Autopsy findings in Boeck’s sarcoid

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Autopsy Findings in Boeck's Sarcoid By HANS JACOB USTVEDT

(From Ullevaal Hospital, Oslo, Norway, Medical Department IX, Chief Physician H. ]. Ustvedt, M.D.) M a x Pinner in i938 published a review of the literature of sarcoidosis, in which I8 post-mortem reports were listed. In I944 Rubin and Pinner collected the clinical and pathological findings in a n o t h e r 25 cases, and added one case, observed b y the authors. I have further been able to find 14 cases with autopsy ( W a h l g r e n - - C a s e ~ - i936; Waldenstrem, I937; H o r t o n , Lincoln and Pinner, I939; P. Gravesen, I942; D. R e i s n c r - - 7 cases--I944; L. Warfwinge, I945; G. F. Hogan, I946; L. Ehrner, I946 ). This makes in all 58 cases, reported in the literature. Thus, in spite & t h e overwhelming n u m b e r of clinical observations, the n u m b e r of autopsies is still restricted. M a n y phases of Boeck's sarcoid arc quite inadequately known, numerous problems need further elucidation, and the question of the relationship between sarcoid and tuber.culosis is far from settled. Autopsy findings are of a special value, and 3 cases are presented here, where the diagnosis was m a d e clinically of Boeck's sarcoid. Case I

H. S., male, born i9oI. i9~ 7 pleurisy. i94o he complained of dyspnoea and cough. X-ray picture of the chest revealed a bilateral hilar adenitis. The Pirqnet test was negative. The Kveim test was positive. Biopsy from a lymph node in the groin revealed globular accumulations of large, pale-staining epithelioid cells, and there was no caseation or necrosis, and few lymphocytes in the surrounding tissues. Diagnosis: Boeck's sarcoid. During subsequent years the cough and dyspnoea increased, and he was admitted to Ullevaal Hospital, Dep. I X on February 3, ~943. No skin lesions were seen. No palpable lymph nodes. The Pi,-quet test was positive (6 ram. infiltration). An x-ray film of the chest disclosed on the right side scattered mottled and linear shadows from apex to the 6th rib, on the left side more discrete mottling and linear shadows, most accentuated in the mid-part of the lung. No hilar adenitis. Tomography disclosed no

cavities. The picture was characteristic of chronic, fibrot[c lung disease, as it may he seen in tuberculosis, sarcoid or bronchiectasis. X-ray examination of hands and feet revealed no osteitis cystoides mahiplex. Sputum examinations did not reveal acid-fast organisms on culture. T h e sedimentation rate was 77 ram. after one hour. The formol-gel test was positive in serum after two hours. T h e Wassermann test was negative. Blood proteins 7.04 per cent. Albumin 3-6 per cent. Globulin 3"4 per cent. Sodium 328 rag. per cent. Potassium 20. 5 mg. per cent. No anaemia. Blood picture, bleeding time, clotting time normal. Bone-marrow smears showed no signs of any blood dyscrasia. EKG: left axis deviation, sinus tachycardia. Urine normah The patient stayed in hospital for five months. A moderate systolic murmur was hem'd at the base of the heart, sometimes also a faint diastolic murmur. Blood-pressure i2o/85 mm.Hg. During his stay in hospital he complained of cardiac discomfort with moderate tachycardia (9o-~oo). The skin was moist but there was no tremor, nor eye symptoms. The thyroid gland was enlarged to a very small degree. The B.M.R. varied between q-e 4 and +56 per cent. On July 5 a subtotal thyroidectomy was performed. T h e B.M.R. dropped to q-=, and the heart symptoms subsided. Histological examinatioi~ of the thyroid revealdd signs of a slight thyrotoxicosis, but no s@,ns whalever qJ" sarcoid (the preparations have been re-examined in I947 by Professor Kreyberg, with confirmation of the diagnosis). One year later, on July 22, r944, the patient was again admitted to the hospital in a very poor condition, with extreme cyanosis and dyspnoea. He died within twenty-four hours. Aulo/)sy findings: Thyroid-rest of about walnut size. The cervical and mediastinal lymph nodes evenly enlm'ged. Marked fibrotic pleuritis bilaterally, with hyaline thickening of the pleura over the apices. Both upper lobes of the lun.v,s showed dense, irregular strands of yellowwhite or black colour without cavities in the hmg parenchyma, but in the strands there were some small cavities the size of a pea, filled with pus. In the remaining lobes definite fibrotic changes. No distinct nodules were felt or seen. No caseation. The hearl weighed 43 ~ grammes. Considerable enlargement of the left ventricle (~7 mm.). In

