Clinico-etiological Characteristics of Cystic Lung Disease: A Retrospective Study

ABBREVIATIONS USED IN THIS ARTICLE

BAL = Bronchoalveolar lavage; BHD = Birt–Hogg–Dube; CLD = Cystic lung diseases; CT = Computed tomography; DIP = Desquamative interstitial pneumonia; FLCN-S = Folliculin gene-associated syndrome; HP = Hypersensitivity pneumonitis; HRCT = High-resolution computed tomography; LAM = Lymphangioleiomyomatosis; LCDD = Light-chain deposition disease; LIP = Lymphocytic interstitial pneumonia; MMP = Matrix metalloproteinase; PLCH = Pulmonary Langerhans cell histiocytosis; PJP = Pneumocystis jirovecii pneumonia; TSC = Tuberous sclerosis complex; TPC = Total pleural covering; VEGF = Vascular endothelial growth factor; VATS = Video-assisted thoracic surgery.

INTRODUCTION

A pulmonary cyst is defined as a usually thin walled (usually < 2 mm), round lucency in lung parenchyma, or a low-attenuating area that has a well-defined interface with normal parenchyma of the lung on chest-computed tomography. Multiple pulmonary cysts can be due to a heterogeneous group of orphan lung diseases clubbed under the umbrella term “cystic lung disease” (CLD). Cystic lung disease needs to be differentiated from cavity, bleb, bullae, emphysema, honeycombing, and pneumatocele, all of which may mimic a cyst. The differentiating features for these lucencies maybe cyst wall thickness, size of air-filled space, the location, and the clustering tendency of true cysts.¹ Awareness about CLDs has recently risen as a consequence to widespread use of high-resolution computed tomography (HRCT) in clinical practice among pulmonologists. Solitary or sporadic cysts can be commonly seen in otherwise-normal individuals. However, multiple pulmonary cysts can be part of various progressive lung diseases. Cysts are rarely found in individuals less than 55 years of age. However, an increase in prevalence is seen with age.^2,3 Etiological heterogeneity exists with CLD. Based on the pathophysiological mechanism involved, CLD can be classified broadly as genetic, congenital, inflammatory, infectious, smoking-related, lymphoproliferative, and neoplastic.^4,5 In this article, we analyze 14 cases retrospectively from a tertiary care center and evaluate the clinical spectrum of their presentation based on etiology.

MATERIALS AND METHODS

This was a retrospective analysis. The hospital electronic database was screened with Boolean operations and keywords for cysts OR pneumothorax. Among a total of 4,479 patients admitted to a respiratory unit /ICU during the period of January 2020–September 2022 at a tertiary care center in northern India, 14 patients with radiological diagnosis of CLD matched the relevant search. All relevant data of these patients were retrieved from the records.

All cases in this study had undergone chest radiograph and HRCT of the chest. One millimeter thin scans were performed on all patients using a 256-slice computed tomography (CT) scanner (Briallance ICT, 256 slice, Philips).

The CT scans were analyzed by a radiologist trained in lung CTs. All CTs with diffuse cysts were considered. An emphasis was made to exclude cyst mimickers like emphysema, bullae, honeycombing, etc.^3,6

The demographic characteristics, symptom profile of patients, laboratory data, serological analysis like vascular endothelial growth factor (VEGF), bronchoscopy and broncho-alveolar results, reports of lung biopsy, and data on follow-up visits were collected from the hospital patient records.

C-reactive protein, antinuclear antibodies, and VEGF were done on case-to-case basis. Transbronchial lung biopsy/video-assisted thoracic surgery (VATS) biopsy was performed on a case-to-case basis based on patient’s consent and risk of pneumothorax.

A multidisciplinary approach was resorted to when histopathological evidence was not available, and the diagnosis was arrived based on clinical profile, radiological features, and other systemic illness histories

RESULTS

In our study, 14 patients with diffuse CLDs were included. Table 1 depicts the salient characteristics of cases included in the study group and other relevant history and diagnostic modalities. The mean age of presentation was 42.14 (standard deviation 12.6, age range 16–62 years). About 64% (n = 9/15) patients were females and n = 5 were males.

Majority of the patients were symptomatic with dyspnea, n = 11/14, i.e., 78%, and cough was present in 28% (n = 4/14). One patient had hemoptysis at presentation, and four had pneumothorax at first presentation. Two patients were asymptomatic and were detected incidentally while evaluated for other conditions. Only three patients among 14 were smokers.

Spirometry and diffusion study data were available for 10 patients. About 40% (n = 4/10) patients had obstruction on spirometry, and n = 4 had no functional impairment. Five patients had shown diffusion impairment. Functional evaluation is depicted in Figure 1.

