Pathology Lab IV - Restrictive Lung Diseases
PATHOLOGY LAB IV-RESTRICTIVE LUNG DISEASES.
Case Presentation #1: John Q.
Idiopathic pulmonary fibrosis (IPF)
Case Presentation #2: George T.
Pulmonary alveolar proteinosis
After completing this unit the student will be able to:
1. Identify ventilator defects in patients with restrictive lung disease
2. Describe morphology, clinical manifestations, disease course, and pathogenesis of idiopathic
3. Define pneumoconiosis, and list the most common types of pneumoconiosis.
4. Describe forms, morphology, and clinical manifestations of coal worker‟s pneumoconiosis.
5. Describe pathogenesis, morphology, clinical manifestations, and forms of silicosis.
6. Describe morphology and clinical manifestations of various types of asbestos-related diseases.
Identify types of asbestos fibers.
7. Describe etiology, morphology of sarcoidosis granuloma, clinical manifestations, organs
involved, hypercalcemia, and clinical course of sarcoidosis.
8. Describe causes, morphology, pathogenesis, and clinical manifestations of hypersensitivity
9. Describe causes, forms, morphology on gross, histologic and ultrastructural levels,
pathogenesis, and clinical manifestations of pulmonary alveolar proteinosis.
1. Robbins and Cotran Pathologic Basis of Disease, 8th edition, Chapter 15, pages 693-706
CASE PRESENTATION #1: JOHN Q.
A 61-year-old white male was admitted with non-productive cough, dyspnea, fatigue and weight
loss in the past 9 months. Physical examination revealed clubbing and cyanosis, and crackles
were detected on chest auscultation. Laboratory findings showed a high ESR (74 mm, normal <
20), C-reactive protein (5.6 mg/dL, normal 0.1) and hypoxemia (pH 7.43, PaO2 52.3 mmHg;
PaCO2 38.0 mmHg); alpha1 antitrypsin, autoimmune studies, serologic evaluation and serum
precipitins were unremarkable. Pulmonary function tests were consistent with restrictive
impairment. CT scan demonstrated a pulmonary fibrosis pattern despite the absence of
distinctive features in the transbronchial biopsies. Therapy with amoxicillin/clavulanate,
azithromycin (for concomitant respiratory tract infection), oxygen, and prednisolone (1 mg/kg
per day) resulted in clinical improvement. The patient was discharged after a 10-day
hospitalization and was referred to the pulmonology outpatient clinic. The patient was readmitted
a week later due to worsening respiratory insufficiency (pH 7.41; PaO2 41.7 mmHg; PaCO2
42.3). Thoracoscopic lung biopsies showed usual interstitial pneumonia (UIP) histopathological
pattern, confirming a diagnosis of idiopathic pulmonary fibrosis. In spite of treatment with
azathioprine (2 mg/kg per day), there was clinical aggravation with refractory hypoxemia and
heart failure requiring mechanical ventilation. The patient died 5 weeks after the first admission.
Restrictive lung diseases are a category of respiratory diseases that restrict lung expansion,
resulting in a decreased lung volume, an increased work of breathing, and inadequate ventilation
INTRINSIC AND EXTRINSIC RESTRICTIVE LUNG DISEASE.
The many disorders that cause restrictive lung disease reduction or restriction of lung volumes
may be divided into 2 groups based on anatomical structures. The first is intrinsic diseases or
diseases that affect lung interstitium (interstitial lung disease). Interstitial lung diseases primarily
involve the alveoli and perialveolar tissues, leading to pulmonary fibrosis, restrictive lung
physiology and derangement of gas exchange.
The second is extrinsic diseases or extraparenchymal diseases. These diseases affect chest wall,
pleura, and respiratory muscles. These are components of the respiratory pump, and they need to
function normally for effective ventilation. Diseases of these structures result in lung restriction,
impaired ventilatory function, and respiratory failure (e.g., nonmuscular diseases of the chest
wall, neuromuscular disorders).
This module will cover the intrinsic restrictive disorders (interstitial lung diseases) only.
PHYSIOLOGIC CHANGES IN RESTRICTIVE LUNG DISEASE.
Restrictive lung diseases are characterized by reduced lung volume. In physiological terms,
restrictive lung diseases are characterized by reduced total lung capacity (TLC). Routine
spirometry reveals decreased measures of forced vital capacity (FVC) and forced expiratory
volume in one second (FEV1). The ratio of FEV1/FVC remains normal, consistent with
Restrictive physiology is the consequence of reduced pulmonary compliance. Changes in
complicance can be attributed to the accumulation of parenchymal scar tissue and the subsequent
distortion of normal lung architecture.
Gas exchange is impaired in interstitial lung diseases, which can be demonstrated by
measurements of the diffusion capacity. The resting arterial blood gas is usually normal. Mild
hypoxemia and mild respiratory alkalosis can occur in end-stage disease. Oxygen desaturation is
commonly found during exercise. The main cause for exercise-induced hypoxemia is ventilator-
perfusion (V/Q) mismatching, as opposed to anatomic shunting or reduced diffusion capacity.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and lethal form of lung disease
characterized by fibrosis of the pulmonary interstitium of unknown etiology.
Synonym: cryptogenic fibrosing alveolitis
The epidemiology of IPF has not been well characterized. The incidence of IPF in the U.S. is
estimated to be 6.8 per 100,000 persons. Idiopathic pulmonary fibrosis mainly affects elderly
persons; the mean age at presentation is 66 years. IPF is more frequent in men.