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the aortic valves, especially posteriorly, considerable calcium deposits, which continued along the inner side of the left ventricle. On the left aortic valve a soft, grey-red excrescence. Aorta smooth. The spleen weighed 92o grammes. No distinct nodules. Liver 1,77o grammes. The surface was irregular with prominent yellow nodules. On cut surface, marked yellow nodules divided by small fibrotic strands. No other pertinent findings. Guinea-pig inoculation from lymph node: no tuberculosis (six weeks). Culture from aortic valve and from splenic pulp: no growth. Hislological examination.--The lungs were penetrated by broad fibrotic and sclerotic strands, with dilated bronchioli, some hyaline fibrosis and alveolar emphysema. The alveoli were mostly collapsed, or filled with fibrinous fluid. In the fibrotic strands numerous nodules consisting of epithelioid cells and fibroblasts, with numerous giant cells, partly of the Langhans type, partly with scattered nuclei. Some nodules were hyalinized and concentrically arranged with giant cells in the centre. No caseation or necrosis. The lymphocyte infiltration was slight. The lymph nodes showed the same picture of considerable fibrosis with nodules of characteristic epithelioid cells with giant cells, but no caseation. In the thyroid rest the alveoli were mostly small, with cubical epithelial cells and thin colloid. Some of the alveoli were empty. The glands were surrounded by a sclerotic fibrous tissue, some in broad strands. Some alveoli had ruptured, with colloid penetrating into the tissue. Here and there distinct nodules with epithelioid cells and giant cells, but no caseation or necrosis. In the other organs no epithelioid-foci. Liver: broad fibrotic strands, with irregular lc)buli. In the strands remnants of liver cells and newly developed bile capillaries. Summa~ of Case z . - - A case is reported of a man aged 39, where the diagnosis of Boeck's sarcoid was made from the characteristic combination of bilateral hilar adenitis, a positive Kveim test, and the histological picture of epithelioid granulomata in a lymph node with few giant cells and no necrosis. The patient developed a slight thyrotoxicosis, a subtotal thyroidectomy was performed, and the gland showed no signs of sarcoid. The patient died four years after the onset of the clinical symptoms. The autopsy showed typical Boeck-grarmlomata in lungs, lymph nodes and thyroid, with

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pronounced fibrosis, calcification of the aortic valve, with fresh endocarditis and an incipient liver cirrhosis. Comment.--Death is supposed to have resulted fi'om progressive lung fibrosis and cot pulmonale. The endocarditis is considered a terminal complication. I would especially like to stress the complete absence o f tuberculosis, or perhaps better of 'ordinary tuberculosis' with necrosis. More than half of the autopsied cases reported died as a direct consequencc of thd disease. The workers who advance the theory that sarcoid is a non-caseating phase of haematogenous tuberculosis stress the frequency with which sarcoid is complicated by or, as Pinner puts it, changed to caseating tuberculosis. From the autopsy material it seems to be doubtful if tuberculosis is more often the cause of death in sarcoid than in individuals of the same age without sarcoid. In the 59 cases which I have collected (58 from the literature and one of my own), tuberculosis was found to be the cause of death eleven times. The cases originate from a series of different countries and from all age-groups.. It is therefore impossible in so small a number of cases to say anything definite as to the probability of fatal tuberculosis under 'normal circumstartces.' About the half of the patients were less than forty years old at the time of death. 18 per cent deaths of tuberculosis does not seem very high, but an adequate comparison is not possible. With regard to the fact that the sarcold in a few cases shows regression when complicated with 'ordinary tuberculosis,' it must be born in mind that the sarcoid has a strong tendency to spontaneous regression, and that one chronic infectious disease may be favourably influenced by another without there being any aetiological relation between the two diseases, as for instance lues and malaria, a fact which I have never seen stressed in this relation. The Thyroid Change I n the reported case the changes in the thyroid are of great interest, and especially the