Radiologically, cysts were seen bilaterally in all patients except one who had unilateral cysts. In addition, one CT showed nodules and one CT showed associated ground glassing. None of the CT scans had shown mediastinal lymphadenopathy. Patients with pneumothorax underwent ICD insertion and pleurodesis with talc. Three patients had recurrent pneumothorax during follow-up. All patients with lymphangioleiomyomatosis (LAM) were started on sirolimus. All patients were counseled regarding symptomatology of pneumothorax and advised to seek immediate medical attention in such scenarios and regular follow-up.

Few representative images are depicted in Figures 2 and 6. Figure 2 shows CT image and bronchoalveolar lavage microscopy of a case of Pneumocystis jirovecii pneumonia (PJP). Figure 3 depicts a CT image and VATS lung biopsy of a case of Birt–Hogg–Dube (BHD) syndrome. Figure 4 shows CT and bronchoscopy image of a patient of Sjogren’s with CLD. Figure 5 depicts a CT image of a patient of LAM presenting with pneumothorax. Figure 6 depicts CT images of a LAM patient.

DISCUSSION

Pulmonary cystic diseases are rare orphan diseases. The term CLD refers to diverse pulmonary disorders grouped together, which are characterized by findings of parenchymal cysts on lung imaging, usually more than five cysts.⁶ Cystic lung disease is not so common among asymptomatic individuals who are below 55 years of age; however, their increasing trend of prevalence has been noticed in literature, with advanced age.² The peak incidence in age varies according to diseases, but commonly, it is seen in the third or fourth decade of life. Sex-based predilection depends on the underlying disease, e.g., LAM almost exclusively affects females, while pulmonary Langerhans cell histiocytosis (PLCH) most commonly affects young adults with a sex distribution equal to slightly female predominant. No particular gender predilection for BHD. Nearly universal association of PLCH with current or former cigarette smoking is well established. Ennis et al. commented that most of the respiratory physicians in their clinical practice will not come across more than a single CLD case per year.^7,8 In our study, we included a total of 14 cases seen by different respiratory physicians over a period of two-and-a-half years. The age and gender-based distribution in our study was in agreement with previous reported incidences. The higher number of patients could be attributed to the center being a tertiary care referral center.

Cystic lung disease in lung parenchyma may be caused by various rare disorders of the lungs. The diseases mainly associated with CLD are LAM, PLCH, folliculin gene-associated syndrome (FLCN-S) or BHD syndrome, lymphocytic interstitial pneumonia (LIP), PJP, pulmonary amyloidosis, light-chain deposition disease (LCDD), and metastases of sarcomas. Other rare causes of CLD include desquamative interstitial pneumonia (DIP), hypersensitivity pneumonitis (HP), follicular and constrictive bronchiolitis, hereditary syndromes like Marfan syndrome, neurofibromatosis 1, Ehlers–Danlos syndrome, Proteus syndrome, infectious causes, e.g., chronic pulmonary paracoccidioidomycosis and coccidioidomycosis and tracheobronchial papillomatosis.^8,9 The cyst formation pathogenesis remains unclear and several mechanisms have been suggested in different diseases for cyst formation. Distal over inflation after a check valve obstruction is one of the common known mechanisms causing lung cysts and this mechanism has been linked with disease such as foreign body, pneumatocele, metastatic neoplasm, PLCH, and LAM.^10–12 Another pathway thought to be inducing cyst formation in lungs is ischemia. Obstruction of small capillaries that supply terminal bronchiole causes airway ischemic necrosis and consequent dilatation.¹³ A molecular mechanism representing LAM, LCH, and LCDD has also been proposed in which various enzymes, e.g., matrix metalloproteinase (MMP), podoplanin (D2-40), and matrix-degradation enzymes, induce remodeling of lung tissue.¹⁴ Genetic mutation also plays a role in pathogenesis of CLD. Birt–Hogg–Dubé syndrome is one such example where the lung cyst is usually found abutting interlobular septa with no inflammation. Here, the abnormality is suggested at the alveolar–septal junction. Loss-of-function mutations on chromosome 17p in the folliculin gene (FLCN) cause BHD.¹⁵

Regardless of the cause of the cyst, the clinical presentation of patients is often asymptomatic with incidental detection of cysts on chest imaging for some other reason. They can also present with cough and shortness of breath. In cases of spontaneous pneumothorax, the patient may present with acute shortness of breath. In our study, most of the cases presented for evaluation of breathlessness and cough. Pneumothorax has been identified as a sentinel event in CLD. In our study, four patients had pneumothorax as the first presentation that assisted in diagnosis. A careful history about previous pneumothoraces and exposure, e.g., smoking, vaping, and drug use should be sought. Thorough past medical history, family, and occupational history, including previous skin and kidney disorders, hematological disorders and malignancy are of importance. Two cases of PJP in our study were HIV positive, while a case of metastatic cyst was a known case of colorectal cancer. Such clues emphasize the importance of past history in reaching a diagnosis and further management of these cases. If tuberous sclerosis complex (TSC) is suspected, then family history of renal disease, epilepsy, or learning difficulties is useful. Since new mutations are common, a negative family history does not exclude the diagnosis.

