Printer Friendly

Core-binding factor acute myeloid leukemia.

As per the World Health Organization (WHO) classification of myeloid neoplasms, patients with the clonal, recurring cytogenetic abnormalities t(8; 21)(q22; q22), inv(16)(p13q22) or t(16; 16)(p13; q22), and t(15; 17)(q22; q12) should be considered to have acute myeloid leukemia (AML) regardless of the blast percentage. These 3 subtypes of AML are categorized as AML with recurrent genetic abnormalities. It is not yet clear if all the cases with other recurrent genetic abnormalities that include t(9; 11)(p22; q23), t(6; 9)(p23; q34), inv(3)(q21q26.2), t(3; 3)(q21; q26.2), or t(1; 22)(p13; q13) should also be categorized as AML when the blast count is less than 20%. (1) Two specific cytogenetic types of AML, t(8; 21)(q22; q22) and inv(16)(p13q22) or t(16; 16)(p13; q22), are called core-binding factor (CBF) AML and are usually grouped and reported together in clinical studies because of similarities between their molecular and prognostic features. (2) The genes RUNX1/ RUNX1T1 (AMLl-ETO)and CBFB/MYH11 are involved in t(8; 21) and inv(16), respectively. (1) Rowley (3) first described the t(8; 21) cytogenetic abnormality in 1973. Le Beau et al (4) in 1983 reported the peculiar association of abnormal marrow eosinophils in AML with inv(16). Both t(8; 21) and inv(16) are characterized at the molecular level by disruption of genes encoding different subunits of CBF. (5)


Core-binding factor is a heterodimeric transcription factor complex that consists of 3 distinct DNA-binding CBF[alpha] subunits (RUNX1, RUNX2, and RUNX3), and a common CBF[beta] subunit, which is non-DNA binding. (5) RUNX1 was the first CBF gene to be isolated and has been known by a number of names including AML1, PEBPA2B, and CBFA2. AML1 remains the most commonly used name in the literature. The Human Genome Organization renamed it as runt-related transcription factor 1 (RUNX1). (5) The binding affinity of RUNX1 subunit to the DNA promoter sequences is significantly increased by association with CBFb, which does not directly interact with DNA and protects RUNX1 subunit from proteolysis. (6) Core-binding factors are involved in hematopoietic development: animal studies have demonstrated that expression of the RUNX1 and CBFB genes is essential for the differentiation associated with normal hematopoiesis. (7) The homozygous loss of either RUNX1 or CBFB alleles, in knockout murine models, resulted in failure to develop definitive hematopoiesis and in embryonic death. (7) In the embryo, RUNX1 and CBF[beta] are required for the differentiation of definitive hematopoietic progenitors and hematopoietic stem cells from a "hemogenic endothelium." (8) The chromosomal aberration t(8; 21) results in the fusion of RUNX1 on 21q22 with RUNX1T1 (ETO) on 8q22, creating a chimeric fusion gene, RUNX1/ RUNX1T1 (AML1-ETO). (6) The breakpoints affect RUNX1 exon 5 and RUNX1T1 exon 2. (9) The aberrations inv(16) and t(16; 16) lead to fusion of CBFB on 16q22 with smooth muscle myosin heavy-chain gene (MYH11) on 16q13, leading to formation of CBFB/MYH11 chimeric gene. (1) The breakpoint in the MYH11 gene is variable and gives origin to at least 10 different fusion variants. In contrast, the breakpoints in the CBFB gene are in intron 5. (9) The normal transcriptional activity of RUNX1 is affected in a negative manner by the chimeric proteins encoded by RUNX1/ RUNX1T1 and CBFB/MYH11 fusion genes. Animal studies (5,7) suggest that the fusion proteins alone are not able to induce leukemia and that additional genetic alterations are required for leukemogenic transformation. Marcucci (2) and his research group proposed that AML1/ETO fusion protein recruits histone deacetylases and DNA methyl-transferase 1 to CBF target genes. This leads to increased chromatin deacetylation and promoter hypermethylation, resulting in gene transcriptional repression and disruption of normal pathways of hematopoiesis.


