Ultrastructural Pathology
ISSN: 0191-3123 (Print) 1521-0758 (Online) Journal homepage: http://www.tandfonline.com/loi/iusp20
Juvenile dermatomyositis: A report of three cases V. Papa ScD, B. Romanin MD, R. Bergamaschi PhD, D. M. Cordelli MD, R. Costa ScD, L. Badiali De Giorgi ScD & G. Cenacchi MD To cite this article: V. Papa ScD, B. Romanin MD, R. Bergamaschi PhD, D. M. Cordelli MD, R. Costa ScD, L. Badiali De Giorgi ScD & G. Cenacchi MD (2016): Juvenile dermatomyositis: A report of three cases, Ultrastructural Pathology, DOI: 10.3109/01913123.2016.1141823 To link to this article: http://dx.doi.org/10.3109/01913123.2016.1141823
Published online: 17 Feb 2016.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iusp20 Download by: [RMIT University Library]
Date: 09 March 2016, At: 22:55
ULTRASTRUCTURAL PATHOLOGY http://dx.doi.org/10.3109/01913123.2016.1141823
CASE REPORT
Juvenile dermatomyositis: A report of three cases V. Papa, ScDa, B. Romanin, MDb, R. Bergamaschi, PhDc, D. M. Cordelli, MDd, R. Costa, ScDa, L. Badiali De Giorgi, ScDe, and G. Cenacchi, MDa Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; bDepartment of Pediatric Emergency, S. OrsolaMalpighi Hospital, Bologna, Italy; cDepartment of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; dOperative Unit of Child Neuropsychiatry, S. Orsola-Malpighi Hospital, Bologna, Italy; eOperative Unit of Anatomy, Pathological Histology, S. Orsola-Malpighi Hospital, Bologna, Italy
Downloaded by [RMIT University Library] at 22:55 09 March 2016
a
ABSTRACT
ARTICLE HISTORY
Juvenile dermatomyositis (JDM), an autoimmune idiopathic myositis, is characterized by rash and proximal muscle weakness. Immunohistopathology typically shows perivascular inflammatory infiltrate with predominance of CD4+ T lymphocytes, perifascicular atrophy, and upregulation of major histocompatibility complex class I. JDM has been attributed to a humoral-driven muscle microangiopathy probably implicating the type I interferon pathway. Tubulo-reticular inclusions present in endothelial cell of muscle are biomarkers of interferon exposure, and so may be an indirect data of this myopathy especially in the absence of rash and inflammatory infiltrate. We report on three patients in which electron microscopy solves the differential diagnosis among infantile myositis showing peculiar inclusions.
Received 2 December 2015 Accepted 11 January 2016 Published online 18 February 2015
Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune myopathies. It comprises at least four conditions, namely polymyositits (PM), dermatomyositis (DM), sporadic inclusion body myositis (sIBM), and immune-mediated necrotizing myopathy (IMNM). DM is characterized by an inflammatory infiltrate represented primarily by B cells, macrophages, and CD4+ cells, and primarily affecting the skeletal muscle and skin with typical cutaneous lesions, which can predate from several months to years muscle or systemic involvement. Different DM subsets have been identified until now. These include classic DM, when muscular and skin involvement coexist; amyopathic DM, when the disease affects only the skin; hypomyopathic DM, when cutaneous manifestation of DM is associated with subclinical evidence of myositis; post-myopathic DM, when patients with previous classic DM present a recovery of myositis but skin rashes remain active; and DM sine dermatitis, when no rash is detected, but histology feature of the muscular biopsy sample is indicative of DM. DM is a rare disease which affects both children and adults. Juvenile dermatomyositis (JDM), the most common of the pediatric IIMs, affects children younger than 18 years with skin and muscle features similar to adult DM. JDM is characterized by proximal muscle weakness and distinctive cutaneous findings, but presenting features are variable and onset often insidious, hence classical features may not be seen at presentation [1–6]. To date, diagnosis is based on the clinical and laboratory criteria proposed by Bohan and Peter [7], with the limitation that many pediatric patients presenting typical rashes do not undergo electromyography or muscle biopsy. These disorders can be classified based on clinical features as well as on the presence of specific autoantibodies generally found in patients
KEYWORDS
Dermatomyositis; infantile myosytis; tubulo-reticular inclusions
suffering from myositis, defined as myositis-specific autoantibodies. Histopathology typically shows perivascular and perimysial inflammatory infiltrates, which above all consist of T lymphocytes, with more CD4+ than CD8+ cells [1–8]. Myofiber alterations include perifascicular atrophy and upregulation of major histocompatibility complex class I antigens (MHC-I) [9]. The etiology is nowadays widely unclear; however, current theories contemplate a combination of environmental triggers, immune dysfunction, and specific tissue responses involving muscle, skin, and small vessel endothelium in genetically susceptible individuals. In particular, JDM has traditionally been attributed to a humoral-driven muscle microangiopathy, and there is increasing evidence implicating the type I interferon pathway in the pathogenesis of the disease. The endothelial cell tubuloreticular inclusions (TRIs) present in affected JDM and DM muscle are biomarkers of type 1 interferon exposure [10] so that TRI evidence by electron microscopy (EM) may be indirect data of DM and JDM, especially in the absence of both clinical pathognomonic signs and inflammatory infiltrate in muscle biopsy. In this article, we report three patients whose clinical signs were not specific of JDM and whose morphological data were pivotal in the differential diagnosis of juvenile IIMs.
