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. Author manuscript; available in PMC: 2024 Feb 13.
Published in final edited form as: Immunol Allergy Clin North Am. 2023 May;43(2):359–377. doi: 10.1016/j.iac.2023.01.003

Lymphangioleiomyomatosis and other Cystic Lung Diseases

Matthew Koslow 1, David A Lynch 2, Gregory P Downey 3
PMCID: PMC10863428  NIHMSID: NIHMS1965150  PMID: 37055093

Introduction

Pulmonary cysts and cavities are commonly encountered on chest imaging. The differential diagnosis is broad because both congenital and acquired processes can cause such findings. The following chapter will review common diffuse cystic lung diseases and a systematic approach to diagnosis.

Definition

Cysts and cavities are foci of decreased lung density with discernible walls as assessed by high-resolution computed tomography (HRCT). In contrast, emphysematous airspaces typically lack a perceptible wall. A “cyst” is typically surrounded by a thin wall (≤ 2mm) of uniform thickness whereas a “lung cavity” is a gas-filled space with a relatively thick wall (>4mm), and may be surrounded by consolidation or mass.1 A cavity often develops from drainage of a necrotic lesion via the bronchial tree and may contain a fluid level. This distinction is useful since “cysts” are rarely malignant, but a cavitary lesion raises concern for malignancy, infection or vasculitis, especially in a high-risk patient.2

The distribution of cysts is classified as focal or multifocal vs diffuse (involving all lobes). The presence of lung cysts in a diffuse distribution limits the differential diagnosis to certain disorders and will be the focus of this chapter.

Lymphangioleiomyomatosis

Background

Lymphangioleiomyomatosis (LAM) is a rare, slowly progressive neoplastic and metastasizing disorder characterized by progressive cystic destruction of the lung with marked female predominance. Clinical manifestations include exertional dyspnea, recurrent pneumothoraces, chylous effusions in the chest and abdomen, and abdominal tumors such as renal angiomyolipomas (AMLs).

LAM can be associated with the tuberous sclerosis complex (TSC-LAM) or sporadic (S-LAM) in which patients do not have TSC gene mutations or its clinical manifestations. TSC is an autosomal dominant genetic disorder that in its most severe form is associated with seizures and cognitive impairment, and CNS, cutaneous, and systemic lesions. Diffuse cystic lung disease has been reported in 10% of men and 30% of women although studies indicate that symptomatic TSC-LAM is nearly completely limited to women.3 In S-LAM, lymphangiomas, AMLs and sclerotic bone lesions may accompany the cystic lung changes but CNS and skin lesions are lacking.4

Variable phenotypes in S-LAM in the face of negative TSC1/TSC2 genetic testing of peripheral blood leukocytes may be explained by genetic mosaicism, the occurrence of somatic cells in a single organism with different genetic compositions which occur from random errors in DNA replication after fertilization and during embryogenesis. For example, Han et al report the case of an otherwise normal man who presented with apparent S-LAM and mosaicism for a TSC2 mutation yet no other TSC manifestations including a normal brain MRI.5 Ogorek et al report a similar case of LAM with mosaicism for a pathogenic TSC2 mutation among 61 female patients with apparent sporadic LAM. The authors hypothesize whether bilateral AMLs and sclerotic bone lesions (present in their index case yet rare among the cohort) could predict mosaicism for TSC2 mutations in sporadic LAM.6

Pathogenesis

LAM is caused by mutations in either of the two known TSC genetic loci; TSC1 on chromosome 9q34 or TSC2 on chromosome 16p13.7,8 Dysregulation of the PI3/Akt signaling pathway enables activation of mechanistic target of rapamycin (mTOR) that promotes abnormal LAM cell proliferation and survival.9,10 Disease progression is aided by abnormal lymphangiogenesis, immune evasion mechanisms, and antiapoptotic effects of sex steroids such as estrogen.

A model for LAM suggests that LAM cells metastasize to the lung from a remote source hypothesized to be the lymphatic system11, the uterus12 or AMLs.9 Recently, single-cell transcriptomic analysis identified a unique population of LAM cells (LAMcore cells). The pulmonary and uterine LAMcore cells demonstrate similar gene expression profiles, and this observation provides support for the concept of a uterine source for pulmonary LAM cells.13 The novel LAMcore cell discovery may serve to develop biomarkers and future therapeutic targets.

