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John Auer and Auer rods; controversies revisited
Leukemia Research 33 (2009) 614–616
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Open forum a r t i c l e
i n f o
Keywords: Historical review Auer rods Hematological malignancy Myelodysplasia
a b s t r a c t John Auer first described needle or rod-shaped intracytoplasmic inclusion bodies in leukemia cells in 1906. Auer rods can be seen in myeloid neoplasms ranging from acute myeloid leukemias (AML) to myelodysplasia, but not in normal or non-neoplastic reactive states. This article briefly describes John Auer’s experience and discusses debates on Auer rods, and criticizes their place in the definition of refractory anemia with excess of blasts-2 (RAEB-2) in the WHO classification of the myelodysplastic syndromes (MDS). © 2008 Elsevier Ltd. All rights reserved.
John Auer and Auer rods; controversies revisited 1. John Auer (1875–1948) John Auer was born in Rochester, New York, in 1875. He graduated from Johns Hopkins Medical School in 1902 (Fig. 1). In April 1903 while working in Dr. William Osler’s ward in Johns Hopkins Hospital, he saw a 21-year-old male with a profound nose bleeding and a throat infection. The patient had a fever, anemia, and splenomegaly. His leukocyte count was 139 × 109 /l, 92% of which were immature leukemic cells. 6–10% of leukemic cells contained rod-shaped cytoplasmic inclusion. At first, he noted the inclusion as “refractile rod-like body” in the wet preparations of the blood. This prompted him to more carefully review the Romanowskystained blood smears. The rods stained azurophilic, were 1–6 m long, needle or spindle form, and mostly seen as one inclusion though occasionally as many as three inclusions in a cell. Since no such inclusions were known, Auer concluded, with permission from Drs. Osler and Thomas McRae, that his observation was worth publishing [1]. The rods-containing cells were originally described as large lymphocytes, but must have been immature myeloid cells in retrospect. He subsequently became more interested in physiology and worked with his father-in-law, Dr. Samuel J. Meltzer, at the Rockefeller Institute for 18 years. He became a professor of pharmacology of St. Louis University, and died of a heart attack in 1948. 2. History of Auer rods research The presence of Auer rods in acute leukemia cells was soon confirmed by Pappenheim, Ottenberg, Issac and Naegeli shortly after Auer’s paper [reviewed in references 2,3]. Though most commonly seen in myeloblasts, the rods can also be found in maturing neutrophilic cells including polymorphonuclear leukocytes in acute myeloid leukemia (AML) [4,5]. In addition, Hawksley [6] and Ackerman [7] reported Auer rods in immature cells of acute monocytic leukemia, thus establishing that Auer rods can occur in both acute myeloid and monocytic leukemia. Electronmicroscopic studies showed structural similarities between Auer rods and cytoplasmic granules [2,3]. Cytochemically, Auer rods are pos0145-2126/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2008.09.014
itive for peroxidase, periodic acid-Schiff (PAS), Sudan black, acid and alkaline phosphatase, but are negative for lipase, glycogen, or nucleic acids [7,8]. These ultrastructural and cytochemical findings also support the origin of Auer rods from azurophilic granules. Thus, the rods are considered to be composed of fused lysosomes [2,3,7,8]. It is unknown why Auer rods are never seen in non-neoplastic cells. Several hypotheses have been proposed as to the genesis of Auer rods. They include infectious microorganisms, abnormal segregation of nucleoplasm, pathologic forms of azurophilic granules, and alteration of cytoplasmic pH. Failure to transmit Auer bodies in inoculation experiments eliminated the infectious microorganisms theory. Ackerman proposed that some alteration of the cytoplasmic acidic pH exist in certain leukemic cells allowing the granules to coalesce into crystal-like rods, although nothing was known about the conditions leading to the alteration of pH [7]. Assuming analogy with certain neoplastic cells often expressing fetal phenotypic characteristics, Newburger examined human fetal peripheral blood in search of Auer rods, and proposed that the rods represent recapitulation of a stage of normal fetal development [9]. The very low frequency of detection, rods containing-cells being 1–5 among 10,000 cells in five out of the nine fetal blood samples of 16–19 weeks of gestation, and absence of similar reports may not support this notion. 3. Implication and controversies As the morphological hallmark of certain AML, the rods are found in AML M1, M2, M3, M4, M5, and M6, but not in AML M0 or M7 of the French–American–British (FAB) classification [10]. Auer rods in granulocytic sarcomas are often hard to detect in routine hematoxylin and eosin-stained sections [11]. In addition, the presence of Auer rods is generally associated with good prognosis in AML [12]. Even in childhood AML M1, the presence of Auer rods is of high prognostic significance in terms of both remission induction and remission duration [13]. This may be related to the origin of Auer rods from azurophilic granules, suggesting Auer rods-positive AML cases being those showing differentiation tendency. Conversely, this may explain why most immature blast cells from AML M0 or blastic crisis of chronic myeloid leukemia (CML) have no Auer rods.
