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Chest Imaging and Pathology for Clinicians |

Association of Pulmonary Cysts and Nodules in a Young Female Patient FREE TO VIEW

Olívia Meira Dias, MD; Ellen Caroline Toledo do Nascimento, MD, PhD; Carlos Roberto Ribeiro Carvalho, MD, PhD; Mariana Sponholz Araujo, MD, PhD; Carolina Salim Gonçalves Freitas, MD; Ronaldo Adib Kairalla, MD, PhD; Marisa Dolhnikoff, MD, PhD; Bruno Guedes Baldi, MD, PhD
Author and Funding Information

CORRESPONDENCE TO: Bruno Guedes Baldi, MD, PhD, Dr Eneas de Carvalho Aguiar Ave, 44, 5th floor, São Paulo 05403-900, Brazil


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(6):e183-e190. doi:10.1016/j.chest.2016.02.652
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A 27-year-old female patient was referred to our outpatient clinic with a 1-year history of shortness of breath when walking fast on level ground or when climbing stairs. Symptoms worsened after a second episode of spontaneous left pneumothorax, when a chest tube was placed in another hospital for complete lung expansion. During this hospitalization, an open lung biopsy was performed. There was no history of rhinorrhea, nasal congestion, cough, hemoptysis, wheezing, or expectoration.

Figures in this Article

Her past medical history revealed bilateral renal tumors that had been diagnosed 10 years previously. Skin lesions were also previously confirmed on biopsy as angiofibroma (fibrotic dermis containing stellate fibroblasts with dilated capillaries). She denied seizures or complaints of dryness in the mouth or eyes. She also denied smoking, alcohol or marijuana consumption, and occupational exposure and was not currently taking any medication. However, she had used oral contraceptive pills for 8 years.

Physical examination results were normal, except for the presence of angiofibroma on her face (Fig 1), and her height was 153 cm and weight was 51 kg. There was no peripheral lymph node enlargement. Her respiratory rate was 18 breaths/min, and her peripheral oxygen saturation was 98% on room air. Routine laboratory results were unremarkable. Autoimmune test results, including anti-nuclear antibody, rheumatoid factor, anti-neutrophil cytoplasmic antibody, anti-Ro/SSA, and anti-La/SSB, were negative. Pulmonary function test results included the following: FEV1, 2.58 L (81% of predicted); FVC, 2.66 L (80% of predicted); FEV1/FVC ratio, 0.97; residual volume, 2.04 L (160% of predicted); ratio of residual volume to total lung capacity, 0.41; and diffusing capacity of the lung for carbon monoxide, 22.4 mL/min/mm Hg (83% of predicted); all results were normal, except for the presence of air trapping.

Figure 1
Figure Jump LinkFigure 1 Skin-colored papules located between the nose and cheeks, which are more prominent on the right side and compatible with angiofibroma (arrow). (The patient provided written consent for the use of this photograph.)Grahic Jump Location

The chest radiograph was unremarkable (Fig 2). A high-resolution CT (HRCT) scan of the chest revealed multiple thin-walled pulmonary cysts and a few solid, noncalcified nodules diffusely distributed in all lung fields. There was no lymph node enlargement or pleural effusion (Fig 3). An abdominal CT scan revealed a 4-cm left renal mass with heterogeneous attenuation and with the presence of fat and soft tissue densities; these were compatible with angiomyolipoma.

Figure 2
Figure Jump LinkFigure 2 Chest radiograph presented no abnormal findings.Grahic Jump Location
Figure 3
Figure Jump LinkFigure 3 A-D, High-resolution CT scan of the chest showing multiple thin-walled pulmonary cysts and scarce solid, noncalcified nodules diffusely distributed in all lung fields.Grahic Jump Location

Open lung biopsy tissue was reviewed, and histologic analysis showed a few cysts that were associated with smooth muscle-like cell proliferation and that were positive for smooth muscle actin and human melanoma black 45 immunostaining. There were multiple foci of the nodular proliferation of type II alveolar pneumocytes and accumulation of alveolar macrophages within the alveolar spaces (Fig 4).