Nearly 1/3 of LAM patients have abdominal or thoracic lymph node enlargement, usually due to lymphangiomyomatous tissue (Fig. 1).14,15 Clusters of LAM cells enter the venous circulation at the thoracic duct, disseminate through the pulmonary capillary bed, and can be found in chylous pleural fluid.11 Expression of lymphatic endothelial markers such as vascular endothelial growth factor receptors are critical to the process. Elevated levels of vascular endothelial growth factor D (VEGF-D > 800 pg/ml)) can be useful to distinguish LAM from other cystic lung diseases16 and predict response to therapy.17

Figure 1. Typical CT findings of LAM.

Figure 1.

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A. Axial CT image shows a moderate right chylous effusion and thin-walled cysts of variable sizes evenly distributed throughout the lungs. B. CXR shows a resolved effusion following 4 months of medical therapy. C. Coronal CT image in a different patient shows bilateral fat-containing renal angiomyolipomas (arrows). Metal artifact in the right kidney is from arterial embolization coils. D. Coronal CT in a different patient shows a large tubular and lobulated fluid attenuating structure in the retroperitoneum (arrows) compatible with retroperitoneal lymphangeioleiomyoma which resolved with prolonged therapy (not shown). A large right chylous effusion is also present.

Estrogen may play a critical role in LAM cell survival, proliferation, and destructive potential. Estrogen regulates gene transcription and may modulate signaling to activate mTOR. Animal studies have shown that estrogen may promote metastases and the survival of TSC-2 deficient cells18 whereas estrogen suppression (by ovariectomy or aromatase inhibition) decreases mTOR activity and inhibits myometrial proliferation.19,20 Targeting the estrogen-ERK pathway, along with the mTOR pathway, could be a potential therapeutic approach for LAM.

The pathogenesis of LAM has many similarities to the mechanisms of other human cancers such as immune evasion strategies and tissue destruction. For example, targeted monoclonal antibodies (e.g. anti-PD-L1) reduced tumor burden and prolonged survival in an animal model of TSC-LAM21,22 and suggests immunotherapy as a potential treatment strategy for human LAM.

Clinicoradiologic manifestations

LAM typically presents during the reproductive years although examples of LAM presenting well after menopause have been reported.23,24 Most patients are nonsmokers and LAM does not appear to be smoking-related.

The most common clinical presentations are exertional dyspnea from disease progression, spontaneous pneumothorax or incidental discovery of lung cysts. Pneumothorax is common (up to 2/3 of patients) with a high recurrence rate (70%),24–26 and may precede the diagnosis of LAM in the majority of patients. The accumulation of chyle in pleural and extrathoracic locations, such as the airway (chyloptysis) and genitourinary tract (chyluria) may occur. Fistulous communication with the gut can result in chyle in stool and retrograde chylous parenchymal congestion can present with ground glass or reticular change in the lung.27

AMLs are tumors composed of fat, smooth muscle and abnormal blood vessels, which most often affect the kidneys but can present anywhere in the chest and abdomen. AMLs are seen in 1/3 of S-LAM and nearly 90% of TSC-LAM patients.4 Renal cysts have been reported in patients with LAM, and concomitant polycystic kidney disease may develop from the genetic deletion of PKD1, which is adjacent to TSC2.28 Lymphangioleiomyomas are masses of LAM cell clusters within lymphatic vessels and lymph nodes that can mimic lymphomas, ovarian or renal cancers or other malignant tumors (Fig. 1D).29

Radiologic-pathologic correlation

On the chest radiograph, early signs of LAM include fine nodular, reticular or reticulonodular opacities. Over time, the reticular pattern may progress into a more irregular pattern, lung volumes may increase (50% of cases) and pulmonary cysts become visible.30 CT will invariably show diffuse cysts of varying size and profusion (Figure 1).31 The lung cysts in LAM are typically round, thin-walled (1–2 mm), and diffusely distributed throughout otherwise normal lung. The number of cysts is typically greater among those with symptomatic pulmonary impairment than in asymptomatic patients.30 The involvement of pulmonary cysts in the costophrenic sulci can distinguish LAM from pulmonary Langerhans Cell Histiocytosis (pLCH) that typically shows upper lung predominance with sparing of the sulci.32

