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Amyloidosis complicating idiopathic myelofibrosis
CASE REPORT
Amyloidosis Complicating Idiopathic Myelofibrosis Kwok Wah Chan, MB, BS, FRCPath, and Chung Ping Ho, MB, BS, FRCP ● An 84-year-old man presented with ankle edema, significant proteinuria, and mild impairment of renal function soon after treatment was started for idiopathic myelofibrosis. Renal amyloidosis was found on biopsy. The amyloid deposit was resistant to potassium permanganate treatment and showed no immunoreactivity to immunoglobulin light chains, beta-amyloid protein, or amyloid A component. A review of the literature showed that the occurrence of amyloidosis in idiopathic myelofibrosis is very rare, and the chemical nature of the amyloid involved remains unclear. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Myelofibrosis; amyloidosis; hydroxyurea.
I
DIOPATHIC myelofibrosis is a myeloproliferative disorder characterized by fibrosis of the bone marrow, myeloid metaplasia mainly in the spleen and liver, and splenomegaly. Amyloidosis has been occasionally described as occurring with idiopathic myelofibrosis. Its occurrence in idiopathic myelofibrosis without an identifiable cause is highly unusual, and there are only two reports in the literature, in which four patients were described.1,2 CASE REPORT
An 84-year-old Chinese man was diagnosed with idiopathic myelofibrosis in 1998. He was treated with hydroxyurea, recombinant erythropoietin, and blood transfusion. In late 1998, he developed bilateral ankle edema and noted his urine was frothy. Renal ultrasonogram showed bilateral slightly contracted kidneys with increased echogenicity compatible with chronic parenchymal renal disease. Urinalysis showed scanty red blood cells and casts. Blood investigations showed a hemoglobin concentration of 11.3 g/L; white blood cell count, 7,900 ⫻ 109/L; platelet count, 442 ⫻ 109/L; urea concentration, 33.1 mg/dL; and creatinine level, 1.4 mg/dL. Twenty-four–hour urine protein excretion was 1.55 g, and creatinine clearance was 54 mL/min. A percutaneous needle renal biopsy was performed. Ten glomeruli were present in the biopsy sample. Three of the glomeruli were globally sclerosed, and the other glomeruli showed diffuse expansion of the mesangium, with eosinophilic and congophilic material and little increase in cellularity (Fig 1). The glomerular capillaries were mildly thickened. The congophilic material showed green birefringence when viewed with polarized light. Congo-red staining
was resistant to treatment with potassium permanganate. Immunoperoxidase studies were performed. The deposits showed no immunoreactivity against polyclonal antisera to kappa (A417; Dako, Carpinteria, CA) and lambda (A418; Dako) light chains and monoclonal antisera to amyloid A component (M759; Dako) and beta-amyloid protein (M872; Dako). Focal tubular atrophy and interstitial inflammation were noted. The arterial vessels were markedly thickened, and the arterioles were hyalinized. Immunofluorescence study showed scanty segmental immunoglobulin M and C3 staining. Deposits of other immunoglobulins and C1q were absent. The antisera were manufactured by Silenus Laboratories (Victoria, Australia). Electron microscopy showed the presence of fibrillary deposits in the glomeruli. The fibrils were nonbranching and had a diameter of approximately 10 nm (Fig 2). DISCUSSION
There are only two reports of amyloidosis complicating idiopathic myelofibrosis. The first report was made by Akikusa et al,1 who described three cases studied at autopsy. Although Akikusa et al1 suggested amyloidosis was only seen in the terminal phase of idiopathic myelofibrosis, Ferhanoglu et al2 described a 54-year-old
From the Department of Pathology, The University of Hong Kong; and the Renal Unit, Hong Kong Baptist Hospital, Hong Kong, China. Received June 2, 1999; accepted in revised form August 10, 1999. Address reprint requests to K. W. Chan, MD, Department of Pathology, The University of Hong Kong, Hong Kong, China. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 1523-6838/99/3406-0008$3.00/0
American Journal of Kidney Diseases, Vol 34, No 6 (December), 1999: E27
1
Fig 1. A representative glomerulus shows a large amount of eosinophilic amyloid deposits. (Hematoxylin and eosin, original magnification ⴛ400.)
Fig 2. Amyloid fibrils found in the glomeruli of the renal biopsy. (Electron micrograph, original magnification ⴛ84,000; scale bar ⴝ 200 nm.)