1. Latency period.
There is a considerable latency period that may last one decade or more. Individuals with latent
IPF are asymptomatic but have histologically-proven IPF. Asymtpmatic OPF progresses slowly
toward symptomatic IPF.
2. Early stage.
Patients have an insidious onset of exertional dyspnea. A dry, nonproductive cough is common.
These symptoms are nonspecific and can be shared with a variety of pulmonary and cardiac
diseases. The onset of symptoms is slow, but symptoms become progressively worse over time.
The initial dyspnea is commonly attributed to aging, cardiac diseases or emphysema, which
results in typical delays of diagnosis. Retrospective analysis of IPF patients suggests that
symptoms precede diagnosis by a period of 6 months to 2 years.
Systemic symptoms such as weight loss, low-grade fevers, fatigue, arthralgias, or myalgias are
unusual for IPF.
Auscultation of the lungs reveals early inspiratory crackles predominantly located in the lower
posterior lung zones upon physical exam. These rales have a fine acustic character reminiscent of
the sound made by Velcro.
Additionally, digital clubbing is seen in 50% to 70% of patients.
There are no other physical manifestations, unless cor pulmonale has developed in association
with end-stage disease. In that case, signs of right heart failure may be present.
3. Late complications.
Respiratory failure with cyanosis, pulmonary hypertension and cor pulmonale are common late
complications. About 20-40% of patients with idiopathic pulmonary fibrosis who are evaluated
or listed for lung transplantation have pulmonary hypertension at rest. Physical examination
findings may be suggestive of the presence of pulmonary hypertension. Patients may have a loud
P2 component of the second heart sound, a fixed split S2, a holosystolic tricuspid regurgitation
murmur, and pedal edema. As right ventricular hypertrophy ensues, a right ventricular heave
may be palpated at the lower left sternal border and increased right atrial pressure may cause
elevation of the jugular venous pressure.
1. Plain chest radiograph.
Radiologically, bilateral reticular markings (curvilinear opacities) are observed, predominately at
the periphery and the bases. Interpretation of interstitial patterns has poor interobserver
agreement. For that reason use of standard radiographs lacks diagnostic accuracy.
2. High-resolution computed tomography.
High-resolution computed tomography (HRCT) is more accurate than conventional radiography.
The typical pattern of IPF on HRCT is characterized by: (a) patchy reticular opacities,
predominantly subpleural and bibasilar; (b) traction bronchiectasis, i.e. secondary involvement of
medium-sized airways; and (c) subpleural honeycombing, i.e. palisades of small, round
translucencies and architectural distortion with basal and peripheral distribution.
Macroscopically lungs are seen only in end-stage disease. Grossly, the pleural surfaces of the
lung are cobblestoned as a result of the retraction of scars along the interlobular septa. This is
reminiscent of cirrhosis of the liver. On the cut surface there are microcysts with intervening
These changes are most marked in the lower lobes, but often the fibrosis spreads in a subpleural
manner into the upper lobes. The nodules seen externally correspond to microscysts which are
dilated bronchioles and alveolar ducts surrounded by fibrosis. Honeycomb change is defined as
cystic, dilated bronchioles (containing mucous and leukocytes) lined by columnar respiratory
epithelium in scarred, fibrotic lung tissue. In end-stage idiopathic pulmonary fibrosis there is
right ventricular hypertrophy.
IPF is a distinctive type of chronic fibrosing interstitial pneumonia of unknown cause limited to
the lungs and associated with a histological pattern of usual interstitial pneumonia (UIP). The
histological hallmark of the UIP pattern is patchy interstitial fibrosis, often in subpleural and/or
paraseptal distribution, alternating with areas of normal lung. The fibrosis is temporally
heterogeneous (meaning that the fibrosis is of different ages) with architectural destruction, and
dense scarring with honeycombing.
Survival is poor in patients with idiopathic pulmonary fibrosis. Recent clinical series of well
defined cases of idiopathic pulmonary fibrosis have identified a mean survival ranging from 2 to
4 years after diagnosis. Conventional management of idiopathic pulmonary fibrosis is primarily
based on the concept that suppressing inflammation prevents progression to pulmonary fibrosis.
However, the response to steroids is usually poor in idiopathic pulmonary fibrosis and the use of
other immunosuppressive or aggressive cytotoxic agents has largely failed to reduce the death
rate in patients with idiopathic pulmonary fibrosis.
The original hypothesis of the pathogenesis of pulmonary fibrosis asserts that unknown stimuli
injure the lung resulting in chronic inflammation, fibrogenesis and finally end-stage fibrotic scar
formation. Recent studies challenged the old concept that inflammation is the driving force in the
development of IPF.
In accordance with the disappointing effects of anti-inflammatory treatment, there is increasing
evidence that inflammation may not be as important in the development of pulmonary fibrosis as
previously thought. It has been suggested that IPF is mainly a disorder of abnormal alveolar
wound repair and remodeling.
Increasing evidence suggests that the changes present in IPF result from sequential alveolar
epithelial injury and abnormal wound repair. Unknown injuries induce alveolar epithelial
damage resulting in alveolar epithelial cell necrosis, fibrin deposition (hyaline membranes) and
hemostasis. Reversibly damaged alveolar epithelial cells secrete growth factors and induce
intraalveolar migration and proliferation proliferation of fibroblasts and their differentiation to
myofibroblasts that secrete extracellular matrix proteins, mainly collagens. Myofibroblasts are
identified by the expression of Alpha-smooth muscle actin and are generally considered to be
responsible for the wound contraction and soft tissue retraction, which takes place during the
development of pulmonary fibrosis. Moreover, myofibroblasts are characterized by the
production and secretion of collagen and a variety of cytokines, including the profibrotic TGF-
An imbalance of pro- and antifibrotic factors may result in the progressive deposition of
extracellular matrix within the alveoli and the interstitium and finally in the development of
pulmonary fibrosis. Hyperplasic alveolar epithelial cells regenerate the alveolar epithelium by
migration over the intraalveolar provisional fibrotic matrix. These processes lead to the
destruction of the alveolocapillary units, with loss of lung function. In addition, myofibroblasts
induce alveolar epithelial cell death, thereby perpetuating the damage of the alveolar epithelium
and inhibiting appropriate and efficient reepithelialization.