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titct that the part of the thyroid which was removed by the thyroidectomy showed no specific alteration, wtmreas the thyroid rest showed typical epithelioid cell-granulomata. The relation between sarcoid and endocrine glands will be taken up in another paper, and I shall confine myself to a few remarks. One would expect that epithelioid-granulomata in endocrine organs would tend to decrease the activity of the glands and cause a hy/Jo function. This is confirmed for the pituitary, where sarcoid in the middle and posterior lobe has been connected with the clinical picture of diabetes insipidus. With regard to the thyroid, in I938 I described a case of myxoedcma in a patient with typical sarcoid, and Stallard and Tait have observed the same. Histological examination of the thyroid was not done in any of these cases. Spencer and Warren have in one case found typical epithelioid nodules in the thyroid, but there had been no clinical symptoms of myxoedema. It seems astonishing that both signs of hj~erlhyroidisT~z and /zype~parathyroidisrn are described in Boeck's sarcoid. The mechanism of the hypercalcmmia is not clear. Some authors point to the hyperproteinacmia which is described in sarcoid, but hyperproteinaemia is not altogether a constant feature in this condition, and has not always been found in the cases with hypcrcalcaemia. The same is to be said of a chronic renal disease as the explanation of the hypercalcaemia. More probably it may be explained b y a secondary hyperparathyroidism on the basis of widespread Boeck's lesions in the skeleton. Epithelioid nodules have not, as far as I know, been described in the parathyroids. With regard to the thyroid Oldberg has reported a case with typical sarcoidosis and thyrotoxicosis, where biopsy fi'om the thyroid showed both intensive Basedow changes and typical epithclioid-cell-foci with giant cells, but without necrosis. Bokstmm, P. Gravesen and Hogan have described thyrotoxicosis in the course of" sarcoid. One of my patients with sarcoid got symptoms of a mild thyro-

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toxicosis during the regression of tlte sarcoid, and had a thyroidectomy. The histological examination revealed a moderate thyrotoxic reaction, but no signs whatever of sarcoid. The question whether sarcoid in the ttlyroid m a y cause a thyrotoxicosis is of the utmost interest, and the same question may be posed with regard to tuberculosis. Rankin and Graham found in the material from the Mayo Clinic 2I cases of tuberculosis of the thyroid. 15 of these cases showed hyperthyroidism with B.M.R. of more than +z 9 per cent. In 8 of these the pathologist found both Basedow's disease and tuberculosis. If the simultaneous occurrence of Basedow arid tuberculosis or sarcoid is not entirely coincidental, this may be explained either by a hyperthyroidism caused by the specific inflammation in the gland, or by a secondary tuberculosis in a thyroid which was previously the seat of Basedow's disease. The fact that in our case there was no sarcoid in the resected gland, but in the rest of: the gland found at the autopsy, might point to tile latter explanation. The possibility that the hyperthyroidism in sarco'id, where no specific alterations are found in the gland itself, may be the result of a localization of sarcoid to the pituitary, m a y also be considered. The incipient liver cirrhosis in our case may perhaps have something to do with his hyperthyroidism. Hogan has reported a case of sarcoidosis with thyrotoxic crisis and hepatomegaly. Case 2

S. C., woman aged 39. When 28 years old she had a typical uveo-parotid fever with enlargement of all salivary glands, both lachrymal glands, cervical and hilar lymph nodes on both sides, with simultaneous paresis of both facial nerves and numerous symptoms ii'om the central nervous system, and a bilateral uveitis. Pirquet's test was negative. The e~e is described in detail by Arne Mohn in Acta Ophl]zalmologica, z933, zl. The patient gradually developed a chronic fibrotic lung disease with severe cough and dyspnoea. X-ray examination of the chest nine years later revealed enormous cavities in both upper lobes, with mottled and lirie~r shadows in middle and basal lung fields. Hands and feet: no signs ofosteitis. No tubercle

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bacilli in the sputum (cultivation). Pirquet -1(6 ram. infiltration). During the following two years :he lung process seemed stationary, but then she had a severe haemoptysis, and died.