Case report Case 1 A 10-year-old boy complains of quick fatigue after muscular effort, muscle pain, and cramps. He presents weakness and moderate strength impairment of proximal and girdle muscles.
CONTACT V. Papa [email protected] Department of Biomedical and Neuromotor Sciences, University of Bologna, via Massarenti, 9, Bologna 40138, Italy. Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/iusp. © 2016 Taylor & Francis
2
V. PAPA ET AL.
Table 1. Serological data of three JDM patients.
Downloaded by [RMIT University Library] at 22:55 09 March 2016
Patient 1 Patient 2 Patient 3
Autoantibodies
Creatin kinase (U/L)
Aldolase (U/L)
Aspartase aminotrasferase (U/L)
Alanine aminotransferasi (U/L)
Lactic dehydrogenase (U/L)
Myoglobin (ng/mL)
1189 8862 6088
25.9 46.5 /
95 317 614
33 157 139
585 1233 1595
197 / 6916
Gower’s sign is slightly positive. He has no skin lesions. Blood tests show increase of muscle enzymes (Table 1), no inflammation indexes, and no clinical signs of an ongoing connective tissue disease. In order to distinguish between an inflammatory and a metabolic myopathy, a magnetic resonance imaging (MRI) is performed resulting diagnostic for the inflammatory one. A muscle biopsy shows mild perifascicular atrophy (Figure 1a), lymphocytes, with more CD4+ than CD8+ T cells and macrophages (Figure 1b), and MHC-I upregulation (Figure 1c). At EM, TRIs are recognizable in endothelial cells (Figure 1d).
Case 2 A 7-year-old girl complains of leg pain while walking without recent neither traumatic nor inflammatory events; she has positive Gower’s sign. Blood tests reveal elevated levels of muscle enzymes (Table 1). After a FANS treatment, painful symptoms worsen. No skin lesions are found and MRI scan let clinicians to think about an IIM. Muscle biopsy: more CD4+ than CD8+ perivascular T cells (Figure 1e and f), MHC-I
DspcANA ENA DNA Centromere ANCA ANCA + + −
− / −
/ + −
/ / −
/ / −
/ / −
upregulation (Figure 1g). At EM, characteristic TRIs are described (Figure 1h). Case 3 A 3-year-old boy presents limbs pain and fatigue. Blood tests reveal iperCKemia. Symptoms worsen in few weeks with the development of severe dysphagia, rhabdomyolysis (Table 1), acute renal failure, and compartmental syndrome. The disease is not responsive to steroids and ICU admission is needed. Muscle biopsy reveals negative myophosphorylase without glycogen (Figure 1i and l), MHC-I upregulation (Figure 1m), and rare positive myotilin areas (Figure 1n), suggesting a potential metabolic, inflammatory, or congenital myopathy. There is no evidence of muscle vessel degeneration. The child receives a cycle of cyclophosphamide; fasciotomies have been necessary to treat compartmental syndrome. Later, he heals until initial symptoms start again and a cutaneous rush becomes pathognomonic for JDM; a second muscle biopsy reveals perifascicular atrophy (Figure 1o), inflammatory infiltrate (Figure 1p), and TRI (Figure 1r).