Figure 4
Figure Jump LinkFigure 4 A, Proliferation of lymphangioleiomyomatosis (LAM) cells within the wall of a cystic air space (solid arrow) and a micronodule composed of proliferated type II pneumocytes (open arrow) (hematoxylin and eosin [H&E] staining, panoramic view). B-D, Proliferation of spindle-shaped myoid cells (LAM cells) within the wall of a cystic air space: B, H&E staining, ×100; C, LAM cells positive for smooth muscle actin immunostaining, ×100; D, LAM cells focally positive for human melanoma black 45 immunostaining, ×100. E-G, Micronodule composed of proliferated type II pneumocytes: E, H&E staining, ×40; F, H&E staining, high magnification of proliferated type II cells, ×400; G, cytokeratin-7 immunostaining of type II pneumocytes, ×400.Grahic Jump Location

What is the diagnosis?

Diagnosis: Tuberous sclerosis complex (TSC) with lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH)

Clinical Discussion

TSC is a rare hereditary autosomal dominant disease characterized by mental retardation, epilepsy, and multiple hamartomatous or neoplastic proliferations involving the skin, heart, kidney, brain, and/or other organs. TSC has an estimated incidence of 1 in 6,000 live births and is caused by mutations in the TSC1 or TSC2 gene. Clinical manifestations include skin angiofibromas, renal angiomyolipomas, and subependymal giant cell astrocytomas.

LAM occurs in 30% to 50% of women with TSC, and may also occur in 10% to 15% of men with TSC; MMPH may be found in this population, as in the patient described here., LAM is a rare disease of unknown etiology, affecting mainly women in their reproductive age; it is considered a low-grade neoplasm with metastatic potential, with main clinical features of progressive dyspnea and pneumothorax., LAM can occur sporadically (85%) or in association with TSC (15%); both are associated with mutations in TSC genes. In sporadic LAM, mutations in TSC genes are found only in neoplastic lesions, whereas in LAM associated with TSC, these mutations are encountered in both tumor and normal tissue. MMPH is characterized by nodular proliferation of type II pneumocytes, and usually affects young female patients with TSC. MMPH may be associated with LAM, rarely manifests with respiratory symptoms or changes in pulmonary function test results, and rarely modifies the course of LAM.,,

Although there is no curative treatment for TSC and LAM, the main treatment strategy is to administer mTOR (mammalian target of rapamycin) inhibitors, including sirolimus, when there is a decline in pulmonary function test results and/or in the presence of extrapulmonary manifestations, including chylothorax, chylous ascites, lymphangioleiomyoma, and large renal angiomyolipoma., In addition, angiomyolipomas that are > 4 cm in diameter are more likely to bleed and embolization should be considered in such cases.

The combination of facial angiofibromas, renal angiomyolipoma, and pulmonary cysts and nodules on HRCT imaging in a young, nonsmoking, female patient with TSC led us to consider the association of TSC, LAM, and MMPH as the first differential diagnosis.

Radiologic Discussion

Pulmonary nodules and cysts are not rare in patients with TSC. As described previously, multiple pulmonary nodules (size range, 2-14 mm) were found in 58% of the 73 patients with TSC on CT scans, were diffusely distributed in the lung, and remained stable in size and number over time. A major limitation of that study was that only four patients provided samples for histopathologic analysis that were compatible with MMPH; pulmonary cysts compatible with LAM occurred in 49% of women in this cohort. Nodules measuring 1 to 10 mm, which were probably the result of MMPH, were found in 43% of 23 patients with TSC, whereas the presence of cysts and nodules was identified in 30% of patients. In another case series, biopsy-confirmed MMPH was more common in female patients; the main findings on thoracic CT scan were random and diffuse nodules, and > 50% patients had nodules and cysts. In summary, MMPH is the most probable cause of pulmonary nodules in patients with TSC. Those nodules are typically multiple, < 10 mm, diffusely distributed, noncalcified (solid and/or ground glass), and remain stable over time.

