration, and invasion. In LAM cells, this results in suppression of autophagy and expression of the metastasis promoting lymphangiogenic vascular endothelial growth factors, VEGF-C and VEGF-D [2]. Genetic analysis of blood [19], lymphatic fuid, and recurrent LAM lesions in donor allografts after lung transplantation [20–22] have revealed that LAM cells circulate and metastasize [23]. Serum levels of VEGF-D are elevated in 50–70% of patients with LAM, and are both diagnostically and prognostically useful [24–26].

Several studies have reported increased LAM symptoms and/or progression when estrogen levels are high, such as during pregnancy [27, 28] or when exogenous estrogen is taken [29, 30], and disease progression slows after menopause when estrogen levels fall [31]. A recent survey-based study of 307 premenopausal women with LAM revealed that about one-third of women have cyclic worsening of their chest symptoms, including shortness of breath and chest tightness during menstruation [32]. Analysis of the MILES cohort showed that there was a greater rate of decline of FEV1 in patients who were premenopausal versus those that

were postmenopausal [33]. The role of estrogen in LAM is not completely understood and is currently a key focus of LAM research.

Pathologic and Radiographic Characteristics

Histopathological evaluation shows smooth muscle cell invasion of the lung parenchyma, airways, lymphatics, and blood vessels associated with nodular accumulation and thin-walled cysts [34]. LAM lesions express VEGF-C and VEGF-D and contain lymphatic channels lined by endothelial cells that express their cognate receptor, VEGFR-3 [35, 36]. LAM cells classically spare tissue planes as they expand the interstitium but can invade and destroy surrounding vessels, airways, and other tissue [37, 38].

Radiographically, pulmonary cysts in LAM are diffusely distributed throughout the lung, vary in size from 2 mm to 2 cm, and are well-de ned, round, and thin-walled (Fig. 20.1) [39].

Diagnostic Approach

The diagnosis of LAM should be considered in any young to middle-aged nonsmoking female with a pneumothorax [40], asymptomatic women with TSC after age 18 [41, 42], patients with an angiomyolipoma [43] or a lymphangiomyoma, cysts in the lung bases on abdominal CT, unexplained chylous ascites or chylous effusions, and progressive dyspnea in females with presentations that are atypical for COPD or asthma.

Per the European Respiratory Society Guidelines, the diagnosis of LAM can be made with characteristic cystic changes on CT in a patient with tuberous sclerosis, angiomyolipoma, lymphadenopathy, or chylothorax [44]. The ATS/JRC extended the diagnostic criterion to include serum VEGF-D level ≥800 pg/mL in a patient with typical HRCT

Fig. 20.1  Patient with lymphangioleiomyomatosis. CT imaging demonstrating small round cysts that are diffusely distributed

ndings [26]. If these associated clinical and serologic features are not present, and diagnostic certainty is required or desired, a biopsy or cytologic evaluation is indicated for diagnosis. Transbronchial biopsy (which has a yield of about 60%) [45, 46], transbronchial cryobiopsy [47], or cytological examination of pleural fuid, lymph nodes, or masses [48] represent appealing, nonsurgical approaches to obtaining a diagnosis. Video-assisted thoracoscopic surgery (VATS) lung biopsy is an option when the diagnosis remains elusive despite deployment of all less invasive approaches. In all cases in which tissue is obtained, evaluation by an expert pathologist who is familiar with LAM is essential. LAM is normally negative on fuoro-deoxyglucose positron emission tomography (FDG-PET), which helps distinguish it from other conditions associated with abdominal and pelvic masses, such as malignant PEComa, lymphoma, or ovarian cancer [49].

Prognosis andManagement

LAM is characterized by progressive dyspnea on exertion, recurrent pneumothoraces, and, less frequently, chylous pleural effusions and chylous ascites [50]. In the pre-­ sirolimus era, 55% of LAM patients had dyspnea with activities of daily living (ADLs), 20% required supplemental oxygen, and 10% died within 10 years of diagnosis [51, 52]. A longitudinal analysis of 217 patients enrolled in the National Heart, Lung, and Blood Institute LAM Registry revealed transplant-free survival at 5, 10, 15, and 20 years to be 94%, 85%, 75%, and 64%, respectively, with a median survival of greater than 20 years (also pre-sirolimus era data) [53]. Poor baseline pulmonary function and premenopausal status at diagnosis were associated with elevated risk of progression and need for transplant [53]. Airfow obstruction and hyperinfation are the most common PFT alterations and forced expiratory volume in 1 s (FEV1) typically declines at a rate of 50–250 cm3 per year [28, 31, 54–56]. In patients with S-LAM, premenopausal status, and elevated VEGF-D levels [24] are associated with a more rapid decline in lung function. All of these prognostic and outcome measures need to be reevaluated to determine the impact that mTOR inhibitor therapy on the natural history of disease.

Angiomyolipomas that are greater than 4 cm in size have an elevated risk for spontaneous bleeding [57] and treatment with an mTOR inhibitor is considered the rst line approach [58]. Embolization is an alternative for large tumors, especially in cases where bleeding has occurred or aneurysmal content is high. Air travel is safe for most patients with LAM [59, 60]. For patients with reversible airfow obstruction on pulmonary function testing or in patients who report symptomatic bene t, bronchodilators are indicated [61]. Pleurodesis should be performed following the rst pneumothorax as the rate of recurrence is about 70% [62].