- Email: [email protected]
Fatal Paraneoplastic Systemic Leukocytoclastic Vasculitis as a Presenting Feature of Chronic Lymphocytic Leukemia
Chronic Lymphocytic Leukemia
Fatal Paraneoplastic Systemic Leukocytoclastic Vasculitis as a Presenting Feature of Chronic Lymphocytic Leukemia Premal Lulla, Salman Bandeali, Kelty Baker Abstract Background: The most common paraneoplastic vasculitis is leukocytoclastic vasculitis (LCV),1 75% of which are caused by hematological malignancies.6 Chronic lymphocytic leukemia (CLL) is associated with a multitude of auto-immune paraneoplastic syndromes. Data on LCV in association with CLL is restricted to isolated case reports,3,4 none of which had systemic LCV. We present a unique case of fatal paraneoplastic, systemic LCV as an initial presentation of CLL in an elderly male with multiple co-morbidities. Case: A 71-year-old man presented with a palpable, symmetric, purpuric rash on the lower extremities and an absolute lymphocytosis (white blood cell count 26.9; 23% lymphocytes). His co-morbidites included coronary artery disease, congestive heart failure, and new critical aortic stenosis. Flow cytometry of peripheral blood demonstrated an abnormal population of B-cells, positive for CD5, CD19, and CD23, consistent with CLL. The skin biopsy specimen revealed neutrophilic inflammation in vessel walls indicative of LCV. Acute renal failure (creatinine 2 mg/dL), urinary red cell casts, and hypocomplementemia were concerning for a systemic vasculitis. The antinuclear antibody, cryoglobulin titer, antineutrophil cytoplasmic antibody, serum protein electrophoresis, viral serologies were negative. On hospital day 6, he developed acute hepatocellular injury and acute respiratory failure. Continuous venovenous hemodialysis was begun for worsening acidemia and hyperkalemia. Two days later he became obtunded on hospital day 8 and had an elevated lactic acid level with generalized abdominal tenderness worrisome for bowel ischemia. The same day he needed intubation with cardiopulmonary resuscitation for a brief episode of asystole. Despite aggressive treatment with high-dose steroids and plasmapheresis, he suffered worsening renal failure and shock. His family sought withdrawal of care on hospital day 11. Autopsy revealed diffuse LCV of the stomach, distal ileum, integument and alveoli with petechial hemorrhages, fibrin thrombi, and gangrenous patchy necrosis. Conclusion: Paraneoplastic LCV is a rare syndrome and seldom occurs in association with CLL. This is the first reported case of fatal systemic paraneoplastic LCV from B-cell CLL. Dermatologic involvement is universal with LCV, and may portend systemic disease. More data on its pathogenesis in CLL is warranted. Clinical Lymphoma, Myeloma & Leukemia, Vol. 11, No. S1, S14-6 © 2011 Published by Elsevier Inc. Keywords: Chronic lymphocytic leukemia, Paraneoplastic leukocytoclastic vasculitis
Introduction Chronic lymphocytic leukemia (CLL) is associated with a multitude of auto-immune paraneoplastic syndromes. Well-described syndromes include auto-immune hemolytic anemias and idiopathic thrombocytopenia.1,2 Data on leukocytoclastic vasculitis (LCV) in association with CLL is restricted to isolated case reports,3,4 none of which had systemic LCV. LCV is commonly a pathological diagnosis of serum-sickness type Baylor College of Medicine, Houston, TX Submitted: Feb 10, 2011; Revised: Mar 15, 2011; Accepted: Mar 15, 2011 Address for correspondence: Premal Lulla, MD, Baylor College of Medicine, Internal Medicine Resident, 7900 Cambridge St. Apt. 10-1F, Houston, TX 77054 Tel: 713-894-3047; e-mail contact: [email protected]
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Clinical Lymphoma, Myeloma & Leukemia June 2011
hypersensitivity reactions (type III).5 In this type there is a deposition of immune complexes within blood vessels associated with surrounding inflammation. This is also the most common cancer-associated vasculitis,6 75% of which are caused by hematological malignancies.6,7 The reported cases of cancer-associated vasculitis demonstrate a cutaneous vasculitis with no systemic involvement. Paraneoplastic systemic involvement has been described with anti-neutrophil-cytoplasmic antibody-associated (ANCA) vasculitis,8 but not with LCV. We present a unique case of fatal, possibly paraneoplastic, systemic LCV as an initial presentation of CLL in an elderly male.