Although the presence of pulmonary cysts in patients with TSC was sufficient for a straightforward diagnosis of LAM without requiring a pulmonary biopsy, the identification solely of pulmonary nodules was not always sufficient to diagnose MMPH. The presence of tiny (< 10 mm), noncalcified, and randomly distributed pulmonary nodules suggests the diagnosis of MMPH in this patient.

Important features associated with the main cystic lung diseases are described in Table 1. In addition, tomographic findings of cysts and nodules would include other differential diagnoses.,,

Table Graphic Jump Location
Table 1 Differential Diagnoses of Cystic Lung Diseases According to Their Imaging Features, Histopathologic and Genetic Features, and Nonpulmonary Pathologies

FLCN = folliculin gene-associated syndrome; HMB-45 = human melanoma black 45; HTLV = human T lymphotropic virus; IH = immunohistochemistry; MMPH = multifocal micronodular pneumocyte hyperplasia; TSC = tuberous sclerosis complex.

Patients with pulmonary Langerhans cell histiocytosis, usually associated with exposure to smoking, characteristically present with multiple bizarre cysts and nodules with upper and middle lung field predominance on HRCT imaging. Nodules usually have a centrilobular distribution.,,

Birt-Hogg-Dubé syndrome is a rare autosomal disease characterized by the presence of pulmonary cysts, spontaneous pneumothoraces, skin lesions (fibrofolliculomas), and renal tumors. Cysts are usually irregular in shape and have a greater diameter than in the patient described here. Pulmonary nodules are not described in this syndrome.,,

Lymphoid interstitial pneumonia is an infiltrative lung disease due to diffuse reactive pulmonary lymphoid hyperplasia of bronchus-associated lymphoid tissue. Its association with follicular bronchiolitis can lead to multiple pulmonary cysts., Nodular lymphoid aggregates can present on HRCT scans as poorly defined centrilobular nodules. Amyloidosis or lymphoma may also present as pulmonary nodules in this population. Here, the patient did not have symptoms or positive autoimmune test results for Sjögren syndrome or acquired immunodeficiency syndrome.

Pulmonary light-chain deposition disease is characterized by the presence of nonfibrillary and amorphous material (nonamyloidal deposits), corresponding to κ light chains. Lung involvement is uncommon; however, the presence of variously sized pulmonary cysts, usually with concomitant nodules, is the most common pattern on HRCT imaging.,

Pulmonary metastases, particularly sarcomas, may be associated with pulmonary cysts and spontaneous pneumothoraces. Cysts can present with air-fluid levels corresponding to blood or partially organized clots, resembling the appearance of nodules.,,

Sarcoidosis can present with micronodules with perilymphatic distribution; however, this was not observed in the patient described here. Micronodule cavitation resulting in pulmonary cysts is extremely rare in sarcoidosis. Other differential diagnoses include granulomatous diseases, for example, histoplasmosis and mycobacterial infection. However, the absence of pulmonary calcifications, commonly seen in patients with inactive histoplasmosis, makes this diagnosis unlikely. Tuberculosis and other mycobacterial infections are often associated with tree-in-bud opacities due to bronchogenic dissemination; moreover, cavitations, not cysts, are usually found.

Pathologic Discussion

The open lung biopsy tissue showed proliferation of spindle-shaped myoid cells (LAM cells) arranged in nodules or within the walls of the cystic air spaces along the lymphatic axis; the tissue, on immunostaining, was positive for smooth muscle actin and human melanoma black 45. There were also scattered micronodules throughout the lung parenchyma, characterized as type II pneumocyte proliferation within atelectatic alveolar tissue, mimicking a lepidic pattern of adenocarcinoma. The proliferated type II cells were cuboidal, with eosinophilic cytoplasm, round nuclei, and vesicular chromatin.

LAM is a lung injury classically associated with TSC. In 1991, Popper et al reported the association of another pulmonary entity in patients with TSC, called micronodular hyperplasia of type II pneumocytes. MMPH occurred in patients with TSC, regardless of associated LAM.

