Cystic Lung Diseases

A Case-Based Discussion

 

Prof. Ravindran Chetambath, Senior Consultant in Pulmonology & Chief of Medical Services

Baby Memorial Hospital, Calicut, Kerala

 

Case Summary 1:

A 58-year-old female presented to the outpatient department with a three-month history of persistent cough and expectoration, associated with intermittent episodes of haemoptysis and low-grade fever. She also complained of dyspnoea on exertion. On further enquiry, she gave a history of recurrent respiratory illnesses over the preceding ten years, characterised by episodes of cough, scanty sputum production, haemoptysis and fever, occurring approximately two to three times annually.

A 2014 CT scan of the thorax reportedly revealed bronchiectasis. She had subsequently been receiving treatment and regular follow-up for bronchiectasis over the past four years. She also gave a history of anti-tuberculous treatment (ATT) approximately 25 years earlier, although the details of the diagnosis, treatment regimen and duration were unavailable. Her medical history was also significant for hypothyroidism, for which she was on regular thyroid hormone replacement therapy.

Clinical findings revealed a febrile, tachypnoeic patient without clubbing. Her oxygen saturation at room air was 90%. Chest examination showed coarse crackles on the right side predominantly in the upper field. Her sputum was negative for AFB and MTB PCR. Routine culture revealed growth of Klebsiella pneumoniae. Pulmonary function testing was not attempted as she had haemoptysis.

Chest radiography revealed a few cystic lesions in the right upper and mid zones (Figure 1A). High-resolution computed tomography (HRCT) of the thorax demonstrated a large cystic lesion in the right upper lobe, surrounded by a cluster of smaller cystic lesions, producing a characteristic bunch-of-grapes appearance (Figure 1B).

In view of the extensive cystic changes and recurrent respiratory symptoms, surgical intervention was advised. However, the patient declined surgery. She was therefore managed conservatively with appropriate medical treatment and advised regular clinical and radiological follow-up.

 

Figure 1A: X-ray chest, PA view showing a few cystic lucencies in the right upper zone. 1B: CT Thorax clearly depicting multiple thin-walled cystic shadows in the right upper lobe, with a large cyst being surrounded by multiple small cysts.

Case Summary 2:

A 26-year-old female was referred to our hospital with a six-day history of fever and cough with purulent expectoration. She had initially been managed at a local healthcare facility for five days; however, in view of the unsatisfactory clinical response, she was referred for further evaluation and management. She also complained of breathlessness on exertion.

On further enquiry, she gave a history of recurrent respiratory symptoms dating back to early childhood. These episodes were characterised by cough, scanty sputum production and fever, occurring approximately two to three times every year. She had been diagnosed with bronchiectasis and was receiving treatment for the same.

Chest radiography revealed multiple cystic lesions in both lungs (Figure 2A). A CT scan of the thorax performed in 2011 had reportedly been interpreted as showing bronchiectasis. However, a review of the HRCT images revealed a distinctive pattern of cystic lung involvement. Multiple cystic lesions were noted in the right upper lobe and left lower lobe. In both locations, a dominant large cyst was surrounded by a cluster of smaller cysts, producing a characteristic bunch-of-grapes appearance (Figures 2B and 2C).

Interestingly, the lung parenchyma surrounding these cystic lesions appeared relatively preserved. There was no evidence of associated pulmonary fibrosis, mucus plugging or significant volume loss. Spirometry demonstrated a restrictive ventilatory pattern.

In view of the bilateral distribution of the cystic lesions and the potential risk of compromising the remaining functional lung tissue, surgical intervention was not considered a preferred treatment option. The patient was therefore managed conservatively with appropriate medical therapy, with advice for regular clinical and radiological follow-up.

                     

Figure 2: A: X-ray chest showing bilateral cystic lesions in the right upper zone and left lower zone. B & C: CT Thorax showing the characteristic cysts.

Discussion

Q1. What are the differential diagnoses to be considered in these clinical scenarios?

The differential diagnosis of cystic lung lesions in patients presenting with recurrent respiratory infections from childhood is broad. It includes congenital developmental abnormalities, acquired cystic lung diseases and certain diffuse cystic lung disorders.

The important differential diagnoses include:

1.     Cystic bronchiectasis: Characterised by irreversible dilatation of the bronchi, often associated with recurrent respiratory infections, haemoptysis and chronic sputum production. It is an important differential diagnosis of CPAM.

2.     Bronchogenic cyst: A congenital developmental abnormality arising from abnormal budding of the tracheobronchial tree. It usually presents as a solitary cyst in the mediastinum or lung parenchyma.

3.     Congenital pulmonary airway malformation (CPAM): A developmental abnormality of the lower respiratory tract characterised by abnormal cystic or adenomatous lung tissue. It may present with recurrent respiratory infections during childhood or later in adult life.

4.     Birt–Hogg–Dubé syndrome: An inherited disorder characterised by multiple pulmonary cysts, spontaneous pneumothorax, characteristic skin lesions and an increased risk of renal tumours.