Case A 71-year-old male presented with shortness of breath and fatigue for 1 week thought to be an exacerbation of his ischemic congestive
2152-2650/$ - see frontmatter © 2011 Published by Elsevier Inc. doi: 10.1016/j.clml.2011.03.030
heart failure from worsening aortic stenosis. He had noted a gradually progressive palpable, symmetric and pruritic rash on his lower extremities over 3 weeks. On further questioning, the rash was first noticed on his right shoulder which resolved spontaneously within 1 week, but a similar painful purpuric rash appeared symmetrically over his ankles and dorsum of the foot, with several 1-cm ulcerated lesions. During this period he complained of low-grade fevers, without any new palpable lumps. Also, noted on routine laboratory tests was an absolute lymphocytosis (white blood cell count: 26.9 K/cu.mm, lymphocytes: 23%, polymorphonuclear cells: 62%, monocytes: 9%, eosinophils: 4%, basophils: 2%), and a new-onset anemia (hemoglobin: 8.3 g/dL), thought to be the cause of his shortness of breath and worsening congestive heart failure. A peripheral blood smear revealed lymphocytes with a small and scant cytoplasm in addition to moderately condensed nuclear chromatin. An abnormal population of B-cells, positive on immunophenotyping for CD 5, CD 19, CD 23 and dim CD 20, CD 22, and surface lambda light chain making up the predominant population of lymphocytes was noted on peripheral blood smear. This, along with the presence of palpable cervical lymphadenopathy on examination, made a provisional diagnosis of CLL or small lymphocytic lymphoma per the most recent guidelines for diagnosis of CLL.9 The absolute lymphocytsis of 6200 K/cu.mm, most of which appeared to be morphologically identical cells possibly representing the clone of B lymphocytes, made a diagnosis of new-onset grade I/A (Rai/Binet) CLL (⬎5000 K/cu.mm of clonal B lymphocytes). Although a cytogenetic profile was not obtained, the presence of CD 23–positive monoclonal B cells differentiated CLL from mantle-cell lymphoma. A skin biopsy specimen showed a localized area in the dermis with necrosis, neutrophils, and demonstrated neutrophilic inflammation in the vessel walls and the perivascular area. These changes were suspicious for LCV. There was no evidence of infection on the biopsy. Bacterial and fungal blood cultures including viral serologies for herpes simplex and varicella zoster virus were negative. C3 and C4 complement levels were found to be low at 75 and 10 mg/dL, respectively. Antinuclear antibody, ANCA, a serum protein electrophoresis, cryoglobulins, and a hepatitis panel including a qualitative polymerase chain reaction for hepatitis C was negative. At admission, he was notably in acute renal failure (creatinine: 2 mg/dL), which worsened (peak: 3.4 mg/dL) during his hospital course. The associated acidemia and hyperkalemia necessitated continuous veno-venous hemodialysis on hospital day 6. A urine analysis showed red cell casts, concerning for glomerulonephritis. This finding in association with hypocomplementemia was highly concerning for a systemic vasculitis. By hospital day 7, he developed an acute hepato-cellular injury (aspartate transaminase: 1558 and alanine transaminase: 1101 U) thought to be a manifestation of the worsening systemic vasculitis. Management of the suspected vasculitis was initiated with methyl prednisolone and plasmapheresis. Two days later he became obtunded with an elevated lactic acid level (8 mg/dL) and a generalized abdominal tenderness worrisome for bowel ischemia. The same day he needed intubation with cardiopulmonary resuscitation for a brief episode of asystole after an episode of massive hemoptysis. Despite aggressive immune-suppression and transfusions he developed pro-
Figure 1 Lymph Node Infiltrated by Mature Lymphoid Tumor Population, on Autopsy (Hematoxylin and Eosin Stain, Original Magnification X 50)
Figure 2 Distal Ileum (Hematoxylin and Eosin Stain; Original Magnification X 50) Variable Infiltrates of Neutrophils in the Vessel Walls
gressive renal failure and shock. The family sought withdrawal of care and the patient died 11 days after initial presentation (Fig 1). An autopsy revealed diffuse LCV of the stomach, distal ileum (Fig 2), integument, and alveoli. These showed deposition of fibrin in the setting of gangrenous patchy necrosis (Fig 3).
