Radiology/Pathology Correlation

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The patient is a 42-year-old woman with a history of progressive shortness of breath and cough. Pulmonary fibrosis was suspected clinically.


Figure 1. Chest Radiography

Frontal chest radiograph shows diminished lung volumes with vague, poorly-defined nodules best visualized in the right lung base.

No evidence of pleural effusion or lymphadenopathy is present.

Figure 2. High-Resolution Computed Tomography: HRCT shows numerous, bilateral, poorly-defined nodules that are centrilobular in distribution.

The centrilobular distribution of the nodules can be discerned by the fact that the nodules approach, but do not contact, the visceral and costal pleural surfaces. The nodules are widespread and equally distributed in upper, middle, and lower lung zones.

What is the differential diagnosis? Answer


The following 2 images are from another patient with the same disease.

Figure 3. Low-power View: Here, two acini (terminal bronchioles and their alveoli) show interstitial infiltrates around bronchioles and a patchy interstitial and alveolar infiltrate. An edematous interlobular septum lies at the upper right. The pleura lies at the left.



Find two terminal bronchioles. Click on the structure in the image to get verification.

Find a respiratory bronchiole.

Find an alveolar duct.

Note: The distribution of the infiltrates here would most likely correspond to an ill-defined ground-glass appearance (also characteristic of this disease) on HRCT rather than the nodules shown above (see later).


Figure 4. Bronchiolar Infiltrate

This bronchiole shows an inflammatory infiltrate in the wall and a bluish stromal matrix indicating active disease. A collection of multinucleated giant cells distorts the wall and lumen on the right.

Figure 5. High Power of Figure 4.

The interstitial infiltrate throughout the biopsy contained occasional clusters of multinucleated giant cells.

What do these giant cells represent?

What types of cells are present in the interstitial infiltrate?



What is the histologic differential diagnosis? What is the diagnosis? Answers

Scroll down after answering the questions.



















Hypersensitivity Pneumonitis (HP) (Extrinsic Allergic Alveolitis)

Discussion: Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis in the UK, is an allergic lung disease that results from the inhalation of one of a variety of antigens. The individual entities are usually named for the responsible organic or chemical antigen or for the circumstance in which the exposure occurs, but the clinical, radiographic, and histologic reaction patterns are surprisingly similar. The diagnosis rests on the presence of some of the following: exposure to an antigen followed by typical symptoms, inspiratory crackles, characteristic findings on HRCT and pulmonary function tests (restriction, obstruction, or a decreased DLco), positive serologic tests for the antigen, or positive results on inhalation challenge [1,2]. The disease has been divided clinically into acute, subacute, and chronic stages.

Clinical Presentation: An acute, heavy exposure to an offending antigen may produce fever, chills, dry cough, and dyspnea, beginning 4 to 12 hours after exposure. Recurrent exposure may result in repeated acute episodes of shortness of breath, fever, and cough; or chronic complaints of shortness of breath with few or minimal systemic symptoms. Chronic HP may present with progressive respiratory impairment. It is not uncommon that, despite extensive questioning, a history of an exposure to an offending antigen cannot be elicited [1]. Thus, radiographic and histologic examinations are frequently useful for diagnosis.

Chest Radiography: In the acute phase, heavy exposure to the responsible antigen may result in ill-defined, bilateral air space disease. Ill-defined air space nodules (acinar nodules, as seen in Figure 1 above) may also be evident. Patients are rarely seen at this stage, and the changes may resolve in several days.

The subacute presentation may be seen following a heavy acute exposure or with repeated, low-level exposures. In the subacute phase, a fine nodular pattern may develop on the chest radiograph. The nodular pattern correlates with cellular bronchiolitis and predominantly peribronchiolar alveolitis. The classic radiographic appearance of HP is recurrent, transient areas of consolidation or ground-glass opacities superimposed on a fine, nodular pattern. However, in many patients the chest radiograph is normal. Lymphadenopathy is uncommon in HP.

In the chronic phase, fibrosis develops months or years following the initial exposure. The fibrosis can be patchy in distribution, often with a predominance in the mid or lower lung. A pattern very similar to UIP, including the presence of honeycombing, may be encountered [3].

