SARCOIDOSIS OF SKELETAL MUSCLE

SARCOIDOSIS OF SKELETAL MUSCLE REPORT OF 6 CASES AND REVIEW OF THE LITERATURE LEON W. POWELL, JR., M.D. Department of Pathology, Duke University School of Medicine, Durham, North Carolina INTRODUCTION Sarcoidosis or Boeck's sarcoid has been described in nearly every tissue in the body, but reports of sarcoid lesions in skeletal muscle are infrequent. 6, u Krabbe, 6 in 1949, stated that he was unable to find more than 8 cases in the literature, and not all of these were proved by microscopic examination. He added 1 case of his own. In their comprehensive monograph, Longcope and Freiman 7 stated that voluntary muscles are occasionally affected. They described 1 case of theirs which was previously reported. 8 Myers and his associates 11 recently described 3 cases in which sarcoid lesions were found in skeletal muscle, despite the absence of localizing signs or symptoms, and they suggested that random muscle biopsy may be helpful in the diagnosis of sarcoidosis. These authors further suggested that the scant attention given muscle lesions in sarcoidosis may be due to the rarity of clinical manifestations related to muscle involvement. A careful review of the literature has revealed 18 reported cases with actual histologic examination of the involved muscle, accompanied in most cases by illustrations. These are summarized in Table 1. Reported cases in which microscopic examination of the involved muscle was not made have been omitted. MATERIALS AND METHODS Three cases of sarcoidosis involving skeletal muscle were recently seen in this hospital, and a search of the files revealed 4 others, 1 of which was previously reported. 4 Biopsy specimens and autopsy tissues were fixed in 10 per cent formalin, Zenker-formol and/or Van de Grift's fixative. Sections were stained with hematoxylin and eosin, Kinyoun's carbol fuchsin for acid-fast organisms and the Hotchkiss-McManus stain for fungi. CASE HISTORIES Case 1 J. C. D., an 18-year-old colored man was admitted to the hospital on July 7,1951, with a history of progressive weakness of the legs, especially the thigh muscles, and a skin rash. The temperature was 38 C. The skin of the face and extremities showed flat, scaly lesions, a few millimeters to 1 centimeter in diameter. There was marked weakness of the large muscles of the upper legs, with slight atrophy. This weakness was principally in the quadriceps region. There was also slight weakness of the arms, and progressive muscular dystrophy was one of the diagnoses considered. Slit-lamp examination of the eyes showed "mutton-fat" keratic precipitates thought compatible with sarcoidosis. X-ray examination of the chest showed bilateral granular nodulations and slight enlargement of the hilar lymph nodes. Received for publication March 20,1953. Dr. Powell is Instructor in Pathology. 881

AUTHOR Mucha and Orzechowski Sundelin Longoope and Pierson Cotter Pautrier Harrell Longoope Castellanos and Galen Skavlem and Ritterhoff Snorrason Bates and Walsh Bates and Walsh REF. NO. 10 16 8 3 12 4 6 2 14 15 1 1 DATE 1919 1925 1937 1939 1939 1940 1941 1946 1946 1947 1948 1948 TABLE 1 CASES OF SARCOIDOSIS OF SKELETAL MUSCLE FOUND IN THE LITERATURE AGE, SEX, RACE 30 F W 35 M W 18 M C 18 M C 26 M C MUSCLESYMPTOMS Muscle pain, difficulty in walking Tumors in muscle Nodules in muscle of legs, arms "Tumor" in muscle Nodules in muscle LOCATIONOFLESIONS Skin, leg muscles (sartorius) Eyes, leg muscles, phalanges Lungs, arm muscles, lymph nodes Lungs, heart, lymph nodes, liver, spleen, arm muscle Biceps, lymph nodes Muscle of arm, lymph nodes, parotid glands, liver O.T.* ** Not done 6 M W 42 M W 36 M W 20 M C 31 M C Nodules in muscle,stiffness Migratory muscular soreness, nodules Pain in calves, weakness Lymph nodes, spleen, joints, eyes, deltoid Lungs, lymph spleen, liver, nodes, heart, diaphragm Hilar nodes, arm and leg muscles Muscle, lymph nodes, parotids, eyes, lungs, heart (?) Lymph nodes, muscle, eyes, parotid glands, spleen, liver, lungs, heart Not done REMARKS Drawing of lesions Photomicrographs and drawings Nodules regressed Subcutaneous nodule in muscle. Autopsy Photographs Photomicrographs No other data. Autopsy O.T. neg., later pos., died with tuberculosis Also had asbestosis. Autopsy (Myositis fibrosa progressiva) Tachycardia Tachycardia. (Muscular dystrophy.) Autopsy