The pulmonary cysts may develop from air-trapping by smooth muscle proliferation in the small airways.33 The LAM muscle cells stain with a monoclonal antibody, HMB-45 (human melanoma black-45), specific for LAM in this context (Fig. 2).34 There is profound lymphatic duct and lymph node involvement and obstruction, which accounts for the chylous accumulation in the pleura and peritoneum among patients with LAM yet unusual among TSC-LAM.35 Other lung findings described include septal thickening, presumed to be consequent to lymphatic obstruction36, centrilobular nodules that may reflect pneumocyte hyperplasia, and ground glass opacities or focal consolidations that may reflect hemosiderosis or hemorrhage.37

Figure 2. Histopathologic findings of LAM.

Figure 2.

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A. H&E stained section at low power shows a cystic structure with a nodule of LAM cells protruding into the cyst space in a polypoid manner. B. High power image of the LAM nodule demonstrating clusters of spindle shaped cells growing in a haphazard manner. C. HMB45 immunohistochemical stain of LAM cells shows patchy cytoplasmic staining. D. SMA (smooth muscle active) immunohistochemistry stain highlights the nodules of smooth muscle cells within the wall of a cyst in LAM. (Images courtesy of Dr. Carlyne D. Cool and Dr. Steve D. Groshong, Division of Pathology, National Jewish Health).

Renal angiomyolipomas are common (30–50% of patients) (Fig. 1). Other intrabdominal findings include hepatic angiomyolipomas, lymphangiomyomas, retroperitoneal lymph nodes and chylous peritoneum. The presence of characteristic lung cysts associated with either hepatic or renal AMLs and/or chylothorax supports a confident diagnosis of LAM.26

Management and Clinical Trails

Based on the landmark MILES trial (Multicenter International LAM Efficacy of Sirolimus),38 inhibition of mechanistic target of rapamycin (mTOR) is indicated for patients with abnormal lung function (FEV1 < 70% predicted), progressive lung disease or clinically significant chylous effusions. mTOR inhibitors are also effective for other presentations such as angiomyolipomas and lymphangeiomyomas and may decrease the frequency of pneumothoracies.39,40 The MILED (Multicenter Interventional LAM Early Disease) trial is investigating the safety and efficacy of low dose treatment to preserve lung function in earlier stages of disease (NCT03150914). Several clinical trials are investigating novel therapies involving mTOR inhibitors and other investigational treatments which can be found at The LAM Foundation website.41

Birt-Hogg-Dubé (BHD) Syndrome

Background

The BHD syndrome was first described in a case report of 2 siblings with unique skin lesions and a strong family history of similar skin lesions; one of the siblings later developed colon cancer.42 In 1977, Birt and colleagues described the autosomal dominance of the disorder among a large kindred with hereditary medullary carcinoma of the thyroid and skin lesions, which they diagnosed histologically as fibrofolliculomas.43 The majority of patients (~80%) currently present with diffuse pulmonary cysts.44

Pathogenesis

Numerous studies have defined the genetics and pathogenesis of BHDS. In 2001, the BHD gene locus was mapped to chromosome 17p45 and later narrowed to a 700kb region on chromosome 17p11.2.46 In 2005, Schmidt and colleagues reported germline mutations in 84% of affected families and more than 150 unique mutations in the folliculin (FLCN) gene have since been reported.47 Most result in loss-of-function mutations and support the role of FLCN as a tumor suppressor gene. The loss of FLCN leads to BHD-associated tumors such as kidney tumors, the most serious manifestation, occurring in up to 34% of patients by age 50.48 BHD syndrome has been associated with other neoplasms such as colorectal cancer,49 melanoma,50 thyroid and parathyroid tumors51 although data is limited to case reports and small series and the risk is uncertain.

Clinicoradiologic manifestations

The phenotypic expression of BHD syndrome is highly variable even among families sharing the same FLCN mutation. Patients may present with any combination of skin, pulmonary and renal findings. However, the absence of skin and renal manifestations does not exclude the diagnosis. Many BHD patients presenting with a pneumothorax are misdiagnosed as primary spontaneous pneumothorax or emphysema given the rarity of the syndrome.52

Skin manifestations include fibrofolliculomas, and acrochordons that are difficult to distinguish and may be spectrums of the same lesion.43 They are characterized by round, grayish-white papules 2–4mm in size and most often distributed along the face, trunk and neck, including the posterior ear (Fig. 3).53 Fibrofolliculomas are the most prevalent lesion and may be subtle so that patients may not seek medical care.

