This case was originally published in 2017. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.
The patient is a 44-year-old man presenting with a six-month history of weakness and mild pain in his upper and lower extremities. Before his symptoms started, he used to be physically active and used to exercise for about 30 to 45 minutes daily on an elliptical machine but had to stop a couple of months ago because he started feeling weak. Also, he has noticed difficulty shaving and combing his hair. His past medical history is unremarkable. On a recent visit to his neurologist, an electromyography (EMG) was performed, showing evidence of a proximal myopathy. Laboratory workup showed elevation of his serum creatine kinase (CK) level up to 2,300 U/L. The patient underwent biopsy of his left biceps brachii.
Skeletal muscle, left biceps brachii
Whole Slide Image
The whole slide image provided is an FFPE H&E stained slide of left biceps brachii muscle from a biopsy.
Which diagnosis is MOST consistent with the patient’s clinical presentation and pathological examination?
Inclusion body myositis
Necrotizing autoimmune myopathy
Which of the following statements is TRUE concerning inflammatory myopathies?
Dermatomyositis and muscular dystrophy have overlapping histological features.
Dermatomyositis and polymyositis usually respond to corticosteroid therapy.
Muscle damage in dermatomyositis is mediated primarily by cytotoxic T-cells.
Polymyositis is usually associated with underlying malignancy.
The predominant inflammatory cells in inclusion body myositis are CD20-positive B-cells.
Which of the following diseases is typically associated with serum CPK in the normal range?
Becker muscular dystrophy
Discussion and Diagnosis
This case is a classic presentation of subacute polymyositis (PM). The diagnosis of a myopathy relies on clinical presentation, laboratory and pathological findings. This patient exhibited progressive proximal muscle weakness of both upper and lower extremities with a markedly elevated CK level, and EMG findings were consistent with a proximal inflammatory myopathy. The muscle biopsy showed multifocal endomysial inflammatory infiltration (Image A, Image B, and Image C) by CD3-positive and CD8-positive T-lymphocytes (Image E and Image F) with a very small population of admixed CD20-positive B-lymphocytes (Image G) and no vasculitis or epithelioid granulomas. There is diffuse aberrant sarcolemmal hyperexpression of MHC-I (Image D). Rare COX-negative myofibers are found. The muscle fibers demonstrated increased variation in their diameters with occasional round atrophic fibers and hypertrophic fibers; however, features of chronicity (eg, prominent endomysial fibrosis, fatty infiltration) or sarcoplasmic inclusions were not seen.
PM generally has a subacute onset, presenting as proximal and symmetrical weakness over a period of weeks to months. Many patients experience difficulty with washing their hair, brushing their teeth, or other arm movements involving abduction. Dysphagia and respiratory symptoms may be associated, with varying severity. PM generally occurs in patients older than 18 years and is extremely rare in infants. The prevalence of PM is higher in women than in men, with a 3:1 ratio. Up to 40% of patients do not experience muscle pain. In some patients the weakness may be generalized, rapidly progressive, and severe enough to confine them to bed in a few days. Myofiber necrosis and resultant myoglobinuria may cause acute renal failure. MRI studies may demonstrate edema in the affected muscles. EMG shows an irritative myopathy pattern with small amplitude and brief polyphasic motor units potentials, fibrillations, and positive sharp waves. In addition to elevated levels of CK, aldolase, and erythrocyte sedimentation rate (ESR), the patient's blood may contain disease-specific and/or disease-associated antibodies, commonly antinuclear antibodies (ANA), anti-t-RNA synthetase antibodies (eg, Jo-1), and anti-signal recognition particle antibodies (anti-SRP). The presence of any of these antibodies is not specific for PM and can also be encountered in other immune-mediated myopathies and overlap syndromes. The first line of immunosuppressive therapy is steroids, to which most PM cases respond. Other immunosuppressive agents include methotrexate, azathioprine, cyclophosphamide, and cyclosporine.
The main subtypes of inflammatory myopathies include: dermatomyositis (DM), PM, inclusion body myositis (IBM), and the emerging and increasingly recognized immune-mediated necrotizing myopathy (IMNM, also known as necrotizing autoimmune myopathy or NAM). The muscle biopsy remains the definitive diagnostic test, and appropriate handling of such fresh specimens is critical for optimal diagnostic interpretation. The histologic hallmark of all inflammatory myopathies is inflammation; however, the site of inflammation, the type of inflammatory cells involved, and other clinical and histopathologic parameters are key in making the correct diagnosis. Furthermore, the extent and degree of tissue inflammation observed in biopsies are known to be reduced by empiric immunosuppressive therapy prior to biopsy. Both PM and IBM are T-cell mediated disorders, characterized by antigen-driven clonal expansion of CD8-positive T-lymphocytes that attack muscle fibers overexpressing MHC-I. These cytotoxic T-cells induce muscle fiber necrosis via released perforins and granzymes.
