Letters to the Editor
* 2014 Lippincott Williams & Wilkins
e5
Two Cases of Macroamylasemia After Autologous Hematopoietic Stem-Cell Transplantation for Advanced Neuroblastoma acroamylasemia is a benign condition when the elevated amylase level results from the presence in the serum of a macromolecular complex of amylase whose large size precluded its excretion in the urine (1). It occurs in up to 1.0% of randomly selected adult patients; however, the incidence in the pediatric population is unknown (2, 3). Macroamylasemia is known to be associated with disturbed humoral immunity, such as autoimmune diseases and cancer (3). We report the first cases of macroamylasemia after autologous stem-cell transplantation (auto-SCT).
M
PATIENT 1 The 33-month-old female patient was diagnosed with a stage 4 neuroblastoma that occurred primarily in the left adrenal gland. The patient underwent five cycles of multiagent chemotherapy, complete resection of the left adrenal tumor, radiation therapy to the primary tumor bed, and subsequently high-dose chemotherapy with buslfan and melphalan followed by auto-SCT. After transplantation, the patient received radiation therapy to the right iliac bone metastasis, and maintenance therapy with isotretinoin was initiated on day +63. Hyperamylasemia (maximum, 607 IU/L) was first noted on day +48 by a screening test, and repeated amylase level continued to be elevated without any significant symptom. Abdominal ultrasonography result was negative. Pancreatic amylase and lipase levels in the serum were within normal limits. Serum creatinine level was not elevated from her baseline values (0.26Y0.36 mg/dL). Macroamylasemia was diagnosed by low amylase-creatinine renal clearance ratio (0.07%; normal range, 1%Y3%) and amylase electrophoresis, which showed abnormal broad band obscuring the separation of amylase isoenzyme (Fig. 1A).
PATIENT 2 The 22-month-old female patient was diagnosed with a stage 4 neuroblastoma that occurred primarily in the left adrenal gland. The patient underwent six cycles of multiagent chemotherapy, complete resection of the left adrenal tumor,
radiation therapy to the primary tumor bed, and subsequently high-dose chemotherapy with thiotepa and melphalan followed by auto-SCT. After transplantation, the patient started maintenance therapy with isotretinoin on day +171. Hyperamylasemia (maximum, 211 IU/L) was first noted on day +171 by a screening test and lasted for 4 months without any symptom. Although serum creatinine level had been elevated by treatment-related renal toxicities, no significant change was observed during hyperamylasemia (0.58Y0.89 mg/dL). Macroamylasemia was diagnosed by amylase electrophoresis, which showed abnormal broad band obscuring the separation of amylase isoenzyme (Fig. 1B).
DISCUSSION Macroamylase represents a complex of normal amylase and immunoglobulin A or G in most patients, and there is also evidence that polysaccharide and other proteins can be linked to amylase in some patients (3). Macroamylasemia has been reported with higher incidence in patients with autoimmune diseases and cancers, reflecting an aberrant state of immunoglobulin production (4Y6). Because both of our patients had normal amylase level before auto-SCT, we hypothesized that their macroamylasemia were not caused by neuroblastoma but by the reconstructed immunity after auto-SCT. Various autoimmune diseases after auto-SCT have been reported, and
FIGURE 1. A and B, The result of amylase electrophoresis in patients 1 and 2, respectively, an abnormal broad band obscuring the separation of amylase isoenzymes. C, The result in a patient with acute pancreatitis; multiple narrow bands represent pancreatic isoenzymes (P1-4). D, The result in a patient with normal serum amylase level; two distinct bands represent salivary isoenzyme (S1) and pancreatic isoenzyme (P1). Other smaller bands represent minor salivary isoenzymes (S2 and S3).
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
e6
www.transplantjournal.com
autoimmune thrombocytopenia is the most common one (7). According to our knowledge, our series is the first report of macroamylasemia after SCT. We conducted a retrospective review of our medical record and identified 16 other children who underwent SCT for highrisk neuroblastoma. Only one of them had experienced hyperamylasemia, and amylase electrophoresis showed the elevation of salivary amylase. Hyperamylasemia after SCT certainly mandates immediate evaluation to rule out acute pancreatitis, a serious complication caused by chemotherapeutics, immunosuppressive drugs, graftversus-host disease, or cytomegalovirus infection (8). However, subclinical hyperamylasemia is relatively common, and macroamylasemia might be overlooked (9). Amylase-creatinine renal clearance ratio of less than 1% is a useful indirect screening test, and amylase electrophoresis or enzyme-linked immunosorbent assay method should be followed as a confirmation (3, 10). Noninvasive and relatively inexpensive tests could help avoid excessive and expensive evaluation, such as sonography, computed tomographic scan, or exploratory laparotomy.
