from LIP is a rare phenomenon [143]; however, these patients are at an increased risk when compared to the general population. The prognosis of patients with LIP is variable in the literature with reported median survival times ranging from 5 years [146] to 11.5 years [145], but it is unclear how these statistics apply to patients with FB-related DCLD and there is a general sense they fare much better.

Amyloidosis

PLCH) or bronchiectases [161]. Management involves identifying and treating the underlying lymphoproliferative disorder, but it is not clear that decline in lung function is affected by pharmacologic interventions [162]. Lung transplantation is an option for advanced cases with chronic respiratory failure [161].

Smoking-Related Difuse Cystic Lung

Disease

Pulmonary amyloidosis is characterized by abnormal deposition of extracellular proteins in a brillary fashion (amyloid brils) within the lung interstitium, vessels, or airways. Amyloidosis can be an isolated process within the lung, but it is more commonly a manifestation of systemic disease. Pulmonary amyloidosis classically presents with multiple pulmonary nodules that may cavitate over time. Occasionally, pulmonary amyloidosis can present as diffuse cystic lung disease [155], either alone or in the setting of SjS [156].

While the mechanism of cyst formation in pulmonary amyloidosis is unclear, the most likely explanation is that deposition of proteins in the lung interstitium triggers infammation and matrix degradation, which results is lung destruction. Other proposed mechanisms include narrowing of the airways by infammation, amyloid protein deposits leading to development of a ball valve phenomenon with distal overdistension [157, 158], or ischemic destruction from disruption of capillaries [156].

The characteristic histologic features of pulmonary amyloidosis include brillar deposits displaying apple-green birefringence when Congo red stained sections are examined under polarizing microscopy. Examination with immunohistochemistry can also reveal immunoglobulin light chain protein deposition within tissue samples [154].

Light Chain Deposition Disease (LCDD)

LCDD presents as a DCLD with deposition of a non brillary amorphous material in the alveolar walls and small airways that does not bind Congo red or exhibit applegreen birefringence under polarized light [159]. It is rare for LCDD to present as an isolated pulmonary process; patients typically have multiple myeloma or another lymphoproliferative disorder, with concurrent renal involvement [160]. HRCT ndings of LCDD can vary from diffuse, small round cysts (mimicking LAM) to large cysts associated with reticulonodular opacities (mimicking

Exposure to cigarette smoke can result in DCLDs other than PLCH, including desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) [163, 164]. RB is characterized by the accumulation of pigmented macrophages in the distal airways and bronchial metaplasia and is nearly ubiquitous in smokers [163]. DIP and RB are part of a spectrum, with DIP being the more extreme, characterized by dense in ltration of distal airspaces with pigmented macrophages [165]. RB-ILD and DIP have signi cant radiographic overlap with common abnormalities, including bronchial wall thickening, centrilobular nodules, and groundglass attenuation [166]. Cysts in DIP and RB are less common, typically involve a small fraction of the parenchyma, and appear within areas of ground-­glass opacities [167]. Given that emphysema and smoking-related DCLDs can mimic other cystic disease processes [168], it is essential to obtain a detailed history of exposures to smoke and dust.

Conclusion

DCLDs are uncommon diseases that have a broad differential diagnosis (see Table 20.4 and Fig. 20.5). LAM, PLCH, and FB are the most common DCLDs seen in clinical practice. HRCT remains the diagnostic modality of choice and can establish the diagnosis in some cases. The use of serum biomarkers has reduced the need for a tissue biopsy in some DCLDs, especially VEGF-D in LAM, and ANA antibodies in autoimmune disease, and SPEP and UPEP in LCDD. Bronchoscopy with transbronchial biopsy and/or cryobiopsy can establish the diagnosis in some cases, especially when the clinical context is compelling, but surgical lung biopsy may be required. Establishing the correct diagnosis is critical for implementation of lifestyle interventions (e.g., avoidance of smoke in PLCH, estrogen containing meds in LAM, etc.), prognostication, and to establish candidacy for established (e.g., sirolimus in LAM) and future effective treatments.

