Granulomatous Myositis Clinicopathologic Study of 12 Cases

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1 Anatomic Pathology / GRANULOMATOUS MYOSITIS Granulomatous Myositis Clinicopathologic Study of 12 Cases Richard A. Pray son, MD Key Words: Granulomas; Granulomatous myositis; Myositis; Granulomatous inflammation is infrequently encountered in skeletal muscle biopsy material. Of 2,985 muscle biopsy specimens reviewed over 12 years, 12 (0.%) with granulomatous inflammation were identified. The patients included 9 women who ranged in age from 2 to 76 years (mean 50.3 years). The most common clinical findings included decreased strength or weakness in the extremities (n 8), muscle pain (n = 5), and weight loss (n = 3). All muscles exhibited nonnecrotizing granulomas; an associated vasculitic process was identified in 2. Endomysial chronic inflammation consisting primarily of lymphocytes and plasma cells was present in 10 muscles, and perivascular chronic inflammation in 8. Degenerating muscle fibers were noted in 10 cases, and regenerating fibers in 11. Evidence of neurogenic atrophy was seen in 8 muscles. Increased endomysial fibrosis was observed in 5 muscles, and type II muscle fiber atrophy in 5 muscles. Stains for acidfast bacilli and Gomori methenamine silver stain were performed in all but 2 cases and failed to demonstrate organisms. In 3 cases, concomitant sural nerve biopsies were performed, and granulomas were identified in 2 of those cases. Clinicopathologic diagnoses included sarcoidosis (n = 6), vasculitis (n = 2), and granulomatous myositis not otherwise specified (n = 2). In 2 cases, there was insufficient clinical information or followup data to determine a cause. In conclusion, granulomatous myositis is infrequently found in muscle biopsy specimens (0.5% of all biopsies in this series); most muscles demonstrate evidence of chronic endomysial or perivascular inflammation accompanied by muscle fiber degeneration and regeneration; and the most common cause for granulomatous myositis was sarcoidosis in this series. Granulomatous inflammation is rarely found in muscle biopsy specimens. Most reports are of individual case reports or small series. Most frequently the association of granulomatous inflammation with sarcoidosis has been described; however, rarely other conditions have been described as causing granulomas in skeletal muscle, including infectious diseases, inflammatory bowel disease (in particular, Crohn disease), foreign body giant cell reaction, remote effect of neoplastic process, and association with thymoma or myasthenia gravis.1 This study retrospectively reviews 1 institution's 12year experience with granulomatous myositis. The clinicopathologic features of these cases are reviewed, and an attempt to determine the cause of the granulomatous process is made. Materials and Methods The surgical pathology files at the Cleveland Clinic were searched for cases with skeletal muscle biopsy that contained granulomas. Of the 2,985 muscle biopsy cases reviewed over the 12 years from 1986 to 1997, 12 cases (0.%) with identifiable granulomatous inflammation were included for study. our additional cases were excluded from study; in 2 of these cases, definite granulomas were not identified, 1 case demonstrated nonnecrotizing vasculitis with no granulomas, and 1 exhibited foreign body giant cell reaction. In each case, all available microscopic sections from the skeletal muscle biopsy specimen and any concomitant biopsy material (peripheral nerve and temporal artery) were reviewed. In all but 2 cases, slides for review included at least 1 H&Estained section, as well as sections stained with adenosine triphosphatase (ATPase) at ph.6 and 9.8, cytochrome C oxidase, nicotinamide adenine dinucleotide (reduced form; DH), Gomori trichrome, sulfonated alcian blue, periodic acidschiff, and oil red O. In all but 2 cases, stains for microorganisms, including Gomori methenamine silver and a stain for acidfast bacilli, were performed. Each focus of Am J ClinPathol 1999;112: Downloaded from by guest on 0 November 2018 Abstract