The circuits that drive such aberrant epithelial repair are not fully understood, but all evidence
points to TGF-Beta1 as the driver of the process. TGF-Beta1 is known to be fibrogenic and is
released from injured type I alveolar epithelial cells. It favors the transformation of fibroblasts
into myofibroblasts and deposition of collagen and other extracellular matrix molecules.
The concept that there is an intrinsic abnormality of tissue repair in IPF is supported by the
finding that TGF-Beta1 down-regulates caveolin-1. Caveolin-1 acts as an endogenous inhibitor
of pulmonary fibrosis by limiting TGF-Beta1-induced production of extracellular matrix and
restoring alveolar epithelial repair processes. Caveolin-1 is decreased in epithelial cells and
fibroblasts of IPF patients, and overexpression of caveolin-1 in a mouse model limits fibrosis.
Pneumoconiosis is a term for a class of lung diseases caused by the inhalation of mineral dust,
nearly always in occupational settings. Most cases of pneumoconiosis develop only after many
years of cumulative exposure; thus they are often diagnosed in older individuals, long after the
onset of exposure. These diseases are incurable and may ultimately result in death.
Pneumoconiosis includes the following forms: (a) coal workers‟ pneumoconiosis, (b) silicosis,
(c) asbestosis, and, (d) less commonly, pneumoconiosis due to a variety of other mineral dusts,
including talc, aluminum, bauxite, and graphite.
COAL WORKER'S PNEUMOCONIOSIS.
Coal worker's pneumoconiosis (CWP) can be defined as the accumulation of coal dust in the
lungs and the tissue's reaction to its presence. The spectrum of lung findings in coal workers is
wide, varying from (a) asymptomatic anthracosis to (b) simple CWP with little to no pulmonary
dysfunction to (c) complicated CWP, or progressive massive fibrosis (PMF), in which lung
function is compromised
2. The spectrum of lung findings.
(A) Anthracosis. Anthracosis is an innocuous coal-induced pulmonary lesion in coal miners and
is also commonly seen in all urban dwellers and tobacco smokers. Inhaled carbon particles are
engulfed by alveolar macrophages which then accumulate in the connective tissue along the
lymphatics and in the lymph nodes along the bronchi or in the lung hilum. The accumulation of
carbon particles causes no cellular reaction. Grossly there is focal black pigmentation scattered
through the lung fields most numerous in the upper zones of the upper and lower lobes.
(B) Simple CWP. In CWP accumulation of carbon-laden macrophages occurs with little or no
pulmonary dysfunction. Simple CWP is characterized by coal macules (1 to 2 mm in diameter)
and the somewhat larger coal nodules. The coal macule consists of carbon-laden macrophages;
the nodule also contains small amounts of a delicate network of collagen fibers. Although these
lesions are scattered throughout the lung, the upper lobes and upper zones of the lower lobes are
more heavily involved. They are located primarily adjacent to respiratory bronchioles, the site of
initial dust accumulation.
(C) Complicated CWP. Complicated CWP (or progressive massive fibrosis) occurs on a
background of simple CWP and generally requires many years to develop. It is characterized by
intensely blackened scars larger than 2 cm, sometimes up to 10 cm in greatest diameter. They are
usually multiple. Histologically lesions consist of dense collagen and pigment. The center of the
lesion is often necrotic, most likely due to local ischemia.
3. Clinical presentation.
CWP is usually a benign disease that causes little decrement in lung function. Even mild forms
of complicated CWP fail to demonstrate abnormalities of lung function. In a minority of cases
(fewer than 10%), progressive massive fibrosis (PMF) develops, leading to increasing pulmonary
dysfunction, dyspnea, respiratory insufficiency, pulmonary hypertension, and cor pulmonale
(with associated hepatomegaly and peripheral edema). Once PMF develops, it may become
progressive even if further exposure to dust is prevented. Unlike silicosis, coal dust does not
increase the susceptibility to tuberculosis.
Silicosis is a potentially fatal, irreversible, fibrotic pulmonary disease that may develop
subsequent to the inhalation of large amounts of silica dust over time. In most circumstances,
silicosis only develops subsequent to substantial occupational exposures. Silicosis usually
presents after decades of exposure as slowly-progressing, nodular, fibrosing pneumoconiosis.
Workers in a large number of occupations are at risk, especially sandblasters and many mine
Silica occurs in both crystalline and amorphous forms, but crystalline forms (including quartz,
crystobalite, and tridymite) are much more fibrogenic. Of these, quartz is most commonly
implicated in silicosis. After inhalation, silica particles are efficiently cleared from the lung by
alveolar macrophages. The surface of these particles generates silicon-based radicals that lead to
the production of hydroxyl, hydrogen peroxide, and other oxygen radicals that damage cell
membranes by lipid peroxidation and inactivate essential cell proteins. Because of the free
radical production these alveolar macrophages become damaged and release mediators include
IL-1, TNF, fibronectin, lipid mediators, oxygen-derived free radicals, and fibrogenic cytokines.