Open forum / Leukemia Research 33 (2009) 614–616
615
rods-positive cases with fewer blasts, do they still belong to RAEB2 group? Or, should they be classified according to the blast cell percentage, although this view is an apparent contradiction to the Auer criteria for RARB-2 in the WHO system. Many MDS scoring systems indicate BM blast cell percentage as the most influential prognostic parameters in [18,19]. One study suggested heterogeneity of such minor subgroup of “low blast count” myeloid disorders with Auer rods [20]. Again, the WHO system does not accept Auer rods in MDS other than in RAEB-2, or in chronic myelomonocytic leukemia-2 (CMML-2). All these problems are centered on the single puzzling notion that Auer rods represent a cytological hallmark of neoplastic cells, which nonetheless show features of myeloid differentiation. In summary, Auer rods are of diagnostic value in determining the neoplastic nature of the cells of the myeloid lineage. However, Auer rods probably do not bear much significance in predicting prognosis of MDS. We propose due attention be drawn to these problematic issues in the future classification of MDS. Acknowledgements All authors contributed equally in preparation of this article and have no conflicts of interest. We thank the Alan Mason Chesney Archives for permission to reproduce the portrait of Dr. Auer. Fig. 1. Portrait of John Auer appearing 1902 album of Johns Hopkins Medical School. Reproduced with permission from the Alan Mason Chesney Archives.
Controversies persist regarding the place of Auer rods in the classification of the myelodysplastic syndromes (MDS). The FAB classification proposed refractory anemia with excess of blasts (RAEB) in transformation (RAEB-t) to be either MDS cases with Auer rods-containing blasts, or those with bone marrow (BM) blasts 21–29% or peripheral blood (PB) blasts ≥5% [14]. Seymour and Estey [15] compared the survival of RAEB-t patients between those having Auer rods and those without rods, and found that the former group had a higher survival probability than the latter, and even within the former group, those patients who, were it not for Auer rods, would be considered RAEB by the FAB system, had a higher probability of survival than patients with RAEB as conventionally defined. Although Auer rods-positive cases were more likely to have a normal karyotype and less likely to have prognostically unfavorable cytogenetic abnormalities, the favorable prognostic impact of Auer rods was still evident when analyzed within cytogenetic groups [15]. The presence of Auer rods thus does not convey a bad prognosis and may not justify placing Auer rods-positive patients in high-risk category of MDS. The category of RAEB-t has been eliminated in the World Health Organization (WHO) classification of MDS [16]. However, one of the criteria of RAEB-2 still defines the presence or absence of Auer rods, in addition to the other criteria such as BM blasts 10–19% or PB blasts 5–19%. This is very ambiguous in two ways. First, if Auer rods are absent, there is no need to mention in the proposal. Auer rods-negative cases would be RAEB2 as long as their blasts percentages fall within the above range. Second, if patients have Auer rods they belong to RAEB-2 if their blast cell percentages meet the range of BM 10–19% or PB blasts 5–19%, but what about cases with blasts less than this threshold? In the former case meeting the blast cell criteria, Auer rods may have no additional significance, although the possibility must be tested if Auer rods may confer somewhat different prognosis, similar to the situation with the FAB RAEB-t [15,17]. In the latter Auer