Figure 1. Muscle biopsy: perivascular infiltrates (a, e) characterized by more CD4+ than CD8+ T cells (b, f, p), MHC-I upregulation (c, g, m, q). Endothelial cells of muscular small vessels show TRI (d, h, r). Case 3: in the first biopsy myophosphorilase (i) and PAS reactions were negative (l); cup-shaped-like aggregates for antimyotilin (n), suggesting a potential congenital myopathy are visible. A marked perifascicular atrophy (o) was evident at the second biopsy.
ULTRASTRUCTURAL PATHOLOGY
Discussion Differential diagnosis among pediatric forms of IIMs is typically established by skin involvement and muscle pathology, but, sometimes, supplementary signs may be necessary, for example evidence of JDM autoantibodies associated (anti-MDA5, -NXP2, -TIF-1, Mi-2) [11] and of TRI. Although these structures are also described in myositis SLE associated, Sjögren syndrome, viral infections, and tumors [8–14], clinical data are of diagnostic reliability. In conclusion, EM may expedite differential diagnosis among infantile IIMs, especially at early stage of disease whether or not all the established criteria are satisfied. Prompt diagnostic definition and aggressive treatment, when needed, improve outcomes.
Downloaded by [RMIT University Library] at 22:55 09 March 2016
References 1. Luo YB, Mastaglia FL. Dermatomyositis, polymyositis and immune-mediated necrotising myopathies. Biochim Biophys Acta. 2015;1852(4): 622–32. 2. Rider LG, Werth VP, Huber AM, et al. Measures of adult and juvenile dermatomyositis, polymiositis and inclusion body myositis. Arthritis Care Res 2011;63(11): S118–57. 3. Salaroli R, Baldin E, Papa V, et al. Validity of internal expression of the Major Histocompatibility Complex Class I in the diagnosis of Inflammatory Myopathies. J Clin Pathol 2012;65(1): 14–9. 4. Auriemma M, Capo A, Meogrossi G, et al. Cutaneous signs of classical dermatomyositis. G Ital Dermatol Venereol 2014;149(5): 505–17.
3
5. Lazarou IN, Guerne PA. Classification, diagnosis and management of idiopathic inflammatory myopathies. J Rheumatol 2013;40(5): 550–64. 6. Vattemi G, Mirabella M, Guglielmi V, et al. Muscle biopsy features of idiopathic inflammatory myopathies and differential diagnosis. Autoimmun Highlights 2014;5:77–85. 7. Iaccarino L, Ghirardello A, Bettio S, et al. The clinical features, diagnosis and classification of dermatomyositis. J Autoimmun 2014;48–49:122–7. 8. Pagnini I, Vitale A, Selmi C, et al. Idiopathic inflammatory myopathies: an update on classification and treatment with special focus on juvenile forms. Clinic Rev Allerg Immunol 2015. Epub ahead of print. 9. Olazagasti JM, Niewold TB, Reed AM. Immunological biomarkers in dermatomyositis. Curr Rheumatol Rep 2015;17: 68. 10. Greenberg SA. Dermatomyositis and type 1 interferons. Curr Rheumatol Rep 2010;12(3): 198–203. 11. Lu X, Peng Q, Wang G. Discovery of new biomarkers of idiopathic inflammatory myopathy. Clin Chim Acta 2015;444:117–25. 12. Varsani H, Charman SC, Li CK, et al. Validation of a score tool for measurement of histological severity in juvenile dermatomyositis and association with clinical severity of disease. Ann Rheum Dis 2015;74(1): 204–10. 13. Bronner IM, Hoogendijk JE, Veldman H, et al. Tubuloreticular structures in different types of myositis: implications for pathogenesis. Ultrastruct Pathol. 2008;32(4): 123–6. 14. Marquart KH. Occurrence of tubuloreticular structures and intracisternal paracrystalline inclusions in endothelial cells of tissue from different epidemiological types of Kaposi’s sarcoma. Ultrastruct Pathol 2005;29(2): 85–93.
