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Lymphoma of lung masquerading as sarcoidosis
Tubercle, Lond., (1961), 42, 507
LYMPHOMA OF LUNG MASQUERADING AS SARCOIDOSIS By J.
GOLDSTEIN
and J. C.
BURNE
from Joyce Green Hospital, 'Dartford, Kent SUMMARY
An unusual case of lymphoma in a woman of fifty-three is described. The infiltration, which resembled that of lymphatic leukaemia, was largely restricted to the lungs, liver, nervous system and salivary glands, the blood, bone marrow and superficial lymph nodes being spared. Clinically a diagnosis of sarcoidosis seemed most likely. Biopsy of the liver and lungs might have enabled us to make a correct diagnosis during life.
Tumours of lymphoid tissues presenting as a primary lung condition are unusual and the case here described was so atypical that it was correctly diagnosed only on histological examination of the necropsy material. During life, the most likely diagnosis was thought to be sarcoidosis. Case History Mrs. D., aged 53, was first seen in December, 1956. She was extremely agitated and complained of increasing shortness of breath for some weeks, and of severe muscular weakness. She had had several attacks of breathlessness in bed at night, cough with white frothy sputum and later, nausea with infrequent vomiting. In March of the same year she had been operated on for glaucoma of both eyes, but her eyesight had further deteriorated since then. She had lost a great deal of weight. On admission in December, she was thin, cyanosed and breathless and any movement increased her dyspnoea. There was dullness on percussion at the right lung base with widespread crepitations over the lower zones of the lungs. The heart was normal in size. The second pulmonary sound was accentuated and there was tachycardia (lOO/min.), and gallop-rhythm. The blood pressure was 160/100 mm. Hg. There were no other relevant findings. Laboratory examinations were as follows: urine normal; haemoglobin, 84%; W.B.C., 6000; differential count, normal, no eosinophils; blood urea 30 mgs./100 ml.; blood Wassermann reaction negative; sputum, no tubercle bacilli, no malignant cells; Mantoux test up to 100 TV negative; liver function tests, normal; serum proteins normal, except for a mild increase in gamma globulin. X-ray examination of the chest (Fig. 1), including tomograms, revealed generalised mottling of both lungs, fine in the upper zones and coarse in the lower. There was no hilar enlargement. Biopsy examination of an axillary lymph node, skin and muscle, showed no significant abnormalities. Course She ran a low sustained pyrexia not exceeding lOO°F. Eleven days after admission a punctate erythematous rash appeared on the legs, forearms and back; it soon spread to other parts, coalescing to a diffuse erythema and covering most of the body. At the same time there was numbness of hands and feet and impairment of all types of sensations. There was also some loss of motor power. Sarcoidosis was thought to be the most likely diagnosis and treatment with cortisone,
508
TUBERCLE
200 mgs. daily, was started. There was an immediate improvement in the symptoms, the rash faded, the pyrexia gradually settled, and the nervous signs became less conspicuous. Her appetite improved and she gained weight. Gradually the mottling of the lung fields cleared (Fig. 2) and she was discharged with all the previous signs and symptoms in abeyance, and advised to continue with 50 mg. of cortisone daily. In May 1957, she had mild paraesthesiae in the hands and feet, but her general condition was
Fig. 1 Chest x-ray before treatment.
excellent, and there were no positive pathological findings. X-ray of the lungs showed only a slight increase of the reticular pattern. In February 1958, it was particularly noted that there was no enlargement of spleen, liver or lymph nodes. In July she was found to have a white cell count of 9000, with 38 % neutrophils and 32 % eosinophils.
She kept well until December 1958, when she was re-admitted to hospital with a left-sided peripheral facial palsy. There was no evidence of any other central or peripheral nervous lesion. Her general condition was good and the facial palsy cleared spontaneously. Xsrays of the lungs and skull were normal, but she showed a slight hypochromic anaemia: haemoglobin 75 %; erythrocytes, 3·5 millions; erythrocyte sedimentation rate (E.S.R.) 50 mm. in the first hour (Westergren). In May 1959 there was, however, a well-marked deterioration in her general condition and she was readmitted. She had again lost considerable weight and looked tired and ill. The dryness of her mouth and the weakness of her arms and legs were once more severe,and she was very depressed. Physical examination confirmed the diagnosis of polyneuritis and f1ucroscopy revealed a recurrence of the pulmonary infiltration, aggregated mainly in the left upper lobe (Fig. 3). The blood count
509
LYMPHOMA OF LUNG
Fig. 2 Chest x-ray after three months treatment with cortisone.
