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The first step in the radiographic evaluation of interstitial lung disease begins with a fundamental knowledge of the anatomy of the pulmonary interstitium and the different patterns of disruption. The anatomy of the pulmonary interstitium as demonstrated on CT of the chest with high resolution cuts is largely essential to establish the various radiological patterns that define interstitial lung disease such as the tree-in-bud, ground-glass opacity, crazy -paving, etc.
KeywordsTuberous Sclerosis Hypersensitivity Pneumonitis Pulmonary Alveolar Proteinosis Open Lung Biopsy Organize Pneumonia
Case 1: Pulmonary Alveolar Proteinosis
Pulmonary alveolar proteinosis (PAP) is an uncommon disease, characterized by alveolar accumulation of lipoproteinaceous material. PAP is classified in two main types: congenital and acquired. Congenital PAP (2 % of the cases) appears in the neonatal period as a clinical picture of acute respiratory distress. Acquired PAP is divided into idiopathic or autoimmune (90 % of the cases) and secondary, associated to exposure conditions (inhalation of silica, cotton, aluminum), infections (P. asteroids, cytomegalovirus), and immune disorders (human immunodeficiency virus infection, posttransplant immunosuppression).
PAP prevalence is 6.2 cases per million people, the disease is more prevalent in the male gender (3:1), and 39 years is the mean age at diagnosis.
The idiopathic or autoimmune type seems to be associated to the presence of antibodies against the granulocyte-macrophage colony-stimulating factor (GM-CSF), which alters the pulmonary surfactant metabolism.
Clinical features are nonspecific and the approximate average time between the onset of symptoms and the diagnosis is 7 months.
Radiological manifestations are diverse. The radiographic appearance most frequently described in the series consists of symmetrical central and basal consolidations. However, predominantly central reticular opacities, mixed opacities with reticulation and consolidation, and asymmetrical patchy parenchymal opacities may be found. In high-resolution computed tomography (HRCT), the most frequent finding is a “crazy paving” pattern (combination of ground-glass and linear opacities). Areas of “crazy paving” are typically bilateral, extensive, and follow a geographic pattern. Nevertheless, in some cases, the distribution can be asymmetrical, predominantly central, peripheral, or patchy. Other HRCT findings in patients with PAP include ground-glass opacities, consolidation, and airway irregularity.
CRX film shows multilobar consolidation (Fig. 9.1.1). HRCT shows crazy paving pattern with lower lobes predominance (Figs. 9.1.2 and 9.1.3). Gross photo of bronchoalveolar fluid shows the characteristic milky aspect (Fig. 9.1.4).
Case 2: Silicone Embolism
Liquid silicone is a highly stable polymer, with minimum tissue reaction, widely used in the cosmetic industry. Subcutaneous injection of liquid silicone can be associated to pulmonary embolism. The preferred sites for subcutaneous injection of liquid silicone are the breasts and gluteus. Silicone pulmonary embolism (SPE) after a subcutaneous injection has been associated to the volume injected and to the local massages following the procedure.
The mechanism of pulmonary injury in these patients is similar to that described in fatty embolism with alveolar hemorrhage and fat globules in lung microcirculation and macrophages.
Sixty percent of the patients with SPE develop acute respiratory distress syndrome (ARDS), and 20 % die due to respiratory insufficiency.
All patients with SPE have abnormal chest x-rays with bilateral and peripheral ground-glass opacities, as the characteristic feature.
The most frequent HRCT abnormality in these patients is the presence of bilateral subpleural ground-glass opacities. Other findings in HRCT include thickening of interlobular septum and subpleural reticulation.
CT scan shows breast enlargement in male patient with increased density and nodular appearance of subcutaneous fat. Left axillary lymphadenopathy (Fig. 9.2.1). HRCT shows subpleural ground-glass opacity (Figs. 9.2.2 and 9.2.3). Bronchoalveolar lavage shows fat droplets and silicone within macrophages (Sudan stain, 40×; Fig. 9.2.4).
Case 3: Hypersensitivity Pneumonitis
Hypersensitivity pneumonitis (HN) is a pulmonary disease with symptoms of cough and dyspnea, produced by the inhalation of an allergen by a previously sensitized individual. Most antigens related with HN originate in bacteria (Saccharopolyspora rectivirgula), mold (Penicillium species), yeast, or poultry (pigeon proteins). Chemical agents such as isocyanates, zinc, tinctures, and dyes can act as haptens to induce NH.
In a study carried out in three European countries, HN represented between 4 and 15 % of pulmonary interstitial diseases.
HN has traditionally been classified in acute, subacute, and chronic. However, recent trials by the HN study group have had difficulties classifying patients in these groups and particularly in cases previously described as subacute.