Especially compelling is evidence incriminating TNF. When the alveolar macrophages
containing silica die, they release silica particles which are then re-engulfed by other alveolar
macrophages, inducing a cycle of injury.
There are two types of silicosis: acute and chronic.
(A) Acute silicosis. Acute silicosis follows massive exposure to dust. Very heavy exposure to
silica stimulates hypersecretion of alveolar surfactant to such an extent that the normal clearance
mechanism is overwhelmed. The alveoli are filled with a lipoproteinaceous material that is
eosinophilic, periodic acid-Schiff-positive (PAS-positive) and diastase resistant. This form is
identical morphologically to pulmonary alveolar proteinosis.
(B) Chronic silicosis. Chronic silicosis can be either (a) simple silicosis or (b) complicated
silicosis (also called progressive massive fibrosis). Chronic simple silicosis is characterized
grossly in its early stages by tiny, barely palpable, discrete pale to blackened (if coal dust is also
present) nodules in the upper zones of the lungs. They measure up to 5 mm in diameter and are
hard and easily palpable.
Histologically, the silicotic nodule reveals a characteristic structure. The nodule is composed of
refractile particles of silica surrounded by whorled collagen in concentric layers, with
macrophages, lymphocytes, and fibroblasts in the periphery. Examination of the nodules by
polarized microscopy reveals the birefringent silica particles.
Complicated silicosis (progressive massive fibrosis) develops when the above described silicotic
nodules coalesce forming pulmonary scars 2 cm or larger. Some nodules may undergo central
softening and cavitation. This change may be due to superimposed tuberculosis or to ischemia.
Fibrotic lesions may also occur in the hilar lymph nodes and pleura. Sometimes, thin sheets of
calcification occur in the lymph nodes and are seen radiographically as eggshell calcification
(i.e., calcium surrounding a zone lacking calcification).
4. Clinical manifestations.
(A) Acute silicosis. Acute silicosis follows massive exposure to dust in unregulated
environments. Acute silicosis causes symptoms weeks to a few years after exposure. Besides
severe dyspnea, other symptoms include cough, fever, and weight loss. Pleuritic pain may be
present. Chest radiograph suggest a ground-glass appearance, similar to pneumonia or
(B) Chronic silicosis. Chronic silicosis can be either simple silicosis or complicated silicosis.
Chronic simple silicosis results from long-term exposure (10 years or more) to relatively low
concentrations of silica dust. Patients with this type of silicosis, especially early on, may be
asymptomatic, but abnormalities may be detected by x-ray. Chronic cough and exertional
dyspnea develop later. Radiographically, chronic simple silicosis reveals the presence of few to
numerous small (<1.0 cm in diameter) opacities, typically rounded, and predominating in the
upper lung zones. Chronic simple silicosis progresses toward chronic complicated silicosis
because of the development of severe scarring (progressive massive fibrosis) where the small
nodules gradually become confluent, reaching a size of 1.0 cm or greater. Complicated silicosis
is associated with more severe symptoms and respiratory impairment than simple silicosis.
In chronic silicosis chest radiography reveals nodular opacities scattered diffusely throughout the
lungs that are more prominent in the upper lung fields. Complicated silicosis (also known as
progressive massive fibrosis) manifests as bilateral upper lobe masses, which are formed by the
coalescence of nodules.
Radiographic features of hilar lymphadenopathy in chronic silicosis are not an unusual
observation. Animal models of dust inhalation have shown that silica is cleared via the
lymphatics to the hilar lymph nodes and that silica accumulates there.
6. Pulmonary physiologic changes.
Pulmonary function tests may be normal early in the course of simple silicosis. However, with
disease progression, a restrictive or mixed pattern of obstruction and restriction may emerge. The
obstructive component may be due to airway obstruction resulting from fibrosis. Progressive
massive fibrosis causes severe restriction, decreased compliance, and hypoxemia.
Asbestos-related diseases are a spectrum of thoracic diseases caused by the inhalation and
retention of asbestos fibers. These diseases usually occur after high intensity and/or long-term
exposure to asbestos (particularly in those individuals working on the production or end-use of
products containing asbestos). Individuals with extensive occupational exposure to mining,
manufacturing, and handling or removal of asbestos are at elevated risk for developing asbestos-
2. Types of asbestos fibers.
Asbestos is a generic name for a variety of naturally occurring fibrous silicate minerals that was
widely used in the past for commercial applications because of its heat-resistance, high tensile
strength and good chemical resistance properties. Asbestos minerals may be separated into two
broad classes: chrysotile (serpentine), which comprises more than 90% of the asbestos used in
this country, and the amphiboles. Amphibole fibers are characteristically straight, rigid, and
needlelike. Chrysotile is different from amphibole in that its fibers are curly, longer and more
flexible. Chrysotile fibers settle in large airways and are eliminated by ciliary action. Amphibole
fibers reach the small bronchi and alveoli and are the most dangerous in regard to all forms of
3. The spectrum of asbestos-related diseases.
The spectrum of asbestos-related diseases includes the following thoracic disorders: (a) benign
pleural effusion, (b) pleural plaques, (c) diffuse pleural thickening, (d) asbestosis, (e)
mesothelioma, and (f) lung carcinoma. Asbestosis is defined as diffuse lung fibrosis due to the
inhalation of asbestos fibers, and it is one of the major causes of occupationally related lung
damage. Mesothelioma is a malignant pleural tumor arising from the mesothelium lining lungs
that rarely occurs in patients who have not been exposed to asbestos.