AMYLOIDOSIS IN IDIOPATHIC MYELOFIBROSIS
man who led an active life with treatment. That patient, however, unlike our patient and those reported by Akikusa et al,1 had amyloid sensitive to potassium permanganate. The clinical manifestation of amyloidosis in that patient included proteinuria, hypogammaglobulinemia, and recurrent diarrhea for which no infectious agent could be identified. Similarly, our patient was diagnosed to have both conditions at an early stage. Significant proteinuria and mild renal impairment were the presenting features of our patient. Amyloid is an extracellular deposit of fibrillar protein that has characteristic staining properties and ultrastructural appearance. The two major types of amyloid are amyloid associated and amyloid light chain. Many types of amyloid have been identified more recently, some of which can be distinguished immunohistologically with the use of the appropriate antisera.3,4 The characteristics of amyloid in our patient were similar to those of the three patients described by Akikusa et al.1 The affinity to Congored was resistant to potassium permanganate treatment. Immunohistochemically, no reactivity to amyloid component A or kappa or lambda light chains could be shown in our patient. In addition, we found that the amyloid deposits in our patient lacked the immunoreactivity of beta-
3
amyloid. The antisera to the light chains we used were polyclonal. The patient described by Ferhanoglu et al2 had amyloid sensitive to permanganate treatment. The immunohistochemical character of the deposits was not mentioned. The chemical nature of the amyloid in the reported cases complicating idiopathic myelofibrosis remains unknown and requires further characterization. It is possible that amyloidosis is only diagnosed in a small number of the cases in which it occurs. The effects of amyloidosis development on the prognosis of idiopathic myelofibrosis and its true incidence can only be shown if searched for specifically. REFERENCES 1. Akikusa B, Komatsu T, Kondo Y, Yokita T, Uchino F, Yonemitsu H: Amyloidosis complicating idiopathic myelofibrosis. Arch Pathol Lab Med 11:525-529, 1987 2. Ferhanoglu B, Erzin Y, Baslar Z, Tuzuner HAN: Secondary amyloidosis in the course of idiopathic myelofibrosis. Leuk Res 21:897-898, 1997 3. Strege RJ, Saeger W, Linke RP: Diagnosis and immunohistochemical classification of systemic amyloidosis: Report of 43 cases in an unselected autopsy series. Virchows Arch 433:19-27, 1998 4. Rocken C, Schwotzer EB, Linke RP, Saeger W: The classification of amyloid deposits in clinicopathological practice. Histopathology 29:325-335, 1996
Amyloidosis Complicating Idiopathic Myelofibrosis Kwok Wah Chan, MB, BS, FRCPath, and Chung Ping Ho, MB, BS, FRCP ● An 84-year-old man presented with ankle edema, significant proteinuria, and mild impairment of renal function soon after treatment was started for idiopathic myelofibrosis. Renal amyloidosis was found on biopsy. The amyloid deposit was resistant to potassium permanganate treatment and showed no immunoreactivity to immunoglobulin light chains, beta-amyloid protein, or amyloid A component. A review of the literature showed that the occurrence of amyloidosis in idiopathic myelofibrosis is very rare, and the chemical nature of the amyloid involved remains unclear. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Myelofibrosis; amyloidosis; hydroxyurea.
I
DIOPATHIC myelofibrosis is a myeloproliferative disorder characterized by fibrosis of the bone marrow, myeloid metaplasia mainly in the spleen and liver, and splenomegaly. Amyloidosis has been occasionally described as occurring with idiopathic myelofibrosis. Its occurrence in idiopathic myelofibrosis without an identifiable cause is highly unusual, and there are only two reports in the literature, in which four patients were described.1,2 CASE REPORT
An 84-year-old Chinese man was diagnosed with idiopathic myelofibrosis in 1998. He was treated with hydroxyurea, recombinant erythropoietin, and blood transfusion. In late 1998, he developed bilateral ankle edema and noted his urine was frothy. Renal ultrasonogram showed bilateral slightly contracted kidneys with increased echogenicity compatible with chronic parenchymal renal disease. Urinalysis showed scanty red blood cells and casts. Blood investigations showed a hemoglobin concentration of 11.3 g/L; white blood cell count, 7,900 ⫻ 109/L; platelet count, 442 ⫻ 109/L; urea concentration, 33.1 mg/dL; and creatinine level, 1.4 mg/dL. Twenty-four–hour urine protein excretion was 1.55 g, and creatinine clearance was 54 mL/min. A percutaneous needle renal biopsy was performed. Ten glomeruli were present in the biopsy sample. Three of the glomeruli were globally sclerosed, and the other glomeruli showed diffuse expansion of the mesangium, with eosinophilic and congophilic material and little increase in cellularity (Fig 1). The glomerular capillaries were mildly thickened. The congophilic material showed green birefringence when viewed with polarized light. Congo-red staining