Figure 3. Characteristic findings of Birt-Hogg-Dube syndrome.

Figure 3.

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A. Axial CT shows elliptical thin-walled pulmonary cysts predominating in the paracardiac regions of the lower lungs. B. Subpleural cystic structure lined by bland alveolar cells without atypical morphology. C. White/gray papules on midface, forehead and post-auricular of a patient with Birt-Hogg-Dube syndrome characteristic of fibrofolliculomas or similar lesions (e.g., acrochordons). (Fig 3B, courtesy of Dr. Carlyne D. Cool, Division of Pathology, National Jewish Health).

Pulmonary cysts are the most common systemic manifestation and typically appear after the 4th and 5th decades but can appear during teenage years. They are elliptical or “floppy”, thin-walled and typically distributed along the basilar medial region of the lungs (Fig. 3). Studies suggest that the number and size of cysts typically remain stable.30 Cysts do not typically impact pulmonary function until the development of a pneumothorax. Histopathologic examination of cysts in BHD patients with recurrent pneumothorax reveal inner surfaces lined with type II pneumocyte-like cells suggesting slow-growing, hamartomatous cysts that may rupture.54

Escalon et al studied 47 subjects with isolated cystic lung disease in which thoracic radiologists were blinded to the final diagnoses, limited to BHD, LIP, or LAM.55 Lower lung-predominant cysts were significantly more likely among BHD or LIP compared with LAM, in which cysts were diffusely distributed. Furthermore, BHD patients were more likely to have elliptical, paramediastinal cysts. The authors propose an algorithm to reliably differentiate BHD from other cystic lung diseases (Fig. 4).55

Figure 4. Algorithm to reliably differentiate BHD from other cystic lung diseases (AJR 2019; 212: 1260–1264.

Figure 4.

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Management

Similar to LAM, pulmonary cysts predispose patients to develop pneumothoraces. Although the risk for pneumothorax is relatively low (~24%), the risk for recurrence is high (75%).56 For this reason, pleurodesis has been suggested with the first event to avoid the morbidity associated with repeat events.57 Certain activities, such as scuba diving, increase the risk of pneumothorax due to potential expansion of cysts from transthoracic pressure changes. Although air travel is considered safe among patients with diffuse cystic lung disease,58 subtle symptoms of pneumothorax may go unrecognized by patients.58 For this reason, patients with extensive cystic disease, prior pneumothoraces, or new symptoms of chest pain should seek evaluation prior to air travel. Tobacco smoking and of other substances is discouraged despite limited data that such exposure increased risk of pneumothorax.56

Screening for renal tumors should begin at age 20 (per expert opinion)59 or at the time of diagnosis preferably with magnetic resonance imaging, which is more sensitive and specific than ultrasonography, and avoids the cumulative radiation exposure with computed tomography. Surveillance should continue at least every 36 months until a mass is identified which will determine management.60 Most tumors have an indolent behavior. The risk of metastases increases with tumor size and kidney-sparing resection is recommended for tumors larger than 3cm in diameter, along with resection of all additional tumors detected during surgery.60

Genetic testing may detect germline mutations in the folliculin (FLCN) gene, which confirms the diagnosis. Some patients (~5%) may be FLCN mutation-negative by DNA sequencing yet carry intragenic deletions/duplications detectable by more advanced molecular diagnostic methods.61 The penetrance of FLCN mutations is high among affected families and genetic counseling should be encouraged for first-degree relatives of patients. Carriers of FLCN mutations should undergo regular (every 3 years) imaging surveillance for kidney tumors.60

Lymphoid interstitial pneumonia

Background

Lymphocytic Interstitial Pneumonia (LIP) is characterized by infiltration of the pulmonary interstitium by dense lymphoid tissue.62 The radiographic LIP pattern is most commonly seen as a pulmonary manifestation of systemic collagen vascular diseases.63 Other disease associations with LIP include dysproteinemias, infections (e.g., EBV or HTLV-1), and rarely drug reactions (e.g., phenytoin).64 The dense accrual of lymphoid tissue implies risk for lymphoproliferative disease, particularly small B cell lymphomas of extranodal marginal zone type, as well as polyclonal lymphoproliferative conditions associated with viral infections.63 Idiopathic LIP is rare and must be distinguished from systemic and lymphoproliferative conditions.