5.     Lymphangioleiomyomatosis (LAM): A rare cystic lung disease predominantly affecting women of reproductive age. HRCT typically demonstrates multiple, bilateral, thin-walled cysts distributed diffusely throughout the lungs.

6.     Lymphocytic interstitial pneumonia (LIP): A lymphoproliferative interstitial lung disease characterised by pulmonary lymphocytic infiltration and multiple cysts, often associated with autoimmune disorders.

7.     Tuberous sclerosis complex (TSC): A genetic disorder that may be associated with pulmonary LAM, particularly in women, in addition to characteristic extrapulmonary manifestations.

8.     Bronchopulmonary sequestration: A congenital lung malformation consisting of non-functioning lung tissue that lacks normal communication with the tracheobronchial tree and receives its arterial supply from the systemic circulation.

9.     Bronchial atresia: A congenital interruption of a bronchus, resulting in distal mucus impaction (bronchocele) and hyperinflation of the affected lung segment.

10.  Post-infectious pneumatoceles: Acquired, thin-walled air-filled cystic spaces that may develop following pulmonary infections, particularly staphylococcal pneumonia.

Although all these conditions may produce cystic abnormalities on imaging, their clinical presentation, distribution and characteristic HRCT features help differentiate them.

Q2. What is the most probable clinical diagnosis and why?

The most probable diagnosis in these two patients is congenital pulmonary airway malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM).

CPAM is a developmental abnormality of the lower respiratory tract characterised by abnormal formation of terminal bronchiolar structures, resulting in cystic or adenomatous changes in the affected lung tissue.

The clinical spectrum is wide. CPAM is frequently detected incidentally during routine antenatal ultrasonography. However, depending on the extent and type of the lesion, it may cause fetal compromise and hydrops, neonatal respiratory distress or remain clinically silent until childhood or adulthood. In older children and adults, recurrent respiratory infections, chronic cough, haemoptysis and occasionally pneumothorax may lead to its diagnosis.

In both the present cases, the history of recurrent respiratory symptoms dating back to early childhood suggests an underlying congenital pulmonary abnormality. The characteristic HRCT appearance of a dominant large cyst surrounded by multiple smaller cysts, resembling a bunch of grapes, further raises the possibility of CPAM.

Both patients had previously been diagnosed and treated as cases of bronchiectasis. This is understandable because cystic bronchiectasis is an important radiological and clinical differential diagnosis of CPAM.

Nevertheless, the diagnosis remains presumptive on the basis of the available clinical and radiological findings. Histopathological examination is required for definitive confirmation. A detailed review of the HRCT images is also essential to exclude other congenital cystic lung malformations.

Q3. How will you confirm the diagnosis?

CPAM is increasingly diagnosed during the antenatal period by routine fetal ultrasonography. Depending on the appearance and extent of the lesion, fetal magnetic resonance imaging (MRI) may be used for further characterisation and assessment of the remaining functional lung tissue.

In patients diagnosed after birth, particularly those presenting during childhood or adulthood, HRCT of the thorax is the principal imaging investigation. It helps determine the number, size and distribution of cysts, the extent of lung involvement and the presence of associated abnormalities.

Contrast-enhanced CT may be particularly useful when bronchopulmonary sequestration or a hybrid congenital lung lesion is suspected, as it helps identify an anomalous systemic arterial supply.

Although characteristic imaging findings may strongly suggest CPAM, HRCT alone cannot always establish the definitive diagnosis. Histopathological examination of the resected lung tissue remains the reference method for confirmation and classification.

A routine percutaneous or transbronchial lung biopsy is not recommended in every patient with suspected CPAM. In selected cases where imaging is atypical or malignancy is suspected, tissue diagnosis may be necessary following multidisciplinary assessment.

Q4. What is the best treatment option for these patients?

The management of CPAM depends on the age of the patient, clinical presentation, type and extent of the lesion, associated complications and the amount of functional lung tissue that can be preserved.

Prenatal management:

Most antenatally detected CPAM lesions can be monitored with serial fetal ultrasonography. Fetal MRI may be considered in selected cases. The development of fetal hydrops, significant mediastinal shift or evidence of cardiovascular compromise indicates a high-risk lesion requiring specialist fetal medicine assessment.

Selected severe cases may require antenatal intervention, including maternal corticosteroids, cyst drainage or thoracoamniotic shunting, depending on the lesion characteristics and gestational age. Pregnancy termination is considered only in exceptional circumstances, after detailed assessment and counselling, when the fetal prognosis is extremely poor.

Postnatal management:

·        Symptomatic neonates and infants with respiratory distress or significant complications generally require early surgical intervention after stabilisation.

·        Elective surgical resection is often considered for asymptomatic lesions detected antenatally, although the optimal management of these patients remains controversial.

·        Older children and adults presenting with recurrent infections, haemoptysis, pneumothorax or other complications are generally considered for surgical resection, provided the lesion is amenable to surgery and adequate functional lung reserve can be maintained.

·        Conservative management with regular clinical and radiological surveillance may be appropriate in selected patients, particularly when lesions are bilateral or extensive, surgical morbidity is expected to be high, or the patient declines surgery.