2 Prayson / GRANULOMATOUS MYOSITIS Results Clinical eatures Clinical features in the 12 patients with histologically confirmed granulomatous inflammation are summarized in Table II. The patients included 9 women and 3 men, who ranged in age from 2 to 76 years (mean 50.3 years). Clinical signs and symptoms at presentation included decreased muscle strength or muscle weakness most commonly involving extremities in 8 patients, muscle pain in 5 patients, weight loss in 3 patients, night sweats or fever in 3 patients, paresthesias involving extremities in 3 patients, and skin "lumps" in 1 patient. Histopathology Salient histopathologic features are summarized in ITable 21. Muscles biopsied included vastus (5 patients), gastrocnemius (2), and quadriceps, triceps, rectus abdominis, muscle from arm region not otherwise specified, and muscle from thigh region not otherwise specified (1 ITable II Clinical eatures in Patients With Granulomatous Myositis Patient Creatine Kinase (U/L) Aldolase (U/L) ACE (U/L) Electromyography 1, Generalized myopathy Generalized myopathy Muscle weakness Skin " l u m p s " Muscle pain, paresthesias Muscle weakness and pain Muscle weakness, weight loss, fever Muscle pain Muscle pain, fever, weight loss, paresthesias Generalized myopathy Sensorimotor polyneuropathy Necrotizing myopathy Necrotizing myopathy Not evaluable Muscle weakness, paresthesias Muscle weakness Muscle weakness and pain, weight loss 1,07 Generalized myopathy, sensorimotor polyneuropathy Necrotizing myopathy Mild myopathic process Generalized myopathy, sensorimotor polyneuropathy Symptoms at Presentation Sex 1 2 Muscle weakness 2 76 Muscle weakness, fever 3 b M M M LL Age (y) Diagnosis Granulomatous myositis, NOS Granulomatous myositis, NOS Vasculitis Not evaluable Vasculitis ACE = angiotensin converting enzyme; = not available; NOS = not otherwise specified. 6 Am J Clin Pathol 1999; 112:63 Downloaded from by guest on 0 November 2018 Electromyographic studies were performed in 10 patients. Six patients had evidence of a nonnecrotizing or generalized myopathy. Evidence of necrotizing myopathy was noted in 3 patients, and sensorimotor polyneuropathy in 3. Creatine kinase levels measured within 1 week of biopsy were known in 9 patients, and were elevated in (range, 10 to 1,120 U/L [normal, 30 to 220 U/L]; mean, 05 U/L). Aldolase levels measured within 1 week of biopsy were known in 7 patients, and were elevated in 3 (range, 3.5 to 1.9 U/L [normal, 2 to 8 U/L]; mean, 7.3 U/L). Angiotensin converting enzyme levels were determined in 6 patients, and were elevated in (range, 3 to 15 U/L [normal, 3 to 8 U/L]; mean, 82.2 U/L). Sedimentation rate was determined in 7 patients with the Westergren method, and was elevated in 5. Based on review of the clinical record and biopsy findings, presumed diagnoses included sarcoidosis in 6 patients, vasculitis in 2 patients, and nonspecific granulomatous myositis in 2 patients. In 2 patients, the clinical information available was not sufficient to categorize the granulomatous inflammation observed in the muscle biopsy material. our patients with sarcoidosis had pulmonary disease. our patients had evidence of granulomas documented on biopsy specimens obtained from other organs prior to the muscle biopsy, including liver, skin, lung, lymph node, and cecum (1 specimen each). granulomatous inflammation was polarized to search for foreign material. When present, chronic endomysial or perivascular inflammation, vasculitis, muscle fiber degeneration, muscle fiber regeneration, evidence of neurogenic atrophy, angular atrophic esterasepositive muscle fibers (muscle fibers or fiber type grouping), and endomysial fibrosis were documented. Concomitant sural nerve or temporal artery biopsy specimens were examined for evidence of granulomatous inflammation or vasculitis. Medical records were examined in each case for patient clinical information including age at time of biopsy, gender, initial symptoms, and electromyographic results. When available, specific values for creatinine kinase, aldolase, and angiotensin converting enzyme were noted. Based on review of the medical record, the presumed clinical diagnosis was documented.