Definitive diagnosis may require bronchoalveolar lavage (BAL) and biopsy for histopathological confirmation depending on the underlying disease suspicion. Certain serological tests can be helpful in establishing the diagnosis of specific lung diseases. For example, in suspected cases of systemic connective tissue disorder that might be associated with LIP, especially Sjogren syndrome, serologic studies such as antinuclear antibody, anti-Ro/SSA, and anti-La/SSB antibodies, and a rheumatoid factor should be obtained. In common variable immunodeficiency suspects, serum immunoglobulin levels and HIV need to be tested. VEGF-D levels in serum are elevated in many patients with sporadic and TSC LAM. A level of VEGF-D above 800 pg/mL is highly specific for LAM and, in a patient with compatible radiographic features, is considered diagnostic and invasive modalities are not recommended.^16,17 FLCN mutation analysis is available as a diagnostic test and detects mutations in 81–88% of patients with BHD.¹⁸ Because of the complexity of understanding of these diseases and the requirement for specialized investigations, reaching a final diagnosis may take some time.^7,19

Radiological assessment of pulmonary cysts primarily needs differentiation from pulmonary cavities because of very different etiologies of these two entities. Careful observation of cyst size and shape, as well as the presence of any ancillary findings, also helps in refining differential diagnosis. Ultimately, histopathology correlation is required in many cases. High-resolution computed tomography appearances of LCH in early stages may present as nodules, while cysts tend to develop later, predominantly distributed diffusely mainly in the upper lobes. The cysts in LAM are thin-walled and round, which usually spares the extreme apices and may involve juxtaphrenic recess. In LIP, universal features are ground-glass opacities and nodules, small cysts (less than 3 cm), which are thin-walled and distributed in random distribution. Identification of small cysts dispersed within the ground-glass opacity is a unique feature of DIP, seen in about a third of patients. In BHD, reports suggest lower zone preponderance for cysts, with a history of recurrent pneumothorax being an important clue.^20,21 Lung function test findings depend upon the underlying disease. In BHD, the lung function is usually preserved with reduced diffusion capacity of lung for carbon monoxide (DLCO), while in LAM and PLCH spirometry, findings of obstruction with reduced DLCO are observed. While LIP, amyloidosis, LCDD, etc., are associated with a restriction on spirometry with reduced DLCO.²²

A comprehensive review of radiologic abnormality, clinical assessment, and laboratory findings pointing toward either pulmonary or systemic disease may be helpful to distinguish from numerous differentials to arrive at a diagnosis. The treatment of diffuse CLD depends on etiology identification. Various modalities of disease-specific treatments available include mTOR inhibitor Sirolimus in LAM, corticosteroids and chemotherapeutic agents in LCH and LIP, antibiotics and corticosteroids in Pneumocystis pneumonia infection, treatment of underlying infection, malignancy and lymphoproliferative disorders and lung transplantation in many advanced diseases.^21,23 Cooley et al. have elucidated in their study that since CLD-associated spontaneous pneumothorax has a very high rate of recurrence and therefore pleurodesis should be offered to these patients after the very first episode.²⁴ Also, pleurodesis is not a contraindication for lung transplant in these patients. Another technique, total pleural covering (TPC), which involves wrapping the visceral pleura in a bioabsorbable mesh, has reported favorable outcomes in preventing pneumothorax recurrence in CLD.²⁵

LIMITATIONS OF THE STUDY

The retrospective single-center design and small cohort size limit the generalizability of our findings. Moreover, patient selection bias as the hospital is a tertiary care referral center. Also, spirometry and biopsy were not available for all patients.

CONCLUSION

Cystic lung disease, though rare, is not infrequent, and most pulmonologists encounter these cases. Due to lack of detailed reliable information about such conditions, patients as well as treating physicians may feel isolated and lonely about CLD. Awareness about CLD and a multidisciplinary approach can assist in identifying the etiology. With the availability of serological tests (like VEGF), biopsy is not mandatory in all cases. Due to myriad presentations and differentials, a holistic insight is required. Detailed history, regular follow-up, pleurodesis, and counseling can impact the patient’s morbidity and mortality. Forthcoming decades will improve upon the prevailing knowledge of such diseases and enable us to better evaluate and prescribe personalized treatment. It is also important to have a national registry for this group of disorders.

ORCID

Priyanka Singh https://orcid.org/0000-0002-2468-8394

Amit Singh Wasan https://orcid.org/0000-0002-6698-0449

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