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Cystic lung disease
  1. Belinda E Clarke
  1. Correspondence to Dr Belinda E Clarke, Anatomical Pathology, Pathology Queensland, The Prince Charles Hospital, Rode Rd, Chermside, Queensland 4032, Australia; Belinda_Clarke{at}health.qld.gov.au

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When our colleagues from Radiology  are confronted with cystic changes on high-resolution CT scans, their differential diagnoses include emphysema; cystic bronchiectasis; honeycomb change; cavitated infective nodules (including mycobacterial infection and septic embolism); other cavitated nodules such as Wegener's granulomatosis and necrotising sarcoid granulomatosis; Langerhans cell histiocytosis (LCH); lymphangioleiomyomatosis; lymphocytic interstitial pneumonia; follicular bronchiolitis; amyloidosis; light chain deposition disease (LCDD); Birt-Hogg-Dubé syndrome (BHDS); and cystic metastases.1

Most of these entities can be readily distinguished in the light of the clinical features and are not often biopsied. The entities to be addressed here are those most likely to be encountered by pathologists when confronted with a clinical scenario of diffuse cystic lung disease, excluding congenital and paediatric cystic diseases.

Langerhans cell histiocytosis

Langerhans cells are differentiated cells of monocyte–macrophage lineage, which represent an immature stage in the development of dendritic cells. They are actively motile and function as antigen-presenting cells. They are found principally in stratified squamous epithelia, but are also present in lymph nodes, thymic epithelium and bronchial mucosa. They express major histocompatibility complex class II molecules, CD1a and S100 protein but not CD68. They are derived from a primitive CD34 monocyte precursor in bone marrow and can be induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) and TNF-α.2–4

At light microscopy, Langerhans cells are 12–15 microns in diameter and have moderate amounts of eosinophilic cytoplasm that contains few, if any, phagocytised particles. Their nuclei are vesicular with finely granular chromatin, inconspicuous nucleoli, and a characteristic grooved or convoluted appearance.2–4 At electron microscopy, pentilaminar Birbeck (Langerhans) granules (bodies) are pathognomonic.2

The terminology surrounding lesions derived from Langerhans cells is confusing. Histiocytosis X was the term applied by Lichtenstein in 1953 to a group of conditions previously designated as eosinophilic granuloma of bone, Letterer-Siwe disease and Hand-Schuller-Christian disease. Letterer-Siwe disease (acute disseminated LCH) is a potentially fatal systemic disease of children under three. Hand-Schuller-Christian disease is a multifocal disease of early childhood commonly affecting lungs and bones and classically presenting with the triad of bone defects, exophthalmos and diabetes insipidus. Single system disease (eosinophilic granuloma and Pulmonary Langerhans cell histiocytosis (PLCH) involves a single organ (bone, lungs or skin), usually follows a benign course and can regress spontaneously. Since proliferation of the Langerhans cell is common to all these conditions, the WHO Committee on Histiocytic/Reticulum Cell Proliferations proposed in 1997 that the term ‘LCH’ be adopted.

PLCH is a chronic, progressive disorder characterised by multiple, interstitial peribronchiolar nodules that frequently cavitate. It occurs either as part of multisystem LCH or as unifocal PLCH. The latter typically affects young adult (20–40 years) cigarette smokers. The most common symptoms are non-productive cough and dyspnoea, but chest pain, fatigue, weight loss and fever may occur.2–4 Spontaneous pneumothorax is the presenting event in 10%–20%. Up to 25% of patients are asymptomatic. Respiratory function tests may demonstrate any pattern of abnormality or may be completely normal, but there is usually evidence of reduced diffusing lung capacity for carbon monoxide (DLCO). Chest x-ray (CXR) typically shows symmetrical diffuse bilateral interstitial infiltrates, often with a reticulonodular appearance. Sparing of the lung bases and costophrenic angles is characteristic (figure 1A). HRCT reveals small nodules, cavitated nodules and irregular thick-walled and thin-walled cysts. If nodules predominate, the radiological differential diagnosis includes sarcoidosis, silicosis and extrinsic allergic alveolitis, but when cysts are seen the major differential diagnosis is pulmonary lymphangioleiomyomatosis (PLAM). Serial CT studies reveal progression from nodules to cavitated nodules to thick-walled cysts to thin-walled cysts.1

Figure 1

Pulmonary Langerhans cell histiocytosis. (A) Explanted lung: note sparing of costophrenic angle. (B) Low-power view of cellular nodule with early cystic change. (C) High-power view of Langerhans cells admixed with eosinophils.