References [1] Auer J. Some hitherto undescribed structures found in the large lymphocytes of a case of acute leukemia. Am J Med Sci 1906;131:1002–15. [2] Freeman JA. The ultrastructure and genesis of Auer bodies. Blood 1960;15:449–65. [3] Freeman JA. Origin of Auer bodies. Blood 1966;27:499–510. [4] Goodwin A. Some observations on Auer bodies in acute myelogenous leukemia. Folia Hematol 1934;51:359–66. [5] Bainton DF, Friedlander LW, Shohet SB. Abnormalities in granule formation in acute myelogenous leukemia. Blood 1977;49:693–704. [6] Hawksley J. A note on the occurrence of Auer’s bodies in monocytic leukemia. J Path Bact 1935;40:365–9. [7] Ackerman GA. Microscopic and histochemical studies on the Auer bodies in leukemic cells. Blood 1950;5:847–63. [8] Goldberg A. Acid phosphatase activity in Auer bodies. Blood 1964;24:305–8. [9] Newburger PE, Novak TJ, McCaffrey RP. Eosinophilic cytoplsmic inclusions in fetal leukocytes: are Auer bodies a recapitulation of fetal morphology. Blood 1983;61:593–5. [10] Bennett JM, Catvsky D, Daniel MT, Flandrin G, Galton DAG, Granlnick HR, et al. Proposed revised criteria for the classification of acute myeloid leukaemia. A report of the French–American–British co-operative group. Ann Intern Med 1985;103:620–5. [11] Byrd JC, Edenfield WJ, Shields DJ, Dawson NA. Extramedullary myeloid cell tumors in acute nonlymphocytic leukemia: a clinical review. J Clin Oncol 1995;13:1800–16. [12] Zittoun R, Cardiou M, Bayle C, Suciu S, Solbu G, Hayat M. Prognostic value of cytologic parameters in acute myelogenous leukemia. Cancer 1984;53:1526–32. [13] Ritter J, Vormoor J, Creuzig U, Schellong G. Prognostic significance of Auer rods in childhood acute myelogenous leukemia. Med Pediatr Oncol 1989;17: 202–9. [14] Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, et al. Proposals for the classification of the myeldysplastic syndromes. Br J Haematol 1982;51:189–99. [15] Seymour JF, Estey EH. The prognostic significance of Auer rods in myelodysplasia. Br J Haematol 1993;85:67–76. [16] Vardiman JW, Harris NL, Brunning RD. The World health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292– 302. [17] Strupp C, Gattermann N, Giagounidis A, Aul C, Haas R, Germing U. Refractory anemia with excess of blasts in transformation: analysis of reclassification according to the WHO classification. Leuk Res 2003;27:397– 404. [18] Greenberg P, Cox C, Lebeau M, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079–88. [19] Malocovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R, et al. Time-dependent prognostic scoring system for predicting
616
Open forum / Leukemia Research 33 (2009) 614–616
survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 2007;25:3503–10. [20] Willis MS, McKenna RW, Peterson LC, Coad JE, Kroft SH. Low blast count myeloid disorders with Auer rods; a clinicopathologic analysis of 9 cases. Am J Clin Pathol 2005;124:191–8.