Discussion LCV is a neutrophilic inflammation of blood vessels. Type III or serum-sickness type reactions, especially to drugs, are known to cause immune complex deposition in cutaneous blood vessels.5 Immune complex deposition causes neutrophilic inflammation of blood vessels, pathologically described as LCV. LCV associated with hypersensitivity reactions (non-paraneoplastic) can invariably be systemic and serious.10 These present with low-grade fevers, purpuric skin rashes, urticaria, glomerulonephritis, diffuse alveolar hemorrhage, and hepatocellular injury similar to this case. However, in all described cancer-related or paraneoplastic cases, the vasculitis is limited to the skin.3,4 The new-onset CLL was thought to be causative of LCV in this case, although studies by Hamblin et Al2,11 have shown
Clinical Lymphoma, Myeloma & Leukemia June 2011
S15
Paraneoplastic Leukocytoclastic Vasculitis Figure 3 Distal Ileum (Hematoxylin and Eosin Stain; Original Magnification X 50) Variable Infiltrates of Neutrophils in the Vessel Walls
scribed a case of a 50-year-old female who had cutaneous LCV associated with a recent diagnosis of CLL that abated with steroids.3 Pamuk et al reported a case of CLL with ANCA-associated vasculitis involving multiple organ systems that was not responsive to immunosuppression.8 The patient tolerated cyclophosphamide for the CLL which induced remission from the vasculitis. Other reported vasculitides associated with malignancies include lymphocytic, leukemic, Henoch-Schonlein purpura (IgA immune complex deposition, HSP) and ANCA-associated vasculitis.6 A diagnosis of LCV can be made with a skin biopsy specimen, although for a diagnosis of a hypersensitivity vasculitis it is necessary to demonstrate an offending agent causing the hypersensitivity. Further assessment of biopsy specimens with immunofixation may be performed to demonstrate the type of involved antibody. This could help differentiate the more systemic HSP (IgA deposition) vasculitis from the IgG deposition vasculitis, as in this case report. The objective of this case report was to highlight a rare but fatal previously unreported possible association between systemic LCV and a new diagnosis of CLL.
Acknowledgment that patients who have CLL do not have a higher incidence of nonhematologic autoimmune phenomena, making it possible that the LCV was an independent process. However, recently, glomerulonephritis and pemphigus vulgaris are the only two non-hematological autoimmune diseases described to be associated with CLL.12,13 Deposition of immunoglobulins (Igs) secreted by the malignant B lymphocytes in CLL and the consequent activation of the complement cascade has been proposed as a mechanism of development of glomerulonephritis in these patients.12,13 It is plausible that without discernible risk factors to explain the advent of LCV, and the possibly related glomerulonephritis, were associated with the new-onset CLL in this case. Although this patient was administered furosemide, which has been reportedly associated with LCV,14,16 this was not thought to be responsible. This is because, furosemide notably causes a bullous cutaneous eruption which has been described as allergic, occurring within 6 weeks of initiation of therapy.14-17 This patient had been receiving a stable dose of furosemide for 16 years before the development of the LCV. Current concepts in autoimmunity with CLL revolve around the inhibition of the normal T-cell suppressor activity leading to dysregulated production of autoantibodies.11 Another less likely proposed mechanism is that CD5-positive leukemic B cells are thought to produce monoclonal autoantibodies resulting in autoimmunity, although the pathogenesis has not been fully explained.3 Paraneoplastic vasculitis invariably precedes a cancer diagnosis.18 In reported literature,18 flares of vasculitis respond to treating the cancer and are rarely the cause of death, although it is important to note that the therapies for CLL being immune-suppressive would also intuitively benefit any autoimmune process. Unfortunately, in this case, the rapid progression of vasculitis precluded any form of definitive therapy for the CLL, which may have abated his vasculitis. Although CLL-associated LCV is rare and data are restricted to a few case reports, making it possible to be independent processes, systemic forms of LCV with glomerulonephritis, a feature known to be associated with CLL, have not been described. Yadav et al de-
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Clinical Lymphoma, Myeloma & Leukemia June 2011
Kent Heck, MD and the Department of Pathology at St. Luke’s Episcopal Hospital for the autopsy slides and interpretations.