Transplantation
We proposed that macroamylasemia should be considered as a differential diagnosis for post-SCT hyperamylasemia. Fumito Yamazaki Keita Terashima Chikako Kiyotani Tetsuya Mori Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan The authors declare no funding or conflicts of interest. Address correspondence to: Keita Terashima, M.D., Ph.D., Children’s Cancer Center, National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan. E-mail: [email protected] F.Y. and K.T. reviewed the cases and wrote the manuscript. F.Y. and C.K. collected and analyzed data. K.T. and T.M. critically revised and finalized the manuscript. Received 30 January 2014. Accepted 31 March 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9801-e5 DOI: 10.1097/TP.0000000000000212
REFERENCES 1.
Berk JE, Kizu H, Wilding P, et al. Macroamylasemia: a newly recognized cause for elevated serum amylase activity. N Engl J Med 1967; 277: 941.
& Volume 98, Number 1, July 15, 2014 2.
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Barrows D, Berk JE, Fridhandler L. MacroamylasemiaVsurvey of prevalence in a mixed population. N Engl J Med 1972; 286: 1352. Klonoff DC. Macroamylasemia and other immunoglobulin-complexed enzyme disorders. West J Med 1980; 133: 392. Barera G, Bazzigaluppi E, Viscardi M, et al. Macroamylasemia attributable to glutenrelated amylase autoantibodies: a case report. Pediatrics 2001; 107: e93. Sagristani M, Guariglia R, Pocali B, et al. Macroamylasemia in a patient with multiple myeloma. Leuk Lymphoma 2002; 43: 1705. Turkcapar N, Ozyuncu N, Idilman R, et al. Macro-amylasemia in a patient with selective IgA deficiency and antiphospholipid antibodies. Turk J Gastroenterol 2006; 17: 140. Bohgaki T, Atsumi T, Koike T. Autoimmune disease after autologous hematopoietic stem cell transplantation. Autoimmun Rev 2008; 7: 198. Ko CW, Gooley T, Schoch HG, et al. Acute pancreatitis in marrow transplant patients: prevalence at autopsy and risk factor analysis. Bone Marrow Transplant 1997; 20: 1081. Kawakami T, Mitsui T, Sendo D, et al. Acute pancreatitis following hematopoietic stem cell transplantation: prevalence and cause of pancreatic amylasemia [in Japanese]. Rinsho Ketsueki 2002; 43: 176. Hortin GL, Summerfield AL, Wilhite TR, et al. Detection of autoantibodies to amylase by ELISA: comparison of detection of macroamylase and free autoantibody. Clin Chem 1994; 40: 2254.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
* 2014 Lippincott Williams & Wilkins
e5
Two Cases of Macroamylasemia After Autologous Hematopoietic Stem-Cell Transplantation for Advanced Neuroblastoma acroamylasemia is a benign condition when the elevated amylase level results from the presence in the serum of a macromolecular complex of amylase whose large size precluded its excretion in the urine (1). It occurs in up to 1.0% of randomly selected adult patients; however, the incidence in the pediatric population is unknown (2, 3). Macroamylasemia is known to be associated with disturbed humoral immunity, such as autoimmune diseases and cancer (3). We report the first cases of macroamylasemia after autologous stem-cell transplantation (auto-SCT).
M
PATIENT 1 The 33-month-old female patient was diagnosed with a stage 4 neuroblastoma that occurred primarily in the left adrenal gland. The patient underwent five cycles of multiagent chemotherapy, complete resection of the left adrenal tumor, radiation therapy to the primary tumor bed, and subsequently high-dose chemotherapy with buslfan and melphalan followed by auto-SCT. After transplantation, the patient received radiation therapy to the right iliac bone metastasis, and maintenance therapy with isotretinoin was initiated on day +63. Hyperamylasemia (maximum, 607 IU/L) was first noted on day +48 by a screening test, and repeated amylase level continued to be elevated without any significant symptom. Abdominal ultrasonography result was negative. Pancreatic amylase and lipase levels in the serum were within normal limits. Serum creatinine level was not elevated from her baseline values (0.26Y0.36 mg/dL). Macroamylasemia was diagnosed by low amylase-creatinine renal clearance ratio (0.07%; normal range, 1%Y3%) and amylase electrophoresis, which showed abnormal broad band obscuring the separation of amylase isoenzyme (Fig. 1A).
PATIENT 2 The 22-month-old female patient was diagnosed with a stage 4 neuroblastoma that occurred primarily in the left adrenal gland. The patient underwent six cycles of multiagent chemotherapy, complete resection of the left adrenal tumor,
radiation therapy to the primary tumor bed, and subsequently high-dose chemotherapy with thiotepa and melphalan followed by auto-SCT. After transplantation, the patient started maintenance therapy with isotretinoin on day +171. Hyperamylasemia (maximum, 211 IU/L) was first noted on day +171 by a screening test and lasted for 4 months without any symptom. Although serum creatinine level had been elevated by treatment-related renal toxicities, no significant change was observed during hyperamylasemia (0.58Y0.89 mg/dL). Macroamylasemia was diagnosed by amylase electrophoresis, which showed abnormal broad band obscuring the separation of amylase isoenzyme (Fig. 1B).
