I DIAGNOSTIC CHALLENGE

EDITOR: DAVID A. OWEN,* MB, B CH, MRC PATH, FRCP[C] CONTRIBUTORS: WILLIAM M. THURLBECK,* B SC, MB, CH B, FRC PATH, FRCPLC]; JOANNE L. WRIGHT,* MD, FRCP[C]; EARL S. HERSHFIELD,t MD, FRCP[C] DAVID PATRY,. MD; MARK R. RIGBY,§ MD, FRCP[C]; EDWARD G. BROWNELL4 MD, FRCP[C] Case presentation

A 78-year-old man was admitted to hospital with dyspnea and ankle edema. The dyspnea, which was so severe that he was unable to walk across a room, had started 12 years previously and had progressed slowly and inexorably. The ankle swelling had developed 4 years before admission. Initially it had been intermittent, but for the past 3 months it had been present continuously. The man had had a mild, nonproductive cough for as long as he could remember but denied paroxysmal nocturnal dyspnea, wheezing, palpitations and angina. He had smoked 30 cigarettes daily for the past 50 years. At the time of admission he was taking digoxin, furosemide, spironolactone, flurazepam, amitriptyline, acetaminophen and allopurinol. His past illnesses included poliomyelitis, which had left him with mild weakness of the left leg, and gout, which had first been diagnosed 6 years before this admission. A further 4 years before he had undergone left carotid artery bypass because of atheromatous occlusion. Between the ages of 25 and 40 years he had been employed as a gold assayer in mines at Herb Lake and Laguna Lake in Manitoba and Favorable Lake in northwestern Ontario. He had worked on the surface only. Physical examination revealed mild central cyanosis, early finger clubbing and some respiratory distress. The pulse rate was 100 beats/mm and the rhythm was regular. The blood pressure was 140/80 mm Hg, the temperature 36.50C and the respiratory rate 24

From the departments of *pathology, trespiratory medicine, .medicine and §diagnostic radiology, Health Sciences Centre, Winnipeg Reprint requests to: Dr. David A. Owen, Department of pathology, Health Sciences Centre, 700 William Ave., Winnipeg, Man. R3E 0Z3

breaths/mm. There was decreased air entry in both lungs, and late inspiratory rales were heard over the lower lobes and the lingula. The volume of the posterior tibialis and dorsalis pedis pulses was reduced bilaterally and there was mild pedal edema. Weakness, shortening and muscular atrophy were noted in the left leg. A chest roentgenogram revealed overinflation and multiple diffusely scattered fine nodules in the lungs (Fig. 1). An electrocardiogram showed right ventricular hypertrophy. The hemoglobin value was 16.3 g/dl, the hematocrit 49% and the erythrocyte sedimentation rate 26 mm/h (Wintrobe). Serologic tests for lupus erythematosus (LE) cells, antinuclear factor and anti-DNA antibody were negative, and the following serum concentrations were noted: sodium 130 mmol/l, potassium 5.4 mmol/l, creatinine 336 .mol/l (3.8 mg/dl), urea nitrogen 31 mmol/l (87 mg/dl), and albumin, total protein, bilirubin and calcium all normal. The creatinine clearance was diminished, at 16 ml/min. The

FIG. 1-Multiple fine nodules throughout both lungs. CMA JOURNAL/SEPTEMBER 22, 1979/VOL. 121 727

urine contained numerous granular and hyaline casts and occasional pus cells; protein and glucose were absent. The specific gravity was 1.015. The Mantoux test, with 5 U of tuberculin, was negative on two occasions. The results of pulmonary function tests and blood gas studies are given in Tables I and II. The patient was treated with 40 mg of prednisone daily and a graduated exercise program. There was marked symptomatic improvement and he was discharged from hospital. Six weeks later he was able to walk 180 m without stopping. However, the results of pulmonary function tests and blood gas studies were unchanged. Two months after discharge from hospital he was readmitted because of recurrence of exercise intolerance and further dyspnea. No substantial alteration in the results of physical examination, chest roentgenography or renal or pulmonary function tests was observed, but the arterial oxygen pressure with the patient breathing room air was reduced to 45 mm Hg. The medications were continued and oxygen was given nasally. On the second hospital day he complained of headache and dizziness. There were no localizing signs or evidence of meningeal irritation and he had no fever. His blood pressure was found to be 190/125 mm Hg. Methyldopa controlled the hypertension, but he remained severely dyspneic. On the 20th day in hospital he was noted to be drowsy and vomited several times. Catheterization of the urinary bladder was required. Because of progressive decline in the level of consciousness and a temperature of 400C computerized tomo-

