J Cutan Pathol 2014: 41: 759–760 doi: 10.1111/cup.12367 John Wiley & Sons. Printed in Singapore
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Letter to the Editor
Cutaneous lesions in a CLIPPERS patient: further confusion between CLIPPERS and grade I lymphomatoid granulomatosis Keywords: CLIPPERS, lymphomatoid granulomatosis, pathophysiology To the Editor , We read with great interest the recent article entitled ‘Neurotrophic T-cell lymphocytosis: a cutaneous expression of CLIPPERS’ by Smith et al.1 Criteria for CLIPPERS include (1) brainstem signs and symptoms, (2) brainstem punctuate and curvilinear gadolinium enhancing lesions, (3) steroid sensitivity with possible clinical and radiological sequelae, (4) relapsing–remitting course with steroid dependence, (5) a lymphohistiocytic infiltrate around and sometimes in vessel walls with predominance of CD4-cells and scarce B-cells on brainstem biopsy, and (6) absent evidence of an alternative diagnosis. The underlying pathophysiology of CLIPPERS remains unknown. An autoimmune hypothesis has been proposed. The CLIPPERS patient reported by Smith et al. had associated painful subcutaneous nodules. Biopsy of one of the cutaneous lesions displayed a perivascular and perineural infiltrate sharing the histopathologic characteristics seen on the CLIPPERS brainstem biopsy. Considering both central and peripheral nervous involvement in their CLIPPERS patient, the authors suggested that the autoantigen of CLIPPERS could have a neural epitope with a common origin between the central and the peripheral nervous system. However, the autoimmune hypothesis of CLIPPERS has been challenged since the publication of two patients fulfilling all CLIPPERS criteria who eventually progressed into central nervous system (CNS) B-cell lymphoma.2,3 CLIPPERS might, therefore, represent a prelymphoma state (e.g. lymphomatoid granulomatosis).
Although lymphomatoid granulomatosis predominantly involves the lungs and less frequently the skin and both the peripheral and CNS, few cases of primary CNS lymphomatoid granulomatosis have been described.4 The diagnostic criteria of lymphomatoid granulomatosis include a lymphohistiocytic infiltrate situated around and in blood vessel walls, including a variable numbers of CD20-positive large B-lymphocytes (often with cytologic atypia) within a background of CD3-positive (including mainly CD4-positive) small T-lymphocytes. Supportive findings, which are sometimes lacking, may include necrosis within the cellular infiltrate, Epstein-Barr virus (EBV) RNA within atypical B-cells, and evidence of extranodal involvement (such as multiple lung nodules or skin or central and peripheral nervous system involvement). The proportion of atypical large B-lymphocytes allows the disease to be classified within a range that extends from an indolent process, in which no atypical large B-lymphocytes are detected (representing grade I), to aggressive B-cell lymphoma (representing grades II and III). In the World Health Organization (WHO) classification, while grades II and III lymphomatoid granulomatosis are pigeonholed as lymphoma, the nosology of grade I lymphomatoid granulomatosis remains elusive.5 Histopathologic features in grade I lymphomatoid granulomatosis consists only of a lymphohistiocytic infiltrate with rare large B-cells. We agree with the authors that the diagnosis of grades II and III lymphomatoid granulomatosis could be ruled out in their patient.
759
Letter to the Editor However, the diagnosis of grade I lymphomatoid granulomatosis remained possible. As already reported, grade I primary CNS lymphomatoid granulomatosis could share all features of CLIPPERS including clinical, radiological, and histopathologic findings, together with a steroid responsive relapsing-remitting course, before progressing into higher grade disease.3 In addition, considering that grade I lymphomatoid granulomatosis does not necessarily progress to grades II or III, primary grade I lymphomatoid granulomatosis and CLIPPERS may be indistinguishable. Besides the very interesting hypothesis of a neural autoantigen proposed by Smith et al. we believe that grade I lymphomatoid granulomatosis with well-defined extranodal localization
(including CNS, skin, and cutaneous nerves) cannot be fully excluded in their patient. Guillaume Taieb, MD1 Dimitri Renard, MD1 Jean Marie Joujoux, MD2 Pierre Labauge, MD, PhD3 1 Department of Neurology CHU Nˆımes, HôpitalCaremeau Nˆımes, France 2 Department of Pathology CHU Nˆımes, HôpitalCaremeau Nˆımes, France 3 Department of Neurology CHU Montpellier, Hôpital Gui de Chauliac Montpellier, France e-mail: [email protected]
References 1. Smith A, Matthews Y, Kossard S, Turner J, Buckland ME, Parratt J. Neurotropic T-cell lymphocytosis: a cutaneous expression of CLIPPERS. J Cutan Pathol 2014; 41: 657. 2. Limousin N, Praline J, Motica O, et al. Brain biopsy is required in steroid-resistant patients with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids
760
(CLIPPERS). J Neurooncol 2012; 107: 223. 3. De Graaff HJ, Wattjes MP, Rozemuller-Kwakkel AJ, Petzold A, Killestein J. Fatal B-cell lymphoma following chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. JAMA Neurol 2013; 70: 915.