Management of the present cases:

Both patients had recurrent respiratory infections, and the HRCT findings suggested CPAM. Surgical intervention was considered. However, in the second patient, the bilateral distribution of the lesions raised concerns regarding the extent of lung resection and preservation of functional lung tissue. Conservative medical management with regular follow-up was therefore adopted.

The decision regarding surgery in such patients should be individualised after discussion involving pulmonologists, thoracic surgeons and radiologists.

Q5. What complications can occur in patients with CPAM?

The important complications associated with CPAM include:

1.     Recurrent pulmonary infections: Abnormal cystic lung tissue may predispose patients to recurrent episodes of pneumonia and chronic respiratory symptoms.

2.     Haemoptysis: Recurrent infection and inflammation involving the abnormal lung tissue may result in haemoptysis, which can occasionally be significant.

3.     Pneumothorax: Rupture of a cyst into the pleural cavity may result in spontaneous pneumothorax.

4.     Respiratory compromise: Extensive lesions may cause compression of the surrounding normal lung tissue, resulting in impaired lung function and respiratory distress, particularly during the neonatal period.

5.     Malignant associations: Although uncommon, certain pulmonary malignancies have been reported in association with congenital cystic lung lesions. Mucinous adenocarcinoma has been described in association with CPAM, particularly in adults. Pleuropulmonary blastoma (PPB), a rare malignant tumour of childhood, may also present as a cystic lung lesion and can mimic CPAM, particularly type 4 CPAM. It is important to recognise that PPB is not simply a routine complication of CPAM; distinguishing between these entities is an important diagnostic consideration.

Q6. What are the important clues that help differentiate CPAM from cystic bronchiectasis in adults?

·        History of recurrent infections from childhood:  Both bronchiectasis and CPAM present with recurrent respiratory infections and haemoptysis. Expectoration is usually copious in bronchiectasis

·        Localised versus diffuse distribution of cysts: CPAM is mostly localised whereas bronchiectasis presents with bilateral involvement.

·        Relationship of cystic spaces to the bronchial tree: Cystic lesions are in communication with the bronchial tree in bronchiectasis.

·        Presence or absence of bronchial wall thickening and mucus plugging: Thick wall, mucus plugging, and air-fluid levels are mostly encountered in bronchiectasis.

·        Associated fibrosis, volume loss and architectural distortion: Associated fibrosis, volume loss, and architectural distortion are common features of bronchiectasis.

·        Histopathological differentiation where available: Histopathological examination of the resected lung tissue remains the reference method for confirmation and classification

 

 

 

Cystic Diseases of the Lungs

Introduction

A lung cyst is defined as a round, circumscribed air-containing space surrounded by a thin epithelial or fibrous wall, usually less than 2 mm in thickness ¹. On computed tomography (CT), lung cysts appear as well-defined, round parenchymal lucencies or low-attenuation areas surrounded by relatively normal lung parenchyma. Although they predominantly contain air, cysts may occasionally contain fluid or solid material ¹.

With the widespread use of CT in routine clinical practice, lung cysts are being increasingly recognised, either as incidental findings or as manifestations of underlying pulmonary diseases. Several mechanisms have been implicated in cyst formation, including check-valve airway obstruction resulting in distal airspace dilatation, ischaemia and necrosis of airway walls, and destruction of lung parenchyma by proteolytic enzymes ².

An important initial step in the radiological evaluation of lung cysts is to distinguish true cysts from other air-filled or cyst-like lesions. These lesions may have overlapping imaging characteristics, and their terminology is sometimes used interchangeably. However, recognising their distinguishing morphological features is essential for arriving at an accurate diagnosis.

Cyst-Like Lesions

Several air-filled lesions of the lung can mimic true lung cysts on imaging. These include cavities, bullae, pneumatoceles, centrilobular emphysema, honeycombing and cystic bronchiectasis. They differ from true lung cysts in their morphology, wall thickness, distribution and relationship with the surrounding lung parenchyma. They include cavity, bulla, pneumatocele, centrilobular emphysema, honeycombing and cystic bronchiectasis

The principal radiological characteristics that help differentiate these entities are summarised in Table 1

Air-Filled Lung Lesions	Characteristics
Cyst	Round Well-defined thin wall (< 2 mm)
Cavity	Irregular Thick wall
Bulla	More than 1 cm in size Imperceptible thin wall
Pneumatocele	Round Thin-wall
Centrilobular emphysema	Usually without visible walls Central dot
Honeycombing	Clustered 3–10 mm cystic lesions Well-defined 1–3 mm thick walls One or more layers
Cystic bronchiectasis	Tubular rather than spherical

 

                    Table 1: Radiological characteristics of true lung cyst and cyst-like lesions

Cystic Lung Diseases

Lung cysts can be classified as solitary/localized cysts or multiple/diffuse cysts. Single or several cysts in a localised area are classified as solitary/localized cysts, while multiple or numerous cysts distributed in both lungs are classified as multiple/diffuse cysts.