Krabbe 5 1949 57 M W Weakness, nodules in muscles Ricker and Clark 13 1949 54 M W Ricker and Clark 13 1949 25 M C Myers et al. 11 1952 33 M W Myers el al. 11 1952 26 M W Myers et al. 11 1952 28 F C * 0. T. indicates intracutaneous skin test with old tuberculin. ** Pirquet test gave minimal reaction. Gastrocnemius, central nervous system (?), other muscles Heart, lungs, lymph nodes, liver, spleen, muscle Lymph nodes, heart, lungs, eyes, central nervous system, muscle Gastrocnemius, liver, lymph nodes, spleen Gastrocnemius, hilar nodes, lungs, eyes Gastrocnemius, hilar nodes, lungs, eyes, parotid glands Not done Not done CNS (?) symptoms cleared. Photomicrographs Died of Addison's disease. Autopsy Died of sarcoid heart lesion. Autopsy Migratory joint pains Had erythema nodosum Had erythema nodosum

884 POWELL Skin test with old tuberculin, in a dilution of 1:10, was negative. Total protein was 7.2 Gm. with 2.4 Gm. of albumin and 5 Gm. of globulin; the albumin-globulin ratio was 0.48. A biopsy of the quadriceps muscle revealed lesions compatible with sarcoidosis that infiltrated the muscle and caused fibrosis and atrophy of muscle fibers (Fig. 1). A section of skin also revealed a chronic granulomatous process compatible with sarcoidosis. Several excretion studies on 24-hour samples of urine showed creatine values ranging from 0.93 to 0.075 Gm., and creatinine ranging from 0.98 to 0.62 Gm. The patient was treated with ACTH and showed slight improvement. He later developed moderate generalized lymphadenopathy. The clinical impression was sarcoidosis involving skin, lymph nodes, lungs and muscle. He was discharged on a regimen of cortisone Cose 2 E. W. P., a 46-year-old colored man was admitted to the hospital for the first time in 1942, complaining of asthma, swelling of the ankles and slight precordial pain. The blood pressure was 170/110; there were linear exudates in the ocular fundi and slight cardiac enlargement. The hemogram was normal. Total serum protein was 6.8 Gm., with 4.3 Gm. of globulin, 2.5 Gm. of albumin; the albumin-globulin ratio was 0.58. The patient was subsequently seen as an outpatient. His blood pressure varied from 140/100 to 190/130. His cardiac and asthmatic status became progressively worse and 4 days prior to death, he was readmitted to the hospital for treatment of congestive failure. Slight weakness and atrophy of the left supraspinatus muscle were noted. Two days before death the electrocardiogram revealed a ventricular rate of 76 and an atrial rate of 118 per minute. There was sagging of the S-T segments, and the T waves were inverted. These findings were interpreted as evidence of complete heart block with intraventricular rhythm. The patient suddenly died on the fourth day of hospitalization. The final clinical diagnoses were asthma, hypertensive cardiovascular disease, generalized arteriosclerosis and complete atrioventricular heart block. An autopsy was performed 16ihours after death. Unexpected findings were Boeck's sarcoidosis of the lungs, trachea, pericardium, atrial myocardium, superior vena cava, pulmonary veins, mediastinal and axillary lymph nodes, left supraspinatus muscle, liver and kidney. Microscopic examination of the heart showed a greatly thickened atrial wall involved by a granulomatous process which infiltrated muscular fibers. This process was composed of epithelioid cells which frequently formed tubercles. Langhans giant cells were present in some of these tubercles. There was an abrupt termination of the process in the atrial myocardium. The wall of the left pulmonary vein and the superior vena cava were thickened, and these areas were also the seat of sarcoidosis. In the lungs and hilar lymph nodes the sarcoid lesions exhibited occasional giant cells containing Schaumann bodies. The left supraspinatus muscle showed infiltration in some areas with epithelioid cells that formed small tubercles surrounded by a zone of lymphocytes. An occasional giant cell was found in the tubercles. Sections from other muscles showed no granulomas. FIG. 1 (left upper). Case 1. Section from muscle of thigh exhibiting sarcoid granulomas with destruction and atrophy of muscle fibers. X 110. FIG. 2 (right upper). Case 3. Section of muscle of the arm showing sarcoid tubercles with destruction of muscle fibers. X 110. FIG. 3 (left middle). Case 4. Section from pectoralis muscle with numerous closely packed sarcoid lesions. X 50. FIG. 4 (right middle). Case 5. Section from muscle of the arm exhibiting extensive destruction and atrophy of fibers associated with sarcoid granulomas. X 85. FIG. 5 (left lower). Case 6. Section from gastrocnemius muscle showing a large sarcoid lesion located between muscle fibers. X 110. FIG. 6 (right lower). Case 2. Section of atrial myocardium showing sarcoid granulomas; Myocardial tissue is seen at upper right. X 90.