Autopsy Findings (Pat/7ological lnslilule, Univ'ersity Clinic, Oslo, Professor Kregberg).--In both upper lobes o[' the hmgs there were large cavities, with smooth walls, containing blood but no caseous material. In the remaining lobes dilated bronchi and enormous fibrosis with asbestos-like infiltrations. No nodules, no caseatiori. The mediastlnal lymph nodes were considerably enlarged. Nothing of special interest in the other organs. Hislolo.gical Examination. The picture is reminiscent of a chronic interstitial pneumonia, with enormous increase of the fibrous tissue, some infiltration of Iymphocytes and plasma cells, but nowhere were there signs of specific inflammation, neither sarcoid ~zor tuberculosis. No giant cells, no caseation. The cavity wall showed fibrous tissue ~,ith some hyaline degeneration and scarce remnants o[" epithelial cells, and some infiltration of lymphocytes and plasma cells. The lymph nodes showed hyaline fibrosis with some calcification, but no signs of saz'coicI or tuberculosis.

S~tmmary of Case 2 . - - W o m a n aged 39 with typical uvco-parotid Fever, bilateral hilar ad'enitis and a negative Pirquet reaction. Gradual development of chronic fit~rotic lung disease, death thirteen years later from haemoptysis. The autopsy shows a chronic, fibrotic h m g disease with cavities and signs of chronic, non-specific inflammation, but no signs r sarc0id or tuberculosis. Comment.--The combination of a uveoparotid fever ~'ith bilateral hilar adenitis a n d negative Pirquet test is highly characteristic o f Boeck's sarcoid. P. Gravesen, who has examined the available literature up to 1942 , states that this picture is only seen in sarcoid. T h e claim that cavities do not appear in sarcoid does not hold true. In the autopsy records I have found 5 cases with one or more cavities without coexisting tuberculosis. Clinically there was good reason to classify the case as Boeck's sarcoid, a n d no positive support for the diagnosis of tuberculosis. T h e histological picture was a

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surprise, but was nearly identical with the picture which is seen in sarcoid in those parts of the lungs and l y m p h nodes where the specific inflammation is completely replaced by fibrosis. However, in no case in the literature have I seen such fibrosis mentioned without any nodules or strands of epithelioid cells with giant cells. Exactly the same picture as in our case m a y also be met with in non-specific lung disease, such as chronic interstitial p n e u m o n i a and bronchiectasis. The question is whether one is entitled on the basis of the clinical picture to consider this .a case of sarcoid where the specific inflammation has been completely displaced by the secondary fibrosis. We would thetl have complete anatomical healing with permanent and irreversible tissue alterations., which have brought about cavities and bronchiectasies. Tl~e histological picture is so similar to fibrotic changes in sarcoid, and tlae clinical picture so characteristic of sarcoid, that I ['eel etatitled to put it as a case of sarcoid. Case 3 K. K., woman aged 48 years, with diabetes and. atypical hyperchromic anaemia. i938 Boeck's sarcoid was diagnosed on the basis of hilar adenitis, rniliary shadows in both lung fields, typical osteitis cystoides multiplex on x-ray examination, and negative Pirquet reaction. One year later the patient was admitted again, highly febrile, with cyanosis and dyspnoea and died after a few days. The autopsy (Pathological Institute, University Clinic, Oslo. Professor Kregberg) showed a severe bilateral tuberculous salpingitis with casealion, numerous caseous tubercles in both lungs and the lymph glands, a typical miliary luberculosis. Comment.--The case demonstrates the fact 1hat 'ordinary' tuberculosis may give a clinical picture which is entirely like that of sarcoidosis, with a negative Pirquet test, and also the radiological picture of an osteitis multiplex of Jangling. In the spleen there were tubercles entirely built u~ of e~i~helioid cel.ls, witheut central necrosis~ Theo~'eticaiiy this fact might be taken as indicating that sarcoidosis had existed, and was complicated with or displaced by ordinary tuberculosis with simuhaneous regression of the

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sarcoid. The probability seems, however, to be very small. In typical miliary tuberculosis we may find tubercles in different stages of evolution, not seldom originating from successive haematogenous spreads. Much more probable is the hypothesis that we here have a case of chronic miliary tuberculosis, which clinically resembled sarcoidosis.

Summary T h r e e cases with a u t o p s y are reported which throw light on different aspects of sarcoidosis. T h e first shows typical sarcoid without tuberculosis in a fatal case, and brings into discussion the relation between sarcoidosis and the thyroid gland. T h e second is supposed to show h o w the specific inflammatory changes may be supplanted entirely by fibrous connective tissue, with secondary f o r m a t i o n o f cavities a n d bronchi-

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ectases. T h e third teaches us t h a t 'ordinary' tuberculosis m a y give a clinical picture t h a t wholly corresponds to w h a t we reckon as characteristic of sarcoidosis.