Histologically, the lesions of LCH are similar whether occurring as part of unifocal or multisystem disease. They comprise a mixture of Langerhans cells, eosinophils, lymphocytes, plasma cells, neutrophils and multinucleate giant cells (figure 1C). Mitoses may be seen. In the lung, the infiltrate is interstitial and peribronchiolar. At low power, the nodular infiltrates are evenly distributed with intervening normal lung parenchyma, and the process resembles bronchiolitis rather than a diffuse infiltrative lung disease (figure 1B). The nodules are usually 1–3 mm in diameter but may be up to 1–2 cm, and often have a stellate outline. Central cavitation is common, and is attributed to destruction of bronchiolar mucosa and infiltration and weakening of the bronchiolar walls with subsequent dilatation. There are variable degrees of associated fibrosis. Cellular lesions comprising >50% Langerhans cells often coexist with fibrotic lesions consisting of paucicellular stellate scars. There may be honeycombing and vascular medial thickening. Adjacent non-lesional lung parenchyma frequently shows organising pneumonia. A DIP-like reaction and respiratory bronchiolitis are also common, reflecting incidence in the smoking population. There may be eosinophilic pleuritis if complicating pneumothorax has occurred.

The histological differential diagnosis includes reactive Langerhans cell proliferation associated with inflammation and fibrosis of other aetiology. PLCH is an interstitial process, in contrast to the intra-alveolar accumulation of macrophages in DIP and of eosinophils in chronic eosinophilic pneumonia. Fibrotic burnt-out lesions may mimic UIP, but show a bronchiolocentric distribution and retain their stellate shape.

Most patients with unifocal PLCH follow an indolent course, and occasional spontaneous remissions occur. Many regress with steroid therapy and smoking cessation, but progression to end-stage pulmonary fibrosis may occur in approximately 10% of cases. Development of pulmonary hypertension is associated with increased mortality.5 No histological features have been found to predict prognosis.

The pathogenesis of PLCH is unknown, but the almost universal association with smoking indicates a likely causal link. It is interesting that this association is true only of PLCH and not extrapulmonary LCH. Cigarette smoke induces production of GM-CSF, TGF-β and TNF-α from bronchial epithelial cells which promote differentiation, activation and survival of Langerhans cells.2–4 Bronchiolar destruction may be the result of induction by the Langerhans cells of a local T cell immune response with cytotoxic effects. Other mediators such as metalloproteinases have been implicated in tissue remodelling, cyst formation and fibrosis, and osteopontin, a glycoprotein with cytokine properties and pro-chemotactic activity for macrophages, monocytes, Langerhans cells and dendritic cells, has been shown to be upregulated in patients with PLCH.6 Proteome analysis of bronchoalveolar lavage7 promises to provide valuable information about pathogenetic mechanisms and biomarkers in PLCH. A recent study found BRAF V600E mutations in concurrent nodules from two of five patients,8 supporting the hypothesis that PLCH is a clonal proliferation, and that targeted therapies may be indicated in some patients.

Pulmonary lymphangioleiomyomatosis

This condition is characterised by proliferation of abnormal smooth muscle-like cells in the lungs and in lymphatics and lymph nodes of the thorax and retroperitoneum.9–14 It affects young women of reproductive age (20–40 years) almost exclusively, although there are rare case reports of PLAM in men and children. PLAM occurs sporadically, affecting ∼1 in 400 000 women, or in patients with tuberous sclerosis complex (TSC) of whom 30%–40% of adult females are affected. The principal presenting symptoms are dyspnoea, cough, recurrent pneumothoraces, haemoptysis and chylous pleural effusions. Respiratory function tests usually show an obstructive picture, and the clinical differential diagnoses include asthma and chronic obstructive pulmonary disease. There is also usually reduced DLCO. PLAM is often associated with renal angiomyolipomas and there is an increased frequency of meningioma.

CXR shows diffuse bilateral reticular opacities with cystic spaces, hyperinflation and sometimes evidence of pneumothorax or pleural effusion. HRCT shows evenly distributed thin-walled cysts, 0.2–2 cm in diameter. There is no sparing of the costophrenic angles1 (figure 2A).

Figure 2

Pulmonary lymphangioleiomyomatosis. (A) Explanted lung. (B) Low-power view of cellular proliferation in walls of cystic spaces. (C) High-power view of LAM cell proliferation.