MMPH is probably a hamartomatous lesion associated with TSC, without malignant potential., Several terminologies, including adenomatoid proliferation of alveolar epithelium; multifocal alveolar hyperplasia; and pneumocyte multinodular hyperplasia, are used to describe this lung injury type.,,

The histologic differential diagnoses for MMPH include benign and malignant pulmonary lesions.,, Papillary adenoma of type II cells usually presents as a solitary nodule and circumscribed neoplasm that contains papillary structures with fibrovascular cores. Atypical adenomatous hyperplasia comprises a small lesion with type II pneumocytes of mild to moderate atypia and/or with club cells. Lepidic adenocarcinoma is neoplastic cell growth with low-grade nuclear atypia along preexisting alveolar structures. Sclerosing pneumocytoma usually presents as a solitary nodule with cuboidal surface and stromal round cells. Minute pulmonary meningothelial-like nodules are interstitial proliferations of cytologically uniform, bland oval to spindle-shaped cells arranged in a “Zellballen” nesting pattern near small veins. Healing miliary inflammatory processes are less circumscribed and have more prominent interstitial inflammation.

Patients with TSC can present with multiple neoplastic and other benign proliferative lesions. LAM is not the only pulmonary manifestation associated with TSC; MMPH, which seems to be one of the hamartomatous lesions, can occur in these patients as well.

For a patient presenting with a combination of pulmonary nodules and cysts, the main clinical and radiologic differential diagnoses include LAM and MMPH; pulmonary Langerhans cell histiocytosis; lymphoid interstitial pneumonia with follicular bronchiolitis; pulmonary light-chain deposition disease; pulmonary metastases; and sarcoidosis. Although the diagnosis can frequently be confirmed on the basis of the association of clinical and radiologic features, it is sometimes necessary to perform a lung biopsy for histopathologic correlation.

At the time of this writing, the patient’s respiratory symptoms are stable; she had been started on sirolimus, at 2 mg orally once daily, because of an increase in the volume of renal angiomyolipoma.

Financial/nonfinancial disclosures: None declared.

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Crino P.B. .Nathanson K.L. .Henske E.P. . The tuberous sclerosis complex. N Engl J Med. 2006;355:1345-1356 [PubMed]journal. [CrossRef] [PubMed]
 
Popper H.H. .Juettner-Smolle F.M. .Pongratz M.G. . Micronodular hyperplasia of type II pneumocytes: a new lung lesion associated with tuberous sclerosis. Histopathology. 1991;18:347-354 [PubMed]journal. [CrossRef] [PubMed]
 
Muzykewicz D.A. .Sharma A. .Muse V. .Numis A.L. .Rajagopal J. .Thiele E.A. . TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex. J Med Genet. 2009;46:465-468 [PubMed]journal. [CrossRef] [PubMed]
 
McCormack F.X. .Travis W.D. .Colby T.V. .Henske E.P. .Moss J. . Lymphangioleiomyomatosis: calling it what it is: a low grade, destructive, metastasizing neoplasm. Am J Respir Crit Care Med. 2012;186:1210-1212 [PubMed]journal. [CrossRef] [PubMed]
 
Baldi B.G. .Freitas C.S. .Araujo M.S. .et al Clinical course and characterisation of lymphangioleiomyomatosis in a Brazilian reference centre. Sarcoidosis Vasc Diffuse Lung Dis. 2014;31:129-135 [PubMed]journal. [PubMed]
 
Carsillo T. .Astrinidis A. .Henske E.P. . Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci U S A. 2000;97:6085-6090 [PubMed]journal. [CrossRef] [PubMed]
 
Muzykewicz D.A. .Black M.E. .Muse V. .et al Multifocal micronodular pneumocyte hyperplasia: computed tomographic appearance and follow-up in tuberous sclerosis complex. J Comput Assist Tomogr. 2012;36:518-522 [PubMed]journal. [CrossRef] [PubMed]
 