FIGS. 1-6 885

886 POWELL Case S L. A., a 16-year-old colored youth entered the hospital November 4,1952, with a history of increasing anorexia, weakness and pleuritic pain. Physical examination showed nontender 1-mm. papules over the forehead, 4-mm. subcutaneous nodules over the arms and thighs, generalized lymphadenopathy, enlargement of the left parotid gland, iritis and pharyngitis. The temperature on admission was 39.6 C, but later was in the neighborhood of 37.5 C. X-ray of the chest showed fine reticular and nodular infiltrations scattered diffusely throughout both lungfieldswith marked hilar enlargement. The liver was enlarged. The hemogram and blood chemical studies were within normal limits, except that the sedimentation rate was 27 mm. in 1 hr. Skin tests with old tuberculin were negative in dilutions of 1:10. A biopsy of a nodule of the right arm revealed a chronic granulomatous process composed of hard tubercles infiltrating muscle fibers; a diagnosis of sarcoidosis was made (Fig. 2). The patient was treated with ACTH and cortisone and showed slight improvement. Case 4 J. C, a 29-year-old colored man entered the hospital on October 3, 1941, complaining of weakness and subcutaneous nodules over his arms, chest and face. Physical examination showed countless, widely scattered, subcutaneous nodules measuring 3 to 5 mm. The skin around the nares and lips contained 2-mm. nodules. There was generalized lymphadenopathy. A hemogram was normal, but the sedimentation rate was 28 in 1 hr. The urine showed 1+ albumin and occasionally contained numerous red cells and a few white cells. An x-ray examination of the lungs showed diffuse bilateral thickening of parenchymal markings and bilateral hilar thickening, consistent with sarcoidosis. The nonprotein nitrogen was 47 mg. per 100 ml. The total protein was 6.3 Gm., with 2.6 Gm. of albumin and 3.7 Gm. of globulin; the albumin-globulin ratio was 0.7. The tuberculin skin tests were negative in dilutions of 1:10,000. A biopsy of a subcutaneous nodule from the anterior chest showed a granulomatous process compatible with sarcoidosis involving striated muscle (Pig. 3). The patient was discharged on supportive therapy. The final clinical impression was sarcoidosis with renal invasion. Case 5 0. B. C., an 18-year-old colored man entered the hospital on May 7, 1948, complaining of nodules on his arms and a productive cough. Physical examination revealed a few 1-mm. cutaneous nodules on the face and a chain of 5-mm. subcutaneous nodules on the forearms. There was generalized lymphadenopathy. The hemogram was normal. The.total serum protein was 7.5 Gm., with 3.5 Gm. of albumin and 4 Gm. of globulin; the albumin-globulin ratio was 0.87. An x-ray film of the chest showed enlargement of both hilar regions, with generalized, moderately increased density throughout both lung fields thought to be compatible with sarcoidosis. An axillary lymph node and a subcutaneous nodule of the forearm were removed. Both showed chronic granulomatous inflammation compatible with sarcoidosis. The nodule from the arm showed sarcoid lesions infiltrating striated muscle fibers and causing atrophy andfibrosisof these fibers (Fig. 4). The patient was discharged to receive supportive therapy. Case 6 M. N., a 38-year-old colored woman entered the hospital December 13, 1952, with swelling of both parotid glands, lacrimation and clouded vision. On physical examination each parotid gland was about 2 or 3 times normal size, slightly tender and firm. The liver extended 4 cm. below the right costal margin. Slit-examination of the eyes showed granulomatous uveitis. X-ray examination of the chest revealed increase in prominence of the pulmonary markings and nodulations about both hilar regions, consistent with sarcoidosis. The total serum protein was 7.9 Gm., with 3.9 Gm. of albumin and 4.0 Gm. of