Fig. 3 Recurrence of mottled shadowing especially in the left upper zone.
Fig. 4 Further clearing after three weeks' treatment with large doses of cortisone.
Fig. 5 Chest x-ray twelve days before death.
510
TUBERCLE
was normal, the eosinophilia having disappeared. The E.S. R. was still raised to 85 mill. and there was considerable increase of gamma globulin in her serum. Treatment with large doses of cortisone, which had been discontinued against advice during 1958, was again successful and brought subjective improvement, reduction of the mental depression and of the polyneuritis. The abnormal radiographic signs cleared (Fig. 4) and the flow of saliva improved. There were however, signs of salt and water retention, so her cortisone was reduced to 100 rngs. daily and treatment with chlorothiazide was begun. She left hospital greatly improved, and this remission of her disease was maintained until December, when she was readmitted for the last time. She was then extremely ill and there was excessive breathlessness. Tendon reflexes were diminished and all forms of sensation were greatly impaired. Her mouth was again very dry and her vision was so poor that she could just distinguish between light and dark with the right eye, and count fingers at a distance of three feet with the left eye, whilst the disc of the optic nerve showed atrophy. X-ray examination of the lungs revealed coarse opacities at the right apex, and increase in the fine miliary shadowing at the left lung base and mottling in the first left interspace (Fig. 5). She was given intensive steroid treatment together with streptomycin and isoniazid. At the beginning of January 1960 it was noted that the liver edge was three lingers' breadth below the costal margin, and on January II th she became jaundiced, the liver being further enlarged. The jaundice increased and she died in a condition resembling hepatic coma. Laboratory examinations during the last stage of her illness were: blood count normal; E.S.R. 58 mms.: serum calcium 10·4 mg.jlOO 1111.; alkaline phosphatase, 28 King-Armstrong units; turbidity tests, normal; serum bilirubin, 7·6 mg./JOO m1. (4'5 mg. % direct). Bilirubin was present in the urine with increased amounts of urobilinogen and urobilin. POSTMORTEM FINDINGS
The body W,lS deeply jaundiced with some wasting. There were firm bilateral pleural adhesions; the lungs were congested generally with sub-pleural induration, chiefly at the right base. The liver was large (2770 gm.) with smooth surface and accentuation of the lobular pattern by grey portal deposits. The spleen (810 gm.) was red with a few pale grey dots. The superficial lymph nodes were slightly enlarged and the para-aortic group moderately so, being soft and pale. Marrow from the shaft of the femur was reddish-brown. No abnormality was noted in other organs.
Histological appearances There was a mainly diffuse infiltration of many organs by round cells the size of large Iym phocytes, The infiltration was extensive in the aortic lymph nodes, spleen, submandibular salivary glands, uterus, kidney and liver, where it was sharply restricted to the portal tracts and appeared to be compressing the bile ducts, with bile plugs in the canaliculi. The sinusoids were congested and some of the liver cells were atrophic with loss of staining properties. There was no evidence of portal fibrosis. A less extensive infiltration was present in the ulnar nerve near the elbow and in the wall of the small intestines. In the lung the infiltration was greatest sub-pleurally at the bases, but extended proximally as a peribronchial and perivascular infiltrate, which had invaded the walls of some bronchi, with narrowing of the lumen. There was some interstitial fibrosis, chiefly subpleurally. In the brain widely scattered capillaries were plugged by round cells. Bone marrow from the middle third of the femur showed reactive hyperplasia with eosinophils conspicuous, but only a few round cells. No plasma cells were seen ill any organ and the lymphoid cells did not have strongly pyroninophilic cytoplasm. The lymph node biopsy taken in 1956 was re-examined and again thought to show no diagnostic change. No tissue from the superficial lymph nodes or skeletal muscle was preserved at necropsy.