(A) Asbestosis. Asbestosis is marked by diffuse pulmonary interstitial fibrosis, which is
indistinguishable from diffuse interstitial fibrosis resulting from other causes, except for the
presence of multiple asbestos bodies. Asbestos bodies appear as golden brown, fusiform or
beaded rods with a translucent center and consist of asbestos fibers coated with an iron-
containing proteinaceous material. They arise when macrophages attempt to phagocytose
asbestos fibers; the iron is presumably derived from phagocyte ferritin. Asbestos bodies occur in
any patient with high-level asbestos exposure and are only a marker of such exposure. Note that
the term „ferruginous bodies‟ is applied to structures similar to asbestos bodies, composed of a
central mineral filament, not necessarily asbestos, coated with a protein-iron complex.
The fibrous tissue induced by asbestos deposition distorts the lung architecture, creating enlarged
airspaces enclosed within thick fibrous walls. Eventually the affected regions become
honeycombed. The American College of Pathologists' scheme for assessing the severity of
asbestosis grades fibrosis in 4 categories. Grade 1 is fibrosis in the wall of a respiratory
bronchiole without extension to distant alveoli. Grades 2 and 3 define more extensive disease,
and Grade 4 correspond to honeycombing, i.e. pulmonary fibrosis with spaces larger than alveoli
ranging up to 1 cm in diameter.
The pattern of fibrosis in asbestosis is similar to that seen in idiopathic pulmonary fibrosis, the
only difference being the presence of numerous asbestos bodies. In contrast to CWP and
silicosis, asbestosis begins in the lower lobes. The middle and upper lobes of the lungs become
affected as fibrosis progresses. The scarring may trap and narrow pulmonary arteries and
arterioles, causing pulmonary hypertension and cor pulmonale.
(B) Pleural plaques. Pleural plaques are the most common manifestation of asbestos exposure.
Pleural plaques are well-circumscribed plaques of dense collagen, often containing calcium.
They develop most frequently on the anterior and posterolateral aspects of the parietal pleura and
over the domes of the diaphragm. The size and number of pleural plaques do not correlate with
the level of exposure to asbestos or the time since exposure.
They do not contain asbestos bodies. Only rarely do they occur in individuals who have no
history or evidence of asbestos exposure. Uncommonly, asbestos exposure induces pleural
effusions, which are usually serous but may be bloody. Rarely, diffuse visceral pleural fibrosis
may occur and, in advanced cases, bind the lung to the thoracic cavity wall.
(C) Lung carcinomas and mesothelioma. Both lung carcinomas and pleural mesotheliomas (and
peritoneal mesotheliomas as well) develop in workers exposed to asbestos. The risk of lung
carcinoma is increased about fivefold for asbestos workers; the relative risk of mesotheliomas,
normally a rare tumor (2 to 17 cases per 1 million persons), is more than 1000-fold greater.
Concomitant cigarette smoking greatly increases the risk of lung carcinoma but not that of
4. Clinical manifestations. The clinical findings in asbestosis are very similar to those caused by
other restrictive lung diseases. Dyspnea is usually the first manifestation; at first, it is provoked
by exertion, but later it is present even at rest. The dyspnea is usually accompanied by a cough
associated with production of sputum. These manifestations rarely appear fewer than 10 years
after first exposure and are more common after 20 years or more. Chest x-rays reveal irregular
linear densities, particularly in both lower lobes. With advancement of the pneumoconiosis, a
honeycomb pattern develops. The disease may remain static or progress to respiratory failure,
cor pulmonale, and death. Pleural plaques are usually asymptomatic and are detected on
radiographs as circumscribed densities. Asbestosis complicated by lung or pleural cancer is
associated with a particularly grim prognosis.
CASE PRESENTATION #2: GEORGE T.
George is a 17 year-old boy who presented to your office in early October, after having spent the
summer working on his family‟s farm to cut and bale hay. He had a 2-month history of
progressive weakness and lethargy and general malaise, and a one-week history of constricting
pain across his chest, night sweats, and occasionally blood-tinged sputum. He has a temperature
of 100.2ºF, pulse 120/min and respirations 40/min. On physical examination you see an
apparently athletic teenager, who was weak and dyspneic. Since crepitations were noted at the
base of the right lung upon auscultation, penicillin was started. His condition worsened over the
next 24 hours, at which time his parents brought him to the local ER, and he was admitted to the
hospital. Upon presentation to ER he appeared anxious, cyanotic, and dyspneic at rest.
Laboratory studies revealed neutrophilic leukocytosis with a left shift and increased ESR.
Chest radiography showed micronodular opacities throughout the lung fields, which were most
marked in the lower and mid-zones. Pulmonary function studies (spirometry) showed restrictive
ventilatory pattern with reduced forced vital capacity, reduced total lung capacity, and preserved
airflow; moderate hypoxemia at rest, and decreased diffusion capacity. The boy‟s pulse rate
remained high at 120-150/minute and respiratory rate at 40-50/minute; blood pressure was
120/60 mm Hg. The boy expired 6 hours later. At the autopsy small numerous nodules were
distributed throughout the cut surface of each lobe, which were firm, discrete, and grey-centered
and ringed with hemorrhage. Histologically, lung nodules consisted of a confluent mass of giant
multinuclear cells, macrophages, lymphocytes, plasma cells, and eosinophils that suggested peri-
bronchiolar non-necrotizing granuloma formation, and were separated either by aerated alveoli
or by interstitial spaces infiltrated with a similar population of inflammatory cells, multifocal
acute and chronic hemorrhage, and protein-rich exudative fluid. Autopsy confirmed the clinical
diagnosis of farmer‟s lung.