Pathogenesis

The histopathologic pattern involves a dense layer of lymphocytes, plasma cells and histiocytes with alveolar septal infiltration and along the bronchi and vasculature. Granulomatous and lymphocytic interstitial lung disease (GLILD) is considered a variant of LIP associated with common variable immunodeficiency (CVID), but cysts are rarely seen in GLILD.65 Germinal centers may become prominent along the airways and lymphatic channels in which lymphoproliferative conditions should be considered. In the idiopathic form of LIP, immunophenotyping would show absence of clonality.66 When the nodular lymphoid hyperplasia is prominent along the bronchioles then Sjogren’s syndrome should be strongly considered67 and co-existing amyloidosis may also be seen in this context.68 (Fig. 5B).

Figure 5.

Figure 5.

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A. Coronal CT in a patient with Sjogren’s syndrome shows multiple lower lung predominant thin-walled cysts with peribronchovascular predominance, compatible with LIP. B. Axial CT through the lower lungs in a patient with biopsy-proven LIP and amyloidosis in Sjogren’s syndrome shows a combination of irregular nodules, cysts and ground glass opacities. C. Low power image demonstrating diffuse interstitial infiltrate by mature lymphocytes and plasma cells. Cysts are seen adjacent to airways. D. Lymphoid follicles with germinal centers in a patient with Sjogren’s syndrome and cystic lung disease. E, F. CT scans two years apart in a patient with LIP and Sjogren syndrome show increased ground glass abnormality and septal thickening indicating progression of lymphocytic infiltrates. BAL demonstrated 60% lymphocytic predominance without monoclonality or infection. (Images C, D, images courtesy of Dr. Carlyne D. Cool, Division of Pathology, National Jewish Health).

Clinicoradiologic manifestations

The cystic airspaces associated with LIP range from 1 to 30mm, are typically peribronchovascular in distribution and appear to represent dilated small bronchi and bronchioles from partial obstruction by lymphocytic infiltration.69,70 Ground glass opacities, poorly defined centrolobular nodules, bronchovascular and septal thickening may also be seen.71 The ground glass opacities may improve with treatment but new cysts may develop in areas of centrilobular nodules and consolidations may evolve into honeycombing.72 Larger nodules (11–30 mm in diameter), consolidations, and pleural effusions are more common among LIP associated with lymphoma.67,73

Management considerations

The natural history of LIP varies according to the underlying disease process. When LIP is associated with autoimmune disease (e.g., Sjogren’s syndrome), management is based on the severity of pulmonary impairment and evidence of progression. Treatment is directed at the underlying condition and some regimens for extrapulmonary manifestations may also benefit the lung disease. It is important to exclude secondary conditions such as granulomatous and lymphocytic interstitial lung disease (GLILD) among patients with common variable immunodeficiency, HIV, and secondary infections from immune deficiency syndromes or secondary to immunosuppression. Lymphoma may develop in approximately 5% of patients with LIP with an increased risk in those with Sjogren’s syndrome.63 Malignant transformation may be suggested by larger nodules or those increasing in size, pleural effusions and alveolar consolidations67,73; polyclonality is key to differentiate LIP from lymphoma.74

Amyloidosis and light chain deposition

Background and pathogenesis

Amyloidosis is the abnormal deposition of low molecular weight proteins into highly structured fibrils which, in their native state, would otherwise circulate in plasma. The deposition of “amyloid deposits” result in a broad range of clinical manifestations depending on their type and location. The major types of systemic amyloidosis include the primary types (light chain [AL] and transthyretin [ATTR]), which account for the majority of systemic amyloid.75 Secondary amyloidosis (AA) is a rare systemic complication of chronic disease resulting in sustained production of serum amyloid A (SAA), an acute phase reactant, and most often affects the kidney leading to proteinuria.76 Light chain deposition disease (LCDD) reflects the presence of monoclonal deposits composed of light chains only and is typically associated with lymphoproliferative diseases with prominent kidney involvement.77

Clinicoradiologic manifestations

Pulmonary amyloidosis typically presents with multiple lung nodules. Cystic pulmonary amyloidosis is rare and may be associated with Sjogren syndrome or mucosa-associated lymphoid tissue (MALT) lymphoma (Fig. 6).78,79 The lung cysts are thought to arise from obstruction of distal airways from amyloid deposits.78 Pulmonary lung function tests may be normal, obstructive, or have an isolated reduction in diffusing capacity.78

Figure 6.