Kobashi Y. .Sugiu T. .Mouri K. .Irei T. .Nakata M. .Oka M. . Clinicopathological analysis of multifocal micronodular pneumocyte hyperplasia associated with tuberous sclerosis in Japan. Respirology. 2008;13:1076-1081 [PubMed]journal. [PubMed]
 
Franz D.N. .Brody A. .Meyer C. .et al Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med. 2001;164:661-668 [PubMed]journal. [CrossRef] [PubMed]
 
McCormack F.X. .Inoue Y. .Moss J. .et al Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011;364:1595-1606 [PubMed]journal. [CrossRef] [PubMed]
 
Freitas C.S.G. .Baldi B.G. .Araujo M.S. .Heiden G.I. .Kairalla R.A. .Carvalho C.R.R. . Use of sirolimus in the treatment of lymphangioleiomyomatosis: favorable responses in patients with different extrapulmonary manifestations. J Bras Pneumol. 2015;41:275-280 [PubMed]journal. [CrossRef] [PubMed]
 
Gupta N. .Vassallo R. .Wikenheiser-Brokamp K.A. .McCormack F.X. . Diffuse cystic lung disease. Part I. Am J Respir Crit Care Med. 2015;191:1354-1366 [PubMed]journal. [CrossRef] [PubMed]
 
Grant L.A. .Babar J. .Griffin N. . Cysts, cavities, and honeycombing in multisystem disorders: differential diagnosis and findings on thin-section CT. Clin Radiol. 2009;64:439-448 [PubMed]journal. [CrossRef] [PubMed]
 
Cordier J.F. .Johnson S.R. . Multiple cystic lung diseases. Eur Respir Mon. 2011;54:46-83 [PubMed]journal
 
Gupta N. .Vassallo R. .Wikenheiser-Brokamp K.A. .McCormack F.X. . Diffuse cystic lung disease. Part II. Am J Respir Crit Care Med. 2015;192:17-29 [PubMed]journal. [CrossRef] [PubMed]
 
Johkoh T. .Ichikado K. .Akira M. .et al Lymphocytic interstitial pneumonia: follow-up CT findings in 14 patients. J Thorac Imaging. 2000;15:162-167 [PubMed]journal. [CrossRef] [PubMed]
 
Sheard S. .Nicholson A.G. .Edmunds L. .Wotherspoon A.C. .Hansell D.M. . Pulmonary light-chain deposition disease: CT and pathology findings in nine patients. Clin Radiol. 2015;70:515-522 [PubMed]journal. [CrossRef] [PubMed]
 
Maruyama H. .Ohbayashi C. .Hino O. .Tsutsumi M. .Konishi Y. . Pathogenesis of multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis and association with tuberous sclerosis genes TSC1 and TSC2. Pathol Int. 2001;51:585-594 [PubMed]journal. [CrossRef] [PubMed]
 
Wu K. .Tazelaar H.D. . Pulmonary angiomyolipoma and multifocal micronodular pneumocyte hyperplasia associated with tuberous sclerosis. Hum Pathol. 1999;30:1266-1268 [PubMed]journal. [CrossRef] [PubMed]
 
Spencer H. . Hamartomas, blastoma and teratoma of the lung.Spencer H.. Pathology of the Lung.  :1061-1075 [PubMed]journal
 
Lantuejoul S. .Ferretti G. .Negoescu A. .Parent B. .Brambilla E. . Multifocal alveolar hyperplasia associated with lymphangioleiomyomatosis in tuberous sclerosis. Histopathology. 1997;30:570-575 [PubMed]journal. [CrossRef] [PubMed]
 
Muir T.E. .Leslie K.O. .Popper H. .et al Micronodular pneumocyte hyperplasia. Am J Surg Pathol. 1998;22:465-472 [PubMed]journal. [CrossRef] [PubMed]
 