DISCUSSION Macroamylase represents a complex of normal amylase and immunoglobulin A or G in most patients, and there is also evidence that polysaccharide and other proteins can be linked to amylase in some patients (3). Macroamylasemia has been reported with higher incidence in patients with autoimmune diseases and cancers, reflecting an aberrant state of immunoglobulin production (4Y6). Because both of our patients had normal amylase level before auto-SCT, we hypothesized that their macroamylasemia were not caused by neuroblastoma but by the reconstructed immunity after auto-SCT. Various autoimmune diseases after auto-SCT have been reported, and
FIGURE 1. A and B, The result of amylase electrophoresis in patients 1 and 2, respectively, an abnormal broad band obscuring the separation of amylase isoenzymes. C, The result in a patient with acute pancreatitis; multiple narrow bands represent pancreatic isoenzymes (P1-4). D, The result in a patient with normal serum amylase level; two distinct bands represent salivary isoenzyme (S1) and pancreatic isoenzyme (P1). Other smaller bands represent minor salivary isoenzymes (S2 and S3).
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
e6
www.transplantjournal.com
autoimmune thrombocytopenia is the most common one (7). According to our knowledge, our series is the first report of macroamylasemia after SCT. We conducted a retrospective review of our medical record and identified 16 other children who underwent SCT for highrisk neuroblastoma. Only one of them had experienced hyperamylasemia, and amylase electrophoresis showed the elevation of salivary amylase. Hyperamylasemia after SCT certainly mandates immediate evaluation to rule out acute pancreatitis, a serious complication caused by chemotherapeutics, immunosuppressive drugs, graftversus-host disease, or cytomegalovirus infection (8). However, subclinical hyperamylasemia is relatively common, and macroamylasemia might be overlooked (9). Amylase-creatinine renal clearance ratio of less than 1% is a useful indirect screening test, and amylase electrophoresis or enzyme-linked immunosorbent assay method should be followed as a confirmation (3, 10). Noninvasive and relatively inexpensive tests could help avoid excessive and expensive evaluation, such as sonography, computed tomographic scan, or exploratory laparotomy.
Transplantation
We proposed that macroamylasemia should be considered as a differential diagnosis for post-SCT hyperamylasemia. Fumito Yamazaki Keita Terashima Chikako Kiyotani Tetsuya Mori Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan The authors declare no funding or conflicts of interest. Address correspondence to: Keita Terashima, M.D., Ph.D., Children’s Cancer Center, National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan. E-mail: [email protected] F.Y. and K.T. reviewed the cases and wrote the manuscript. F.Y. and C.K. collected and analyzed data. K.T. and T.M. critically revised and finalized the manuscript. Received 30 January 2014. Accepted 31 March 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9801-e5 DOI: 10.1097/TP.0000000000000212
REFERENCES 1.
Berk JE, Kizu H, Wilding P, et al. Macroamylasemia: a newly recognized cause for elevated serum amylase activity. N Engl J Med 1967; 277: 941.
& Volume 98, Number 1, July 15, 2014 2.
3. 4.
5.
6.
7.
8.
9.
10.
Barrows D, Berk JE, Fridhandler L. MacroamylasemiaVsurvey of prevalence in a mixed population. N Engl J Med 1972; 286: 1352. Klonoff DC. Macroamylasemia and other immunoglobulin-complexed enzyme disorders. West J Med 1980; 133: 392. Barera G, Bazzigaluppi E, Viscardi M, et al. Macroamylasemia attributable to glutenrelated amylase autoantibodies: a case report. Pediatrics 2001; 107: e93. Sagristani M, Guariglia R, Pocali B, et al. Macroamylasemia in a patient with multiple myeloma. Leuk Lymphoma 2002; 43: 1705. Turkcapar N, Ozyuncu N, Idilman R, et al. Macro-amylasemia in a patient with selective IgA deficiency and antiphospholipid antibodies. Turk J Gastroenterol 2006; 17: 140. Bohgaki T, Atsumi T, Koike T. Autoimmune disease after autologous hematopoietic stem cell transplantation. Autoimmun Rev 2008; 7: 198. Ko CW, Gooley T, Schoch HG, et al. Acute pancreatitis in marrow transplant patients: prevalence at autopsy and risk factor analysis. Bone Marrow Transplant 1997; 20: 1081. Kawakami T, Mitsui T, Sendo D, et al. Acute pancreatitis following hematopoietic stem cell transplantation: prevalence and cause of pancreatic amylasemia [in Japanese]. Rinsho Ketsueki 2002; 43: 176. Hortin GL, Summerfield AL, Wilhite TR, et al. Detection of autoantibodies to amylase by ELISA: comparison of detection of macroamylase and free autoantibody. Clin Chem 1994; 40: 2254.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