Figure 6.

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A. Axial CT image of thin-walled pulmonary cysts and nodules, some calcified, in a patient with biopsy-proved LIP and amyloidosis. B. Axial CT image of diffuse lung cysts in the mid and upper lung zones in a patient with advanced LCDD of the kidney secondary to multiple myeloma C. Nodular amyloidosis characterized by intraalveolar and interstitial deposits of amorphous eosinophilic material. D. Congo red stain highlights the amyloid material. (Image C, courtesy of Dr. Carlyne D. Cool, Division of Pathology, National Jewish Health. Image D, with permission, Rosane Duarte Achcar MD, FCAP, FASCP, Steve D. Groshong MD, PhD, Carlyne D. Cool MD, Differential Diagnoses in Surgical Pathology: Pulmonary Pathology, copyright 2017 Wolters Kluwer Health, Inc.

Management

The diagnosis of pulmonary amyloidosis requires lung biopsy to demonstrate amyloid deposits which stain with Congo red dye or exhibit apple-green birefringence under polarized light. Biopsy is usually considered for growth of a nodule to exclude other processes (e.g., lung cancer or lymphoma). LCDD can be progressive and lead to respiratory failure. Treatment is directed at the underlying lymphoproliferative disease, if present.80

Pulmonary Langerhans Cell Histiocytosis

Background

Pulmonary Langerhans Cell Histiocytosis (pLCH), previously called pulmonary eosinophilic granuloma or Histiocytosis X, is a smoking-related lung disease predominantly seen in young adults.81 By contrast, systemic Langerhans Cell Histiocytosis (LCH) is a rare histiocytic disorder characterized by single or multiple osteolytic lesions although histocytes can infiltrate any organ, particularly bones (although sparing the heart and kidneys). Systemic LCH may be diagnosed at any age but is more common in children (especially younger children) and has no apparent association with cigarette smoking.82 The two conditions appear to be unrelated yet are indistinguishable histologically when the systemic eosinophilic granuloma of LCH involves the lung.83

Pathogenesis

PLCH has two distinct histopathologic manifestations; a cellular and fibrotic phase. The natural history of pLCH includes the early cellular form with abundance of Langerhans cells and tissue eosinophilia.84 As the lesions age, Langerhans and other immune cells become progressively depleted and overshadowed by fibrosis. In some patients, only the residual stellate scar may be left with pulmonary function significantly compromised.85,86 In such cases, imaging may demonstrate diffuse disease yet biopsied tissue may exhibit only stellate fibrotic lesions centered on the terminal airways without any identifiable interstitial inflammatory disease. (Fig. 7).

Figure 7.

Figure 7.

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A,B Coronal CT images in a patient with pLCH show characteristic irregular cysts with mid to upper zone predominance, relative sparing of the costophrenic sulci, and scattered small nodules. C. Bronchiolocentric stellate (star-like) scars develop with aging of the lesions and depletion of the Langerhans cells. D. Immunohistochemical stain for CD1a highlights the Langerhans cells. (Images C, D courtesy of Dr. Steve D. Groshong, Division of Pathology, National Jewish Health).

Clinicoradiologic manifestations

pLCH typically presents in young adults (ages 20–40) who are cigarette smokers, with non-specific pulmonary symptoms (cough, dyspnea, chest pain), pneumothorax or may be incidentally diagnosed on imaging. Some may present with systemic symptoms (fatigue, weight, fever). Pulmonary cysts are seen in almost call cases; these may be thin- or thick-walled, often irregular in outline, and usually predominate in the mid and upper lungs (Fig. 7). Nodules are seen in many cases, and the combination of cysts and nodules in a cigarette smoker should always suggest pLCH. Extrapulmonary manifestations may involve the pituitary, bone, skin and lymph nodes and patients may present with bone pain or pathologic fractures, signs of diabetes insipidus or atypical skin lesions. Longitudinal study suggests that 5% of patients with pulmonary involvement alone at diagnosis may subsequently develop extrapulmonary manifestations.87