ISSN: 0191-3123 (Print) 1521-0758 (Online) Journal homepage: http://www.tandfonline.com/loi/iusp20
Juvenile dermatomyositis: A report of three cases V. Papa ScD, B. Romanin MD, R. Bergamaschi PhD, D. M. Cordelli MD, R. Costa ScD, L. Badiali De Giorgi ScD & G. Cenacchi MD To cite this article: V. Papa ScD, B. Romanin MD, R. Bergamaschi PhD, D. M. Cordelli MD, R. Costa ScD, L. Badiali De Giorgi ScD & G. Cenacchi MD (2016): Juvenile dermatomyositis: A report of three cases, Ultrastructural Pathology, DOI: 10.3109/01913123.2016.1141823 To link to this article: http://dx.doi.org/10.3109/01913123.2016.1141823
Published online: 17 Feb 2016.
Submit your article to this journal
Article views: 26
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iusp20 Download by: [RMIT University Library]
Date: 09 March 2016, At: 22:55
ULTRASTRUCTURAL PATHOLOGY http://dx.doi.org/10.3109/01913123.2016.1141823
CASE REPORT
Juvenile dermatomyositis: A report of three cases V. Papa, ScDa, B. Romanin, MDb, R. Bergamaschi, PhDc, D. M. Cordelli, MDd, R. Costa, ScDa, L. Badiali De Giorgi, ScDe, and G. Cenacchi, MDa Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; bDepartment of Pediatric Emergency, S. OrsolaMalpighi Hospital, Bologna, Italy; cDepartment of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; dOperative Unit of Child Neuropsychiatry, S. Orsola-Malpighi Hospital, Bologna, Italy; eOperative Unit of Anatomy, Pathological Histology, S. Orsola-Malpighi Hospital, Bologna, Italy
Downloaded by [RMIT University Library] at 22:55 09 March 2016
a
ABSTRACT
ARTICLE HISTORY
Juvenile dermatomyositis (JDM), an autoimmune idiopathic myositis, is characterized by rash and proximal muscle weakness. Immunohistopathology typically shows perivascular inflammatory infiltrate with predominance of CD4+ T lymphocytes, perifascicular atrophy, and upregulation of major histocompatibility complex class I. JDM has been attributed to a humoral-driven muscle microangiopathy probably implicating the type I interferon pathway. Tubulo-reticular inclusions present in endothelial cell of muscle are biomarkers of interferon exposure, and so may be an indirect data of this myopathy especially in the absence of rash and inflammatory infiltrate. We report on three patients in which electron microscopy solves the differential diagnosis among infantile myositis showing peculiar inclusions.
Received 2 December 2015 Accepted 11 January 2016 Published online 18 February 2015
Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune myopathies. It comprises at least four conditions, namely polymyositits (PM), dermatomyositis (DM), sporadic inclusion body myositis (sIBM), and immune-mediated necrotizing myopathy (IMNM). DM is characterized by an inflammatory infiltrate represented primarily by B cells, macrophages, and CD4+ cells, and primarily affecting the skeletal muscle and skin with typical cutaneous lesions, which can predate from several months to years muscle or systemic involvement. Different DM subsets have been identified until now. These include classic DM, when muscular and skin involvement coexist; amyopathic DM, when the disease affects only the skin; hypomyopathic DM, when cutaneous manifestation of DM is associated with subclinical evidence of myositis; post-myopathic DM, when patients with previous classic DM present a recovery of myositis but skin rashes remain active; and DM sine dermatitis, when no rash is detected, but histology feature of the muscular biopsy sample is indicative of DM. DM is a rare disease which affects both children and adults. Juvenile dermatomyositis (JDM), the most common of the pediatric IIMs, affects children younger than 18 years with skin and muscle features similar to adult DM. JDM is characterized by proximal muscle weakness and distinctive cutaneous findings, but presenting features are variable and onset often insidious, hence classical features may not be seen at presentation [1–6]. To date, diagnosis is based on the clinical and laboratory criteria proposed by Bohan and Peter [7], with the limitation that many pediatric patients presenting typical rashes do not undergo electromyography or muscle biopsy. These disorders can be classified based on clinical features as well as on the presence of specific autoantibodies generally found in patients
KEYWORDS