3 Anatomic Pathology / ORIGIL ARTICLE Table 21 Histopathologic eatures in Patients With Granulomatous Myositis Patient Triceps "Arm" Gastrocnemius "Thigh" Rectus abdominis Gastrocnemius Quadriceps Endomysial AB GMS ibrosis Stain Stain f NE NE Downloaded from by guest on 0 November Muscle Angular Atrophic Nonnecrotizing Endomysial Perivascular Esterase Granuloma Vasculitis Inflammation Inflammation Degeneration Regeneration ibers AB = acidfast bacilli; GMS = Gomori methenamine silver; = not done; NE = not evaluable. each). Nonnecrotizing granulomas were identified in all 12 specimens llmage II; necrotizing granulomatous inflammation was not observed. Two specimens demonstrated evidence of vasculitis associated with granulomas llmage 21. Polarizable material was not seen in association with any granulomas. All but 2 muscle biopsy specimens exhibited foci of chronic endomysial inflammation separate from the granulomas, consisting primarily of lymphocytes and smaller numbers of plasma cells llmage 31. oci of perivascular chronic inflammation were observed in 8 biopsy specimens. Scattered regenerating muscle fibers characterized by large nuclei with small prominent nucleoli, basophilic cytoplasm, or positive staining with alkaline phosphatase were observed in 11 of 12 specimens llmage 1. Scattered degenerating muscle fibers, highlighted on acid phosphatase staining, were seen in 10 specimens. Angular atrophic esterase positive muscle fibers were identified in 8 of 10 cases in which the stain was performed; fiber type grouping, highlighted on fm ' *** llmage I I (Patient 11) Nonnecrotizing granulomatous llmage 21 (Patient 7) Nonnecrotizing vasculitis associated inflammation in a patient with sarcoidosis (H&E, x100). with granulomatous inflammation (H&E, x00). Am J Clin Pathol 1999;112:

4 Prayson / GRANULOMATOUS MYOSITIS Image 1 (Patient 12) Alkaline phosphatase stain highlights regenerating myofibers near a granuloma in sarcoid myopathy (alkaline phosphatase, x200). the ATPase stains, was observed in only 1 case. ive biopsy specimens demonstrated increased fibrous tissue, which was focal and mild in cases and extensive in 1. Additional stains for microorganisms including an acidfast stain and Gomori methenamine silver stain were negative in all 10 specimens in which both stains were performed. Other less frequent findings in the muscle biopsy specimens included evidence of type II muscle fiber atrophy in 5. Scattered cytochrome C oxidasenegative muscle fibers were identified in 3 specimens, but ragged red fibers were not observed. Nuclear bag formation was associated with muscle fiber atrophy in 3 specimens. Target fibers were identified in 2 biopsy specimens with the DH stain. One biopsy specimen each showed evidence of increased central nuclei and split myofibers. A concomitant sural nerve biopsy was performed in 3 patients. In 1 biopsy specimen, no important pathologic abnormalities were noted; in the remaining 2 specimens, nonnecrotizing granulomatous inflammation, situated in the epineurial region, was observed. Both nerves had evidence of mild axonal loss and changes consistent with axonopathy. A temporal artery biopsy specimen obtained in 1 patient at the same time as the muscle biopsy showed evidence of temporal arteritis and mild intimal fibroplasia. Definite granulomas were not seen in association with the temporal arteritis. years. In most of these cases, the cause of granulomatous inflammation was not readily discernible at histologic evaluation of the biopsy specimen. With the exception of a recognizable foreign body giant cell reaction or rare instance of a granulomatous response to infectious agents such as fungus or mycobacteria, which can potentially be identified with special stains, most granulomatous myositis cases require careful correlation with clinical findings and other laboratory data to arrive at a diagnosis. In this series, sarcoidosis was the single most commonly identifiable cause of granulomatous inflammation. In 2 cases, a prominent vasculitic component was identified in association with granulomatous inflammation in the absence of a clinical history of sarcoidosis; in 2 additional cases, granulomatous myositis did not appear to be associated with sarcoidosis but was part of a polymyositislike picture. In the remaining 2 cases, the clinical information available was not adequate to definitively assign a cause to the granulomatous process. Evidence of other systemic diseases rarely associated with granulomatous myositis, such as myasthenia gravis in the setting of thymoma, inflammatory bowel disease, or collagen vascular disorders, was not noted in these patients. Discussion The prevalence of granulomatous myositis in skeletal muscle biopsy specimens is low, 0.% in this series over Am J Clin Pathol 1999;112:6368 With the exception of specific identification of vasculitis in 2 cases, the histopathologic features observed in the muscle biopsy specimens in this group of patients showed considerable overlap. In addition to the presence of nonnecrotizing granulomas, most biopsy specimens demonstrated evidence of endomysial chronic inflammation consisting primarily of lymphocytes and plasma cells, degenerating muscle fibers, and scattered regenerating muscle fibers. All of these features are the mainstay of most inflammatory myopathic conditions. Downloaded from by guest on 0 November 2018 Image 31 (Patient 10) Partial fibrofatty replacement of muscle with rare degenerating muscle fiber and endomysial chronic inflammation in a patient with sarcoid (H&E, x200).