SARCOIDOSIS OF SKELETAL MUSCLE 887 globulin; the albumin-globulin ratio was 0.97. Skin tests with old tuberculin were negative in dilutions of 1:100. A nomogram was normal. Biopsies of a submandibular salivary gland and gastrocnemius muscle showed chronic granulomatous lesions compatible with sarcoidosis (Fig. 5). The diagnosis of sarcoidosis with uveoparotid fever was made, and the patient was treated with ACTH. She improved subjectively. SUMMARY OF OBSERVATIONS Five of the 6 patients in the present report were believed to have sarcoidosis. In x-ray examinations of the chest, all 5 showed hilar enlargement with an increase in bronchial markings compatible with sarcoidosis. In 1 case the serum proteins were normal, but 4 showed reversed albumin-globulin ratios. Four patients had negative skin tests to old tuberculin in low dilutions, while the tuberculin reaction of a fifth was not recorded. Three had granulomatous iritis, which, on slitlamp examination was compatible with sarcoidosis. The sixth patient (Case 2) came to autopsy undiagnosed. Sarcoid lesions were found in many organs. The histologic sections from all cases showed a chronic granulomatous inflammatory reaction involving skeletal muscle. The individual lesions were the socalled "hard" tubercles composed almost entirely of plump epithelioid cells, but containing an occasional Langhans giant cell near the center. A few lymphocytes surrounded some of the lesions, but no caseous necrosis was observed. In cases where these hard tubercles were widely scattered they appeard to be located in the connective tissue between muscle fibers (Fig. 5). But in most cases the lesions were closely packed and were associated with destruction, atrophy and fibrosis of the involved and adjacent muscle fibers (Figs. 3 and 4). Acid-fast and Hotchkiss-McManus stains failed to demonstrate any organisms. Occasional Schaumann bodies were found in the lesions from the autopsied case. COMMENT Clinical Manifestations of Muscle Lesions It has been suggested that clinical manifestations of skeletal muscle lesions in sarcoidosis are rare. 11 Yet from Table 1 it is seen that 9 of 18 cases showed some type of symptoms or signs related to muscle lesions. The most common clinical manifestation was the presence of nodules in the muscles, particularly of the extremities. These were found in 7 of the cases. In 3 cases in our series "subcutaneous nodules" were described clinically but microscopically the sarcoid lesions involved skeletal muscle. We include these 3 cases as clinically showing nodules in muscle, even though their actual location in muscle was not appreciated until after microscopic examination. These nodules were sometimes associated with other signs or symptoms such as weakness, soreness or atrophy, but often the presence of nodules in muscles was the only clinical manifestation. Pain or soreness of the muscles occurred in 3 patients and stiffness in 1, but most of these patients also showed nodules in the muscles (Table 1). Muscular weakness and atrophy were the most striking symptoms although they were present in only 5 cases, 3 in the literature and 2 in the present series. The clinical picture may sometimes simulate a form of muscular dystrophy.

888 POWELL Case 1 of the present series was an example. The patient showed marked weakness and atrophy, especially of the thigh muscles. There were no gross nodules in the muscles, the involvement apparently being diffuse. This patient could not rise to a standing position from a chair without the aid of his arms. The symptoms were suggestive of progressive muscular dystrophy, and clinical studies showed a urinary excretion of creatine ranging from 0.93 to 0.075 Gm. per 24 hours. A muscle biopsy from the thigh showed sarcoidosis with atrophy and fibrosis of muscle fibers (Fig. 1). Two similar cases were found in the literature; one, reported by Mucha and Orzechowski, 10 was a woman who had difficulty rising to a standing position after sitting on the ground. She had pain in the muscles of her thighs and difficulty in walking, particularly uphill. The thigh muscles were partly hypertrophic. A biopsy of the sartorius muscle revealed sarcoidosis infiltrating the muscle fibers and causing focal atrophy of these fibers. This patient also had skin lesions characteristic of sarcoidosis. The second case, observed by Bates and Walsh, 1 was a 31-year-old colored man who had pain in the calves accompanied by weakness of these muscles. This patient was thought at one time to have pseudohypertrophic muscular dystrophy, and at another, progressive muscular dystrophy. He later developed uveoparotid fever and eventually died. At autopsy sarcoidosis was found in multiple organs, including the heart. Also of interest here is a case described by Snorrason 15 with multiple nodules in the muscles of the extremities accompanied by stiffness of these muscles. This patient, like our Case 1, showed creatine in the urine ranging from 0.02854 to 1.053 Gm. per 24 hours. A biopsy of the biceps brachii showed sarcoid lesions infiltrating the muscle with atrophy and fibrosis in some areas. Snorrason thought his case met the criteria of myositis fibrosa progressiva. Muscular and Myocardial Sarcoidosis Six autopsied cases of sarcoid of muscle were found in the literature, and Case 2 in the present series adds a seventh. Six of these 7 (86 per cent) also showed sarcoidosis of the myocardium (Table 1). In the autopsied case reported by Longcope 6 (Table 1, No. 7) no data were given on cardiac lesions, but myocardial sarcoidosis was stated to occur in only about 20 per cent of autopsied cases. 7 The presence of myocardial lesions in 6 of 7 cases suggests a direct relationship between myocardial and muscular sarcoidosis, at least in the cases studied at autopsy. In Case 2 of the present series complete heart block was revealed by electrocardiogram about 2 days before death of the patient. At autopsy, extensive sarcoidosis of the atrial myocardium was thought to have caused the heart block (Fig. 6). Similar cases have been reported. 7,9 In Case 2 sarcoid lesions were also found in the walls of the superior vena cava and pulmonary veins, and represent an unusual finding. Longcope and Freiman 7 mentioned adventitia of great vessels last in their list of uncommon sites for sarcoid lesions. In the present case the entire wall of the vein was involved.

