Rare Dermatologic Condition That Belongs in the Differential of Granulomatous Cutaneous Disorders
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1 Rare Dermatologic Condition That Belongs in the Differential of Granulomatous Cutaneous Disorders 2013 Annual Meeting of the Medical Dermatology Society February 28, 2013 Amanda Champlain MD, Emily Keimig MD Northwestern University
2 HPI 53 y/o female with autoimmune thyroiditis presented with dry cough and weight loss Laboratory findings included leukopenia and elevated serum alkaline phosphatase Bone marrow biopsy Hypercellularity with trilineage hematopoiesis Multiple, non-caseating granulomas Microorganism stains negative
3 HPI CT abdomen/pelvis showed a complex cystic mass along the right ureter and right common iliac artery Bilateral palpable inguinal LAD Non-caseating granulomas HR CT chest showed a background of diffuse perilymphatic nodules Diagnosed with Sarcoidosis
4 HPI Excellent response to prednisone Developed severe constitutional symptoms + dyspnea and a new, enlarged and tender right inguinal lymph node Initiated methotrexate (MTX) Received five weekly oral doses Total MTX dose of 75mg
5 HPI Continued enlargement of inguinal lymph node Majority of cells Epstein-Barr virus (EBV) + Serum PCR + for EBV Iatrogenic immunodeficiency associated lymphoproliferative disorder polymorphic type MTX discontinued and prednisone tapered
6 Additional Workup HIV negative Quantitative Immunoglobulins Low IgG Low IgM IgA near lower limits of normal Common Variable Immune Deficiency IVIg initiated Cutaneous lesions appeared one week later
7 Initial Presentation
8 Initial Presentation
9 Four Weeks Later
10 Four Weeks Later
11 Left Thigh
12 Atypical Granulomas
13 Angiocentricity
14 Atypical Cellularity
15 CD3
16 CD20
17
18
19 Interval Course Repeat PET CT imaging showed progression Multi-agent chemotherapy with R-CHOP x 2 cycles Sinus congestion with nasal airway obstruction requiring nasal sinus debridement Atypical polymorphous lymphoid infiltrate with necrotizing granulomas ANCA negative x 2 Lymphocyte analysis Low CD4 and CD8 Decreased CD4:CD8
20 Cutaneous Progression
21 EBER
22 Lymphomatoid Granulomatosis Infectious work-up negative Granulomatosis with polyangiitis (Wegener s) excluded Multiple biopsies showing granulomatous vasculitis Persistent serum PCR for EBV Recent biopsies with weakly positive EBER-1
23 Lymphomatoid Granulomatosis Interferon α-2b Bexarotene 75mg BID Antimicrobial prophylaxis Future considerations
24 Lymphomatoid Granulomatosis Mature B-cell neoplasm An angiocentric and angiodestructive lymphoproliferative disease involving extranodal sites, composed of Epstein-Barr virus (EBV)-positive B-cells mixed with reactive T cells, which usually predominate WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue 2008 Colby TV. Current histological diagnosis of lymphomatoid granulomatosis. Mod Pathol Jan;25 Suppl 1:S Liebow A, Carrington, C, Friedman P. Lymphomatoid granulomatosis. Human Pathology 1972;3:
25 Pathogenesis EBV drives the disease process Abnormal lymphocytes Perpetuated by immune defect Infiltrative, nodular lesions Angiodestruction Direct invasion of T-cells Chemokines induced by EBV Roschewski M, Wilson WH. Lymphomatoid Granulomatosis. Cancer J Sep-Oct;18(5): Dunleavy K, Roschewski M, Wilson WH. Lymphomatoid granulomatosis and other Epstein-Barr virus associated lymphoproliferative processes. Curr Hematol Malig Rep Sep;7(3): Rezk SA, Weiss LM. Epstein-Barr virus-associated lymphoproliferative disorders. Hum Pathol Sep;38(9):
26 Involved Anatomic Sites at Diagnosis Pulmonary > 90 % Constitutional (fever and malaise) 50-60% Kidneys 40-50% Skin 25-50% Central Nervous System 25-50% Peripheral Nervous System 15-20% Liver 10% Spleen 10% Lymph node < 10% Bone marrow rare Most common presenting symptoms are fever, cough and dyspnea Lungs most commonly involved as bilateral nodular infiltrates Lymph nodes and spleen typically become involved later in disease course Roschewski M, Wilson WH. Lymphomatoid Granulomatosis. Cancer J Sep-Oct;18(5): Colby TV. Current histological diagnosis of lymphomatoid granulomatosis. Mod Pathol Jan;25 Suppl 1:S39-42.