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Table 20.4  Summary of clinical and diagnostic features of selected diffuse cystic lung diseases

BAL bronchioalveolar lavage, BHD Birt-Hogg-Dubé syndrome, BRAF v-Raf murine sarcoma viral oncogene homolog B, CTD connective tissue disease, CVID common variable immune deciency, EBV Epstein-Barr virus, FB follicular bronchiolitis, FLCN folliculin, LAM lymphangioleiomyomatosis, LCDD light-chain deposition disease, LIP lymphoid interstitial pneumonia, PLCH pulmonary langerhans cell histiocytosis, SS sjögren syndrome, TBBx transbronchial biopsy, TSC tuberous sclerosis complex, VEGF-D vascular endothelial growth factor-D

(From Am J Respir Crit Care Med Vol 192, Iss 1, pp.17–29, Jul 1, 2015, permission requested)

Disease Lung Cystic Difuse  20

361

I. Clinical presentation

II. HRCT review

III. Likely diagnosis

IV. Confirmatory features

V. Other tips to consider

Fig. 20.5  Algorithm to guide approach to the diagnosis of diffuse cystic lung diseases. AML angiomyolipoma, BAL bronchoalveolar lavage, BHD Birt-Hogg-Dubé syndrome, BRAF v-Raf murine sarcoma viral oncogene homologue, DI diabetes insipidus, DIP desquamative interstitial pneumonia, DCLD diffuse cystic lung disease, FB follicular bronchiolitis, FLCN folliculin, HRCT high-resolution computed tomography, HP hypersensitivity pneumonitis, IHC immunohisto-

chemistry, ILD interstitial lung disease, LAM lymphangioleiomyomatosis, LCDD light chain deposition disease, LIP lymphoid interstitial pneumonia, PLCH pulmonary Langerhans cell histiocytosis, SS Sjögren syndrome, Tbbx transbronchial biopsy, TSC tuberous sclerosis complex, VATS video-assisted thoracoscopic surgery, VEGF-D vascular endothelial growth factor D

Box 20.1

LAM

Based on ATS/JRS Diagnostic criteria, a diagnosis of LAM can be established when there is a compatible clinical history and characteristic HRCT plus one or more of the following:

•\ TSC.

•\ Renal angiomyolipoma*.

•\ Serum VEGF-D ≥ 800 pg/mL.

•\ Chylous pleural effusion or ascites (con rmed by biochemical fuid analysis).

•\ Lymphangioleiomyomas*.

•\ Cytology showing LAM cells or LAM cell clusters in chylous effusions or lymph nodes.

•\ Lung or extra pulmonary biopsy con rming LAM.

*Angiomyolipoma and lymphangioleiomyomas can normally be diagnosed by a characteristic radiographic appearance. Adapted from reference.

PLCH

A diagnosis of PLCH can be established entirely on clinical grounds when there is a compatible clinical history that includes exposure to particulates and characteristic HRCT that exhibits upper-lobe predominant nodules and/or cysts. When doubts remain, any one of the following additional elements can establish the diagnosis:

•\ CD1a positive cells >5% on BAL.

•\ Lung or extrapulmonary biopsy con rming PLCH.

FB/LIP

A diagnosis of FB/LIP can established entirely on clinical grounds when there is a compatible clinical history that includes autoimmune disease and characteristic HRCT. When doubts remain, any one of the following additional elements can establish the diagnosis:

•\ Lung biopsy con rming FB or LIP.

LCDD

A diagnosis of LCDD can be strongly suspected on clinical grounds when there is a compatible clinical history that includes a monoclonal gammopathy or plasma cell dyscrasia and a characteristic HRCT. The diagnosis generally requires the following:

•\ Lung biopsy con rming FB or LIP.

Clinical Anecdote

A nonsmoking 28-year-old woman who had a CT of the abdomen obtained as part of a trauma evaluation after a traf c accident is found to an incidental nding of scattered thin-walled cysts in the lung bases and a fat containing 2 cm angiomyolipoma on her left kidney. She runs daily for exercise and has no respiratory symptoms, but is referred to a pulmonary physician for further evaluation. A high-resolution chest CT is obtained, which reveals a mild profusion of scattered thin-walled cysts. Her pulmonary function tests are normal, with an FEV1 and DLCO of 90% of predicted, but she has gas trapping with an RV of 120% predicted. Her VEGF-D is 590 pg/mL. A diagnosis of LAM is made based on the presence of typical cystic changes on HRCT and an angiomyolipoma on her abdominal CT. The VEGF-D is in the normal range and is uninformative. Since the patient is asymptomatic, the pulmonary physician and patient make a joint decision to follow along conservatively with spirometry every 3 months. Over the course of a year, she has a steady downward trend in FEV1, with an overall annual loss of 250 cc, but she remains asymptomatic without exercise limitation and her FEV1 remains greater than 85% of predicted. Based on ATS/ERS Guidelines, she qual- i es for treatment with sirolimus given that her FEV1 is declining at a rapid rate. She is started on 1 mg sirolimus per day, with a plan to adjust the dose based on lung function trajectory over time.

Financial Support  There was no nancial support for this manuscript.

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