Discussion The presenting symptoms and signs, the high E.S,R. and the radiographic appearances, in the absence of any abnormal findings in the blood, suggested the diagnosis of sarcoidosis, even though the biopsy specimens from lymph node, skin and muscle were negative. The severe dyspnoea,
LYMPHOMA OF LUNG
511
somewhat rare in sarcoidosis, was assumed to be the result of an alveolar-capillary block, which can occur in this disease (Israel and Sones, 1957). The involvement of extrapulmonary organs excluded the alternative diagnosis of a diffuse interstitial fibrosing pneumonitis (Hamman-Rich syndrome), which also does not appear to respond to cortisone (Whitfield, 1958). We could probably have made a correct diagnosis early in the disease by means of a lung biopsy, for it would seem that this patient is similar to those described by Nathan and Sanders (1955) and Bower (1958), in whom leukaemia and lymphosarcoma of the lung presented with the picture of alveolar capillary block. This is an unusual mode of presentation; for instance, in a study of 196 cases of lymphoblastoma verified by biopsy, Sugarbaker and Craver (1940) found that in only 3'6 % were the initial symptoms pulmonary. Throughout the illness there was a persistent train of puzzling neurological symptoms, manifestations of lymphomas and Ieukaemias which have recently been fully reviewed by Williams, and others (1959). The final stage of the patient's illness was dominated by acute liver failure and it is possible that liver biopsy might have been diagnostic early in the disease, for Hougie (1956) considered that portal infiltration of the liver is an early change in chronic lymphatic leukaemia. Jaundice in Hodgkin's disease is usually thought to result from toxic hepatitis, produced by tissue breakdown products and only exceptionally from extrahepatic obstruction by enlarged lymph nodes. There were no enlarged lymph nodes in the portal area, nor extensive damage to liver cells, so it is possible that the jaundice was due to compression of the bile ducts by the portal infiltration, a suggestion supported by the high alkaline phosphatase. REFERENCES BOWER, G. C. (1958). ArneI'. Rev. Tuberc., 78, 468. ROUGIE, C. (1956). Ann. interm. Med., 45, 39. ISRAEL, L. H., & SONES, M. (1957). In Clinical Cardiopulmonary Physiology, Grune and Stratton, New York and London. Sponsored by the American College of Chest Physicians, p, 399. NATHAN, D. J., & SANDERS, M. (1955). New Engl. J. Med., 252, 797. SUOARBAKER, E. D., & CRAVER, L. F. (1940). J. Amer, Med. Ass., 115, 112. WHITFIELD, A. G. W. (1958). Brit. med. J., ii, 154. WILLIAMS, H. M., DIAMOND, H. P., CRAVER, L. F., & PARSONS, H. (1959). Neurological complications ofLymphomas and Leukaemias, ArneI'. Lecture Ser.. Charles C. Thomas, Springfield.
LYMPHOMA OF LUNG MASQUERADING AS SARCOIDOSIS By J.
GOLDSTEIN
and J. C.
BURNE
from Joyce Green Hospital, 'Dartford, Kent SUMMARY
An unusual case of lymphoma in a woman of fifty-three is described. The infiltration, which resembled that of lymphatic leukaemia, was largely restricted to the lungs, liver, nervous system and salivary glands, the blood, bone marrow and superficial lymph nodes being spared. Clinically a diagnosis of sarcoidosis seemed most likely. Biopsy of the liver and lungs might have enabled us to make a correct diagnosis during life.
Tumours of lymphoid tissues presenting as a primary lung condition are unusual and the case here described was so atypical that it was correctly diagnosed only on histological examination of the necropsy material. During life, the most likely diagnosis was thought to be sarcoidosis. Case History Mrs. D., aged 53, was first seen in December, 1956. She was extremely agitated and complained of increasing shortness of breath for some weeks, and of severe muscular weakness. She had had several attacks of breathlessness in bed at night, cough with white frothy sputum and later, nausea with infrequent vomiting. In March of the same year she had been operated on for glaucoma of both eyes, but her eyesight had further deteriorated since then. She had lost a great deal of weight. On admission in December, she was thin, cyanosed and breathless and any movement increased her dyspnoea. There was dullness on percussion at the right lung base with widespread crepitations over the lower zones of the lungs. The heart was normal in size. The second pulmonary sound was accentuated and there was tachycardia (lOO/min.), and gallop-rhythm. The blood pressure was 160/100 mm. Hg. There were no other relevant findings. Laboratory examinations were as follows: urine normal; haemoglobin, 84%; W.B.C., 6000; differential count, normal, no eosinophils; blood urea 30 mgs./100 ml.; blood Wassermann reaction negative; sputum, no tubercle bacilli, no malignant cells; Mantoux test up to 100 TV negative; liver function tests, normal; serum proteins normal, except for a mild increase in gamma globulin. X-ray examination of the chest (Fig. 1), including tomograms, revealed generalised mottling of both lungs, fine in the upper zones and coarse in the lower. There was no hilar enlargement. Biopsy examination of an axillary lymph node, skin and muscle, showed no significant abnormalities. Course She ran a low sustained pyrexia not exceeding lOO°F. Eleven days after admission a punctate erythematous rash appeared on the legs, forearms and back; it soon spread to other parts, coalescing to a diffuse erythema and covering most of the body. At the same time there was numbness of hands and feet and impairment of all types of sensations. There was also some loss of motor power. Sarcoidosis was thought to be the most likely diagnosis and treatment with cortisone,
508
TUBERCLE
200 mgs. daily, was started. There was an immediate improvement in the symptoms, the rash faded, the pyrexia gradually settled, and the nervous signs became less conspicuous. Her appetite improved and she gained weight. Gradually the mottling of the lung fields cleared (Fig. 2) and she was discharged with all the previous signs and symptoms in abeyance, and advised to continue with 50 mg. of cortisone daily. In May 1957, she had mild paraesthesiae in the hands and feet, but her general condition was
Fig. 1 Chest x-ray before treatment.