728 CMA JOURNAL/SEPTEMBER 22, 1979/VOL 121

graphy was performed. The findings were normal apart from moderate enlargement of the ventricles, which was thought to be due to cerebral atrophy. A spinal tap produced turbid fluid with a leukocyte count of 365 x 100/1 (88% neutrophils, 11% lymphocytes and 1 % monocytes) and occasional erythrocytes. The glucose concentration was 167 mg/dl (blood glucose value 360 mg/dl) and the protein concentration 135 mg/dl. The urine contained many pus cells. The patient was treated with gentamicin, carbenicillin and chloramphenicol but his condition deteriorated and he died on the 21st day in hospital, before the results of urine and cerebrospinal fluid culture were available. Dr. David A. Owen, assistant professor, department of pathology, University of Manitoba and Health Sciences Centre, Winnipeg: In this clinicopathological conference we are adopting a procedure that is the reverse of normal. Dr. Thurlbeck, a pathologist, will discuss the clinical diagnosis; afterwards, Dr. Hershfield, a physician, will comment on the pathological findings. Clinical discussion Dr. W.M. Thurlbeck, professor and head, department of pathology, University of Manitoba, and head, department of pathology, Health Sciences Centre, Winnipeg: I would first like to dismiss a number of this patient's complaints, not because they are trivial but because they are not relevant to what I perceive to be the main features of this case: the nature of the lung disease and the events surrounding the patient's death. From the history he likely had widespread atherosclerosis, which was severe in his carotid arteries and presumably was the reason for the carotid artery surgery 10 years previously. It was also the probable cause of his peripheral vascular disease, as evidenced by the decreased volume of the posterior tibialis and dorsalis pedis pulses. The cause for his moderate renal failure is not clear, but the most logical explanation may be nephrosclerosis related to renovascular disease. Renal failure on the basis of nephrosclerosis is uncommon, however; therefore, other causes should be considered. Renal failure of significant degree is described as occurring in some 10% to 40% of patients with gout.1' Gout in this patient was not substantiated, although he was treated for it. In the absence of evidence of active gout, a high serum uric acid level or treatment with nephrotoxic analgesics I do not believe that we should seriously entertain the diagnosis of gout or analgesic nephropathy.4 However, there is another possible cause of renal disease that I will discuss subsequently. The patient also had mild cerebral atrophy, which could be attributed to senility or atherosclerosis. I should now like to consider the patient's pulmonary problem. Being an anatomical pathologi.t I should like to see the analogue of the gross appearance of the lung - namely, the chest film. Dr. Mark Rigby, section head, respiratory radiology, Health Sciences Centre, Winnipeg: The first chest roentgenogram available was made 2 years before the patient's second-last admission to hospital. It shows a diffuse nodular pattern throughout both lungs, mainly

in the mid-zone but also, to a lesser extent, in the bases and apices. The involvement is most pronounced in the right lung. The heart size is normal but the right ventricle is difficult to evaluate owing to the overlying pulmonary nodularity. Two years later the heart had enlarged about 1 cm in diameter and the nodularity had not changed (Fig. 1). The computerized tomography scan done shortly before death shows moderate dilatation of the ventricles. Dr. Thuribeck: Can you see the hilar nodes? Is there calcification of these nodes? Dr. Rigby: The initial film is too light but in the later film enlarged hilar nodes are apparent and at least one has calcification at its margin ("eggshell calcification") (Fig. 2). Dr. Thuribeck: On the basis of the available data there is a divergence between the radiologic evidence and the evidence from clinical examination concerning the lung disease in this patient. The ILO U/C classification of radiologic abnormalities in the pneumoconioses' is shown in Table III. The classification was originally devised by the International Labour Organization (ILO) and was modified at a meeting of the International Union Against Cancer (U) in Cincinnati (C). Radiologically there is dominantly a well defined nodular pattern. The nodules are mainly between 1.5 and 3 mm in diameter (type q), though some are between 3 and 10 mm (type r) and some are less than 1.5 mm in diameter (type p). In addition, there are some medium irregular opacities (type t). There are several lymph