Yataro Yoshida ∗ Shigeru Oguma Hitotshi Ohno The Center for Hematological Diseases, Takeda General Hospital, Japan
∗ Corresponding
author at: 28-1 Ishida-Moriminami, Fushimi-ku, Kyoto 601-1495, Japan. Tel.: +8175 572 6331; fax: +81 75 571 8877. E-mail address: [email protected] (Y. Yoshida) 20 August 2007 29 August 2007 1 September 2008 Available online 22 October 2008
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Open forum a r t i c l e
i n f o
Keywords: Historical review Auer rods Hematological malignancy Myelodysplasia
a b s t r a c t John Auer first described needle or rod-shaped intracytoplasmic inclusion bodies in leukemia cells in 1906. Auer rods can be seen in myeloid neoplasms ranging from acute myeloid leukemias (AML) to myelodysplasia, but not in normal or non-neoplastic reactive states. This article briefly describes John Auer’s experience and discusses debates on Auer rods, and criticizes their place in the definition of refractory anemia with excess of blasts-2 (RAEB-2) in the WHO classification of the myelodysplastic syndromes (MDS). © 2008 Elsevier Ltd. All rights reserved.
John Auer and Auer rods; controversies revisited 1. John Auer (1875–1948) John Auer was born in Rochester, New York, in 1875. He graduated from Johns Hopkins Medical School in 1902 (Fig. 1). In April 1903 while working in Dr. William Osler’s ward in Johns Hopkins Hospital, he saw a 21-year-old male with a profound nose bleeding and a throat infection. The patient had a fever, anemia, and splenomegaly. His leukocyte count was 139 × 109 /l, 92% of which were immature leukemic cells. 6–10% of leukemic cells contained rod-shaped cytoplasmic inclusion. At first, he noted the inclusion as “refractile rod-like body” in the wet preparations of the blood. This prompted him to more carefully review the Romanowskystained blood smears. The rods stained azurophilic, were 1–6 m long, needle or spindle form, and mostly seen as one inclusion though occasionally as many as three inclusions in a cell. Since no such inclusions were known, Auer concluded, with permission from Drs. Osler and Thomas McRae, that his observation was worth publishing [1]. The rods-containing cells were originally described as large lymphocytes, but must have been immature myeloid cells in retrospect. He subsequently became more interested in physiology and worked with his father-in-law, Dr. Samuel J. Meltzer, at the Rockefeller Institute for 18 years. He became a professor of pharmacology of St. Louis University, and died of a heart attack in 1948. 2. History of Auer rods research The presence of Auer rods in acute leukemia cells was soon confirmed by Pappenheim, Ottenberg, Issac and Naegeli shortly after Auer’s paper [reviewed in references 2,3]. Though most commonly seen in myeloblasts, the rods can also be found in maturing neutrophilic cells including polymorphonuclear leukocytes in acute myeloid leukemia (AML) [4,5]. In addition, Hawksley [6] and Ackerman [7] reported Auer rods in immature cells of acute monocytic leukemia, thus establishing that Auer rods can occur in both acute myeloid and monocytic leukemia. Electronmicroscopic studies showed structural similarities between Auer rods and cytoplasmic granules [2,3]. Cytochemically, Auer rods are pos0145-2126/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2008.09.014
itive for peroxidase, periodic acid-Schiff (PAS), Sudan black, acid and alkaline phosphatase, but are negative for lipase, glycogen, or nucleic acids [7,8]. These ultrastructural and cytochemical findings also support the origin of Auer rods from azurophilic granules. Thus, the rods are considered to be composed of fused lysosomes [2,3,7,8]. It is unknown why Auer rods are never seen in non-neoplastic cells. Several hypotheses have been proposed as to the genesis of Auer rods. They include infectious microorganisms, abnormal segregation of nucleoplasm, pathologic forms of azurophilic granules, and alteration of cytoplasmic pH. Failure to transmit Auer bodies in inoculation experiments eliminated the infectious microorganisms theory. Ackerman proposed that some alteration of the cytoplasmic acidic pH exist in certain leukemic cells allowing the granules to coalesce into crystal-like rods, although nothing was known about the conditions leading to the alteration of pH [7]. Assuming analogy with certain neoplastic cells often expressing fetal phenotypic characteristics, Newburger examined human fetal peripheral blood in search of Auer rods, and proposed that the rods represent recapitulation of a stage of normal fetal development [9]. The very low frequency of detection, rods containing-cells being 1–5 among 10,000 cells in five out of the nine fetal blood samples of 16–19 weeks of gestation, and absence of similar reports may not support this notion. 3. Implication and controversies As the morphological hallmark of certain AML, the rods are found in AML M1, M2, M3, M4, M5, and M6, but not in AML M0 or M7 of the French–American–British (FAB) classification [10]. Auer rods in granulocytic sarcomas are often hard to detect in routine hematoxylin and eosin-stained sections [11]. In addition, the presence of Auer rods is generally associated with good prognosis in AML [12]. Even in childhood AML M1, the presence of Auer rods is of high prognostic significance in terms of both remission induction and remission duration [13]. This may be related to the origin of Auer rods from azurophilic granules, suggesting Auer rods-positive AML cases being those showing differentiation tendency. Conversely, this may explain why most immature blast cells from AML M0 or blastic crisis of chronic myeloid leukemia (CML) have no Auer rods.