Sarcoidosis is a systemic disease of unknown cause characterized by noncaseating granulomas in
many tissues and organs. Sarcoidosis presents many clinical patterns, but bilateral hilar
lymphadenopathy or lung involvement is visible on chest radiographs in 90% of cases. Eye and
skin lesions occur next in frequency. Since other diseases, including mycobacterial and fungal
infections and berylliosis, can also produce noncaseating granulomas, the histologic diagnosis of
sarcoidosis is made by exclusion.
2. Etiology and pathogenesis.
Although the etiology of sarcoidosis remains unknown, several lines of evidence suggest that it
is a disease of disordered immune regulation in genetically predisposed individuals exposed to
certain environmental agents. A. There are several immunological abnormalities in the local
milieu of sarcoid granulomas that suggest the development of a cell-mediated response to an
unidentified antigen. The process is driven by CD4+ helper T cells. B. Additionally, there are
systemic immunological abnormalities in individuals with sarcoidosis, such as anergy to
common skin test antigens such as Candida or tuberculosis purified protein derivative (PPD). C.
Evidence of genetic influences is the familial and racial clustering of cases and the association
with certain HLA genotypes (e.g., HLA-A1 and HLA-B8). D. Several putative organisms have
been proposed as the inciting agent for sarcoidosis (e.g., mycobacteria, Propionibacterium acnes,
and Rickettsia species). Alas there is no unequivocal evidence that sarcoidosis is caused by an
Histologically, all involved tissues show the classic well-formed non-caseating granulomas, each
composed of an aggregate of tightly clustered epithelioid cells, often with Langhans or foreign
body-type giant cells. Central necrosis is unusual. With chronicity the granulomas may become
enclosed within fibrous rims or may eventually be replaced by hyaline fibrous scars. Laminated
concretions composed of calcium and proteins known as Schaumann bodies and stellate
inclusions known as asteroid bodies enclosed within giant cells are found in approximately 60%
of the granulomas.
Though characteristic, these microscopic features are not pathognomonic of sarcoidosis, because
asteroid and Schaumann bodies may be encountered in other granulomatous diseases (e.g.,
tuberculosis). Pathologic involvement of virtually every organ in the body has been cited at one
time or another.
4. Sites of involvement.
The lungs are common sites of involvement. Macroscopically there is usually no demonstrable
alteration, although in advanced cases the coalescence of granulomas produces small nodules
that are palpable or visible as 1 to 2 cm, noncaseating consolidations. Histologically, the lesions
are distributed primarily along the lymphatics, around bronchi and blood vessels, although
alveolar lesions are also seen. The relative frequency of granulomas in the bronchial submucosa
accounts for the high diagnostic yield of bronchoscopic biopsies. There seems to be a strong
tendency for lesions to heal in the lungs, so varying stages of fibrosis and hyalinization are often
found. The pleural surfaces are sometimes involved.
Lymph nodes are involved in almost all cases, particularly the hilar and mediastinal nodes, but
any other node in the body may be involved. Nodes are characteristically enlarged, discrete, and
sometimes calcified. The tonsils are affected in about one quarter to one third of cases.
Other organs involved in sarcoidosis are the spleen (granulomas and splenomegaly), liver (one
third of patients have liver granulomas and hepatomegaly), bone marrow, skin (erythema
nodosum, macules, papules, and plaques), eye (iritis and iridocyclitis) and muscle (weakness,
aches, tenderness, and fatigue).
Epitheloid cells in sarcoidosis granulomas can produce calcitriol (1,25 vitamin D) and cause
hypercalcemia, which is seen in about 10-13% of patients, whereas hypercalciuria is 3 times
more common. This process can ultimately result in nephrocalcinosis and renal failure.
6. Clinical manifestations.
Because of its varying severity and the inconstant distribution of the lesions, sarcoidosis is a
protean clinical disease. It may be discovered unexpectedly on routine chest films as bilateral
hilar adenopathy or may present with peripheral lymphadenopathy, cutaneous lesions, eye
involvement, splenomegaly, or hepatomegaly.
In the great majority of cases, however, individuals seek medical attention because of the
insidious onset of respiratory abnormalities (shortness of breath, cough, chest pain, hemoptysis)
or of constitutional signs and symptoms (fever, fatigue, weight loss, anorexia, night sweats).
7. Disease course.
Sarcoidosis follows an unpredictable course characterized by either progressive chronicity or
periods of activity interspersed with remissions, sometimes permanent, that may be spontaneous
or induced by steroid therapy. Overall, 65% to 70% of affected patients recover with minimal or
no residual manifestations. Twenty percent have permanent loss of some lung function or some
permanent visual impairment. Of the remaining 10% to 15%, some die of cardiac or central
nervous system damage, but most succumb to progressive pulmonary fibrosis and cor pulmonale.
The term hypersensitivity pneumonitis describes a spectrum of immunologically mediated,
predominantly interstitial, lung disorders caused by intense, often prolonged exposure to inhaled
Synonym: extrinsic allergic alveolitis
Most commonly, hypersensitivity pneumonitis results from the inhalation of organic dust
containing antigens made up of spores of thermophilic bacteria, true fungi, animal proteins, or
bacterial products. Numerous specifically named syndromes are described, depending on the
occupation or exposure of the individual. Farmer's lung results from exposure to dusts generated
from harvested humid, warm hay that permits the rapid proliferation of the spores of
thermophilic actinomycetes. Pigeon breeder's lung (bird fancier's disease) is provoked by
proteins from serum, excreta, or feathers of birds. Humidifier or air-conditioner lung is caused
by thermophilic bacteria in heated water reservoirs.