 

 

Incidental Cysts

Solitary or a few small pulmonary cysts may be detected incidentally on chest CT. One study reported pulmonary cysts in 25% of individuals over 75 years of age, with none detected in those younger than 55 years ³. Another study reported lung cysts in 7.6% of subjects, with multiple cysts observed in only 0.9%. These cysts are typically solitary, located in the peripheral lower lungs, and remain stable or increase slightly in size over time. They are not associated with impaired lung function and may represent part of the normal ageing process ⁴. Differentiating incidental cysts from cystic lung diseases is important. Advanced age, a solitary or small number of cysts, lower peripheral distribution, and absence of associated parenchymal or extrapulmonary abnormalities favour an incidental finding.

Intrapulmonary Bronchogenic Cyst

A bronchogenic cyst is a congenital developmental anomaly resulting from abnormal budding or branching of the primitive foregut during early embryogenesis, usually between the 26th and 40th days of gestation ⁵. Although these cysts most commonly occur in the middle mediastinum along the tracheobronchial tree, approximately one-third are intrapulmonary, with a predilection for the lower lobes ⁶. Intrapulmonary bronchogenic cysts are usually fluid-filled, while air-filled cysts are uncommon. On CT, they typically appear as well-defined, homogeneous, spherical lesions with smooth or occasionally lobulated margins. They may contain fluid or, rarely, air, with or without an air-fluid level ⁷. Air-filled cysts may be difficult to distinguish from lung abscesses or infected bullae. Clinical presentation, associated inflammatory changes, and comparison with previous chest radiographs or CT scans may help establish the diagnosis.

Cystic Bronchiectasis

Bronchiectasis is an irreversible, localised or diffuse dilatation of the bronchi, usually resulting from chronic infection, proximal airway obstruction, or congenital abnormalities ¹. Based on their morphological appearance, dilated bronchi are classified as cylindrical, varicose, or cystic ¹. Cystic bronchiectasis may mimic pulmonary cysts, particularly when dilated airways are viewed in cross-section. Careful assessment of contiguous CT sections helps distinguish the two. Tubular rather than spherical morphology, continuity with branching airways, bronchial wall thickening, centrilobular nodules or opacities, and associated air-trapping favour bronchiectasis over true pulmonary cysts.

Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare, progressive multisystem disease that predominantly affects the lungs of women of childbearing age ⁸. It occurs either sporadically or in association with tuberous sclerosis complex (TSC-LAM), an autosomal-dominant neurocutaneous disorder characterised by hamartomatous lesions in multiple organs⁹. Histologically, LAM is characterised by proliferation of abnormal smooth muscle-like cells (LAM cells) around small airways, blood vessels, lymphatics, and within the pulmonary interstitium ⁹. Cyst formation is thought to result from a combination of airway obstruction with distal air trapping and progressive destruction of lung parenchyma mediated by protease–antiprotease imbalance ⁹.

Lymphatic involvement may lead to chylous pleural effusion (chylothorax) or chylous ascites. Spontaneous or recurrent pneumothorax is a common complication and may be the presenting manifestation in up to 50% of patients ¹⁰.

On CT, LAM is characterised by numerous, thin-walled, well-defined, round or oval cysts, diffusely and relatively symmetrically distributed throughout both lungs, without lobar predominance (Figure 3). Cysts typically measure 2–10 mm, although some may reach 30 mm. The intervening lung parenchyma is usually preserved¹⁰. Less commonly, small nodules, reticulation, or ground-glass opacities may be present¹⁰. Associated findings include pneumothorax, chylothorax, and other manifestations of lymphatic involvement. Extrapulmonary abnormalities, particularly renal angiomyolipomas and other renal lesions associated with TSC, may provide important diagnostic clues ⁹.

Figure 3: Multiple diffuse thin-walled cysts with normal intervening lung in LAM

Birt-Hogg-Dubé Syndrome

Birt-Hogg-Dubé syndrome (BHD) is a rare, autosomal-dominant, multisystem disorder characterised by cutaneous fibrofolliculomas, pulmonary cysts, and an increased risk of renal neoplasms ^11,12. It is caused by pathogenic variants in the FLCN gene, which encodes folliculin. On CT, multiple pulmonary cysts are detected in more than 80% of affected adults, while the intervening lung parenchyma is generally normal ^2,11. Pulmonary cysts are associated with an increased risk of spontaneous pneumothorax, which may be the initial manifestation of the disease ². Histologically, BHD-associated cysts may resemble emphysematous spaces ².

On CT, BHD is characterised by multiple, thin-walled cysts of variable size and shape, predominantly distributed in the lower and medial lung zones, particularly in the subpleural and paramediastinal regions ¹³. Cysts may be round, oval, lentiform, lobulated, or irregular, and are typically surrounded by normal lung parenchyma (Figure 4). Larger cysts, particularly in the lower lobes, may have a lobulated or multiseptated appearance. Cysts may also abut or incorporate adjacent lower-lobe pulmonary vessels, including the proximal portions of pulmonary arteries and veins ¹⁴. The predominance of cysts in the lower medial lung regions, with relative sparing of the upper lungs, is a useful diagnostic feature.