SARCOIDOSIS OP SKELETAL MUSCLE 889 SUMMARY Six cases of sarcoidosis of skeletal muscle are added to 18 cases reported in the literature. The sarcoid lesions in muscle produced clinical manifestations in half of the cases. In 6 of 7 autopsied cases with sarcoidosis of skeletal muscle, myocardial sarcoidosis was found. In 1 patient with complete heart block postmortem study showed sarcoidosis of the myocardium and of the walls of the great veins. REFERENCES 1. BATES, G. S., AND WALSH, J. M.: Boeok's sarcoid. Observations on 7 patients; 1 autopsy. Ann. Int. Med., 29: 306-317, 1948. 2. CASTBLLANOS, A., AND GALAN, E.: Sarcoidosis (Besnier-Boeck-Schaumann's disease); report of a case in a child simulating Still's disease. Am. J. Dis. Child., 71: 513-529, 1946. 3. COTTER, E. F.: Boeck's sarcoid: autopsy in a case with visceral lesions. Arch. Int. Med., 64: 286-295, 1939. 4. HARRELL, G. T.: Generalized sarcoidosis of Boeck; a clinical review of eleven cases with studies of the blood and the etiologic factors. Arch. Int. Med., 65: 1003-1034, 1940. 5. KRABBE, K. H.: Muscular localization of benign lymphogranulomatosis. Acta med. Scandinav., supp., 234: 193-198, 1949. 6. LONGCOPE, W. T.: Sarcoidosis, or Besnier-Boeck-Schaumann disease. J.A.M.A., 117: 1321-1327, 1941. 7. LONGCOPE, W. T., AND FREIMAN, D. G.: A study of sarcoidosis. Medicine, 31: 1-132, 1952. 8. LONGCOPE, W. T., AND PIERSON, J. W.: Boeck's sarcoid (sarcoidosis). Bull. Johns Hopkins Hosp., 60: 223-296, 1937. 9. MOYER, J. H., AND ACKERMAN, A. J.: Sarcoidosis; a clinical and roentgenological study of twenty-eight cases. Am. Rev. Tuberc, 61: 299-322, 1950. 10. MUCHA, V., AND ORZECHOWSKI, K.: Ein Fall von tuberkulbser Dermatomyositis (Typus Boeck). Wien. klin. Wchnschr., 32: 25-30, 1919. 11. MYERS, G. B., GOTTLIEB, A. M., MATTMAN, P. E., ECKLEY, G. M., AND CHASON, J. L.: Joint and skeletal muscle manifestations in sarcoidosis. Am. J. Med., 12: 161-169, 1952. 12. PAUTRIER, L. M.: Les lesions musculaires de la maladie de Besnier-Boeck-Schaumann. Ann. de dermat. et syph., 10: 97-103, 1939. 13. RICKER, W., AND CLARK, M.: Sarcoidosis; a clinicopathologic review of three hundred cases including twenty-two autopsies. Am. J. Clin. Path., 19: 725-749, 1949. 14. SKAVLEM, J. I-L, AND RITTERHOFP, R. J.: Coexistent pulmonary asbestosis and sarcoidosis. Am. J. Path., 22: 493-517, 1946. 15. SNORBASON, E.: Myositis fibrosa progressiva in patient with lymphogranulomatosis benigna Boeck.. Nord. med., 36: 2424-2425, 1947. 16. SUNDELIN, F.: Tumeurs multiples disseminees dans les muscles des extremites et reppelant la tuberculose par leur structure histologique. Acta med. Scandinav., 62: 442-460, 1925.