Microscopically PM and IBM share many histologic features, including variation in myofiber diameter, patchy to widespread endomysial and perimysial mononuclear inflammatory infiltrates, degenerating and regenerating myofibers, myofiber atrophy and hypertrophy. Intact myofibers may show invasion by inflammatory cells in single files. In PM there is minimal endomysial fibrosis, in contrast to IBM which often shows features of chronicity, such as moderate endomysial fibrosis and endomysial fatty infiltration. Additional features seen in IBM are sarcoplasmic rimmed vacuoles containing basophilic granules (readily identified on H&E and Gomori trichrome preparations of frozen sections), accumulation of degenerative and stressor molecules (eg, beta-amyloid peptides, ubiquitin, p62 and, recently claimed to be IBM-specific, transactive response DNA-binding protein 43 kDa [TDP-43]), and COX-negative myofibers.
DM is a complement-mediated microangiopathy characterized by a triad of skin changes, myositis, and vasculitis. The complement-mediated damage targets primarily capillary endothelium, resulting in capillary loss, perimysial and perivascular inflammation, and fascicular hypoperfusion. The latter, in turn, produces the characteristic atrophy and degeneration of perifascicular myofibers. The inflammatory infiltrate in DM consists predominantly of CD20-positive B-lymphocytes and CD4-positive T-lymphocytes. NAM is characterized by destruction of myofibers with minimal inflammation, and its damage to myofiber is macrophage-mediated and elicited by drugs and toxins (most commonly statins), viral infections, neoplasms, or autoimmune disorders. DM and PM are responsive to immunosuppressive and immunomodulating treatment, while IBM is considered to be refractory to all treatment. Although both PM and DM are associated with interstitial lung disease, up to one-third of adult DM cases and very rare juvenile DM as well as PM cases have been associated with various malignancies as a paraneoplastic syndrome.
Take Home Points
- Inflammatory myopathy is a heterogeneous group of diseases characterized by mononuclear muscle inflammation, myofiber damage, and characteristic clinicopathologic manifestations.
- It is important for general surgical pathologists to be familiar with the salient histopathology of inflammatory myopathy.
- The diagnosis of inflammatory myopathy is aided by pertinent clinical history, laboratory findings (CK and autoantibodies levels), and EMG results.
- Typical polymyositis shows diffuse or patchy mononuclear endomysial and perimysial inflammatory infiltration by CD8-positive T-lymphocytes, occasional macrophages, degenerating and regenerating myofibers, and scattered atrophic muscle fibers.
- Inclusion body myositis shares histopathologic similarity with polymyositis and, additionally, displays rimmed vacuoles and frequently more prominent endomysial fibrosis.
- The classic pathology of dermatomyositis includes perifascicular atrophy/degeneration of myofibers with perimysial inflammatory infiltrates consisting of mixed B-lymphocytes and T-lymphocytes.
- Dalakas MC. Pathophysiology of inflammatory and autoimmune myopathies. Presse Med. 2011 Mar 15;40(4 Pt 2):e237-47.
- Dubowitz V, Sewry CA, Oldfors A. Muscle Biopsy: A Practical Approach. 4th ed. Saunders Elsevier; 2013:513-37.
- Greenberg SA. Inflammatory myopathies: evaluation and management. Semin Neurol. 2008;28:241-9.
- Hiniker A, Daniels BH, Lee HS, Margeta M. Comparative utility of LC3, p62 and TDP-43 immunohistochemistry in differentiation of inclusion body myositis from polymyositis and related inflammatory myopathies. Acta Neuropathol Commun. 2013;1:29.
- Mantegazza R, Bernasconi P. Inflammatory myopathies: dermatomyositis, polymyositis and inclusion body myositis. Madame Curie Bioscience Database. Austin, TX: Landes Bioscience; 2000-2013.
- Washington University in St. Louis (WUSTL). Neuromuscular disease center: muscle biopsy procedure. WUSTL website. http://neuromuscular.wustl.edu.... Accessed June 23, 2017.
- Washington University in St. Louis (WUSTL). Neuromuscular disease center: polymyositis. WUSTL website. http://neuromuscular.wustl.edu.... Accessed June 23, 2017.
- Which diagnosis is MOST consistent with the patient’s clinical presentation and pathological examination?
- A. Dermatomyositis
- B. Inclusion body myositis
- C. Muscular dystrophy
- D. Necrotizing autoimmune myopathy
- E. Polymyositis (PM)
- Which of the following statements is TRUE concerning inflammatory myopathies?
- A. Dermatomyositis and muscular dystrophy have overlapping histological features.
- B. Dermatomyositis and polymyositis usually respond to corticosteroid therapy.
- C. Muscle damage in dermatomyositis is mediated primarily by cytotoxic T-cells.
- D. Polymyositis is usually associated with underlying malignancy.
- E. The predominant inflammatory cells in inclusion body myositis are CD20-positive B-cells.
- Which of the following diseases is typically associated with serum CPK
in the normal range?
- A. Becker muscular dystrophy
- B. Dermatomyositis
- C. Myasthenia gravis
- D. Polymyositis
- E. Statin-induced myopathy