Lung biopsies show air-filled cysts and multifocal nodular proliferation of immature smooth muscle and perivascular epithelioid cells (LAM cells) (figure 2B). They have less cytoplasm and are less eosinophilic than normal smooth muscle (figure 2C), and show positive immunohistochemical staining for actin, desmin and HMB45.9 HMB45 positivity, seen predominantly in the epithelioid cells, has been shown to correlate with the presence of premelanosomes at electron microscopy. In contrast, matrix metalloproteinase expression is seen in the more spindle-shaped cells, which may be HMB45-negative.10 Oestrogen and progesterone receptors can be demonstrated in some, but not all, cases. The LAM cells are not confined to the walls of lymphatics, but are also present around bronchioles, arteries and veins, and in alveolar septa and the pleura. The adjacent lung parenchyma may contain haemosiderin-laden macrophages if there has been previous haemorrhage, and there may be reactive eosinophilic pleuritis if pneumothorax has occurred. Other findings described in the lungs in PLAM include micronodular pneumocyte hyperplasia, regional proliferation of HMB45-positive clear cells, clear cell micronodules, clear cell (‘sugar’) tumour and pulmonary angiomyolipoma.

The cysts have been postulated to be the result of air-trapping secondary to bronchiolar obstruction, but are more likely due to metalloproteinase-mediated destruction of elastic tissue. Haemorrhage is thought to be due to occlusion of small veins. The relative amount of cellular proliferation versus cyst formation differs, and extensive cyst formation has been correlated with worse prognosis.15

The histological differential diagnosis of PLAM includes emphysema when cysts predominate and the LAM cell proliferation is subtle and inconspicuous. Smooth muscle hyperplasia (‘muscular cirrhosis’) and cystic change (honeycombing) are found in idiopathic pulmonary fibrosis/usual interstitial pneumonia, but the cellular proliferation is recognisable as discrete bundles of normal smooth muscle cells and is HMB45-negative. So-called benign metastasising leiomyoma usually consists of more nodular proliferation of bland mature smooth muscle cells. Other spindle cell neoplasms such as metastatic endometrial stromal sarcoma may show cyst formation. The finding of oestrogen and progesterone receptor positivity in these lesions can contribute to diagnostic difficulty, but they are HMB45-negative. If haemosiderin deposition is prominent and LAM cell proliferation inconspicuous, the various alveolar haemorrhage syndromes may enter into the differential diagnosis, but the cysts should be a clue to the underlying pathology.

The normal counterpart and origin of LAM cells is unknown. Although they appear histologically benign, they have been shown to circulate in the blood, to be present in chylous effusions, ascitic fluid and lymphatics, and to express the lymphangiogenic growth factors, VEGF-C and VEGF-D (serum levels of VEGF-D have been used to assist in the distinction of sporadic PLAM from other forms of cystic lung disease).10–13 LAM cells in both sporadic and TSC-associated forms of the disease harbour biallelic, inactivating TSC gene mutations.9–12 Mutations in the TSC2 tumour suppressor gene (on chromosome 16; protein product: tuberin) and less commonly in TSC1 (on chromosome 9; protein product: hamartin) result in constitutive activation of the mammalian target of rapamycin (mTOR) signalling pathway, which regulates multiple cellular functions including growth, motility and survival. The metastatic potential of LAM cells has been confirmed by clinical and genetic evidence of recurrence in transplanted lungs, and a recent study has shown uterine and adnexal involvement.16 Thus PLAM is now considered to be a neoplastic process belonging to the ‘PEComa’ family of tumours. The role of oestrogen in initiating or potentiating LAM cell proliferation has not been elucidated.

The prognosis of PLAM is variable, but there is usually progressive deterioration in respiratory function, which is particularly marked in pregnancy or with administration of oestrogens. The disease is generally less severe and follows a more indolent course in TSC-LAM than in sporadic PLAM. Treatment has traditionally relied upon hormonal manipulation by oophorectomy or administration of progesterone, tamoxifen or gonadotropin-releasing hormone antagonists, but there is little evidence for efficacy. Lung transplantation remains an effective treatment option for some patients. A recent multicentre trial of the mTOR antagonist, Sirolimus, shows promise.17

Alveolar septal amyloidosis and LCDD with cystic change

Pulmonary amyloidosis is not generally associated with cyst formation. There are three recognised forms of the disease: tracheobronchial, nodular parenchymal and diffuse alveolar septal amyloidosis.18 The latter may occur with disseminated amyloidosis (primary, multiple myeloma-associated (AL) or secondary (AA)) or as primary lung involvement without extrapulmonary amyloidosis (mostly AL). Patients usually present with progressive dyspnoea and are found to have fine reticulonodular interstitial infiltrates on imaging. There is typically an inexorable downhill course with progressive restrictive ventilatory defect. Histologic diagnosis relies on recognition of Congo red-positive amorphous eosinophilic material within alveolar septa and vessel walls (figure 3A–C) and may be confirmed and subtyped by immunohistochemistry.