27 Clinical Features Male : Female approximately 2:1 Between fourth and sixth decades of life Underlying immune dysregulation Wiscott Aldrich, CVID Autoimmune disease HIV Iatrogenic/transplant Dunleavy K, Roschewski M, Wilson WH. Lymphomatoid granulomatosis and other Epstein-Barr virus associated lymphoproliferative processes. Curr Hematol Malig Rep Sep;7(3):
28 Cutaneous Features Erythematous to violaceous maculopapular eruptions are the most common presenting morphology Systematic review of 32 skin biopsies from 20 patients: 55% tan to plum colored dermal and/or subcutaneous nodules 27% ulcerations 20% dermal nodules and multiple erythematous papules 15% well-demarcated indurated plaques only 10% atrophic, white oval plaques with violaceous borders Extremities and trunk ± head & neck (40%), extremities only (30%) trunk only (10%), head & neck only (10%) EBV demonstrated by ISH in 6 patients Beaty MW, Toro J, Sorbara L, Stern JB, Pittaluga S, Raffeld M, Wilson WH, Jaffe ES. Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features. Am J Surg Pathol Sep;25(9): Roschewski M, Wilson WH. Lymphomatoid Granulomatosis. Cancer J Sep-Oct;18(5):
29 Histologic Features Mixed mononuclear cell infiltrate with an abundance of T-cells Vascular infiltration Areas of necrosis CD20-positive, CD15-negative B-cells that are positive for EBER by ISH Numerous CD3-positive small lymphocytes Colby TV. Current histological diagnosis of lymphomatoid granulomatosis. Mod Pathol Jan;25 Suppl 1:S Katzenstein AL, Doxtader E, Narendra S. Lymphomatoid granulomatosis: insights gained over 4 decades. Am J Surg Pathol Dec;34(12):e35-48.
30 Grading Based on proportion of EBV+ B-cells Grade 1: < 5 EBV+ cells per HPF Grade 2: 5-20 EBV+ cells per HPF Grade 3: > 50 EBV + cells per HPF Distinguishing between low and high-grade is important for determining therapeutic approach Colby TV. Current histological diagnosis of lymphomatoid granulomatosis. Mod Pathol Jan;25 Suppl 1:S39-42.
31 Therapeutic Considerations Observation may be justified in patients with low-grade disease Immediate therapy for high-grade disease Discontinue immunosuppression Mortality due to pulmonary complications Roschewski M, Wilson WH. Lymphomatoid Granulomatosis. Cancer J Sep-Oct;18(5):469-74
32 Therapy No standard treatment Corticosteroids Rituximab IFN alpha Bexarotene Combined chemotherapy Autologous stem cell transplantation Roschewski M, Wilson WH. Lymphomatoid Granulomatosis. Cancer J Sep-Oct;18(5): Johnston A, Coyle L, Nevell D. Prolonged remission of refractory lymphomatoid granulomatosis after autologous hemopoietic stem cell transplantation with post-transplantation maintenance interferon. Leuk Lymphoma Feb;47(2): Lemieux J, Bernier V, Martel N, Delage R. Autologous hematopoietic stem cell transplantation for refractory lymphomatoid granulomatosis. Hematology Dec;7(6):355-8.
33 Rituximab Targets neoplastic B-cells harboring EBV Favorable response to therapy has been reported in the medical literature Both as a single agent and in combination with multi-agent chemotherapy One report of grade 3 lymphomatoid granulomatosis with progression of disease while receiving R-CHOP therapy Oosting-Lenstra SF, van Marwijk Kooy M. Failure of CHOP with rituximab for lymphomatoid granulomatosis. Neth J Med Dec;65(11):442-7.