Based on the length and intensity of exposure and subsequent duration of illness, clinical
presentations of hypersensitivity pneumonitis are categorized as acute, subacute, and chronic
Prevalence varies by region, climate, and farming practices. Hypersensitivity pneumonitis affects
0.4-7% of the farming population. The male to female ratio is 1.2:1. Hypersensitivity
pneumonitis is usually seen in the fourth to sixth decade of life. The mean age is 53 years.
Most patients have circulating IgG antibodies that are specific for the offending antigen. The
antibody (called precipitating antibody) reacts with a specific antigen to form a precipitation.
However, approximately 50% of asymptomatic persons exposed to the sensitizing antigen also
have these antibodies. Hypersensitivity pneumonitis was initially thought to be an
immunocomplex-mediated process (type III hypersensitivity) since complement and
immunoglobulins have been demonstrated within vessel walls by immunofluorescence.
Subsequent studies showed that cell-mediated immunity (type IV hypersensitivity) is more
important since noncaseating granulomas are found in more than two-thirds of the patients.
(A) Early stage. If the biopsy is undertaken very early in the course of the disease, it will show
alveolitis with fibrinous exudates and neutrophils within the alveolar lumina. This early
pneumonia will not resolve (as in lobar pneumonia) but will lead to the organization of the
alveolar exudate by granulation tissue growing and filling the alveoli and respiratory
(B) Later stage. Biopsy specimens taken later in the course of the disease will show non-
necrotizing granulomas in the lungs. These are smaller than those seen in sarcoidosis, and are
accompanied by widespread thickening of the alveolar walls by a diffuse lymphocytic infiltrate.
In contrast to sarcoidosis, the hilar lymph nodes are unaffected. Granulomas show
peribronchiolar preponderance, these airways being the portal of entry of the etiological agent.
(C) Resolution. Granulomas resolve within 6 months unless is further exposure. Most patients
recover completely after the inciting exposure ceases. But if the exposure continues, the
inflammation may progress to an irreversible scarring. In fatal cases lungs show
“honeycombing” with dense fibrosis.
5. Clinical manifestations.
The clinical manifestations are varied. Acute attacks, which follow inhalation of antigenic dust in
sensitized patients, consist of recurring episodes of fever, dyspnea, cough, and leukocytosis.
Diffuse and nodular infiltrates appear in the chest radiograph, and pulmonary function tests show
an acute restrictive disorder. Symptoms usually appear 4 to 6 hours after exposure. If exposure is
continuous and protracted, a chronic form of the disease supervenes with progressive respiratory
failure, dyspnea, and cyanosis and a decrease in total lung capacity and compliance-a picture
similar to other forms of chronic interstitial disease.
6. Laboratory studies.
Leukocytosis and neutrophilia, elevated ESR, and C-reactive protein, and
hypergammaglobulinemia are observed in many patients. Precipitating antibodies to the
offending antigen are commonly present; however, this observation is considered marker of
exposure and not the cause of the disease.
Pulmonary alveolar proteinosis (PAP) is a rare disease that is characterized radiologically by
bilateral patchy asymmetric pulmonary opacifications and histologically by accumulation of
acellular surfactant in the intra-alveolar and bronchiolar spaces.
There are three distinct classes of this disease: primary (or acquired), secondary and congenital
PAP. Each form has a different pathogenesis but histologic changes are similar for all three
forms. Primary PAP accounts for 90% of cases, congenital form represents only 2% of cases.
The estimated prevalence of PAP is 1 case per 100,000 population. Incidence for males is 4
times higher than for females. Patients with primary PAP are typically aged 20-50 years at
PAP is characterized by a peculiar granular precipitate within the alveoli, causing focal-to-
confluent consolidation of large areas of the lungs with minimal inflammatory reaction. On
section, turbid fluid exudes from these areas. As a consequence there is a marked increase in the
size and weight of the lung. The alveolar precipitate is periodic acid-Schiff positive and also
contains cholesterol clefts. Immunohistochemical staining reveals abundant accumulation of
surfactant protein. Electron microscopy of the material in the alveoli shows multilamellated
structures and membranous vesicles.
1. Congenital PAP.
Congenital PAP is a heterogeneous group of disorders caused my mutations in two genes that
encode for (a) surfactant proteins B or C (SP-B and SP-C), or (b) the beta chain of the receptor
for granulocyte–macrophage colony-stimulating factor (GM-CSF). Most cases of congenital
PAP are transmitted in an autosomal recessive fashion.
GM-CSF is a hematologic growth factor which stimulates the production of myeloid cells from
hematopoietic precursors. Targeted disruption of GM-CSF gene causes accumulation of
abundant surfactant in alveoli. The mechanism is not increased secretion of surfactant but a
defect in the catabolism of surfactant by alveolar macrophages. Alveolar macrophages from GM
CSF –/– patients have defects in cellular adhesion, expression of pathogen-recognition receptors,
phagocytosis, superoxide production, microbial killing, and secretion of proinflammatory
cytokines. The diversity of the abnormalities in alveolar macrophages in GM CSF –/– patients
indicates that the maturation of these macrophages is defective. Indeed, pulmonary GM-CSF
stimulates the production of high levels of PU.1 in alveolar macrophages. PU.1 is a transcription
factor that promotes the growth and differentiation of myeloid progenitors and that is required
for the production of macrophages. Transfection of the PU.1 gene into cultured alveolar
macrophages from GM–/– mice corrected all the alveolar-macrophage abnormalities described
above and, it is important to note, also corrected abnormalities in the catabolism of surfactant
lipids and protein.