Open forum / Leukemia Research 33 (2009) 614–616
615
rods-positive cases with fewer blasts, do they still belong to RAEB2 group? Or, should they be classified according to the blast cell percentage, although this view is an apparent contradiction to the Auer criteria for RARB-2 in the WHO system. Many MDS scoring systems indicate BM blast cell percentage as the most influential prognostic parameters in [18,19]. One study suggested heterogeneity of such minor subgroup of “low blast count” myeloid disorders with Auer rods [20]. Again, the WHO system does not accept Auer rods in MDS other than in RAEB-2, or in chronic myelomonocytic leukemia-2 (CMML-2). All these problems are centered on the single puzzling notion that Auer rods represent a cytological hallmark of neoplastic cells, which nonetheless show features of myeloid differentiation. In summary, Auer rods are of diagnostic value in determining the neoplastic nature of the cells of the myeloid lineage. However, Auer rods probably do not bear much significance in predicting prognosis of MDS. We propose due attention be drawn to these problematic issues in the future classification of MDS. Acknowledgements All authors contributed equally in preparation of this article and have no conflicts of interest. We thank the Alan Mason Chesney Archives for permission to reproduce the portrait of Dr. Auer. Fig. 1. Portrait of John Auer appearing 1902 album of Johns Hopkins Medical School. Reproduced with permission from the Alan Mason Chesney Archives.
Controversies persist regarding the place of Auer rods in the classification of the myelodysplastic syndromes (MDS). The FAB classification proposed refractory anemia with excess of blasts (RAEB) in transformation (RAEB-t) to be either MDS cases with Auer rods-containing blasts, or those with bone marrow (BM) blasts 21–29% or peripheral blood (PB) blasts ≥5% [14]. Seymour and Estey [15] compared the survival of RAEB-t patients between those having Auer rods and those without rods, and found that the former group had a higher survival probability than the latter, and even within the former group, those patients who, were it not for Auer rods, would be considered RAEB by the FAB system, had a higher probability of survival than patients with RAEB as conventionally defined. Although Auer rods-positive cases were more likely to have a normal karyotype and less likely to have prognostically unfavorable cytogenetic abnormalities, the favorable prognostic impact of Auer rods was still evident when analyzed within cytogenetic groups [15]. The presence of Auer rods thus does not convey a bad prognosis and may not justify placing Auer rods-positive patients in high-risk category of MDS. The category of RAEB-t has been eliminated in the World Health Organization (WHO) classification of MDS [16]. However, one of the criteria of RAEB-2 still defines the presence or absence of Auer rods, in addition to the other criteria such as BM blasts 10–19% or PB blasts 5–19%. This is very ambiguous in two ways. First, if Auer rods are absent, there is no need to mention in the proposal. Auer rods-negative cases would be RAEB2 as long as their blasts percentages fall within the above range. Second, if patients have Auer rods they belong to RAEB-2 if their blast cell percentages meet the range of BM 10–19% or PB blasts 5–19%, but what about cases with blasts less than this threshold? In the former case meeting the blast cell criteria, Auer rods may have no additional significance, although the possibility must be tested if Auer rods may confer somewhat different prognosis, similar to the situation with the FAB RAEB-t [15,17]. In the latter Auer