34 Interferon α-2b Anti-viral, anti-proliferative, and immunomodulatory effects Three of four patients with low-grade disease in complete remission at median 43 months follow-up One report of successful use of interferon α-2a as maintenance therapy after autologous stem cell transplantation Johnston A, Coyle L, Nevell D. Prolonged remission of refractory lymphomatoid granulomatosis after autologous hemopoietic stem cell transplantation with post-transplantation maintenance interferon. Leuk Lymphoma Feb;47(2): Wilson WH, Kingma DW, Raffeld M, Wittes RE, Jaffe ES. Association of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferon-alpha 2b. Blood Jun 1;87(11):
35 Bexarotene Case report of successful treatment of relapsed disease Grade I disease Relapse after 6 cycles of R-CHOP CT chest 3 weeks later showed improvement Remains asymptomatic two years later Berg SE, Downs LH, Torigian DA, Chong EA, Tsai DE, Wasik MA, Schuster SJ. Successful treatment of relapsed lymphomatoid granulomatosis with bexarotene. Cancer Biol Ther Oct;7(10):
36 Current NCI Trial NCI-94-C-0074 Treatment and Natural History Study of Lymphomatoid Granulomatosis. Grade 1 and 2 receive interferon α 3 times per week for 1 year beyond best response Grade 3 (or grade 1 or 2 progressing on IFN α) receive dose-adjusted EPOCH-R chemotherapy Roschewski M, Wilson WH. Lymphomatoid Granulomatosis. Cancer J Sep-Oct;18(5):
37 Current NCI Trial First 31 patients: Grade 1 and 2 Complete remission 60% Progression-free survival 56% (median 5yr follow-up) Grade 3 Complete remission 66% Progression-free survival 40% (median 28mo follow-up) Overall survival 68% Relapse is common Patients with low-grade disease can relapse with highgrade disease and vice versa Low threshold to re-biopsy patients in order to guide treatment strategy Roschewski M, Wilson WH. Lymphomatoid Granulomatosis. Cancer J Sep-Oct;18(5): Dunleavy K, Roschewski M, Wilson WH. Lymphomatoid granulomatosis and other Epstein-Barr virus associated lymphoproliferative processes. Curr Hematol Malig Rep Sep;7(3):
38 Summary
39 Acknowledgements Dr. Joan Guitart Dr. Jonathan Cotliar Dr. Adam Petrich Dr. Rakesh Chandra Dr. Tina Stosor Dr. Pedram Yazdan
40 References Beaty MW, Toro J, Sorbara L, Stern JB, Pittaluga S, Raffeld M, Wilson WH, Jaffe ES. Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features. Am J Surg Pathol Sep;25(9): Berg SE, Downs LH, Torigian DA, Chong EA, Tsai DE, Wasik MA, Schuster SJ. Successful treatment of relapsed lymphomatoid granulomatosis with bexarotene. Cancer Biol Ther Oct;7(10): Colby TV. Current histological diagnosis of lymphomatoid granulomatosis. Mod Pathol Jan;25 Suppl 1:S Dunleavy K, Roschewski M, Wilson WH. Lymphomatoid granulomatosis and other Epstein-Barr virus associated lymphoproliferative processes. Curr Hematol Malig Rep Sep;7(3): Johnston A, Coyle L, Nevell D. Prolonged remission of refractory lymphomatoid granulomatosis after autologous hemopoietic stem cell transplantation with post-transplantation maintenance interferon. Leuk Lymphoma Feb;47(2): Katzenstein AL, Doxtader E, Narendra S. Lymphomatoid granulomatosis: insights gained over 4 decades. Am J Surg Pathol Dec;34(12):e Lemieux J, Bernier V, Martel N, Delage R. Autologous hematopoietic stem cell transplantation for refractory lymphomatoid granulomatosis. Hematology Dec;7(6): Liebow A, Carrington, C, Friedman P. Lymphomatoid granulomatosis. Human Pathology 1972;3: Oosting-Lenstra SF, van Marwijk Kooy M. Failure of CHOP with rituximab for lymphomatoid granulomatosis. Neth J Med Dec;65(11): Rezk SA, Weiss LM. Epstein-Barr virus-associated lymphoproliferative disorders. Hum Pathol Sep;38(9): Roschewski M, Wilson WH. Lymphomatoid Granulomatosis. Cancer J Sep-Oct;18(5): Wilson WH, Kingma DW, Raffeld M, Wittes RE, Jaffe ES. Association of lymphomatoid granulomatosis with Epstein- Barr viral infection of B lymphocytes and response to interferon-alpha 2b. Blood Jun 1;87(11):
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