The diagnosis of BHD should be suspected in patients presenting with spontaneous or recurrent pneumothorax, particularly when accompanied by a family history of pneumothorax, characteristic skin lesions, or renal tumours. Cutaneous manifestations may include multiple fibrofolliculomas, typically involving the face, neck, and upper trunk. Renal manifestations include bilateral or multifocal renal tumours, often with chromophobe or hybrid oncocytic-chromophobe histology.

Diagnosis: Clinical diagnosis is based on established major and minor criteria. One major criterion or two minor criteria are required. The major criterion is the presence of more than five fibrofolliculomas or trichodiscomas, with at least one lesion confirmed histologically. Minor criteria include:

·        Bilateral, basally located pulmonary cysts without another identifiable cause.

·        Renal cell carcinoma occurring before 50 years of age.

·        Multifocal or bilateral renal cell carcinoma.

·        Renal cell carcinoma with mixed chromophobe and oncocytic histology.

·        A first-degree relative with BHD.

Molecular diagnosis is established by identifying a heterozygous germline pathogenic variant in the FLCN gene in a patient with suggestive clinical or radiological findings.

Management: Management is directed towards the cutaneous, pulmonary, and renal manifestations. Fibrofolliculomas can be treated with laser ablation or surgical excision for cosmetic reasons, although recurrence is common. Pneumothorax is managed according to standard principles; surgical pleurodesis should be considered following recurrent episodes because of the high risk of recurrence. Renal surveillance is essential, as patients have an increased lifetime risk of renal malignancy. Renal tumours smaller than 3 cm can generally be monitored with periodic imaging. Once a tumour approaches or exceeds 3 cm, nephron-sparing surgery, such as partial nephrectomy, is preferred whenever feasible to preserve renal function. Lifelong renal surveillance is recommended.

Figure 4: Bilateral thin-walled cysts mostly distributed peripherally with left-sided pneumothorax suggestive of BHD

 

Desquamative Interstitial Pneumonia

Desquamative interstitial pneumonia (DIP) is characterized histopathologically by the accumulation of numerous pigmented alveolar macrophages within the distal airspaces ¹⁵. It is classified as a smoking-related interstitial lung disease in the international multidisciplinary classification of idiopathic interstitial pneumonias ¹⁶. Up to 90% of patients have a history of cigarette smoking, although DIP may also occur in association with occupational exposure to inhaled toxins, drug reactions, viral infections, and autoimmune diseases ¹⁵.

On CT, DIP typically presents with bilateral, patchy ground-glass opacities, predominantly involving the lower and peripheral lung regions. Fine reticular opacities may also be present. An important feature is the presence of small, usually less than 2 cm, thin-walled cysts within areas of ground-glass opacity ¹⁷. These cysts are generally discrete, with imperceptible or barely perceptible walls, although occasional clustering may occur. Honeycombing can be seen in advanced disease but is uncommon ¹⁸. Cysts are thought to result from dilatation of bronchioles and alveolar ducts; in advanced disease, they may also reflect early emphysematous changes or fibrotic remodelling ¹⁰. The coexistence of small cysts and ground-glass opacities is a useful radiological clue to DIP and has been reported in approximately one-third of patients ¹⁵.

Pulmonary Langerhans Cell Histiocytosis

Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon smoking-related interstitial lung disease that predominantly affects young adults, with a strong association with cigarette smoking ^9,10. It is characterised histopathologically by the accumulation of Langerhans cells and other inflammatory cells around small airways, resulting in the formation of bronchiolocentric granulomatous nodules ¹⁰. These nodules may undergo cavitation and subsequent destruction of the bronchiolar walls, leading to the formation of irregular, thick- or thin-walled cysts. With disease progression, cysts may enlarge and coalesce, producing characteristic bizarre or irregular shapes.

Histopathologically, lesions at different stages of evolution are often present. Early lesions consist of cellular bronchiolocentric infiltrates containing Langerhans cells, lymphocytes, and eosinophils. These evolve into stellate granulomatous nodules, followed by progressive fibrosis and destruction of the involved airways, eventually leaving fibrotic scars surrounded by enlarged airspaces ¹⁰.

On CT, PLCH typically demonstrates a combination of small centrilobular nodules, cavitating nodules, and cysts of variable wall thickness and size. Cysts may be round or oval in the early stages but become irregular, branching, or bizarre-shaped as the disease progresses. The abnormalities predominantly involve the upper and middle lung zones, with relative sparing of the lower lobes and costophrenic angles. The coexistence of nodules and bizarre-shaped cysts in a young smoker, particularly with this characteristic distribution, strongly suggests PLCH.

Lymphoid Interstitial Pneumonia

Lymphoid interstitial pneumonia (LIP) is an uncommon lymphoproliferative interstitial lung disease characterized by diffuse infiltration of the pulmonary interstitium by polyclonal lymphocytes and plasma cells ⁹. Although idiopathic LIP is classified as a rare idiopathic interstitial pneumonia ¹⁶, most cases occur secondary to underlying systemic disorders. Important associations include Sjögren's syndrome and other connective tissue diseases, HIV infection, Hashimoto's thyroiditis, and systemic lupus erythematosus ^9,16.