excellent, and there were no positive pathological findings. X-ray of the lungs showed only a slight increase of the reticular pattern. In February 1958, it was particularly noted that there was no enlargement of spleen, liver or lymph nodes. In July she was found to have a white cell count of 9000, with 38 % neutrophils and 32 % eosinophils.
She kept well until December 1958, when she was re-admitted to hospital with a left-sided peripheral facial palsy. There was no evidence of any other central or peripheral nervous lesion. Her general condition was good and the facial palsy cleared spontaneously. Xsrays of the lungs and skull were normal, but she showed a slight hypochromic anaemia: haemoglobin 75 %; erythrocytes, 3·5 millions; erythrocyte sedimentation rate (E.S.R.) 50 mm. in the first hour (Westergren). In May 1959 there was, however, a well-marked deterioration in her general condition and she was readmitted. She had again lost considerable weight and looked tired and ill. The dryness of her mouth and the weakness of her arms and legs were once more severe,and she was very depressed. Physical examination confirmed the diagnosis of polyneuritis and f1ucroscopy revealed a recurrence of the pulmonary infiltration, aggregated mainly in the left upper lobe (Fig. 3). The blood count
509
LYMPHOMA OF LUNG
Fig. 2 Chest x-ray after three months treatment with cortisone.
Fig. 3 Recurrence of mottled shadowing especially in the left upper zone.
Fig. 4 Further clearing after three weeks' treatment with large doses of cortisone.
Fig. 5 Chest x-ray twelve days before death.
510
TUBERCLE
was normal, the eosinophilia having disappeared. The E.S. R. was still raised to 85 mill. and there was considerable increase of gamma globulin in her serum. Treatment with large doses of cortisone, which had been discontinued against advice during 1958, was again successful and brought subjective improvement, reduction of the mental depression and of the polyneuritis. The abnormal radiographic signs cleared (Fig. 4) and the flow of saliva improved. There were however, signs of salt and water retention, so her cortisone was reduced to 100 rngs. daily and treatment with chlorothiazide was begun. She left hospital greatly improved, and this remission of her disease was maintained until December, when she was readmitted for the last time. She was then extremely ill and there was excessive breathlessness. Tendon reflexes were diminished and all forms of sensation were greatly impaired. Her mouth was again very dry and her vision was so poor that she could just distinguish between light and dark with the right eye, and count fingers at a distance of three feet with the left eye, whilst the disc of the optic nerve showed atrophy. X-ray examination of the lungs revealed coarse opacities at the right apex, and increase in the fine miliary shadowing at the left lung base and mottling in the first left interspace (Fig. 5). She was given intensive steroid treatment together with streptomycin and isoniazid. At the beginning of January 1960 it was noted that the liver edge was three lingers' breadth below the costal margin, and on January II th she became jaundiced, the liver being further enlarged. The jaundice increased and she died in a condition resembling hepatic coma. Laboratory examinations during the last stage of her illness were: blood count normal; E.S.R. 58 mms.: serum calcium 10·4 mg.jlOO 1111.; alkaline phosphatase, 28 King-Armstrong units; turbidity tests, normal; serum bilirubin, 7·6 mg./JOO m1. (4'5 mg. % direct). Bilirubin was present in the urine with increased amounts of urobilinogen and urobilin. POSTMORTEM FINDINGS
The body W,lS deeply jaundiced with some wasting. There were firm bilateral pleural adhesions; the lungs were congested generally with sub-pleural induration, chiefly at the right base. The liver was large (2770 gm.) with smooth surface and accentuation of the lobular pattern by grey portal deposits. The spleen (810 gm.) was red with a few pale grey dots. The superficial lymph nodes were slightly enlarged and the para-aortic group moderately so, being soft and pale. Marrow from the shaft of the femur was reddish-brown. No abnormality was noted in other organs.