Dermatomyositis; infantile myosytis; tubulo-reticular inclusions
suffering from myositis, defined as myositis-specific autoantibodies. Histopathology typically shows perivascular and perimysial inflammatory infiltrates, which above all consist of T lymphocytes, with more CD4+ than CD8+ cells [1–8]. Myofiber alterations include perifascicular atrophy and upregulation of major histocompatibility complex class I antigens (MHC-I) [9]. The etiology is nowadays widely unclear; however, current theories contemplate a combination of environmental triggers, immune dysfunction, and specific tissue responses involving muscle, skin, and small vessel endothelium in genetically susceptible individuals. In particular, JDM has traditionally been attributed to a humoral-driven muscle microangiopathy, and there is increasing evidence implicating the type I interferon pathway in the pathogenesis of the disease. The endothelial cell tubuloreticular inclusions (TRIs) present in affected JDM and DM muscle are biomarkers of type 1 interferon exposure [10] so that TRI evidence by electron microscopy (EM) may be indirect data of DM and JDM, especially in the absence of both clinical pathognomonic signs and inflammatory infiltrate in muscle biopsy. In this article, we report three patients whose clinical signs were not specific of JDM and whose morphological data were pivotal in the differential diagnosis of juvenile IIMs.
Case report Case 1 A 10-year-old boy complains of quick fatigue after muscular effort, muscle pain, and cramps. He presents weakness and moderate strength impairment of proximal and girdle muscles.
CONTACT V. Papa [email protected] Department of Biomedical and Neuromotor Sciences, University of Bologna, via Massarenti, 9, Bologna 40138, Italy. Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/iusp. © 2016 Taylor & Francis
2
V. PAPA ET AL.
Table 1. Serological data of three JDM patients.
Downloaded by [RMIT University Library] at 22:55 09 March 2016
Patient 1 Patient 2 Patient 3
Autoantibodies
Creatin kinase (U/L)
Aldolase (U/L)
Aspartase aminotrasferase (U/L)
Alanine aminotransferasi (U/L)
Lactic dehydrogenase (U/L)
Myoglobin (ng/mL)
1189 8862 6088
25.9 46.5 /
95 317 614
33 157 139
585 1233 1595
197 / 6916
Gower’s sign is slightly positive. He has no skin lesions. Blood tests show increase of muscle enzymes (Table 1), no inflammation indexes, and no clinical signs of an ongoing connective tissue disease. In order to distinguish between an inflammatory and a metabolic myopathy, a magnetic resonance imaging (MRI) is performed resulting diagnostic for the inflammatory one. A muscle biopsy shows mild perifascicular atrophy (Figure 1a), lymphocytes, with more CD4+ than CD8+ T cells and macrophages (Figure 1b), and MHC-I upregulation (Figure 1c). At EM, TRIs are recognizable in endothelial cells (Figure 1d).
Case 2 A 7-year-old girl complains of leg pain while walking without recent neither traumatic nor inflammatory events; she has positive Gower’s sign. Blood tests reveal elevated levels of muscle enzymes (Table 1). After a FANS treatment, painful symptoms worsen. No skin lesions are found and MRI scan let clinicians to think about an IIM. Muscle biopsy: more CD4+ than CD8+ perivascular T cells (Figure 1e and f), MHC-I
DspcANA ENA DNA Centromere ANCA ANCA + + −
− / −
/ + −
/ / −
/ / −
/ / −
upregulation (Figure 1g). At EM, characteristic TRIs are described (Figure 1h). Case 3 A 3-year-old boy presents limbs pain and fatigue. Blood tests reveal iperCKemia. Symptoms worsen in few weeks with the development of severe dysphagia, rhabdomyolysis (Table 1), acute renal failure, and compartmental syndrome. The disease is not responsive to steroids and ICU admission is needed. Muscle biopsy reveals negative myophosphorylase without glycogen (Figure 1i and l), MHC-I upregulation (Figure 1m), and rare positive myotilin areas (Figure 1n), suggesting a potential metabolic, inflammatory, or congenital myopathy. There is no evidence of muscle vessel degeneration. The child receives a cycle of cyclophosphamide; fasciotomies have been necessary to treat compartmental syndrome. Later, he heals until initial symptoms start again and a cutaneous rush becomes pathognomonic for JDM; a second muscle biopsy reveals perifascicular atrophy (Figure 1o), inflammatory infiltrate (Figure 1p), and TRI (Figure 1r).