Disclosure There are no disclusures.
References 1. Hamblin TJ. Autoimmune complications of chronic lymphocytic leukemia. Semin Oncol 2006;33:230-9. 2. Hamblin TJ, Oscier, Young BJ. Autoimmunity in chronic lymphocytic leukaemia. J Clin Pathol 1986; 39:713-16. 3. Yadav BS, Sharma SC, Kapoor RK. Paraneoplastic leukocytoclastic vasculitis in chronic lymphoid leukemia. J Cancer Res Ther 2006; 2:206-8. 4. Cabuk M, Inanir I, Türkdog˘an P, et al. Cyclic lymphocytic vasculitis associated with chronic lymphocytic leukemia. Leuk Lymphoma 2004; 45:811-3. 5. Tosca N, Stratigos JD. Possible pathogenetic mechanisms in allergic cutaneous vasculitis. Int J Dermatol 1988; 27:291-6. 6. Buggiani G, Krysenka A, Grazzini M, et al. Paraneoplastic vasculitis and paraneoplastic vascular syndromes. Dermatol Ther 2010; 23:597-605. 7. Kurzrock R, Cohen PR, Markowitz A. Clinical manifestations of vasculitis in patients with solid tumors. Arch Intern Med 1994; 154:334-40. 8. Pamuk GE, Uyanik MS, Demir M, et al. Systemic antineutrophil cytoplasmic antibody vasculitis in a patient with chronic lymphocytic leukemia: quite a rare diagnosis. Leuk Res 2007; 8:1149-51. 9. Hallek M, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111: 5446-56. 10. Michel BA, Hunder GG, Bloch DA, et al. Hypersensitivity vasculitis and HenochSchonlein purpura: a comparison between the 2 disorders. J Rheumatol 1992; 19: 721-8. 11. Hamblin TJ. Non-hemic autoimmunity in CLL. Leuk Res 2009; 33:366-7. 12. Qian SX, Li JY, Hong M, et al. Nonhematological autoimmunity (glomerulosclerosis, paraneoplastic pehigus and paraneoplastic neurological syndrome) in a patient with chronic lymphocytic leukemia: diagnosis, prognosis and management. Leuk Res 2009; 33:500-5. 13. Ziakas PD, Giannouli S, Psimenou E, et al. Membranous glomerulonephritis in chronic lymphocytic leukemia. Am J Hematol 2004; 76:271-74. 14. Hendricks WM, Ader RS. Furosemide-induced cutaneous necrotizing vacuIitis. Arch Dermatol 1977; 113:375. 15. Guin JD, Bullous hemorrhagic eruption: a drug-induced disease. Cutis 1980; 25: 534-36. 16. Bigby M, Jick S, Jick H, et al. Drug-induced cutaneous reaction: a report from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975 to 1982. JAMA 1986; 256:3358-63. 17. Cobb MW, Furosemide-induced eruption simulating Sweet’s syndrome. J Am Acad Dermatol 1989;21:339-43. 18. Robak E, Robak T. Skin lesions in chronic lymphocytic leukemia. Leuk Lymphoma 2007; 48:855-65.