Cho H.H. .Shim S.S. .Kima Y. .Han W.S. . Sporadic lymphangioleiomyomatosis with multiple atypical adenomatoid hyperplasia: differentiation from multifocal micronodular pneumocyte hyperplasia. Clin Radiol. 2010;65:765-767 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 Skin-colored papules located between the nose and cheeks, which are more prominent on the right side and compatible with angiofibroma (arrow). (The patient provided written consent for the use of this photograph.)Grahic Jump Location
Figure Jump LinkFigure 2 Chest radiograph presented no abnormal findings.Grahic Jump Location
Figure Jump LinkFigure 3 A-D, High-resolution CT scan of the chest showing multiple thin-walled pulmonary cysts and scarce solid, noncalcified nodules diffusely distributed in all lung fields.Grahic Jump Location
Figure Jump LinkFigure 4 A, Proliferation of lymphangioleiomyomatosis (LAM) cells within the wall of a cystic air space (solid arrow) and a micronodule composed of proliferated type II pneumocytes (open arrow) (hematoxylin and eosin [H&E] staining, panoramic view). B-D, Proliferation of spindle-shaped myoid cells (LAM cells) within the wall of a cystic air space: B, H&E staining, ×100; C, LAM cells positive for smooth muscle actin immunostaining, ×100; D, LAM cells focally positive for human melanoma black 45 immunostaining, ×100. E-G, Micronodule composed of proliferated type II pneumocytes: E, H&E staining, ×40; F, H&E staining, high magnification of proliferated type II cells, ×400; G, cytokeratin-7 immunostaining of type II pneumocytes, ×400.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Differential Diagnoses of Cystic Lung Diseases According to Their Imaging Features, Histopathologic and Genetic Features, and Nonpulmonary Pathologies

FLCN = folliculin gene-associated syndrome; HMB-45 = human melanoma black 45; HTLV = human T lymphotropic virus; IH = immunohistochemistry; MMPH = multifocal micronodular pneumocyte hyperplasia; TSC = tuberous sclerosis complex.

References

Crino P.B. .Nathanson K.L. .Henske E.P. . The tuberous sclerosis complex. N Engl J Med. 2006;355:1345-1356 [PubMed]journal. [CrossRef] [PubMed]
 
Popper H.H. .Juettner-Smolle F.M. .Pongratz M.G. . Micronodular hyperplasia of type II pneumocytes: a new lung lesion associated with tuberous sclerosis. Histopathology. 1991;18:347-354 [PubMed]journal. [CrossRef] [PubMed]
 
Muzykewicz D.A. .Sharma A. .Muse V. .Numis A.L. .Rajagopal J. .Thiele E.A. . TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex. J Med Genet. 2009;46:465-468 [PubMed]journal. [CrossRef] [PubMed]
 
McCormack F.X. .Travis W.D. .Colby T.V. .Henske E.P. .Moss J. . Lymphangioleiomyomatosis: calling it what it is: a low grade, destructive, metastasizing neoplasm. Am J Respir Crit Care Med. 2012;186:1210-1212 [PubMed]journal. [CrossRef] [PubMed]
 
Baldi B.G. .Freitas C.S. .Araujo M.S. .et al Clinical course and characterisation of lymphangioleiomyomatosis in a Brazilian reference centre. Sarcoidosis Vasc Diffuse Lung Dis. 2014;31:129-135 [PubMed]journal. [PubMed]
 
Carsillo T. .Astrinidis A. .Henske E.P. . Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci U S A. 2000;97:6085-6090 [PubMed]journal. [CrossRef] [PubMed]
 
Muzykewicz D.A. .Black M.E. .Muse V. .et al Multifocal micronodular pneumocyte hyperplasia: computed tomographic appearance and follow-up in tuberous sclerosis complex. J Comput Assist Tomogr. 2012;36:518-522 [PubMed]journal. [CrossRef] [PubMed]
 
Kobashi Y. .Sugiu T. .Mouri K. .Irei T. .Nakata M. .Oka M. . Clinicopathological analysis of multifocal micronodular pneumocyte hyperplasia associated with tuberous sclerosis in Japan. Respirology. 2008;13:1076-1081 [PubMed]journal. [PubMed]
 