High-Resolution Computed Tomography: HRCT findings in the acute phase of HP include bilateral air-space consolidation and small, (1-3 mm diameter) ill-defined nodules. Patients are uncommonly imaged in this phase. HRCT findings of HP in the subacute phase (weeks or months following the first exposure) include ground glass opacities with or without poorly-defined centrilobular nodules. Occasionally, the poorly-defined centrilobular nodules (scroll down to Figure 2) may be the predominant finding. Both opacities and nodules tend to predominate in the mid and lower lungs [1,4,5].

On HRCT, the differential diagnosis of the ground-glass opacities of HP includes desquamative interstitial pneumonia (DIP), nonspecific interstitial pneumonia (NSIP), pulmonary hemorrhage, alveolar proteinosis, and certain infections, particularly Pneumocystis carinii pneumonia. Acute and subacute HP may be very difficult to distinguish from DIP or NSIP: centrilobular nodules favor diagnosis of the former. Alveolar proteinosis typically shows extensive interlobular septal thickening. Clinical and laboratory data frequently aid in distinguishing among the diseases that may resemble HP on HRCT, but a tissue diagnosis may be required to confirm or establish the diagnosis.

Mosaic Perfusion: Areas of decreased lung attenuation on inspiratory HRCT images (mosaic perfusion) may be seen in subacute HP, and air trapping may be demonstrated on postexpiratory scans. Occasionally, air trapping on postexpiratory scans may be the only finding of HP. Mosaic perfusion and air trapping are likely related to small airway obstruction resulting from bronchiolitis. The finding of ground-glass opacity, mosaic perfusion, and normal lung on the same inspiratory scan image (the "head-cheese" sign) may be encountered and reflects the combination of alveolitis and air-flow obstruction that characterizes HP [6,7].

Chronic HP: The chronic phase of HP is characterized by fibrosis on HRCT, although the findings of active disease are frequently evident, as well. Fibrosis in HP often shows a mid-lung predominance, although the findings may be distributed evenly throughout the upper, mid, and lower lungs. The extreme lung bases are often relatively spared in HP, a finding that may be useful for distinguishing chronic HP from UIP [3]. The "head-cheese" sign may also be observed in chronic HP.

Utility of HRCT in HP: HRCT is more sensitive than chest radiographs in the assessment of patients with HP, although the sensitivity of HRCT is not 100%. HRCT may demonstrate areas of ground-glass opacity or poorly-defined centrilobular nodules not evident on chest radiographs. HRCT is also useful for directing the site of surgical lung biopsy in indeterminate cases. HRCT abnormalities in patients with HP may resolve following cessation of antigen exposure, although in patients with chronic HP, findings of fibrosis are not reversible.

Histologic appearance: A histologic triad of interstitial lympho-plasmacellular infiltrates around small airways (bronchiolitis) and in alveolar parenchyma (alveolitis) along with ill-defined, non-necrotizing granulomas suggests the diagnosis, which must be confirmed clinically. Eosinophils are not a feature of this disease. Other common histologic features include: endogenous lipoid pneumonia caused by airway obstruction, and organization of alveolar or airway exudate (organizing pneumonia) [8]. With chronicity (scroll down when you get there), there may be fibrosis and honeycombing. Giant cells in granulomas may show cholesterol clefts, asteroid bodies, or Schaumann bodies with or without birefringent calcium oxalate crystals. Granulomas do not undergo fibrosis as in sarcoidosis (scroll down when you get there). In cases without granulomas, the histologic picture resembles nonspecific interstitial pneumonia, the differential diagnosis of which includes HP [9,10].

Pathogenesis: HP is a collection of different diseases believed to result from an immune response to one of a variety of antigens including bacteria, fungi, animal proteins, and chemical sensitizers [1]. Many people exposed to a causative antigen do not get the disease, and predisposing factors are elusive. There is some evidence that in farmer's lung, viruses can potentiate a low-grade asymptomatic inflammation to produce disease by upregulating inflammatory mediators such as TNF-alfa, interferon-gamma, and other cytokines [11].

Summary of HRCT Features



Summary of Pathologic Features

Diagnosis: Hypersensitivity pneumonitis (allergic alveolitis), subacute stage

References: To return to reference section after viewing abstract, click here before clicking on "abstract".