Fatal Paraneoplastic Systemic Leukocytoclastic Vasculitis as a Presenting Feature of Chronic Lymphocytic Leukemia Premal Lulla, Salman Bandeali, Kelty Baker Abstract Background: The most common paraneoplastic vasculitis is leukocytoclastic vasculitis (LCV),1 75% of which are caused by hematological malignancies.6 Chronic lymphocytic leukemia (CLL) is associated with a multitude of auto-immune paraneoplastic syndromes. Data on LCV in association with CLL is restricted to isolated case reports,3,4 none of which had systemic LCV. We present a unique case of fatal paraneoplastic, systemic LCV as an initial presentation of CLL in an elderly male with multiple co-morbidities. Case: A 71-year-old man presented with a palpable, symmetric, purpuric rash on the lower extremities and an absolute lymphocytosis (white blood cell count 26.9; 23% lymphocytes). His co-morbidites included coronary artery disease, congestive heart failure, and new critical aortic stenosis. Flow cytometry of peripheral blood demonstrated an abnormal population of B-cells, positive for CD5, CD19, and CD23, consistent with CLL. The skin biopsy specimen revealed neutrophilic inflammation in vessel walls indicative of LCV. Acute renal failure (creatinine 2 mg/dL), urinary red cell casts, and hypocomplementemia were concerning for a systemic vasculitis. The antinuclear antibody, cryoglobulin titer, antineutrophil cytoplasmic antibody, serum protein electrophoresis, viral serologies were negative. On hospital day 6, he developed acute hepatocellular injury and acute respiratory failure. Continuous venovenous hemodialysis was begun for worsening acidemia and hyperkalemia. Two days later he became obtunded on hospital day 8 and had an elevated lactic acid level with generalized abdominal tenderness worrisome for bowel ischemia. The same day he needed intubation with cardiopulmonary resuscitation for a brief episode of asystole. Despite aggressive treatment with high-dose steroids and plasmapheresis, he suffered worsening renal failure and shock. His family sought withdrawal of care on hospital day 11. Autopsy revealed diffuse LCV of the stomach, distal ileum, integument and alveoli with petechial hemorrhages, fibrin thrombi, and gangrenous patchy necrosis. Conclusion: Paraneoplastic LCV is a rare syndrome and seldom occurs in association with CLL. This is the first reported case of fatal systemic paraneoplastic LCV from B-cell CLL. Dermatologic involvement is universal with LCV, and may portend systemic disease. More data on its pathogenesis in CLL is warranted. Clinical Lymphoma, Myeloma & Leukemia, Vol. 11, No. S1, S14-6 © 2011 Published by Elsevier Inc. Keywords: Chronic lymphocytic leukemia, Paraneoplastic leukocytoclastic vasculitis
Introduction Chronic lymphocytic leukemia (CLL) is associated with a multitude of auto-immune paraneoplastic syndromes. Well-described syndromes include auto-immune hemolytic anemias and idiopathic thrombocytopenia.1,2 Data on leukocytoclastic vasculitis (LCV) in association with CLL is restricted to isolated case reports,3,4 none of which had systemic LCV. LCV is commonly a pathological diagnosis of serum-sickness type Baylor College of Medicine, Houston, TX Submitted: Feb 10, 2011; Revised: Mar 15, 2011; Accepted: Mar 15, 2011 Address for correspondence: Premal Lulla, MD, Baylor College of Medicine, Internal Medicine Resident, 7900 Cambridge St. Apt. 10-1F, Houston, TX 77054 Tel: 713-894-3047; e-mail contact: [email protected]
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Clinical Lymphoma, Myeloma & Leukemia June 2011
hypersensitivity reactions (type III).5 In this type there is a deposition of immune complexes within blood vessels associated with surrounding inflammation. This is also the most common cancer-associated vasculitis,6 75% of which are caused by hematological malignancies.6,7 The reported cases of cancer-associated vasculitis demonstrate a cutaneous vasculitis with no systemic involvement. Paraneoplastic systemic involvement has been described with anti-neutrophil-cytoplasmic antibody-associated (ANCA) vasculitis,8 but not with LCV. We present a unique case of fatal, possibly paraneoplastic, systemic LCV as an initial presentation of CLL in an elderly male.