In the acute phase, radiological abnormalities are similar to those described in pulmonary edema, with multilobar areas of consolidation. In the subacute phase, the main HRCT manifestations are: centrilobular nodule (ill defined), areas of ground-glass opacity (variable distribution and extension), and cystic lesions in 13 % of the cases. In the chronic phase, changes associated to pulmonary fibrosis are found, usually respecting lung bases, with reticular opacities, traction bronchiectasis, and limited areas of honeycombing.
CRX film shows diffuse micronodular opacities (Fig. 9.3.1). CT scan shows multiple ground-glass nodules with centrilobular distribution (Figs. 9.3.2 and 9.3.3). Bronchoalveolar lavage with lymphocyte proliferation (Diff-Quick stain, 10×; Fig. 9.3.4).
Case 4: P. jiroveci Pneumonia
P. jiroveci pneumonia (PJP) has been described in immunocompromised patients and particularly in patients with human immunodeficiency virus (HIV) infection. The current incidence of PCP in HIV (+) patients has decreased due to the use of high impact antiretroviral therapy and prophylaxis with trimethoprim/sulfamethoxazole. Nevertheless, PJP incidence remains high in HIV (+) patients in underdeveloped countries.
The clinical picture of PJP in HIV (+) patients is subacute and characterized by dry cough and progressive dyspnea (2–4 weeks).
Radiologic manifestations of P. jiroveci pneumonia include: predominantly central reticular opacities, ground-glass opacities, and mixed opacities. In HRCT, the predominant manifestation is the presence of ground-glass opacities with diverse distributions: central, in a “mosaic” pattern, or diffuse. As the infection progresses, areas of consolidation and reticular opacities may appear. The presence of cystic lesions in PJP is variable according to the series (10–20 % of patients). Cysts appear mainly in apical segments; have variable sizes, irregular margins, and thin or thick walls; and are associated with spontaneous pneumothorax.
HRCT shows thin-walled cystic appearance lesions without communication with airway. Peribronchial consolidation adjacent cystic lesions. Right pneumothorax. Upper lobes predominance of cystic appearance lesions (Figs. 9.4.1, 9.4.2, and 9.4.3). Bronchoalveolar fluid shows numerous trophozoites of pneumocystis (Diff-Quick stain, 40×; Fig. 9.4.4).
Case 5: Chronic Eosinophilic Pneumonia
Chronic eosinophilic pneumonia (CEP) is an uncommon idiopathic disorder characterized by subacute or chronic respiratory and systemic symptoms, blood and/or alveolar eosinophilia, and peripheral opacities in the chest x-ray.
CEN is considered to represent between 0 and 2.5 % of pulmonary interstitial disease cases. This disorder is more frequent in women (2:1) and between one-third and half of the patients with CEP have a history of asthma.
Most CEP patients are symptomatic and the most frequent manifestations are: progressive dyspnea, cough, and general symptoms (asthenia, weight loss, and night sweats).
Eosinophilia is found in BAL (12–95 % of cellular count, with an average of 59 %). Lung biopsy shows evidence of predominantly eosinophilic alveolar and interstitial inflammatory infiltration.
The classic radiographic finding is the “inverse pulmonary edema” (peripheral, mainly apical, nonsegmental consolidation). However, this finding is seen in less than 50 % of the patients. HRCT manifestations are variable and related to disease evolution. Predominantly peripheral areas of ground-glass opacities and/or consolidation are more common in early stages. With disease progression, septal lines, reticular opacities, nodules, and subpleural parenchymal bands may be found.
CRX film shows multilobar and peripheral consolidation (Fig. 9.5.1; HRCT). Pulmonary architecture distortion. Parenchymal bands with traction bronchiectasis, ground-glass and subpleural consolidation (Figs. 9.5.2 and 9.5.3). Lung biopsy shows numerous eosinophils filling an alveolar space (HE, 40×; Fig. 9.5.4).
Case 6: Pulmonary Langerhans Cell Histiocytosis
Pulmonary Langerhans cell histiocytosis (PLCH) is an isolated form of Langerhans cell histiocytosis (LCH) that mainly affects smokers. Disease pathogenesis remains uncertain. LCH represents a clonal proliferation of cells similar to that typical of neoplastic diseases. In the particular case of the pulmonary type, pathogenesis may be different, as it has been demonstrated that most nodules do not follow clonal proliferation. It has been suggested that this disorder corresponds to an exaggerated immune response to an antigen, in which Langerhans cells can serve as accessory cells in T lymphocyte activation.
From the histological viewpoint, histiocytosis is a temporary heterogeneous disorder characterized by peribronchiolar proliferation of Langerhans cells, which form nodules. Nodular lesions frequently cavitate forming thick- or thin-walled cysts according to the evolutional stage. These cysts represent the lumen of the dilated airway. In the most severe cases, the presence of fibrosis can reach the alveolar wall, forming scars and distorting pulmonary architecture.