nodes in each hilus that are calcified at the margin the so-called eggshell calcification classically associated with silicosis. While the chest film is not pathognomonic, silicosis must be the primary diagnosis to be excluded. Sarcoidosis may present a similar pattern, although the reticular component is usually more prominent and the nodular component less discrete. Narrative descriptions exist of eggshell calcification in sarcoidosis, but it must be very uncommon.6 There is no positive information in this case favouring sarcoidosis other than the two negative tuberculin tests. Conceivably the appearance of the chest roentgenogram at the time of admission might represent multiple metastatic tumour nodules or a bronchiolar-alveolar tumour. However, the lack of progression over more than 2 years militates against these diagnoses. The roentgenographic appearance is also unusual for widespread interstitial fibrotic lung disease (fibrosing alveolitis). This is true whether the fibrosis is of the idiopathic type, consequent upon extrinsic allergic alveolitis, or due to any of the other causes of diffuse fibrosis. The differences are primarily the striking nodularity, the eggshell calcification of the lymph nodes and the relative preservation of lung volume. Although the roentgenographic appearance would be unusual, we must consider tuberculosis superimposed on the silicosis. Tuberculosis is common and very hard to diagnose in persons with silicosis. In view of the patient's subsequent treatment it may be important to bear this in mind in trying to explain the patient's terminal illness. The most important feature in favour of silicosis is the history. Aphorisms from two wise men come to mind: The late Averill Liebow pointed out that anyone who worked in an industrial environment was likely to be exposed to deleterious agents. Many is the night watchman at a factory or a mine who has industrially caused disease limiting his physical activity and restricting him to his present occupation. A more important aphorism, however, comes from Dr. Edward Gaensler; in fact, it might even be called Gaensler's law. It states: "No industrial history taken by a physician is complete." In Gaensler's experience 24.8% of diffuse infiltrative lung disease resulted from environmentally determined conditions.7 Although this figure may be artificially high because of Gaensler's interest in asbestosis it underlines the importance of history-taking in any patient with infiltrative lung disease.

FIG. 2-Hilar lymph nodes with characteristic "eggshefl calcification" (arrows). CMA JOURNAL/SEPTEMBER 22, 1979/VOL 121 729

We are told that our patient had never worked underground and that between the ages of 25 and 40 years he had been employed as a gold assayer. This would be in the 15 years prior to World War II in northern Manitoba and northwestern Ontario, regions not noted for the sophistication of their environmental health protection. 1 was able to obtain details about the mine at Laguna Lake and other mines in that region. They were all primarily concerned with the mining of goldbearing quartz. The mine near Favorable Lake appears to be similar. Is it possible for a person in a mining environment to get silicosis without going underground? My initial concept of a gold assayer was a man who went to work in a white shirt and a tie, and who delicately and accurately weighed out minute amounts of gold. After consulting the Department of Energy, Mines and Resources I have learned that this is not so. The instructions for assaying gold start: "First, take several hundred, or even more than a thousand pounds of rock." The rock is crushed and dried, and then pulverized. Following this, flux is added to aid fusion of the dust. When sulfur is present (and zinc sulfide is present in adjacent areas) silica may be used as flux. The pulverized rock, plus flux, is then heated to nearly 10000C before being poured into a cone where the heaviest metals - lead, silver and gold - settle to the bottom. The lead is removed by evaporation, the silver is dissolved in nitric acid and the remaining gold is weighed. At the Laguna mine assays showed about 0.4 to 0.7 oz (11.2 to 19.6 g) of gold per ton of rock; perhaps the measurements on record were obtained by our patient. Large quantities of finely powdered quartz dust are produced in the initial process and adequate ventilation is essential. In northern Manitoba and northwestern Ontario in 1930 it seems likely that working conditions might have been far from ideal. Our gold assayer was in the middle of this, wearing a blue collar rather than a white one. The long lag between the last exposure and the onset of symptoms is consistent with the progressive nature of silicosis.8 Interestingly, gold assayers are now surveyed regularly, but only for evidence of lead poisoning. The evaporation of the lead may expose them to considerable quantities of lead fumes, and excellent ventilation has to be provided to prevent plumbism. Some of the physical features in our patient are at variance with the diagnosis of uncomplicated silicosis. Clubbing is most unusual and this patient was said to have "early finger clubbing". Physical abnormalities in the chest, particularly late inspiratory rales, are usually not present in silicosis and are more consistent with fibrosing alveolitis, idiopathic or otherwise. It is here that the results of the pulmonary function tests are of some value (Table I). The lung volumes were essentially normal, except for a modestly diminished vital capacity, so that diffuse fibrosis is unlikely on this account. The ratio of the forced expiratory volume in 1 second to the forced vital capacity varied from about 60% to 65% on the several occasions it was measured, and this is not consistent with diffuse fibrosing alveolitis. It does, however, suggest mild airflow obstruction. In the presence of normal airway resistance, as observed, it indicates obstruction of the peripheral airways or 730 CMA JOURNAL/SEPTEMBER 22, 1979/VOL. 121