Case A 71-year-old male presented with shortness of breath and fatigue for 1 week thought to be an exacerbation of his ischemic congestive
2152-2650/$ - see frontmatter © 2011 Published by Elsevier Inc. doi: 10.1016/j.clml.2011.03.030
heart failure from worsening aortic stenosis. He had noted a gradually progressive palpable, symmetric and pruritic rash on his lower extremities over 3 weeks. On further questioning, the rash was first noticed on his right shoulder which resolved spontaneously within 1 week, but a similar painful purpuric rash appeared symmetrically over his ankles and dorsum of the foot, with several 1-cm ulcerated lesions. During this period he complained of low-grade fevers, without any new palpable lumps. Also, noted on routine laboratory tests was an absolute lymphocytosis (white blood cell count: 26.9 K/cu.mm, lymphocytes: 23%, polymorphonuclear cells: 62%, monocytes: 9%, eosinophils: 4%, basophils: 2%), and a new-onset anemia (hemoglobin: 8.3 g/dL), thought to be the cause of his shortness of breath and worsening congestive heart failure. A peripheral blood smear revealed lymphocytes with a small and scant cytoplasm in addition to moderately condensed nuclear chromatin. An abnormal population of B-cells, positive on immunophenotyping for CD 5, CD 19, CD 23 and dim CD 20, CD 22, and surface lambda light chain making up the predominant population of lymphocytes was noted on peripheral blood smear. This, along with the presence of palpable cervical lymphadenopathy on examination, made a provisional diagnosis of CLL or small lymphocytic lymphoma per the most recent guidelines for diagnosis of CLL.9 The absolute lymphocytsis of 6200 K/cu.mm, most of which appeared to be morphologically identical cells possibly representing the clone of B lymphocytes, made a diagnosis of new-onset grade I/A (Rai/Binet) CLL (⬎5000 K/cu.mm of clonal B lymphocytes). Although a cytogenetic profile was not obtained, the presence of CD 23–positive monoclonal B cells differentiated CLL from mantle-cell lymphoma. A skin biopsy specimen showed a localized area in the dermis with necrosis, neutrophils, and demonstrated neutrophilic inflammation in the vessel walls and the perivascular area. These changes were suspicious for LCV. There was no evidence of infection on the biopsy. Bacterial and fungal blood cultures including viral serologies for herpes simplex and varicella zoster virus were negative. C3 and C4 complement levels were found to be low at 75 and 10 mg/dL, respectively. Antinuclear antibody, ANCA, a serum protein electrophoresis, cryoglobulins, and a hepatitis panel including a qualitative polymerase chain reaction for hepatitis C was negative. At admission, he was notably in acute renal failure (creatinine: 2 mg/dL), which worsened (peak: 3.4 mg/dL) during his hospital course. The associated acidemia and hyperkalemia necessitated continuous veno-venous hemodialysis on hospital day 6. A urine analysis showed red cell casts, concerning for glomerulonephritis. This finding in association with hypocomplementemia was highly concerning for a systemic vasculitis. By hospital day 7, he developed an acute hepato-cellular injury (aspartate transaminase: 1558 and alanine transaminase: 1101 U) thought to be a manifestation of the worsening systemic vasculitis. Management of the suspected vasculitis was initiated with methyl prednisolone and plasmapheresis. Two days later he became obtunded with an elevated lactic acid level (8 mg/dL) and a generalized abdominal tenderness worrisome for bowel ischemia. The same day he needed intubation with cardiopulmonary resuscitation for a brief episode of asystole after an episode of massive hemoptysis. Despite aggressive immune-suppression and transfusions he developed pro-
Figure 1 Lymph Node Infiltrated by Mature Lymphoid Tumor Population, on Autopsy (Hematoxylin and Eosin Stain, Original Magnification X 50)
Figure 2 Distal Ileum (Hematoxylin and Eosin Stain; Original Magnification X 50) Variable Infiltrates of Neutrophils in the Vessel Walls
gressive renal failure and shock. The family sought withdrawal of care and the patient died 11 days after initial presentation (Fig 1). An autopsy revealed diffuse LCV of the stomach, distal ileum (Fig 2), integument, and alveoli. These showed deposition of fibrin in the setting of gangrenous patchy necrosis (Fig 3).