It is a clinically rare disease (5 % of interstitial diseases). Patients are sometimes asymptomatic. However, the most frequent symptoms are cough and dyspnea. Other clinical manifestations can be hemoptysis, fever, weight loss, and night sweats. Pneumothorax, sometimes recurrent, can occur in one out of every four patients.
Radiological manifestations depend on the evolution of the disease.
Chest x-rays can be interpreted as normal in early stages of disease. In advanced cases, the most frequent semiological findings are reticular opacities corresponding to the visualization of the walls of contiguous cystic lesions and predominantly apical small nodules.
In HRCT, the most frequent manifestation of early disease is the presence of small, irregular, peribronchiolar nodules, with different degrees of cavitation in an otherwise healthy lung. With disease progression, cystic lesions increase in number and size and their walls become thinner. The presence of cystic lesions larger than 1 cm, with irregular margins, and distortion of pulmonary architecture suggests an advanced stage of the disease. Related findings include ground-glass opacities and changes due to emphysema associated to the habit of smoking.
CRX film shows ill-defined nodular opacities (arrows). Peribronchial thickening (Fig. 9.6.1).
CT scan shows ground-glass small nodules (black arrows) and soft tissue nodules (arrowheads), with varying degree of cavitation (white arrows) and random distribution (Figs. 9.6.2 and 9.6.3). Lung biopsy shows the typical nuclear and cytoplasmic staining of Langerhans cells (S-100 stain, 40×; Fig. 9.6.4).
Case 7: Lymphocytic Interstitial Pneumonia
Lymphocytic interstitial pneumonia (LIP) is considered a nonneoplastic inflammatory reaction of bronchial associated lymphoid tissue (BALT). This pattern of pulmonary response can be associated to systemic diseases (Sjögren syndrome, systemic lupus erythematosus), dysproteinemias, human immunodeficiency virus infection, and adverse reaction to drugs (diphenylhydantoin). In its idiopathic presentation, it is included in the group of idiopathic interstitial pneumonias, due to the presence of fibrosis during the course of the disease in some patients.
LIP may appear in pediatric population associated to HIV infection. Most adults with LIP are women between the 5th and 7th decades of life. Clinical manifestations are nonspecific and include cough and dyspnea of gradual onset. Less frequently, weight loss, chest pain, fever, and arthralgia are described.
Histologically, LIP is characterized by a lymphocitary infiltrate extensively compromising alveolar septa. Hyperplasia of type II pneumocytes and granuloma formation are described. Immunohistochemistry using CD20 shows that B cells are predominantly located in germ centers.
Radiological findings described in LIP are nonspecific, with predominantly basal reticular or reticulonodular opacities as the main manifestations. Areas of consolidation and ill-defined nodules may also be found. The most frequent alterations found in HRCT are ground-glass opacities, centrilobular nodules, thickening of peribronchovascular interstitium, interlobular septum thickening, areas of consolidation, and cysts. Pathogenesis of cysts is related to partial obstruction of bronchioles and air trapping due to peribronchial lymphocytic infiltration and occasionally due to focal amyloid deposits.
Chest x-ray film shows ill-defined nodules (arrow) and ground-glass patchy areas. Thin-walled cystic appearance lesion in right lower lobe (arrowhead) (Fig. 9.7.1). HRCT shows soft tissue nodules and diffuse ground-glass and thin-walled cystic lesions of variable size (Figs. 9.7.2 and 9.7.3). This photomicrograph shows the typical densely cellular appearance of widened alveolar septa (HE stain, 10×; Fig. 9.7.4).
Case 8: Varicella Pneumonia
Pneumonia due to Varicella-Zoster virus is the most severe complication of a systemic infection, with a mortality rate ranging between 9 and 50 %.
Disease course in children is self-limited and benign. However, in adults, it tends to be a significant cause of complications. More than 90 % of cases of viral pneumonia due to Varicella-Zoster occur in immunocompromised adult patients and pregnant women.
There is no gender predilection. Conditions causing immunosuppression as leukemia, lymphoma, and corticosteroid therapy are considered risk factors. Pregnancy, advanced age, chronic obstructive pulmonary disease, and severe cutaneous eruption are other predisposing conditions.
Symptoms of pneumonia develop a few days after cutaneous vesicles appear and include cough, dyspnea, hemoptysis, tachypnea, pleuritic pain, and fever.
Histologically, they are nodules formed by areas of hyalinized collagen or necrotic tissue with a fibrous capsule that can resolve and calcify in various ways or form areas of mononuclear inflammatory interstitial infiltration with an intra-alveolar proteinaceous exudate and hyaline membrane formation (diffuse alveolar damage).