loss of elastic recoil. This is because only about 20% of resistance to airflow in the lung lies in airways less than 2 mm in internal diameter. Thus, considerable obstruction may occur in these airways, leading to slowed expiration, without there being a significant increase in airways resistance. For example, if the peripheral airway resistance was doubled, the total airway resistance would increase to only 20% to 120% of the predicted, a change well within the wide range of normal. The maximum expiratory flow-volume curve in this patient was slightly diminished, with a flow of 50% of predicted at 50% of the vital capacity; this also suggests some obstruction of the peripheral airways. The slope of phase 3 was grossly abnormal, indicating one or both of two things: irregular narrowing of the peripheral airways or varying compliance of the lung units, which could be brought about by irregular distribution of emphysema and fibrosis. In contrast to the relatively normal pulmonary function the gas exchange in this patient was grossly abnormal (Table II): the alveolar-arterial gradient was 38 mm Hg, the ratio of dead space to tidal volume was 0.59 and the diffusing capacity for carbon monoxide was 8.44 (predicted 26.2). Despite the man's huge minute ventilation of about 211 (due to a tidal volume of nearly three quarters of a litre and a respiratory rate of 29 breaths/mm) the arterial oxygen and carbon dioxide pressures (Po2 and Pco2) were only 61 and 36 mm Hg respectively. The hemoglobin value of 16.3 g/dl and the hematocrit of 49% suggested polycythemia secondary to hypoxemia of some duration. I do not have sufficient data to analyse the patient's appalling gas exchange properly. After he had been breathing 100% oxygen the arterial Po2 rose to 510 mm Hg. Theoretically one would expect the Po2 to be in the region of 600 mm Hg in the absence of a rightto-left shunt. However, the increase was sufficiently high to suggest that hypoxemia was not primarily due to anatomic shunting. One wonders how completely and carefully equilibration was reached. I prefer to interpret these results as meaning that he had severe enough ventilation/perfusion problems that insufficient time was used to fill all the air spaces with 100% oxygen. This led to a small shunt-like effect. We cannot determine with certainty whether ventilation/perfusion imbalance or diffusion limitation was the main defect since exercise studies, blood gas studies with low oxygen intake and multiple gas studies as developed by West were not done.9 Ventilation/perfusion imbalance is the most likely since this is the usual cause for impaired gas exchange even in patients with restrictive lung disease.7 Despite evidence of hyperventilation and a high-normal Pco2 on several occasions, the blood gas data suggest that the patient had large areas of lung with a low ventilation/perfusion ratio. Diffusion limitation affects oxygen transfer across the blood-air barrier more than carbon dioxide transfer since carbon dioxide is about 20 times more diffusible. An additional observation that argues against primary diffusion limitation in this case is the large alveolararterial gradient for oxygen when the patient was breathing 100% oxygen. Uncomplicated silicosis characteristically involves the centre of the lobule. The nodules lie in a perivascular

