Fig. 20.2  Patient with pulmonary Langerhans cell histiocytosis. CT imaging showing symmetric lesions that are predominantly located in the upper and mid-lung zones with sparing of the costophrenic angles

Diagnostic Approach

PLCH should be considered in individuals with cystic or nodular upper-lobe predominant in ltrates on chest imaging, in current or former cigarette smokers with or without a history of spontaneous or recurrent pneumothorax, and in any patient with lung in ltrates and a history of skin rash, bone lesions, or diabetes insipidus. Pulmonary function testing may be normal, or may reveal obstructive, restrictive, or mixed abnormalities [74]. Normal lung function or mild restrictive impairment is typically present in earlier phases of disease, while obstructive defects with air trapping and reduced diffusing capacity for carbon monoxide can predominate in advanced stages [74, 101]. In patients with advanced PLCH, hypoxemia with rest, exercise and sleep may develop, resulting in a requirement for supplemental oxygen.

It is possible to make the diagnosis of PLCH with CT alone in patients with classical imaging and a history of smoke exposure. In cases where uncertainty remains, bronchoscopy with transbronchial lung biopsy can be diagnostic in about 30% of cases [45, 102]. Surgical lung biopsy may be required for de nitive diagnosis in some cases. PLCH lesions are often FDG avid and PET scanning may be helpful to detect occult extrapulmonary disease or to follow the response to therapy [103].

Prognosis andManagement

Smoking cessation and avoidance of second-hand smoke are the cornerstones of PLCH management. Stabilization and even regression following these interventions are well established in the literature [73, 104]. The recent discovery of MAPK mutations in PLCH has suggested the possibility that targeted therapeutic interventions could be effective, similar to other histiocytic disorders and malig-

nancies harboring activating mutations in key signaling pathways. Pharmacotherapy with MAPK pathway inhibitors is effective in children with LCH, but there have been no trials in adults, and it should only be considered in patients with potentially reversible disease. Assessment and treatment of complications, including pneumothorax, hypoxemic respiratory failure, diabetes insipidus, and secondary pulmonary hypertension, apply to important subsets of PLCH patients.

Some patients experience very little decline in lung function, while others develop progressive lung disease, even after smoking cessation [101]. Serial PFTs at 3–6-month intervals are useful for tracking disease trajectory in new patients and in those with disease that is evolving [101]. Oral corticosteroid therapy is often attempted but is rarely ef cacious. Case reports and small series suggest that chlorodeoxyadenosine (cladribine) may induce stabilization or even improvement of nodular lesions [105–107] and in some cases has been shown to improve lung function, CT ndings, and pulmonary hemodynamics when smoking cessation has failed to halt disease progression [108–110].

Patients should be screened for pulmonary hypertension by echocardiography at the time of diagnosis and if there are any changes in exercise tolerance. Spontaneous pneumothorax tends to recur frequently, with rates approaching 60% [76, 111]. Surgical pleurodesis can substantially reduce the risk of recurrence to 0–20% [76, 111]. Lung transplantation outcomes for PLCH is similar to other advanced pulmonary diseases, although recurrence in the transplanted lung has been reported [112–115]. In a study of 39 patients from France, there was a recurrence rate of about 20% in the transplanted lung [116].

Birt-Hogg-Dubé Syndrome (BHD)

BHD is a rare, autosomal dominant disorder that is characterized by renal neoplasms, hair follicle tumors, and pulmonary cysts. Cystic lung lesions in BHD are typically discovered in the fourth or fth decade of life [117, 118], but rarely can been seen in teenagers and octogenarians [119]. Although pneumothorax has been described in BHD in the absence of detectable cysts by HRCT, by age 50, there is >80% penetrance of pulmonary cysts [120, 121].

Approximately 24% of patients with BHD develop a pneumothorax, and there is a very high (75%) rate of recurrence, so pleurodesis is recommended with the rst event [122]. In an epidemiological study of 312 patients with BHD, the median age of initial pneumothorax was 38 years old (range 15–69) [123].

Pathogenesis

BHD is caused by mutations in the folliculin (FLCN) gene, which encodes the tumor suppressor protein folliculin, a sig-