Radiological findings include ill-defined nodules, randomly distributed, ranging between 5 and 10 mm in diameter. Nodules can disappear or calcify late after cutaneous lesions have disappeared. Nodular lesions of soft tissue density, ranging between 1 and 10 mm in diameter, which may have a perilesional ground-glass halo, are described in HRCT. Nodular lesions can coalesce and combine with patchy ground-glass opacities.
Chest x-ray film shows nodular opacities, ill defined (arrowhead) (Fig. 9.8.1). Random soft tissue small nodules with ground-glass halo (Figs. 9.8.2 and 9.8.3). Vesicular lesions in the patient’s forehead (Fig. 9.8.4).
Case 9: Cryptogenic Organizing Pneumonia
Organizing pneumonia (OP) is a nonspecific histopathological pattern of pulmonary response to injuries of diverse nature, characterized by the presence of granulation tissue buds in the distal airways. This process occurs mainly in alveoli, but may extend to alveolar duct lumen and bronchioles. OP can be classified in three categories: idiopathic (cryptogenic organizing pneumonia), of known cause (infection, radiation), or of unknown cause associated to a specific clinical context (collagen vascular disease, posttransplant).
The histological hallmark of organizing pneumonia is a distinct, usually patchy type of fibrosis that predominantly involves bronchiolar lumen and peribronchiolar airspaces. The fibrosis is composed of elongated fibroblasts and myofibroblasts arranged in parallel and embedded in a myxoid or pale staining matrix.
The typical or classical presentation of OP described in chest x-rays consists of bilateral patchy airspace consolidations, most prominent in the peripheral lower lung zones, with a tendency to progress and change location over time. CT reflects the findings of the chest x-ray demonstrating that the areas of consolidation are predominantly peribronchovascular and/or subpleural. Bronchial dilation in consolidated areas is described in 55 % of patients. Other findings in HRCT of patients with OP pattern are: nodule(s) – mass(es), ground-glass opacities, parenchymal bands, nodules with halo and reverse halo signs, and reticular opacities.
Chest x-ray film shows consolidation and ground-glass patchy (Fig. 9.9.1). CT scan (lung window) shows multilobar consolidation and ground-glass halo sign (Figs. 9.9.2 and 9.9.3). Lung biopsy shows fibroblast plugs within alveolar spaces (trichrome stain, 10×; Fig. 9.9.4).
Case 10: Lymphangioleiomyomatosis
Lymphangioleiomyomatosis (LLM) is a rare, progressive, multisystemic disorder characterized by the proliferation of pulmonary parenchyma bronchiolar, venular, and lymphatic smooth muscle. The pathogenesis is not clearly established but it probably has its bases in TSC2 gene mutations of the tuberous sclerosis complex located in chromosome 16.
Although classified as a different entity, LLM shares its physiopathology with tuberous sclerosis, and LLM patients may have extrapulmonary manifestations such as angiomyolipomas (15–30 % of patients). These similarities lead some researchers to consider LLM as a frustrated form of tuberous sclerosis or that both entities correspond to the same disease with a different degree of expression.
LLM affects almost exclusively women of childbearing age and can occur as a complication associated to tuberous sclerosis in women (men with tuberous sclerosis usually do not develop cystic changes of LLM in the lung).
Histologically, abnormal proliferation of immature smooth muscle cells within the airway, lymph vessels, and blood vessels causes mechanic obstruction with secondary cyst formation, pneumothorax, lymphatic flow obstruction, lymph node enlargement, chylothorax, and pulmonary arterial and venous hypertension that can lead to hemorrhage and hemothorax. A biochemical explanation for cyst formation in this disease is metalloprotease production by LAM cells, which destroy pulmonary collagen and elastin. LAM cells can be identified by immunohistochemistry techniques that demonstrate the presence of antigens to smooth muscle actin- and melanoma-associated HMB-45.
In chest x-rays, the most frequent manifestations are an increase in pulmonary volume and reticular opacities in relation to cyst overlapping.
HRCT shows multiple thin-walled cysts, of similar size and regular margins, uniformly distributed in lungs. Lung parenchyma in between cystic lesions is normal. These findings can simulate changes due to emphysema; the diagnostic key relies on the identification of cyst walls and the population group.
Chest x-ray film shows fine reticular opacities (Fig. 9.10.1). CT scan (lung window) shows diffuse and uniform small thin-walled cystic lesions (Fig. 9.10.2). Lung biopsy shows the characteristic smooth muscle in the cyst wall (HE and trichrome stain, 10×; Figs. 9.10.3 and 9.10.4).
Pulmonary Alveolar Proteinosis
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Chronic Eosinophilic Pneumonia
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