position and distort adjacent small airways (Fig. 3). This is precisely the lesion that might produce the functional abnormalities found in this case. The question is whether this model has any basis in reality. There are few substantive data available concerning lung function in silicosis. The consensus is that "it is difficult to propound general statements about lung function in silicosis".8 No functional measurement or combination of measurements is specific for silicosis because there is such a wide variation in the way that silicosis involves the lung. On the one hand there may be relatively few nodules less than 1.5 mm in diameter (type q); in general this produces little or no disturbance of function. On the other hand there may be masses that occupy more than one third of the lung (category C). These usually cause significant functional abnormalities. In advanced disease large areas of lung are incorporated into the silicotic masses, and the remaining lung is distorted and emphysematous, and contains smaller scattered nodules. The airways may also be distorted by the silicotic tissue. It is in this situation that the classical mixture of obstruction and restriction occurs that accounts for the nonspecificity of the pulmonary function test results. The diffusing capacity for carbon monoxide is generally abnormal in siicosis,10 and the abnormalities in the mechanical properties of the lung are greater than expected from the abnormalities in vital capacity or the forced expiratory volume. Most studies have been in patients with pneumoconiosis due to a mixture of dusts, such as coal and silica. Many disabled miners have been smokers, so that there is often a significant component of cigaretteinduced chronic .tirflow obstruction. Our patient had smoked 30 cigarettes per day for 50 years; therefore, he probably had some emphysema. In view of the results of the lung function studies the emphysema was almost certainly mild. What of the patient's heart? Dr. Brownell has agreed

to interpret the electrocardiogram. Dr. E.G. Brownell, section head, general medicine, University of Manitoba and Health Sciences Centre, Winnipeg: The patient's heart was in sinus rhythm, showing sinus tachycardia (heart rate 110 beats/mm). There was marked right axis deviation at a frontal axis of +1100. Tall P waves in lead II suggested right atrial hypertrophy. There was also incomplete right bundle branch block with an RSR' complex in leads Vi and V2. In summary, the changes are consistent with cor pulmonale, either acute or chronic. Dr. Thuribeck: There is good electrocardiographic evidence of right ventricular abnormality, with right atrial dilatation and hypertrophy, gross right axis deviation and probable right ventricular hypertrophy. I suspect that this was the result of an additional disease. He had had shortness of breath for 12 years and had been treated for heart failure for at least 4 years. This protracted course is unlikely on the basis of right ventricular disease, since the course of right ventricular failure complicating fibrosing lung disease is usually shorter than this. Further, his heart was large and he had clinical evidence of widespread atherosclerosis. At one stage in his hospital course, he was hypertensive. While left ventricular hypertrophy complicates cor pulmonale in 10% to 20% of instances, this is most commonly on the basis of intrinsic heart disease." Thus, it seems likely that he had another form of heart disease, probably ischemic, and that both ventricles were enlarged. Renal disease has been found in patients with silicosis. There are recent isolated case reports of renal dysfunction in patients with acute silicosis and in a patient with presumed silicosis.12'" In both there was evidence of glomerular hypercellularity, with abnormalities of the lysosomes in the epithelial and endothelial cells and granular deposits of 1gM in the glomeruli. In other reports the results have been variable.14-17 Little or no evidence of renal disease has been recorded in some studies, but in others 20% to 30% of the patients have had proteinuria and sometimes hematuria and casts. Proteinuria has been a constant feature. In view of the absence of proteinuria in this patient and the poor documentation of the lesions in previous studies, one cannot make the diagnosis of silicosis-related renal disease. I will be interested to hear the pathologist's interpretation of the renal lesion and whether he thinks this could be glomerulonephritis. Now I will consider the terminal events. Therapy with prednisone was started during the second-last admission to hospital. The reason for this is not clear since he had no clinical evidence of collagen-vascular disease, with negative LB cell, antinuclear factor and DNA binding tests. Some 10% to 20% of patients with silicosis may, however, show evidence of a collagenvascular disease. For example, scleroderma, lupus erythematosus and rheumatoid arthritis have been reported.8'18 In one study 44% of patients with acute silicosis had a positive antinuclear factor test.19 In such patients steroid treatment may be beneficial. The value of steroid treatment in other patients with silicosis is not convincing, and such treatment is not indicated in most CMA JOURNAL/SEPTEMBER 22, 1979/VOL. 121