Discussion LCV is a neutrophilic inflammation of blood vessels. Type III or serum-sickness type reactions, especially to drugs, are known to cause immune complex deposition in cutaneous blood vessels.5 Immune complex deposition causes neutrophilic inflammation of blood vessels, pathologically described as LCV. LCV associated with hypersensitivity reactions (non-paraneoplastic) can invariably be systemic and serious.10 These present with low-grade fevers, purpuric skin rashes, urticaria, glomerulonephritis, diffuse alveolar hemorrhage, and hepatocellular injury similar to this case. However, in all described cancer-related or paraneoplastic cases, the vasculitis is limited to the skin.3,4 The new-onset CLL was thought to be causative of LCV in this case, although studies by Hamblin et Al2,11 have shown
Clinical Lymphoma, Myeloma & Leukemia June 2011
S15
Paraneoplastic Leukocytoclastic Vasculitis Figure 3 Distal Ileum (Hematoxylin and Eosin Stain; Original Magnification X 50) Variable Infiltrates of Neutrophils in the Vessel Walls
scribed a case of a 50-year-old female who had cutaneous LCV associated with a recent diagnosis of CLL that abated with steroids.3 Pamuk et al reported a case of CLL with ANCA-associated vasculitis involving multiple organ systems that was not responsive to immunosuppression.8 The patient tolerated cyclophosphamide for the CLL which induced remission from the vasculitis. Other reported vasculitides associated with malignancies include lymphocytic, leukemic, Henoch-Schonlein purpura (IgA immune complex deposition, HSP) and ANCA-associated vasculitis.6 A diagnosis of LCV can be made with a skin biopsy specimen, although for a diagnosis of a hypersensitivity vasculitis it is necessary to demonstrate an offending agent causing the hypersensitivity. Further assessment of biopsy specimens with immunofixation may be performed to demonstrate the type of involved antibody. This could help differentiate the more systemic HSP (IgA deposition) vasculitis from the IgG deposition vasculitis, as in this case report. The objective of this case report was to highlight a rare but fatal previously unreported possible association between systemic LCV and a new diagnosis of CLL.
Acknowledgment that patients who have CLL do not have a higher incidence of nonhematologic autoimmune phenomena, making it possible that the LCV was an independent process. However, recently, glomerulonephritis and pemphigus vulgaris are the only two non-hematological autoimmune diseases described to be associated with CLL.12,13 Deposition of immunoglobulins (Igs) secreted by the malignant B lymphocytes in CLL and the consequent activation of the complement cascade has been proposed as a mechanism of development of glomerulonephritis in these patients.12,13 It is plausible that without discernible risk factors to explain the advent of LCV, and the possibly related glomerulonephritis, were associated with the new-onset CLL in this case. Although this patient was administered furosemide, which has been reportedly associated with LCV,14,16 this was not thought to be responsible. This is because, furosemide notably causes a bullous cutaneous eruption which has been described as allergic, occurring within 6 weeks of initiation of therapy.14-17 This patient had been receiving a stable dose of furosemide for 16 years before the development of the LCV. Current concepts in autoimmunity with CLL revolve around the inhibition of the normal T-cell suppressor activity leading to dysregulated production of autoantibodies.11 Another less likely proposed mechanism is that CD5-positive leukemic B cells are thought to produce monoclonal autoantibodies resulting in autoimmunity, although the pathogenesis has not been fully explained.3 Paraneoplastic vasculitis invariably precedes a cancer diagnosis.18 In reported literature,18 flares of vasculitis respond to treating the cancer and are rarely the cause of death, although it is important to note that the therapies for CLL being immune-suppressive would also intuitively benefit any autoimmune process. Unfortunately, in this case, the rapid progression of vasculitis precluded any form of definitive therapy for the CLL, which may have abated his vasculitis. Although CLL-associated LCV is rare and data are restricted to a few case reports, making it possible to be independent processes, systemic forms of LCV with glomerulonephritis, a feature known to be associated with CLL, have not been described. Yadav et al de-
S16
Clinical Lymphoma, Myeloma & Leukemia June 2011
Kent Heck, MD and the Department of Pathology at St. Luke’s Episcopal Hospital for the autopsy slides and interpretations.