Figure 1. Muscle biopsy: perivascular infiltrates (a, e) characterized by more CD4+ than CD8+ T cells (b, f, p), MHC-I upregulation (c, g, m, q). Endothelial cells of muscular small vessels show TRI (d, h, r). Case 3: in the first biopsy myophosphorilase (i) and PAS reactions were negative (l); cup-shaped-like aggregates for antimyotilin (n), suggesting a potential congenital myopathy are visible. A marked perifascicular atrophy (o) was evident at the second biopsy.
ULTRASTRUCTURAL PATHOLOGY
Discussion Differential diagnosis among pediatric forms of IIMs is typically established by skin involvement and muscle pathology, but, sometimes, supplementary signs may be necessary, for example evidence of JDM autoantibodies associated (anti-MDA5, -NXP2, -TIF-1, Mi-2) [11] and of TRI. Although these structures are also described in myositis SLE associated, Sjögren syndrome, viral infections, and tumors [8–14], clinical data are of diagnostic reliability. In conclusion, EM may expedite differential diagnosis among infantile IIMs, especially at early stage of disease whether or not all the established criteria are satisfied. Prompt diagnostic definition and aggressive treatment, when needed, improve outcomes.
Downloaded by [RMIT University Library] at 22:55 09 March 2016
References 1. Luo YB, Mastaglia FL. Dermatomyositis, polymyositis and immune-mediated necrotising myopathies. Biochim Biophys Acta. 2015;1852(4): 622–32. 2. Rider LG, Werth VP, Huber AM, et al. Measures of adult and juvenile dermatomyositis, polymiositis and inclusion body myositis. Arthritis Care Res 2011;63(11): S118–57. 3. Salaroli R, Baldin E, Papa V, et al. Validity of internal expression of the Major Histocompatibility Complex Class I in the diagnosis of Inflammatory Myopathies. J Clin Pathol 2012;65(1): 14–9. 4. Auriemma M, Capo A, Meogrossi G, et al. Cutaneous signs of classical dermatomyositis. G Ital Dermatol Venereol 2014;149(5): 505–17.
3
5. Lazarou IN, Guerne PA. Classification, diagnosis and management of idiopathic inflammatory myopathies. J Rheumatol 2013;40(5): 550–64. 6. Vattemi G, Mirabella M, Guglielmi V, et al. Muscle biopsy features of idiopathic inflammatory myopathies and differential diagnosis. Autoimmun Highlights 2014;5:77–85. 7. Iaccarino L, Ghirardello A, Bettio S, et al. The clinical features, diagnosis and classification of dermatomyositis. J Autoimmun 2014;48–49:122–7. 8. Pagnini I, Vitale A, Selmi C, et al. Idiopathic inflammatory myopathies: an update on classification and treatment with special focus on juvenile forms. Clinic Rev Allerg Immunol 2015. Epub ahead of print. 9. Olazagasti JM, Niewold TB, Reed AM. Immunological biomarkers in dermatomyositis. Curr Rheumatol Rep 2015;17: 68. 10. Greenberg SA. Dermatomyositis and type 1 interferons. Curr Rheumatol Rep 2010;12(3): 198–203. 11. Lu X, Peng Q, Wang G. Discovery of new biomarkers of idiopathic inflammatory myopathy. Clin Chim Acta 2015;444:117–25. 12. Varsani H, Charman SC, Li CK, et al. Validation of a score tool for measurement of histological severity in juvenile dermatomyositis and association with clinical severity of disease. Ann Rheum Dis 2015;74(1): 204–10. 13. Bronner IM, Hoogendijk JE, Veldman H, et al. Tubuloreticular structures in different types of myositis: implications for pathogenesis. Ultrastruct Pathol. 2008;32(4): 123–6. 14. Marquart KH. Occurrence of tubuloreticular structures and intracisternal paracrystalline inclusions in endothelial cells of tissue from different epidemiological types of Kaposi’s sarcoma. Ultrastruct Pathol 2005;29(2): 85–93.