731

patients with sarcoidosis or fibrosing alveolitis, which are the other possible diagnoses in this case. It has recently been shown that some patients with fibrosing alveolitis have features of an immune complex disease and histologic evidence of active pulmonary inflammation. These problems may respond to steroid therapy. What is surprising, however, is that a lung biopsy was not done in our patient. As a result, the patient was treated with a potentially dangerous drug that is not effective in silicosis. The reason for the second admission was clinical deterioration substantiated by an arterial Po2 of 45 mm Hg. On the second hospital day he complained of headache and dizziness, without localizing signs or evidence of meningeal irritation. His blood pressure was elevated, but it responded rapidly to methyldopa administration. On the 20th hospital day he became much worse, with a fever of 400C and deterioration of consciousness. There was evidence of meningeal infection: the leukocyte count in the cerebrospinal fluid was 365 x 106/1, and 88% were neutrophils, occasional erythrocytes were present, and the glucose concentration was 167 mg/dl when the blood glucose value was 360 mg/dl. The urine contained many pus cells. On the following day the patient died. One diagnosis comes immediately to mind: tuberculosis. This should be considered in any patient with silicosis, and doubly so when the patient has been treated with prednisone. Also, tuberculous meningitis can present in many ways. However, this seems an unlikely diagnosis. The course was abrupt, although it may be that the disease was symptomatic shortly after admission, when the patient complained of headache and dizziness. A high fever appeared later. The cells in the cerebrospinal fluid were predominantly neutrophils and the glucose concentration was about the projected one third to one half of the blood glucose level. Tuberculosis does not explain the pyuria. Thus, one would have to diagnose a very atypical presentation of tuberculous meningitis together with a genitourinary infection. A more likely explanation is that he had meningitis related to a genitourinary infection. Such an association is well documented.."1 The site of infection may be the urethra, the prostate, the bladder or the kidney. Nearly always it is the left kidney that is involved, and the organism most commonly cultured is Escherichia coil. The route of infection is the paravertebral veins that drain the prostatic plexus and presumably also the left kidney. The organisms pass along the vertebral veins to enter the veins at the base of the skull and thus reach the meninges. This venous system is usually known as Batson's plexus..' It is considered to be the explanation for the common observation that vertebral metastases from cancer of the prostate may occur without lung involvement. This patient had no urinary symptoms, so that the infection may have been in the kidneys, probably at least the left kidney. The cerebrospinal fluid findings were consistent with gram-negative meningitis; in most of the similar reported cases there was a moderate cell count, the cells were predominantly polymorphonuclear and the glucose level was low to normal. An interesting feature of gramnegative meningitis is the frequent finding of erythro732 CMA JOURNAL/SEPTEMBER 22, 1979/VOL. 121

cytes in the cerebrospinal fluid. Significant blood in the cerebrospinal fluid was not present in this case, and the enlargement of the ventricles was thought to be due to atrophy of the brain. My specific diagnoses are as follows: * Lungs: nodular silicosis, with involvement of small airways and arteries; emphysema - mixed, centrilobular, panacinar, irregular and mild, with a panel score.. of 15. * Brain: cortical atrophy, ischemic; acute purulent meningitis secondary to urinary tract infection. * Kidneys: acute pyelonephritis or cystitis or prostatitis or all three, perhaps due to E. ccli; nephrosclerosis. * Cardiovascular system: right ventricular hypertrophy; left ventricular hypertrophy due to arteriosclerotic heart disease and perhaps hypertension; generalized atherosclerosis, severe in carotid arteries. * Other: gout (no lesions at necropsy). I have some specific questions for the pathologist to answer: 1. What is the nature of the lung tissue between the silicotic nodules? Is there diffuse fibrosis or interstitial pneumonia? Does the patient have histologic evidence of systemic sclerosis in other organs? 2. What organism caused the meningeal infection and the genitourinary infection? Was it the same one at both sites? 3. What were the precise abnormalities in the heart? Was there solely right ventricular hypertrophy or was the whole heart, including the left ventricle, also enlarged? What did the various components of the heart weigh? The left ventricle? The right ventricle? The interventricular septum? What was the ratio of the weight of the left ventricle plus septum to that of the right ventricle? 4. Was there any evidence of recurrent pulmonary thromboembolism? I briefly considered this as arising as a complication of the patient's pulmonary heart disease since there was such striking enlargement of the heart and right ventricle. There was, however, no evidence for pulmonary embolism. 5. What precisely was the renal lesion? Pathological discussion Dr. Earl S. Hershfield, director, Respiratory Centre, Winnipeg; associate professor of medicine, University of Manitoba: At autopsy the brain was found to weigh 1280 g. There was thickening and opacification of the leptomeninges, particularly over the convexity of the cerebral hemispheres. The underlying cortex was atrophic, with accentuation of the gyral pattern. There was mild symmetric dilatation of the lateral and third ventricles. Microscopy confirmed the presence of purulent meningitis (Fig. 4). Listeria monocytogenes was cultured from cerebrospinal fluid obtained before death and at autopsy. L. monocytogenes is characterized as a small grampositive microaerophilic bacillus with fiagellae. Under appropriate conditions it exhibits characteristic tumbling motility. Seven serotypes have been identified on