Disclosure There are no disclusures.
References 1. Hamblin TJ. Autoimmune complications of chronic lymphocytic leukemia. Semin Oncol 2006;33:230-9. 2. Hamblin TJ, Oscier, Young BJ. Autoimmunity in chronic lymphocytic leukaemia. J Clin Pathol 1986; 39:713-16. 3. Yadav BS, Sharma SC, Kapoor RK. Paraneoplastic leukocytoclastic vasculitis in chronic lymphoid leukemia. J Cancer Res Ther 2006; 2:206-8. 4. Cabuk M, Inanir I, Türkdog˘an P, et al. Cyclic lymphocytic vasculitis associated with chronic lymphocytic leukemia. Leuk Lymphoma 2004; 45:811-3. 5. Tosca N, Stratigos JD. Possible pathogenetic mechanisms in allergic cutaneous vasculitis. Int J Dermatol 1988; 27:291-6. 6. Buggiani G, Krysenka A, Grazzini M, et al. Paraneoplastic vasculitis and paraneoplastic vascular syndromes. Dermatol Ther 2010; 23:597-605. 7. Kurzrock R, Cohen PR, Markowitz A. Clinical manifestations of vasculitis in patients with solid tumors. Arch Intern Med 1994; 154:334-40. 8. Pamuk GE, Uyanik MS, Demir M, et al. Systemic antineutrophil cytoplasmic antibody vasculitis in a patient with chronic lymphocytic leukemia: quite a rare diagnosis. Leuk Res 2007; 8:1149-51. 9. Hallek M, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111: 5446-56. 10. Michel BA, Hunder GG, Bloch DA, et al. Hypersensitivity vasculitis and HenochSchonlein purpura: a comparison between the 2 disorders. J Rheumatol 1992; 19: 721-8. 11. Hamblin TJ. Non-hemic autoimmunity in CLL. Leuk Res 2009; 33:366-7. 12. Qian SX, Li JY, Hong M, et al. Nonhematological autoimmunity (glomerulosclerosis, paraneoplastic pehigus and paraneoplastic neurological syndrome) in a patient with chronic lymphocytic leukemia: diagnosis, prognosis and management. Leuk Res 2009; 33:500-5. 13. Ziakas PD, Giannouli S, Psimenou E, et al. Membranous glomerulonephritis in chronic lymphocytic leukemia. Am J Hematol 2004; 76:271-74. 14. Hendricks WM, Ader RS. Furosemide-induced cutaneous necrotizing vacuIitis. Arch Dermatol 1977; 113:375. 15. Guin JD, Bullous hemorrhagic eruption: a drug-induced disease. Cutis 1980; 25: 534-36. 16. Bigby M, Jick S, Jick H, et al. Drug-induced cutaneous reaction: a report from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975 to 1982. JAMA 1986; 256:3358-63. 17. Cobb MW, Furosemide-induced eruption simulating Sweet’s syndrome. J Am Acad Dermatol 1989;21:339-43. 18. Robak E, Robak T. Skin lesions in chronic lymphocytic leukemia. Leuk Lymphoma 2007; 48:855-65.