References [1] Auer J. Some hitherto undescribed structures found in the large lymphocytes of a case of acute leukemia. Am J Med Sci 1906;131:1002–15. [2] Freeman JA. The ultrastructure and genesis of Auer bodies. Blood 1960;15:449–65. [3] Freeman JA. Origin of Auer bodies. Blood 1966;27:499–510. [4] Goodwin A. Some observations on Auer bodies in acute myelogenous leukemia. Folia Hematol 1934;51:359–66. [5] Bainton DF, Friedlander LW, Shohet SB. Abnormalities in granule formation in acute myelogenous leukemia. Blood 1977;49:693–704. [6] Hawksley J. A note on the occurrence of Auer’s bodies in monocytic leukemia. J Path Bact 1935;40:365–9. [7] Ackerman GA. Microscopic and histochemical studies on the Auer bodies in leukemic cells. Blood 1950;5:847–63. [8] Goldberg A. Acid phosphatase activity in Auer bodies. Blood 1964;24:305–8. [9] Newburger PE, Novak TJ, McCaffrey RP. Eosinophilic cytoplsmic inclusions in fetal leukocytes: are Auer bodies a recapitulation of fetal morphology. Blood 1983;61:593–5. [10] Bennett JM, Catvsky D, Daniel MT, Flandrin G, Galton DAG, Granlnick HR, et al. Proposed revised criteria for the classification of acute myeloid leukaemia. A report of the French–American–British co-operative group. Ann Intern Med 1985;103:620–5. [11] Byrd JC, Edenfield WJ, Shields DJ, Dawson NA. Extramedullary myeloid cell tumors in acute nonlymphocytic leukemia: a clinical review. J Clin Oncol 1995;13:1800–16. [12] Zittoun R, Cardiou M, Bayle C, Suciu S, Solbu G, Hayat M. Prognostic value of cytologic parameters in acute myelogenous leukemia. Cancer 1984;53:1526–32. [13] Ritter J, Vormoor J, Creuzig U, Schellong G. Prognostic significance of Auer rods in childhood acute myelogenous leukemia. Med Pediatr Oncol 1989;17: 202–9. [14] Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, et al. Proposals for the classification of the myeldysplastic syndromes. Br J Haematol 1982;51:189–99. [15] Seymour JF, Estey EH. The prognostic significance of Auer rods in myelodysplasia. Br J Haematol 1993;85:67–76. [16] Vardiman JW, Harris NL, Brunning RD. The World health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292– 302. [17] Strupp C, Gattermann N, Giagounidis A, Aul C, Haas R, Germing U. Refractory anemia with excess of blasts in transformation: analysis of reclassification according to the WHO classification. Leuk Res 2003;27:397– 404. [18] Greenberg P, Cox C, Lebeau M, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079–88. [19] Malocovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R, et al. Time-dependent prognostic scoring system for predicting
616
Open forum / Leukemia Research 33 (2009) 614–616
survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 2007;25:3503–10. [20] Willis MS, McKenna RW, Peterson LC, Coad JE, Kroft SH. Low blast count myeloid disorders with Auer rods; a clinicopathologic analysis of 9 cases. Am J Clin Pathol 2005;124:191–8.
Yataro Yoshida ∗ Shigeru Oguma Hitotshi Ohno The Center for Hematological Diseases, Takeda General Hospital, Japan
∗ Corresponding
author at: 28-1 Ishida-Moriminami, Fushimi-ku, Kyoto 601-1495, Japan. Tel.: +8175 572 6331; fax: +81 75 571 8877. E-mail address: [email protected] (Y. Yoshida) 20 August 2007 29 August 2007 1 September 2008 Available online 22 October 2008