Bibliography Bukstrom (I936) &'enska IZ4kartidn., xxxm, I438. Ehrner, L. (I946) Acta Tub. Scand., xx, i38. Gravesen, P. B. (z94.~) Lymt'ogranulomatosis benigna. Odense. Hogan, G. I". (z946) Am. Rev. Tub., lJV, i66. Horton, Lincoln and Pinner (I939) Am. Rev. Tub., xxxtx,

~86. Oldberg, S. (I943) Aria Medica &and., cxv, I63. Pinner, M. (z938) Am. Rev. 75lb., xxxvlh 690. Rankin and Graham (t93~) Ann. Surg., xcw, 6.~5. Reisner, D. (t944) Am. Rev. Tub., xLrx, ~89 and 437. Rubln and Plnner (i944) Am. Rev. Tub., XLIX,I46. Spencer and Warren (1938) Arch. Ira. Med., 1.xrl,086. Stallard and Tait (1939) Lancet, ,14o. Ustvedt, H.J. 0939) Nordisk Medidn, u, 2837; 1II, 1677. Wahlgren, F. (1937) Nordlsk Medicin, xm, 965. Waldenstrom, J. (z937) Acla Med. &and., Xel, 53. Warfwinge, L. (1945) Aaa Tub. Sca~M., xlx, 195.

Abstracts .JOURNAL F R A N C A I S DE M E D E C I N E ET CHIRURGIE THORACIQUE. i94 7 z 97 R.Oux-BERGER-BLANCHY, MARCIti;LLE: CINFECTION PLEURALE, R~EXPANSION PULMONAIRE, R~'-

TRACTION PULMONAIR~ RgFLEXE.' (Pleural Infection, Pulmonary Re-expansion, Reflex Shrinkage of the Lung.) Theinteresting suggestion is made in this article that the shrinkage or apparent atelectasis of the underlying lung which occurs in the presence of pleural infection is a reflex active process which can be reversed by sterilization of the infection. When this has been achieved the shrunken lung re-expands spontaneously and rapidly to reach the chest wall, even in.many cases after long-standing well-established collapse--seeming to fulfil Simmonds' dictum that 'You can't keep a good lung down.' This has been deduced from a series of interesting observations beginning with the radioscopic study of a case where the pleura was accidentally infected by pyogenic organisms during an adhesion section. A case is quoted in which the totally collapsed lung came out so f'apidly after sterilization of a tuberculous empyema of a year's standing that fi'equent refills had to be made to control it. Two cases are quoted where a lung remained collapsed for many months until loci of o~teomyelitis in the ribs were extirpated, and then re-expanded in two to three weeks. T w o further cases of neglected post-pneumonic e m p y e m a are quoted,

one with a bronchial fistula, in which after penicillin therapy the lung re-expanded to fill the chest in five and three days respectively despite open drainage. It is pointed out that this reflex shrinkage of the lung follows also the introduction of chemical irritants into the pleura. Other manifestations of this reflex from pleural irritation noted on the affected side were 'failing in' of the chest wall, dropping of the shoulder, narrowing of the intercostal spaces, flattening of the diaphragm, and the contraction of the lung m a y be so great that the mediastinum is displaced towards the affected side. S C H W E I Z . Z E I T S C H R . F. T U B E R K U L O S E i94 7 LXXVu z25-I52 FROEHLICH, W., DE RHAM, O., AND STEIL, S.: EARLY 'rHORACOPLASTY IN THE TREA'I'NIENT OF POST-PLEURITIC APICAL TUBERCULOSIS.

Thoracoplasty has lost much of its horrors and dangers in recent years. This is especially so in the limited apical operation. Technical details of the procedure are given. T h e authors claim 5o-6o pet" cent healed, 20-30 per cent imp.roved and 20 per cent failures with this operation at Leysin. T h e y are impressed by. the poor results of conservative treatment m post-pleuritic apical tuberculosis. Months or years after the pleurisy these apical lesions show a marked tendency to develop progressive phthisis. Thoracoplasty is advocated at the stage when tubercle bacilli can be demonstrated by gastric lavage