Figure 3

Alveolar septal amyloid with cystic change. (A) Explanted lung. (B) Interstitial amyloid deposition and cystic change. (C) Congo red positive amyloid deposition in alveolar septa.

The association of cystic change with pulmonary amyloidosis is rare.19–21 It has been postulated to be the result either of airway narrowing by inflammation, increased fragility and rupture of alveolar walls due to amyloid deposition, or ischaemia resulting from amyloid deposition around capillaries. Some reported cases have shown both pulmonary lymphocytic infiltration and amyloid deposition, often in association with Sjögren's syndrome, raising the possibility that the cyst formation is related to the lymphocytic infiltration rather than the amyloid deposition, since cystic change is recognised to occur in lymphocytic interstitial pneumonia (LIP).

Lung involvement in LCDD is rare and histologically mimics amyloidosis but lacks apple green birefringence with Congo red stain.22 The deposits are mostly composed of κ light chains and electron microscopy reveals coarsely granular electron-dense deposits along alveolar basement membranes rather than the fine fibrils typical of amyloid. Cyst formation in LCDD presumably has similar pathogenesis.

Birt-Hogg-Dubé syndrome

This syndrome is a rare autosomal dominant genodermatosis characterised by the presence of cutaneous hamartomas (predominantly fibrofolliculomas), renal tumours (hybrid oncocytic tumours and chromophobe renal cell carcinomas) and cystic lung disease.23–27 BHDS patients have a 7-fold risk of developing renal neoplasia and a 50-fold risk of spontaneous pneumothorax. Patients aged 20–40 years frequently develop pneumothoraces, usually without prior diagnosis of the underlying genetic syndrome, and may have isolated lung cysts without involvement of skin and/or kidney. Renal tumours, when present, are usually diagnosed at age 40–70. The majority of patients have identifiable mutations in the folliculin gene (FLCN, also known as BHD, and considered to be a tumour suppressor gene) located on chromosome 17p11.2 (deletions, substitutions, duplications and insertions) but a negative test does not rule out the diagnosis. Interestingly, dysfunction of the FLCN gene is associated with dysregulation of mTOR signalling pathway, also seen in PLAM.

Radiologically, the cysts are multiple and thin-walled with lower medial zone predominance.1 The pulmonary histology is non-specific, showing intraparenchymal air-filled spaces surrounded by normal lung parenchyma and closely associated with peripheral interlobular septa or the septal-pleural intersection.24 ,25 ,27 The cysts are lined by cytokeratin-positive epithelial cells, which express surfactant proteins and TTF-1, sometimes with predominance of type II pneumocyte-like cuboidal cells.

Diffuse cystic lung disease associated with small airways disease

A recent paper28 has reported a series of five non-smoking patients with variably-sized thin-walled cysts and evidence of chronic bronchiolitis (two patients), eosinophilic bronchiolitis, probable asthma (one patient) and diffuse idiopathic neuroendocrine cell hyperplasia (two patients). The authors hypothesise that chronic damage to small airways may lead to cystic changes in a minority of patients.

Follicular bronchiolitis and lymphocytic interstitial pneumonia

These entities, which belong to the benign end of the spectrum of pulmonary lymphoproliferative disease, are a reflection of reactive pulmonary lymphoid hyperplasia, either localised to bronchiolar walls (follicular bronchiolitis) or diffusely involving the lung parenchyma. Both may be associated with connective tissue diseases, particularly Sjögren's syndrome and rheumatoid arthritis, or may result from immune deficiency syndromes, either congenital or acquired, or infection. Radiologically, it is not uncommon to find evidence of cystic change1 although this is not often appreciated in biopsy specimens. The underlying mechanism of the cystic change is believed to be chronic damage to small airways.

Cystic pulmonary metastases

Rarely metastatic tumours can present as diffuse cystic lung disease. Reports include so-called benign metastasising leiomyoma, endometrial stromal sarcoma and cellular fibrous histiocytic tumours.29–31

References

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