2. Primary PAP.
Primary PAP is an autoimmune disease targeting GM-CSF. Circulating antibodies inhibit GM-
CSF activity and leads to the accumulation of proteinaceous fluid in the alveoli. These antibodies
have not been identified in patients with congenital or secondary PAP.
3. Secondary PAP.
Secondary PAP develops in association with conditions involving functional impairment or
reduced numbers of alveolar macrophages. PAP may be associated with (a) hematologic
malignancies, particularly chronic myeloid leukemia and lymphomas; (b) occupational
exposures, particularly mineral dusts (silica) and fumes; and (c) infections, including those
caused by Nocardia, Mycobacterium tuberculosis, nontuberculous mycobacteria,
cytomegalovirus, and fungal infections, such as histoplasmosis and cryptococcosis.
Adult patients, for the most part, present with nonspecific respiratory difficulty of insidious
onset, cough, and abundant sputum that often contains chunks of gelatinous material. Some have
symptoms lasting for years, often with febrile illnesses. These patients are at risk for developing
secondary infections with a variety of organisms. Progressive dyspnea, cyanosis, and respiratory
insufficiency may occur, but some patients tend to have a benign course, with eventual resolution
of the lesions. Whole-lung lavage remains the current standard of care, while GM-CSF therapy is
effective in 50% of patients.
Congenital PAP is a fatal respiratory disorder that is usually immediately apparent in the
newborn. Typically, the infant is full term and rapidly develops progressive respiratory distress
shortly after birth. Without lung transplantation, death ensues between 3 and 6 months of age.
The overall prognosis for primary PAP is very good, with achievement of complete remissions in
many patients. Patients usually improve dramatically with whole-lung lavage, but relapses may
occur. Some patients require repeated lavages, and these patients usually progress to pulmonary
fibrosis and have a poor outcome (approximately 10% of patients). Congenital PAP responds
favorably to lung transplantation.
A 40 years-old stone-cutter was referred to your occupational medicine clinic with dyspnea, dry
cough, fever, and chest pain. He had a 2-year history of dyspnea beginning 1 year after
employment in a stone-cutting plant. A chest radiography film revealed a ground-glass
appearance especially in upper lung zones. You suspect this patient is suffering from silicosis.
Which of the following forms of silicosis is this patient most likely to have?
Complicated silicosis (progressive massive fibrosis)
Simple chronic silicosis
Hypercalcemia in a patient with sarcoidosis indicates:
Production of ACE by epithelioid cells
Production of ACE by T lymphocytes
Production of 1,25 vitamin D by epithelioid cells
Production of 1,25 vitamin D by T lymphocytes
Metastatic bone lesions
The fully developed idiopathic pulmonary fibrosis is characterized by all of the following
morphological lesions except:
Cobblestone appearance pattern of the lung surface at gross examination
Patchy interstitial fibrosis alternating with areas of normal lung at histologic examination
Patchy interstitial inflammation
A bronchospastic component associated with increased bronchial wall thickness
Interstitial fibrosis of different ages
Previously healthy two brothers of one family worked illegally abroad in one of European
countries in mining between 2003 and 2007. Man #1 and #2 were 56 and 49 years old,
respectively. Both of them were employed together in the same working conditions. However,
work duration was different: 21 years and 10 years, respectively. They reported working in a
private mine, which was not provided with effective ventilation, about four hours per day. A
major part of their occupational activity was tunneling in solid and shelf-like rock layers
containing silica. They claimed that no general dust control was provided at the workplace. The
older brother (patient No. 1) suddenly experienced breathlessness, he returned home and applied
for physician„s consultation. However, the patient became worse and he died in the hospital due
to progressing respiratory trouble. The final clinical diagnosis was: acute respiratory failure of
unknown etiology. Ante mortem chest X-ray indicated pulmonary edema and numerous small
nodular opacities. Autopsy revealed acute silicosis (lipoproteinosis). Examination of necropsy
specimens showed dilated alveolar spaces filled with lipoproteinaceous materials and a few small
silicotic nodules. The other brother was feeling quite well, but he stopped working in the mine.
After his brother had died he was insistently invited to examine the respiratory function. On
examination, he reported no respiratory symptoms. He did not have cough, sputum production or
dyspnea on exertion. Auscultation of the lung revealed no rales. A chest radiograph revealed a
few small nodes, but CT scan revealed numerous a small nodules, foci of pneumofibrosis in the
upper lobes, pleural thickening, and enlarged hilar lymph nodes. Which of the following forms
of silicosis is the younger brother most likely to have?
Simple chronic silicosis
Complicated silicosis (progressive massive fibrosis)
All of the following characterize restrictive lung disease except:
Inflammatory infiltrates in the interstitial space
Progressive evolution toward diffuse interstitial fibrosis
Decreased lung volume
Enlargement of the alveoli and respiratory bronchioles
Decreased oxygen-diffusing capacity on pulmonary function studies
Idiopathic pulmonary fibrosis is clinically characterized by all of the following except:
Clubbing of the fingers
Dyspnea on exertion at disease onset
Evolution toward respiratory failure and cor pulmonale
Reticular pattern in the lower lobes on chest X-rays
Self-limiting character with complete spontaneous remissions
All of the following are components of sarcoidosis granuloma except:
Multinucleated giant cells