Histopathologically, LIP is characterized by diffuse infiltration of alveolar septa and the interstitium by small lymphocytes and plasma cells, often with reactive lymphoid follicles ^9,10. Pulmonary cysts are thought to develop predominantly through bronchiolar narrowing or obstruction by lymphoid infiltrates, producing a check-valve mechanism and distal airspace dilatation. Vascular obstruction and associated ischaemic changes may also contribute to cyst formation ⁹.

On CT, LIP typically shows a combination of ground-glass opacities, poorly defined centrilobular nodules, small subpleural nodules, interlobular septal thickening, and thickening of the bronchovascular bundles, often accompanied by scattered pulmonary cysts ⁹. Cysts are reported in up to 68% of patients and are generally few in number, bilateral, and variable in size and shape, usually measuring less than 3 cm (Figure 5). They tend to have a lower lung, subpleural, and peribronchovascular distribution, although a more diffuse distribution may occur ¹⁹. Ground-glass opacities may resolve during follow-up, leaving residual cysts as the predominant abnormality in chronic disease. Mediastinal or hilar lymphadenopathy may occasionally be present, whereas pleural effusion is uncommon ²⁰.

The presence of scattered pulmonary cysts in a patient with Sjögren's syndrome or other autoimmune disorders should raise suspicion of LIP. However, cysts associated with pulmonary amyloidosis or lymphoproliferative disorders, including mucosa-associated lymphoid tissue (MALT) lymphoma, should also be considered, particularly when pulmonary nodules, masses, or progressive radiological abnormalities are present.

Figure 5: Multiple thin-walled cysts with surrounding ground-glass opacity suggestive of LIP

Congenital Pulmonary Airway Malformation (CPAM)

Congenital pulmonary airway malformation (CPAM), formerly known as congenital cystic adenomatoid malformation (CCAM), is a developmental anomaly of the lower respiratory tract characterised by abnormal proliferation and differentiation of pulmonary airway structures, resulting in replacement of a variable portion of normal lung by cystic or solid dysplastic tissue. CPAM is the most common congenital pulmonary malformation and encompasses a heterogeneous group of lesions with distinct morphological and, increasingly recognised, molecular characteristics. ^21-24

The lesion was first described by Ch’in and Tang in 1949 as “congenital adenomatoid malformation of one lobe of a lung with general anasarca.” ²¹ Stocker and colleagues subsequently proposed the classic pathological classification in 1977, initially recognising three types. ²² The classification was subsequently expanded to include types 0 and 4.^23. The terminology CPAM is now preferred because many lesions are neither predominantly cystic nor truly adenomatoid. ²⁴

The clinical spectrum is broad. CPAM may be detected incidentally during routine antenatal ultrasonography, may produce severe fetal compromise and hydrops, may cause respiratory distress in the neonate, or may remain clinically silent until childhood or adulthood, when recurrent respiratory infection, cough, hemoptysis or pneumothorax may lead to its discovery.²⁴

Incidence and Epidemiology

CPAM is uncommon, but its reported incidence has increased substantially with the widespread use of antenatal ultrasonography. Estimates vary according to the population studied and the extent of prenatal screening, with contemporary estimates for congenital lung malformations overall of approximately 4 per 10,000 live births, and CPAM accounting for a substantial proportion of these lesions. ²⁴

Embryology and Pathogenesis

The precise cause of CPAM remains incompletely understood. The traditional concept was that CPAM resulted from localised arrest or abnormal development of the fetal bronchial tree. Current evidence suggests a more heterogeneous developmental pathogenesis involving abnormal epithelial–mesenchymal interactions, dysregulated airway branching and aberrant cellular proliferation. ²³

Recent molecular studies have provided additional insight. Somatic activating mutations involving the RAS–MAPK pathway, particularly KRAS, have been identified in a proportion of CPAM type 1 lesions and may contribute to abnormal epithelial proliferation. Alterations involving the FGF10–FGFR2 signalling pathway have also been implicated in abnormalities of lung development. ²³

Classification

The modified Stocker classification remains the principal histopathological classification and recognizes five types (0–4). ^22,23

Type 0 – Acinar dysplasia

Type 0 is extremely rare and involves diffuse abnormality of the respiratory epithelium at the tracheobronchial level. The lung contains small, irregular airway structures with cartilage, smooth muscle and glands but lacks normally developed alveoli.

The lesion is generally bilateral and incompatible with postnatal survival because of severe pulmonary hypoplasia.