was resistant to treatment with potassium permanganate. Immunoperoxidase studies were performed. The deposits showed no immunoreactivity against polyclonal antisera to kappa (A417; Dako, Carpinteria, CA) and lambda (A418; Dako) light chains and monoclonal antisera to amyloid A component (M759; Dako) and beta-amyloid protein (M872; Dako). Focal tubular atrophy and interstitial inflammation were noted. The arterial vessels were markedly thickened, and the arterioles were hyalinized. Immunofluorescence study showed scanty segmental immunoglobulin M and C3 staining. Deposits of other immunoglobulins and C1q were absent. The antisera were manufactured by Silenus Laboratories (Victoria, Australia). Electron microscopy showed the presence of fibrillary deposits in the glomeruli. The fibrils were nonbranching and had a diameter of approximately 10 nm (Fig 2). DISCUSSION
There are only two reports of amyloidosis complicating idiopathic myelofibrosis. The first report was made by Akikusa et al,1 who described three cases studied at autopsy. Although Akikusa et al1 suggested amyloidosis was only seen in the terminal phase of idiopathic myelofibrosis, Ferhanoglu et al2 described a 54-year-old
From the Department of Pathology, The University of Hong Kong; and the Renal Unit, Hong Kong Baptist Hospital, Hong Kong, China. Received June 2, 1999; accepted in revised form August 10, 1999. Address reprint requests to K. W. Chan, MD, Department of Pathology, The University of Hong Kong, Hong Kong, China. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 1523-6838/99/3406-0008$3.00/0
American Journal of Kidney Diseases, Vol 34, No 6 (December), 1999: E27
1
Fig 1. A representative glomerulus shows a large amount of eosinophilic amyloid deposits. (Hematoxylin and eosin, original magnification ⴛ400.)
Fig 2. Amyloid fibrils found in the glomeruli of the renal biopsy. (Electron micrograph, original magnification ⴛ84,000; scale bar ⴝ 200 nm.)
AMYLOIDOSIS IN IDIOPATHIC MYELOFIBROSIS
man who led an active life with treatment. That patient, however, unlike our patient and those reported by Akikusa et al,1 had amyloid sensitive to potassium permanganate. The clinical manifestation of amyloidosis in that patient included proteinuria, hypogammaglobulinemia, and recurrent diarrhea for which no infectious agent could be identified. Similarly, our patient was diagnosed to have both conditions at an early stage. Significant proteinuria and mild renal impairment were the presenting features of our patient. Amyloid is an extracellular deposit of fibrillar protein that has characteristic staining properties and ultrastructural appearance. The two major types of amyloid are amyloid associated and amyloid light chain. Many types of amyloid have been identified more recently, some of which can be distinguished immunohistologically with the use of the appropriate antisera.3,4 The characteristics of amyloid in our patient were similar to those of the three patients described by Akikusa et al.1 The affinity to Congored was resistant to potassium permanganate treatment. Immunohistochemically, no reactivity to amyloid component A or kappa or lambda light chains could be shown in our patient. In addition, we found that the amyloid deposits in our patient lacked the immunoreactivity of beta-
3
amyloid. The antisera to the light chains we used were polyclonal. The patient described by Ferhanoglu et al2 had amyloid sensitive to permanganate treatment. The immunohistochemical character of the deposits was not mentioned. The chemical nature of the amyloid in the reported cases complicating idiopathic myelofibrosis remains unknown and requires further characterization. It is possible that amyloidosis is only diagnosed in a small number of the cases in which it occurs. The effects of amyloidosis development on the prognosis of idiopathic myelofibrosis and its true incidence can only be shown if searched for specifically. REFERENCES 1. Akikusa B, Komatsu T, Kondo Y, Yokita T, Uchino F, Yonemitsu H: Amyloidosis complicating idiopathic myelofibrosis. Arch Pathol Lab Med 11:525-529, 1987 2. Ferhanoglu B, Erzin Y, Baslar Z, Tuzuner HAN: Secondary amyloidosis in the course of idiopathic myelofibrosis. Leuk Res 21:897-898, 1997 3. Strege RJ, Saeger W, Linke RP: Diagnosis and immunohistochemical classification of systemic amyloidosis: Report of 43 cases in an unselected autopsy series. Virchows Arch 433:19-27, 1998 4. Rocken C, Schwotzer EB, Linke RP, Saeger W: The classification of amyloid deposits in clinicopathological practice. Histopathology 29:325-335, 1996