the basis of 0 and H antigens. The organism is widely distributed in nature and is present in soil, water and dry vegetation. Infection of humans, however, is uncommon, and the organism is rarely isolated from any site by hospital microbiology departments.. Listeriosis characteristically affects two categories of individuals: a perinatal group and immunosuppressed adults.. Transplacental infection of the fetus may result in abortion or premature birth. In neonates listerial infection may present as meningitis or as a diffuse disseminated disease. In adults meningitis is the predominant form of listerial infection; on clinical grounds it cannot be distinguished from meningitis due to the more common causative organisms. The bacillus has been cultured from the feces of symptom-free individuals, and it is postulated that the gastrointestinal tract is the usual portal of entry. Culture of our patient's urine produced a heavy growth of Kiebsiella sp. and Streptococcus faecalis, and at autopsy purulent inflammation of the bladder and prostate was noted. I believe this resulted from catheterization and was not related to the meningitis. Both kidneys were somewhat shrunken and had cortical thickening and subcapsular granularity. The intrarenal vessels and main arteries showed patches of atheroma. Microscopically the changes were those of simple nephrosclerosis. There were no hypertensive changes, uric acid crystals or proliferative glomerular lesions. Prominent right ventricular hypertrophy and dilatation were noted. The weight of the isolated right ventricle was 85 g and the weight of the left ventricle plus the interventricular septum was 130 g. The ratio of the two weights was 1:1.5, whereas the normal ratio is 1:2.3 to 1:3.3.26 These figures confirm significant right ventricular hypertrophy and no appreciable enlargement of the left ventricle. The arteries of the circle of Willis were heavily atheromatous. Narrowing of these vessels was felt to account for the diffuse cerebral atrophy. The left carotid artery graft was intact and patent, with no mural thrombus. Multiple calcific intimal plaques were present in the lower abdominal aorta and iliac vessels. There was moderate generalized muscular wasting in the left leg, corresponding to the history of poliomyelitis. I will ask Dr. Wright to discuss the pulmonary findings: Dr. Joanne L. Wright, fellow in pulmonary pathology, Health Sciences Centre, Winnipeg: The lungs were heavy, with the right weighing 550 g and the left 700 g. The pleura was thickened and there was diffuse pebbling. The lungs were inflated with formalin via the bronchus at a standard pressure of 30 cm H20 to best preserve structure. A parasagittal section (Fig. 5) showed that the architecture was distorted by what appeared to be a combination of disease processes. In the upper lobe, and most prominent in the apices, was a centrilobular and paraseptal pattern of emphysema. This was interpreted as a panel score of 25. This destructive type of lesion was in direct contrast to the fibrotic process most prominent in the lower lobes, where multiple fine, firm nodules were scattered throughout the parenchyma. The bronchovascular CMA JOURNAL/SEPTEMBER 22, 1979/VOL. 121 733