1. Glazer C, Rose C, Lynch D. Clinical and radiologic manifestations of hypersensitivity pneumonitis. J Thorac Imaging 2002; 17:261-272. Abstract

2. Ramirez-Venegas A, Sansores R, Perez-Padilla R, Carrillo G, Selman M. Utility of a provocation test for diagnosis of chronic pigeon breeder's disease. Am J Respir Crit Care Med 1998; 158:862-869. Abstract

3. Lynch D, Newell J, Logan P, King T Jr., Muller N. Can CT distinguish hypersensitivity pneumonitis from idiopathic pulmonary fibrosis? AJR Am J Roentgenol 1995; 165:807-811. Abstract

4. Hansell D, Wells A, Padley S, Müller N. Hypersensitivity pneumonitis: correlation of individual CT patterns with functional abnormalities. Radiology 1996; 199:123-128. Abstract

5. Patel R, Sellami D, Gotway M, Golden J, Webb W. Hypersensitivity pneumonitis: patterns on high-resolution CT. J Comput Assist Tomogr 2000; 24:965-970. Abstract

6. Webb W, Müller N, Naidich D. High Resolution CT of the Lung. Lippincott-Raven. New York, 2000, p 168-172.

7. Chung M, Edinburgh K, Webb E, McCowin M, Webb W. Mixed infiltrative and obstructive disease on high-resolution CT: differential diagnosis and functional correlates in a consecutive series. J Thorac Imaging 2001; 16:69-75. Abstract

8. Coleman A, Colby T. Histologic diagnosis of extrinsic allergic alveolitis. Am J Surg Pathol 1988; 12:514-518. Abstract

9. Travis W, Matsui K, Moss J, Ferrans V. Idiopathic nonspecific interstitial pneumonia: prognostic significance of cellular and fibrosing patterns. Survival comparison with usual interstitial pneumonia and desquamative intestitial pneumonia. Am J Surg Pathol 2000; 24:19-33. Abstract

10. Vourlekis J, Schwarz M, Cool C, Tuder R, King Jr T, Brown K. Nonspecific interstitial pneumonitis as the sole histologic expression of hypersensitivity pneumonitis. Am J Med 2002; 112:490-493. Abstract

11. Cormier Y, Israël-Assayag E. The role of viruses in the pathogenesis of hypersensitivity pneumonitis. Curr Opin Pulm Med 2000; 6:420-423. Abstract

12. Lacasse Y, Fraser R, Fournier M, Cormier Y. Diagnostic accuracy of transbronchial biopsy in acute farmer's lung disease. Chest 1997; 112:1459-1465. Abstract

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Radiographic Differential Diagnosis: The differential diagnosis of the chest radiographic abnormalities is extensive, including numerous infectious etiologies, non-infectious inflammatory lesions such as rheumatoid nodules, amyloidosis, and hypersensitivity pneumonitis, and malignant disease, particularly metastases.

The differential diagnosis of centrilobular, ground-glass attenuation nodules on HRCT is also extensive, and includes hypersensitivity pneumonitis, respiratory-bronchiolitis-interstitial lung disease, pulmonary edema, various infections (including bacteriologic, viral, and fungal), pneumoconioses, lymphocytic interstitial pneumonia, and Langerhans' cell histiocytosis. However, the absence of interlobular septal thickening, cystic lung abnormalities, and pleural effusion combined with the extremely widespread and uniform distribution of the nodules essentially eliminates most of the above entities, and strongly favors one of them (answer given after Pathology).





























Terminal bronchiole




























Respiratory bronchiole




























Alveolar duct




























The multinucleated giant cells along with some mononuclear histiocytes represent an ill-defined, non-necrotizing granuloma. The inflammatory cells in the infiltrate consist of both lymphocytes, as well as plasma cells, which cannot be distinguished in this image. Mast cells (scroll down when you get there), not apparent here, are also part of the infiltrate.




























Histologic differential diagnosis: Hypersensitivity pneumonitis, infection, and especially when granulomas are sparse or absent, nonspecific interstitial pneumonia (NSIP). An NSIP pattern can be idiopathic or caused by collagen vascular diseases, drug reaction, infection, or allergens that cause hypersensitivity pneumonitis. Lymphocytic interstitial pneumonia (LIP) and sarcoidosis might also be considered. LIP typically has a heavier infiltrate of lymphocytes. The granulomas of sarcoidosis are well-formed, and a lymphocytic bronchiolitis and alveolitis are not characteristic of the disease.

Diagnosis: With a triad of granulomas and lympho-plasmacellular bronchiolitis and alveolitis, the diagnosis of hypersensitivity pneumonitis can be suggested based on the biopsy alone. Both the radiographic findings and histologic changes are typical of hypersensitivity pneumonitis. With this in mind, further questioning revealed that both patients presented here owned birds.