Histological appearances There was a mainly diffuse infiltration of many organs by round cells the size of large Iym phocytes, The infiltration was extensive in the aortic lymph nodes, spleen, submandibular salivary glands, uterus, kidney and liver, where it was sharply restricted to the portal tracts and appeared to be compressing the bile ducts, with bile plugs in the canaliculi. The sinusoids were congested and some of the liver cells were atrophic with loss of staining properties. There was no evidence of portal fibrosis. A less extensive infiltration was present in the ulnar nerve near the elbow and in the wall of the small intestines. In the lung the infiltration was greatest sub-pleurally at the bases, but extended proximally as a peribronchial and perivascular infiltrate, which had invaded the walls of some bronchi, with narrowing of the lumen. There was some interstitial fibrosis, chiefly subpleurally. In the brain widely scattered capillaries were plugged by round cells. Bone marrow from the middle third of the femur showed reactive hyperplasia with eosinophils conspicuous, but only a few round cells. No plasma cells were seen ill any organ and the lymphoid cells did not have strongly pyroninophilic cytoplasm. The lymph node biopsy taken in 1956 was re-examined and again thought to show no diagnostic change. No tissue from the superficial lymph nodes or skeletal muscle was preserved at necropsy.
Discussion The presenting symptoms and signs, the high E.S,R. and the radiographic appearances, in the absence of any abnormal findings in the blood, suggested the diagnosis of sarcoidosis, even though the biopsy specimens from lymph node, skin and muscle were negative. The severe dyspnoea,
LYMPHOMA OF LUNG
511
somewhat rare in sarcoidosis, was assumed to be the result of an alveolar-capillary block, which can occur in this disease (Israel and Sones, 1957). The involvement of extrapulmonary organs excluded the alternative diagnosis of a diffuse interstitial fibrosing pneumonitis (Hamman-Rich syndrome), which also does not appear to respond to cortisone (Whitfield, 1958). We could probably have made a correct diagnosis early in the disease by means of a lung biopsy, for it would seem that this patient is similar to those described by Nathan and Sanders (1955) and Bower (1958), in whom leukaemia and lymphosarcoma of the lung presented with the picture of alveolar capillary block. This is an unusual mode of presentation; for instance, in a study of 196 cases of lymphoblastoma verified by biopsy, Sugarbaker and Craver (1940) found that in only 3'6 % were the initial symptoms pulmonary. Throughout the illness there was a persistent train of puzzling neurological symptoms, manifestations of lymphomas and Ieukaemias which have recently been fully reviewed by Williams, and others (1959). The final stage of the patient's illness was dominated by acute liver failure and it is possible that liver biopsy might have been diagnostic early in the disease, for Hougie (1956) considered that portal infiltration of the liver is an early change in chronic lymphatic leukaemia. Jaundice in Hodgkin's disease is usually thought to result from toxic hepatitis, produced by tissue breakdown products and only exceptionally from extrahepatic obstruction by enlarged lymph nodes. There were no enlarged lymph nodes in the portal area, nor extensive damage to liver cells, so it is possible that the jaundice was due to compression of the bile ducts by the portal infiltration, a suggestion supported by the high alkaline phosphatase. REFERENCES BOWER, G. C. (1958). ArneI'. Rev. Tuberc., 78, 468. ROUGIE, C. (1956). Ann. interm. Med., 45, 39. ISRAEL, L. H., & SONES, M. (1957). In Clinical Cardiopulmonary Physiology, Grune and Stratton, New York and London. Sponsored by the American College of Chest Physicians, p, 399. NATHAN, D. J., & SANDERS, M. (1955). New Engl. J. Med., 252, 797. SUOARBAKER, E. D., & CRAVER, L. F. (1940). J. Amer, Med. Ass., 115, 112. WHITFIELD, A. G. W. (1958). Brit. med. J., ii, 154. WILLIAMS, H. M., DIAMOND, H. P., CRAVER, L. F., & PARSONS, H. (1959). Neurological complications ofLymphomas and Leukaemias, ArneI'. Lecture Ser.. Charles C. Thomas, Springfield.