Management considerations

Evaluation should exclude other causes of cystic lung disease, including testing for alpha-1 antitrypsin deficiency particularly if there is airflow obstruction, and identify symptoms suggestive of extrapulmonary involvement. Lung function impairment, especially airflow obstruction, is predictive of adverse outcomes,84 and early diagnosis with lung function testing may facilitate early intervention. Once the diagnosis is confirmed, management includes (1) smoking cessation and avoidance of all second-hand smoking exposure, (2) consideration for pharmacotherapy (e.g., bronchodilators and chemotherapy), and (3) assessment for pulmonary-related complications such hypoxemic respiratory failure, pneumothoraces and secondary pulmonary hypertension.88

For systemic LCH and other histiocytic disorders, somatic mutations in the MAPK pathway, such as BRAF V600E, appear to correlate with more severe disease89 and treatment with vemurafenib, an inhibitor of BRAF V600 kinase, may decrease risk for disease progression.90 The role of targeted therapy for MAPK pathway mutations remains unclear, particularly for pLCH, however testing at the time of diagnosis should be considered whenever possible (ie., surgical lung biopsy) given the future potential for treatment in refractory cases.

Clinicoradiologic correlation

A systematic approach can narrow the differential diagnosis of diffuse cystic lung disease and starts with a detailed history and physical exam. For example, sicca symptoms may suggest autoimmune-related LIP, and smoking exposure is requisite for pLCH. A family history of recurrent pneumothoraces, skin lesions or kidney cancer may suggest BHD and physical exam may reveal BHD skin lesions or clues to TSC-LAM. Additional testing may provide diagnostic confirmation such as elevated serum VEGF-D level for LAM or pathogenic FLCN gene mutation for BHD. Other diseases such as amyloidosis and LCDD typically require tissue diagnosis. Gupta et al proposed an algorithmic approach to support the clinical evaluation for such diffuse cystic lung diseases. (Fig. 8)

Figure 8. An algorithmic approach to the diagnosis of diffuse cystic lung disease.

Figure 8.

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Modified from Gupta et al. 2015, Diffuse Cystic Lung Disease Part II, AJRCCM, Vol 192 p17–29, with permission of the American Thoracic Society. Copyright © 2022 American Thoracic Society. All rights reserved.

Conclusions

Lung cysts are commonly encountered with chest imaging and can be a diagnostic challenge. Expert review of chest HRCT is still the most valuable tool to narrow the diagnostic possibilities.91 An accurate diagnosis is required to facilitate treatment and, in some conditions, adequate surveillance of extrapulmonary manifestations for patients and affected family members.

Key Points:

  • Distinguish cysts from cavities and define anatomic distribution as focal vs diffuse

  • Identify tempo of disease progression and the clinical context

  • Review of high resolution computerized tomography (HRCT) scan with expert radiologists will help identify key features and refine diagnostic possibilities

  • Blood biomarkers and genetic testing may be required to establish diagnosis

  • Some conditions (ie. LAM and BHD) require surveillance of extrapulmonary manifestations such as renal and other abdominal tumors

Synopsis.

Cysts and cavities in the lung are commonly encountered on chest imaging. It is necessary to distinguish thin-walled lung cysts (≤ 2mm) from cavities and characterize their distribution as focal or multi-focal vs diffuse. Focal cavitary lesions are often caused by inflammatory, infectious, or neoplastic processes in contrast to diffuse cystic lung diseases. An algorithmic approach to diffuse cystic lung disease can help narrow the differential diagnosis and additional testing such as skin biopsy, serum biomarkers and genetic testing can be confirmatory. An accurate diagnosis is essential for management and disease surveillance of extrapulmonary complications.

Abbreviations:

LAM

lymphangioleiomyomatosis

BHD

Birt-Hogg-Dubé

LIP

Lymphoid interstitial pneumonia

pLCH

Pulmonary Langerhans Cell Histiocytosis

AML

Angiomyolipoma

HRCT

High-Resolution Computed Tomography

Footnotes

Disclosure statement: The authors have no disclosures related to the content of this work.

Contributor Information

Matthew Koslow, Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Associate Co-Director of LAM and Rare Lung Disease Clinic, National Jewish Health.

David A. Lynch, Department of Radiology, National Jewish Health.

Gregory P. Downey, Executive Vice President for Academic Affairs, Professor, Departments of Medicine, Pediatrics and Immunology and Genomic Medicine, National Jewish Health.

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