5 Anatomic Pathology / ORIGIL ARTICLE Nonnecrotizing vasculitis associated with granulomatous inflammation is an interesting finding in 2 cases. requently.granulomas seen in the setting of sarcoidosis are perivascular.8 The concomitant finding of vasculitis in association with granulomatous inflammation in the setting of sarcoidosis is well documented in the lung. 9 " Descriptions of this phenomenon in muscle are scarce. A rare case was documented in a 36yearold woman with sarcoidosis.12 Both patients in the current study were women who had slightly elevated creatine kinase levels. Angiotensin converting enzyme levels were not determined in either case. Nevertheless, in both cases sarcoidosis was not considered an explanation for the granulomatous angiitis. Whether these cases represent a form of unrecognized sarcoidosis or are part of an unrecognized collagen vascular disease process or vasculitis is uncertain. osis has been documented in patients initially thought to have polymyositis. 131 Three patients were reported who had generalized muscle weakness and in whom muscle biopsy specimens revealed welldefined nonnecrotizing granulomas.7 In 1 of these patients, additional evidence of widespread muscle degeneration and regeneration, similar to most cases in this series, was observed. It was concluded that the granulomas did not appear to exert a significant adverse effect on surrounding muscle cells. The presence of more widespread muscle fiber degeneration suggested that, perhaps contrary to the theories that welldeveloped granulomas in the setting of sarcoidosis in muscle are primarily interstitial and exert destructive effects by compression on adjacent myofibers, sarcoidosis may represent a more widespread process. Alternatively, the diffuse nature of the endomysial inflammation, muscle fiber degeneration, and myofiber regeneration raise the possibility of polymyositis in the differential diagnosis. Granulomatous inflammation is not typically noted in polymyositis. In 2 patients in this series, the lack of other convincing clinical evidence in support of a diagnosis of sarcoidosis raises the possibility that in a small percentage of cases of granulomatous myositis the underlying cause may be related to polymyositis or collagen vascular disease. Distinction between these entities, however, may be based more on the clinical history than the histopathologic findings, because endomysial inflammation, muscle fiber degeneration, and muscle fiber regeneration were observed in most of the clearcut sarcoidosis cases in this series in a more diffuse distribution and in locations not obviously adjacent to granulomas. Immunophenotypically, most of the T lymphocytes that compose the inflammatory infiltrate are CD8 positive, in contrast to the predominance of CDpositive lymphocytes in sarcoidosis.115 Nevertheless, failure to sample the granulomatous component in this setting would generally suggest a diagnosis of polymyositis. Muscle involvement in patients with sarcoidosis is common; 50% to 80% of patients with sarcoidosis have muscle biopsy findings that include granulomas, despite the absence of accompanying signs and symptoms.1 It appears that most patients with sarcoidosis and muscle involvement by granulomatous inflammation have relatively few signs and symptoms related to muscle disease. Symptomatic muscle weakness in sarcoidosis is relatively uncommon, and was noted in 2.3% of patients in 1 analysis of 15 patients with sarcoidosis. 16 Symptomatic involvement most frequently includes either palpable muscle nodules, acute myositis, chronic muscle weakness and wasting, and rarely pseudohypertrophy. Certainly the role of biopsy in the evaluation of patients with symptoms of sarcoidosis is unquestionable; the role of muscle biopsy in evaluation of asymptomatic (ie, no muscle symptoms) suspected sarcoidosis is less clear. Although the incidence of granulomatous inflammation in these patients is high, muscle biopsy would not provide a definitive diagnosis in all instances. In addition, granulomatous inflammation may be focal and therefore potentially missed on a biopsy specimen. Although found relatively infrequently in muscle biopsy specimens, recognition of granuloma formation in such cases is important from a prognostic and potentially therapeutic standpoint. Prediction of the precise cause for granulomatous inflammation does not appear to be readily ascertainable by examination of biopsy material, with few exceptions. Certainly, polarizing granulomas to search for evidence of foreign body giant cell reaction is a relatively simple procedure and should be routinely performed in these cases. In addition, stains for organisms including mycobacteria and fungi should also be routinely performed, although the likelihood of a positive result is small. Otherwise, close correlation with the clinical history is important for arriving afinaldiagnosis. rom the Department of Anatomic Pathology, Cleveland Clinic oundation, Cleveland, OH. Address reprint requests to Dr Prayson: Department of Anatomic Pathology (L25), Cleveland Clinic oundation, 9500 Euclid Ave, Cleveland, OH 195. Acknowledgment: Special thanks to Denise Egletonfor assistance in preparation of the manuscript. Am J ClinPathol 1999;112: Downloaded from by guest on 0 November 2018 In addition, most of the nonvasculitic cases also demonstrated some evidence of perivascular inflammation. A concomitant component of neurogenic atrophy was observed in most cases, as evidenced by the presence of angular atrophic esterasepositive muscle fibers. Most of the myopathic changes have been previously documented in a number of small studies.2"8 In most of these reports, specific mention of concomitant neurogenic atrophy is not present. It is not entirely surprising, however, that neurogenic changes would be found in selected biopsy specimens, because sarcoidosis can affect the peripheral nerve.38

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