Type 1 – Macrocystic CPAM

Type 1 is the most common form, accounting for approximately 60–70% of CPAMs. It consists of one or more large cysts, traditionally defined as greater than 2 cm in diameter, although cyst size may vary considerably. The cysts are lined predominantly by ciliated columnar or pseudostratified epithelium. Mucus-producing cells may be present. Type 1 lesions generally have the best prognosis among the conventional CPAM types. They are also the lesions most often associated with mucinous proliferation and the rare development of mucinous adenocarcinoma. ^22-24

Type 2 – Microcystic CPAM

Type 2 consists of multiple relatively small cysts, generally less than 2 cm in diameter, lined by ciliated cuboidal or columnar epithelium. Type 2 lesions may be associated with other congenital abnormalities, including cardiac, renal, skeletal and gastrointestinal anomalies. The association with other congenital abnormalities is particularly important when counselling families following prenatal diagnosis. ^22-24

Type 3 – Solid or microcystic CPAM

Type 3 is characterised by a predominantly solid-appearing lesion composed of small bronchiole-like structures. The cysts are usually microscopic or less than 0.5 cm and therefore may not be apparent on imaging. Large lesions may produce considerable mediastinal shift and pulmonary hypoplasia. Type 3 lesions are uncommon and are more frequently associated with severe neonatal respiratory compromise.

Type 4 – Peripheral cystic lesion

Type 4 consists of large peripheral cystic lesions lined by flattened pneumocyte-like epithelium and is usually located in the distal acinar region.

Clinical Presentation

The clinical presentation varies widely.

Antenatal presentation

Most CPAMs diagnosed today are detected during routine fetal ultrasonography. The lesion may appear as:

·        A multicystic intrapulmonary mass

·        A predominantly echogenic or solid mass

·        A unilateral lung lesion with mediastinal shift

·        A lesion associated with hydrops or pleural effusion.

Serial assessment is important because the size of a CPAM may increase rapidly during the second trimester and subsequently decrease or become sonographically inconspicuous later in pregnancy. Importantly, sonographic regression does not necessarily indicate complete anatomical resolution; residual lesions may still be present postnatally. ^25,26

Neonatal presentation

Symptomatic neonates usually present with:

·        Respiratory distress

·        Tachypnoea

·        Cyanosis or hypoxaemia

·        Asymmetric breath sounds

·        Chest asymmetry

·        Mediastinal shift

Severe disease may result from pulmonary hypoplasia, mass effect or extensive cystic involvement.

Presentation in infancy and childhood

Children with smaller lesions may present with:

·        Recurrent pneumonia

·        Persistent or recurrent cough

·        Fever

·        Wheezing

·        Dyspnoea

·        Haemoptysis

·        Failure to thrive, occasionally.

Recurrent infection may occur because of impaired drainage and abnormal communication between the lesion and the airway.

Presentation in adulthood

Although uncommon, CPAM may remain undiagnosed until adulthood. Adult patients may present with recurrent localized pneumonia, chronic cough, haemoptysis, chest pain or spontaneous pneumothorax. ²⁷

Diagnosis

Fetal ultrasonography is the principal diagnostic investigation.

The lesion should be evaluated for:

1.     Size and location

2.     Macrocystic versus microcystic appearance

3.     Mediastinal shift

4.     Cardiac compression

5.     Pleural effusion

6.     Ascites and other manifestations of hydrops

7.     Polyhydramnios

8.     Growth behaviour on serial examination.

Fetal MRI

Fetal MRI is not required in every case but can provide valuable additional anatomical information when:

·        The diagnosis is uncertain

·        The lesion is large

·        Associated anomalies are suspected

·        The extent of pulmonary involvement needs clarification

·        Fetal intervention is being considered

·        Differentiation from congenital diaphragmatic hernia or other thoracic lesions is difficult.

MRI can provide more accurate assessment of total fetal lung volume and the relationship between the lesion and mediastinal structures.

Postnatal Imaging

Chest Radiography

The radiographic appearance depends on the timing of imaging.

Immediately after birth, a CPAM may appear as a homogeneous opacity because the cysts contain fluid. As the lesion becomes aerated, cystic lucencies become increasingly apparent.

Findings may include:

·        Multicystic lucencies

·        Air-fluid levels

·        A large air-filled cyst

·        Homogeneous opacity in microcystic lesions

·        Mediastinal displacement

·        Compression of the normal lung.

A normal or nearly normal chest radiograph does not completely exclude CPAM, particularly following apparent antenatal regression.

Computed Tomography

Postnatal contrast-enhanced CT remains an important investigation for anatomical characterization, particularly before surgery.

CT can define:

·        The extent and morphology of the lesion

·        Cyst size

·        Relationship to normal lung

·        Mediastinal anatomy

·        Associated pulmonary sequestration

·        Anomalous systemic arterial supply

·        Other congenital lung malformations.

MRI

Postnatal MRI may be useful in selected patients when radiation exposure is undesirable or when CT findings are inconclusive. However, CT generally remains more practical for detailed preoperative assessment of pulmonary anatomy.

CPAM and Pleuropulmonary Blastoma

One of the most important developments in the understanding of congenital cystic lung lesions is recognition of the relationship between CPAM and pleuropulmonary blastoma. Pleuropulmonary blastoma is a rare malignant mesenchymal tumour occurring predominantly in young children. Type I PPB is predominantly cystic and may closely resemble a congenital pulmonary cystic lesion. Type II contains both cystic and solid components, while type III is predominantly solid.

Complications

Complications depend on the size and biological characteristics of the lesion.

Respiratory complications

·        Neonatal respiratory distress

·        Pulmonary hypoplasia

·        Recurrent lower respiratory tract infection

·        Persistent cough

·        Wheezing

·        Hypoxaemia

·        Air trapping

·        Spontaneous pneumothorax

·        Haemoptysis.