4. Lucantoni C, De Bonis P, Doglietto F, et al. Primary cerebral lymphomatoid granulomatosis: report of four cases and literature review. J Neurooncol 2009; 94: 235. 5. Katzenstein AL, Doxtader E, Narendra S. Lymphomatoid granulomatosis: insights gained over 4 decades. Am J Surg Pathol 2010; 34: e35.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Letter to the Editor
Cutaneous lesions in a CLIPPERS patient: further confusion between CLIPPERS and grade I lymphomatoid granulomatosis Keywords: CLIPPERS, lymphomatoid granulomatosis, pathophysiology To the Editor , We read with great interest the recent article entitled ‘Neurotrophic T-cell lymphocytosis: a cutaneous expression of CLIPPERS’ by Smith et al.1 Criteria for CLIPPERS include (1) brainstem signs and symptoms, (2) brainstem punctuate and curvilinear gadolinium enhancing lesions, (3) steroid sensitivity with possible clinical and radiological sequelae, (4) relapsing–remitting course with steroid dependence, (5) a lymphohistiocytic infiltrate around and sometimes in vessel walls with predominance of CD4-cells and scarce B-cells on brainstem biopsy, and (6) absent evidence of an alternative diagnosis. The underlying pathophysiology of CLIPPERS remains unknown. An autoimmune hypothesis has been proposed. The CLIPPERS patient reported by Smith et al. had associated painful subcutaneous nodules. Biopsy of one of the cutaneous lesions displayed a perivascular and perineural infiltrate sharing the histopathologic characteristics seen on the CLIPPERS brainstem biopsy. Considering both central and peripheral nervous involvement in their CLIPPERS patient, the authors suggested that the autoantigen of CLIPPERS could have a neural epitope with a common origin between the central and the peripheral nervous system. However, the autoimmune hypothesis of CLIPPERS has been challenged since the publication of two patients fulfilling all CLIPPERS criteria who eventually progressed into central nervous system (CNS) B-cell lymphoma.2,3 CLIPPERS might, therefore, represent a prelymphoma state (e.g. lymphomatoid granulomatosis).
Although lymphomatoid granulomatosis predominantly involves the lungs and less frequently the skin and both the peripheral and CNS, few cases of primary CNS lymphomatoid granulomatosis have been described.4 The diagnostic criteria of lymphomatoid granulomatosis include a lymphohistiocytic infiltrate situated around and in blood vessel walls, including a variable numbers of CD20-positive large B-lymphocytes (often with cytologic atypia) within a background of CD3-positive (including mainly CD4-positive) small T-lymphocytes. Supportive findings, which are sometimes lacking, may include necrosis within the cellular infiltrate, Epstein-Barr virus (EBV) RNA within atypical B-cells, and evidence of extranodal involvement (such as multiple lung nodules or skin or central and peripheral nervous system involvement). The proportion of atypical large B-lymphocytes allows the disease to be classified within a range that extends from an indolent process, in which no atypical large B-lymphocytes are detected (representing grade I), to aggressive B-cell lymphoma (representing grades II and III). In the World Health Organization (WHO) classification, while grades II and III lymphomatoid granulomatosis are pigeonholed as lymphoma, the nosology of grade I lymphomatoid granulomatosis remains elusive.5 Histopathologic features in grade I lymphomatoid granulomatosis consists only of a lymphohistiocytic infiltrate with rare large B-cells. We agree with the authors that the diagnosis of grades II and III lymphomatoid granulomatosis could be ruled out in their patient.
759
Letter to the Editor However, the diagnosis of grade I lymphomatoid granulomatosis remained possible. As already reported, grade I primary CNS lymphomatoid granulomatosis could share all features of CLIPPERS including clinical, radiological, and histopathologic findings, together with a steroid responsive relapsing-remitting course, before progressing into higher grade disease.3 In addition, considering that grade I lymphomatoid granulomatosis does not necessarily progress to grades II or III, primary grade I lymphomatoid granulomatosis and CLIPPERS may be indistinguishable. Besides the very interesting hypothesis of a neural autoantigen proposed by Smith et al. we believe that grade I lymphomatoid granulomatosis with well-defined extranodal localization
(including CNS, skin, and cutaneous nerves) cannot be fully excluded in their patient. Guillaume Taieb, MD1 Dimitri Renard, MD1 Jean Marie Joujoux, MD2 Pierre Labauge, MD, PhD3 1 Department of Neurology CHU Nˆımes, HôpitalCaremeau Nˆımes, France 2 Department of Pathology CHU Nˆımes, HôpitalCaremeau Nˆımes, France 3 Department of Neurology CHU Montpellier, Hôpital Gui de Chauliac Montpellier, France e-mail: [email protected]
References 1. Smith A, Matthews Y, Kossard S, Turner J, Buckland ME, Parratt J. Neurotropic T-cell lymphocytosis: a cutaneous expression of CLIPPERS. J Cutan Pathol 2014; 41: 657. 2. Limousin N, Praline J, Motica O, et al. Brain biopsy is required in steroid-resistant patients with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids
760
(CLIPPERS). J Neurooncol 2012; 107: 223. 3. De Graaff HJ, Wattjes MP, Rozemuller-Kwakkel AJ, Petzold A, Killestein J. Fatal B-cell lymphoma following chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. JAMA Neurol 2013; 70: 915.
4. Lucantoni C, De Bonis P, Doglietto F, et al. Primary cerebral lymphomatoid granulomatosis: report of four cases and literature review. J Neurooncol 2009; 94: 235. 5. Katzenstein AL, Doxtader E, Narendra S. Lymphomatoid granulomatosis: insights gained over 4 decades. Am J Surg Pathol 2010; 34: e35.