bundles were prominent, with radiating strands of grey, firm tissue. An unexpected finding was a rubbery, grey, well circumscribed nodule 1 cm in diameter in the periphery of the left lower lobe. This did not appear to have a connection with the bronchial tree. The hilar lymph nodes were large, displayed prominent anthracosis and gave a gritty sensation suggesting calcification when cut. Microscopy showed the classic lesions of silicosis. The nodules were composed of whorled dense collagen and often showed prominent calcification (Fig. 6). Birefringent irregular crystalline material was prominent in both the nodules and the adjacent alveolar septa, which showed pronounced silica-related fibrosis (Fig. 7). A mild lymphocytic infiltrate was also present within the septa in these areas. There was no evidence of superimposed tuberculosis. In general the alveolar walls between the nodules were either normal or emphysematous. The pulmonary vasculature showed mild medial thickening. This is, however, a common finding in fibrotic lungs and is not an indication of an immune vascular disorder.27 Pulmonary emboli were not noted. The solitary nodule exhibited the characteristic features of a carcinoid tumour. The small, uniform cells were arranged in broad trabeculae and had a rich vascular supply. Peripheral pulmonary carcinoids have been well described by Bonikos, Bensch and Jamplis,28 who suggested they be distinguished from the more common central, bronchus-related carcinoid. Silicosis is not associated with an increased frequency of pulmonary neoplasia,29 and I assume, therefore, that this small tumour was an unrelated finding. The pathogenesis of pulmonary fibrosis in silicosis is of considerable scientific interest, although the complete mechanism remains to be elucidated. There is general agreement'8 that inhaled silica particles are ingested by macrophages and enter phagosomal vacuoles (phagosomes). Lysosomes are attracted to these vacuoles and discharge their hydrolytic enzymes into them. Within hours, however, the phagosomes rupture, resulting in release of their toxic contents into the cell's cytoplasm. This results in cell death and release of the silica particle, which then becomes available for ingestion by another macrophage and the whole process is repeated. The exact method by which the phagosomal membrane is ruptured is not fully understood. One theory postulates that the silica is partially dissolved, with production of a toxic factor.30 A more widely accepted suggestion has centred on the stereochemical nature of the silica particles.31 It has been shown that only tetrahedral particles are fibrogenic, and the importance of exposed silanol groups has been emphasized. The formation of hydrogen-bonded complexes between silica particles and active phospholipid on the phagosomal membrane may be the method of rupture. Immune mechanisms may also be important in the genesis of silicosis. Dr. Thurlbeck has already mentioned the immunologic aspects of this condition and the association with collagen-vascular diseases. The current view is that immune systems do not play a direct role in macrophage killing or fibrosis but are 734 CMA JOURNAL/SEPTEMBER 22, 1979/VOL. 121

merely responsible for attracting large numbers of macrophages to the site of particle deposition.18 Dr. D. Patry, chief resident, department of medicine, Health Sciences Centre, Winnipeg: In retrospect, should it have been possible to detect the carcinoid tumour on the chest roentgenogram?

FIG. 6-Silicotic nodule: whorled dense collagen (H-E;

X 160).

FIG. 7-Fibrosis of alveolar septa distinct from silicotic nodules (H-E; X 63).

Dr. Rigby: No. This was a small lesion and, in the posteroanterior view, was hidden behind the heart.

9. WAGNER PD, LARAVUSO RB, UHL RR, et al: Continuous distributions of ventilation-perfusion ratios in normal subjects breathing air and 100% 02. J Clin Invest 54: 54, 1974

Final anatomical diagnosis Central nervous system * Purulent meningitis due to L. monocytogenes * Ischemic cerebral atrophy Respiratory system * Silicosis * Emphysema * Peripheral carcinoid tumour Urinary system * Lower urinary tract infection due to S. faecalis and Kiebsiella sp. * Nephrosclerosis Cardiovascular system * Cor pulmonale * Widespread atherosclerosis Postscript When the autopsy findings were known and the diagnosis of silicosis was established, the facts were reported to the Workers' Compensation Board of Manitoba. In due course appropriate financial compensation was awarded to the patient's widow.

23. THURLBECK WM, DUNNILL MS. HARTUNG W, et al: A

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This paper is the first of a series supported by a grant from Glaxo Canada Ltd. on behalf of Glaxo Labo. ratories and Allen & Hanburys.

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