·        Large lesions may cause severe mediastinal compression

 

Malignancy

The relationship between CPAM and malignancy is complex.

Rare cases of mucinous adenocarcinoma have been reported arising in association with CPAM, particularly lesions with mucinous epithelial proliferation and somatic KRAS alterations. ²³

However, the absolute malignant risk in an individual child with CPAM is uncertain and is probably very low. The previously used blanket statement that every CPAM carries a clearly defined high risk of malignant transformation is therefore not justified.

The more important clinical issue is that a cystic lesion initially diagnosed as CPAM may occasionally represent type I PPB, particularly when the lesion is atypical or evolves over time.²⁸

Management

Management should be individualized and ideally undertaken by a multidisciplinary team involving fetal medicine specialists, neonatologists, pediatric pulmonologists, pediatric radiologists and pediatric surgeons.

Antenatal Management

Most isolated CPAMs without hydrops can be managed expectantly with serial ultrasonographic assessment.

The frequency of follow-up depends on:

·        Lesion size

·        Cyst- volume ratio (CVR)

·        Growth trajectory

·        Mediastinal shift

·        Presence or absence of hydrops

·        Gestational age.

Maternal corticosteroids

Maternal corticosteroid therapy, particularly with betamethasone, has been used for large microcystic CPAMs, especially when there is significant mediastinal compression or evolving hydrops. Evidence is based predominantly on observational studies and institutional experience rather than randomized controlled trials.

Steroids should therefore be considered in selected high-risk cases under specialist fetal medicine supervision rather than used routinely for all CPAMs.

Fetal intervention

Fetal intervention is reserved for selected severe cases.

Possible interventions include:

·        Thoraco-amniotic shunting for large macrocystic lesions with significant compression or hydrops

·        Open fetal surgery in highly selected circumstances

·        Fetoscopic procedures in specialised centres

·        Percutaneous ablative techniques, including radiofrequency ablation, in selected severe microcystic lesions at experienced fetal therapy centres.

These procedures are associated with significant maternal and fetal risks and should be performed only in specialised centres.

Delivery Planning

Mode of delivery should generally be based on obstetric indications rather than CPAM alone.

Large lesions associated with severe airway or thoracic compression may require delivery at a tertiary centre with neonatal intensive care, pediatric surgery service and extracorporeal life support capability when appropriate.

Planned EXIT procedures are reserved for highly selected fetuses in which severe airway or thoracic compression is anticipated.

Surgical Treatment

Surgical resection remains the standard treatment for:

·        Symptomatic CPAM

·        Lesions causing recurrent infection

·        Lesions complicated by pneumothorax or significant haemoptysis

·        Large lesions producing substantial mass effect

·        Lesions in which malignancy cannot be confidently excluded.

Anatomic lobectomy remains the standard surgical procedure for most localized CPAMs because the abnormal tissue is usually confined to a pulmonary lobe and segmental resection may leave residual abnormal lung (Figure 6). In selected patients with localized lesions, parenchyma-sparing segmentectomy or limited resection may be feasible, particularly with modern minimally invasive techniques.

Thoracoscopic surgery

Video-assisted thoracoscopic surgery (VATS) and thoracoscopic lobectomy are now established approaches in experienced paediatric surgical centres.

Figure 6A: X-ray chest AP view showing a large cystic lesion on the right side with a shift of the mediastinum to the left. 6B: CT Scan of the infant showing multiple cysts on the right side, pushing the mediastinum to the left, causing compression on the left lung. 6C: Per-operative view showing the cysts being separated and removed from the right lung.

Prognosis

The prognosis of CPAM is generally excellent when the lesion is isolated, and hydrops is absent. The principal adverse prognostic factors in the antenatal period include rapid increase in lesion size, severe mediastinal shift, fetal hydrops, pulmonary hypoplasia and associated major congenital anomalies.

Multiple Choice Questions

1-     A lung cyst is diagnosed by the radiological criteria based on

a.     Cyst size

b.     Cyst Content

c.      Wall thickness

d.     Associated lung lesion

2-     Which type of CPAM has a favourable outcome according to the Stocker classification

a.     Type 1

b.     Type 2

c.      Type 3

d.     Type 4

3-     Malignancy associated with CPAM is

a.     Squamous cell carcinoma

b.     Mucinous Adenocarcinoma

c.      Pleuropulmonary Blastoma

d.     Pulmonary Adenocystic Carcinoma

4-         The genetic alteration in Birt-Hogg-Dubé syndrome is…..

a.     FGF10–FGFR2 signalling pathway

b.     KRAS-MAPK Pathway

c.      EGFR mutation

d.     Folliculin Gene Mutation

5-     Lymphocytic interstitial pneumonia is usually associated with which collagen vascular disease

a.     Systemic Lupus Erythematosus

b.     Sjogren’s syndrome

c.      Polymyositis- Dermatomyositis complex

d.     Rheumatoid Arthritis

 

Correct Answers: 1c, 2a, 3c, 4d, 5b

 

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