Franz D.N. .Brody A. .Meyer C. .et al Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med. 2001;164:661-668 [PubMed]journal. [CrossRef] [PubMed]
 
McCormack F.X. .Inoue Y. .Moss J. .et al Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011;364:1595-1606 [PubMed]journal. [CrossRef] [PubMed]
 
Freitas C.S.G. .Baldi B.G. .Araujo M.S. .Heiden G.I. .Kairalla R.A. .Carvalho C.R.R. . Use of sirolimus in the treatment of lymphangioleiomyomatosis: favorable responses in patients with different extrapulmonary manifestations. J Bras Pneumol. 2015;41:275-280 [PubMed]journal. [CrossRef] [PubMed]
 
Gupta N. .Vassallo R. .Wikenheiser-Brokamp K.A. .McCormack F.X. . Diffuse cystic lung disease. Part I. Am J Respir Crit Care Med. 2015;191:1354-1366 [PubMed]journal. [CrossRef] [PubMed]
 
Grant L.A. .Babar J. .Griffin N. . Cysts, cavities, and honeycombing in multisystem disorders: differential diagnosis and findings on thin-section CT. Clin Radiol. 2009;64:439-448 [PubMed]journal. [CrossRef] [PubMed]
 
Cordier J.F. .Johnson S.R. . Multiple cystic lung diseases. Eur Respir Mon. 2011;54:46-83 [PubMed]journal
 
Gupta N. .Vassallo R. .Wikenheiser-Brokamp K.A. .McCormack F.X. . Diffuse cystic lung disease. Part II. Am J Respir Crit Care Med. 2015;192:17-29 [PubMed]journal. [CrossRef] [PubMed]
 
Johkoh T. .Ichikado K. .Akira M. .et al Lymphocytic interstitial pneumonia: follow-up CT findings in 14 patients. J Thorac Imaging. 2000;15:162-167 [PubMed]journal. [CrossRef] [PubMed]
 
Sheard S. .Nicholson A.G. .Edmunds L. .Wotherspoon A.C. .Hansell D.M. . Pulmonary light-chain deposition disease: CT and pathology findings in nine patients. Clin Radiol. 2015;70:515-522 [PubMed]journal. [CrossRef] [PubMed]
 
Maruyama H. .Ohbayashi C. .Hino O. .Tsutsumi M. .Konishi Y. . Pathogenesis of multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis and association with tuberous sclerosis genes TSC1 and TSC2. Pathol Int. 2001;51:585-594 [PubMed]journal. [CrossRef] [PubMed]
 
Wu K. .Tazelaar H.D. . Pulmonary angiomyolipoma and multifocal micronodular pneumocyte hyperplasia associated with tuberous sclerosis. Hum Pathol. 1999;30:1266-1268 [PubMed]journal. [CrossRef] [PubMed]
 
Spencer H. . Hamartomas, blastoma and teratoma of the lung.Spencer H.. Pathology of the Lung.  :1061-1075 [PubMed]journal
 
Lantuejoul S. .Ferretti G. .Negoescu A. .Parent B. .Brambilla E. . Multifocal alveolar hyperplasia associated with lymphangioleiomyomatosis in tuberous sclerosis. Histopathology. 1997;30:570-575 [PubMed]journal. [CrossRef] [PubMed]
 
Muir T.E. .Leslie K.O. .Popper H. .et al Micronodular pneumocyte hyperplasia. Am J Surg Pathol. 1998;22:465-472 [PubMed]journal. [CrossRef] [PubMed]
 
Cho H.H. .Shim S.S. .Kima Y. .Han W.S. . Sporadic lymphangioleiomyomatosis with multiple atypical adenomatoid hyperplasia: differentiation from multifocal micronodular pneumocyte hyperplasia. Clin Radiol. 2010;65:765-767 [PubMed]journal. [CrossRef] [PubMed]
 
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