Although the cytogenetic abnormalities t(8; 21) and inv(16) are commonly associated with CBF AML, there are significant differences with regard to demographic and clinical characteristics. Whereas t(8; 21) occurs predominantly in younger patients and is found in up to 5% of AML cases, inv(16) or t(16; 16) occurs in all age groups and accounts for 5% to 8% of all AML cases. (1) In the Cancer and Leukemia Group B (CALGB) study, (10) both t(8; 21) and inv(16) are found to be more prevalent in white persons; however, among the nonwhite ethnic groups, t(8; 21) is more prevalent than inv(16). The clinical features are similar to those for any other type of AML, caused by the replacement of normal blood cells with leukemic cells, and include anemia and thrombocytopenia. A lack of normal white blood cell production makes the patient susceptible to infections. The early signs of AML are often vague and nonspecific and may be similar to those of influenza or other common illnesses. Some generalized symptoms include fever, fatigue, weight loss or loss of appetite, shortness of breath, anemia, bruising or bleeding, petechiae, bone and joint pain, and persistent or frequent infections. Some patients with AML may experience swelling of the gums because of infiltration of leukemic cells into the gum tissue. Rarely, the first sign of AML may be the development of a solid leukemic mass or tumor outside of the bone marrow, a condition called myeloid sarcoma. Extramedullary involvement at diagnosis is found to be more frequent in inv(16) than in t(8; 21) AML. (10,11) In such cases, the patient should be diagnosed with AML if the distinct cytogenetic abnormalities described above are present, even if the blast count is less than 20%. (1) The presence of these recurring cytogenetic abnormalities correlates with a rapid rise in the blast count, and therefore supports the WHO approach of diagnosing these cases as AML even if the blast count is less than 20%. (12) A person may show no symptoms, and the leukemia may be discovered incidentally during a routine blood test.


The t(8; 21) and inv(16) subtypes of AML are both associated with cytogenetic rearrangements that disrupt genes that encode subunits of CBF. These 2 cytogenetic subtypes are grouped together because of these common molecular features. However, the morphologic features of both are distinctly different. Patients with t(8; 21) frequently present with the French-American-British (FAB) morphologic subtype M2 or acute myeloid leukemia with differentiation, while patients with inv(16) more often are diagnosed with FAB subtype M4Eo or acute myelomonocytic leukemia with eosinophilia. (6) On rare occasions, inv(16) is also encountered with other FAB subtypes, such as M2 (myeloid leukemia with maturation), M5 (acute monoblastic/monocytic leukemia), M4 (myelomonocytic leukemia) without eosinophilia, or transformation of myelodysplastic syndrome to AML. (13)

The t(8; 21) subtype is characterized by large blasts with abundant basophilic cytoplasm, with perinuclear clearing or hofs, and numerous azurophilic granules. Very large cytoplasmic granules in the blasts are reminiscent of pseudo-Chediak-Higashi granules (Figure A). Occasional blasts, especially the more mature forms, may contain blunted Auer rods (Figure B). The maturing myeloid cells may exhibit variable dysplasia in the form of abnormal nuclear segmentation and/or cytoplasmic staining abnormalities. In contrast to inv(16) AML, this subtype shows cytologically normal eosinophils, although they might be present in greater numbers. The erythroblastic and megakaryoblastic series show normal maturation and morphology. (1) In addition to the usual morphologic features of AML, the inv(16) subtype shows a generally increased eosinophil count. All stages of eosinophilic maturation can be identified, which exhibit immature eosinophilic cytoplasmic granules, mainly evident at the promyelocyte and myelocyte stages (Figure C). These immature eosinophilic granules are larger than normal, may contain granules that are purple-violet in color (Harlequin cells), and in some cases can be dense enough to obscure the cell morphology (Table 1). The abnormal eosinophils demonstrate faint positivity for the naphthol AS-D choloroacetate esterase reaction, which is normally negative in eosinophils. Some rare cases might not exhibit the abnormal eosinophils in spite of classic cytogenetic abnormalities. (1)




The blast cells in t(8; 21) subtype show high-intensity expression of CD34, HLA-DR (human leukocyte antigenDR), myeloperoxidase, CD13, with weak CD33 expression. Some blast subsets occasionally show maturation asynchrony with coexpression of CD34 and CD15. (1) CD19 and CD56 are characteristically expressed in de novo cases of t(8; 21) AML. (14) Multiple blast populations characterize inv(16) immature blasts with high CD34 and CD117 expression and populations differentiating toward mono cytic (CD14, CD4, CD11b, CD11c, CD64 positive) and granulocytic (CD13, CD33, CD15, myeloperoxidase positive) lineages. Coexpression of the T-cell marker, CD2, is a frequent finding. (13) Many cases exhibit maturational asynchrony. (1)

The distinct morphologic features of marrow blasts, mentioned above, or a suggestive immunophenotype raises suspicion of acute myeloid leukemia with t(8; 21) or inv(16). This can be confirmed by using standard cytogenetic analysis, as shown in Figures D and E for t(8; 21) and inv(16), respectively; however, this traditional methodology can miss cases in which the gene fusions occur without cytogenetically detectable chromosome rearrangements. Fluorescence in situ hybridization (FISH) [Figures F and G for t(8; 21) & inv(16), respectively] and reverse transcription-polymerase chain reaction (RTPCR) are increasingly used for this purpose, owing to their high sensitivity and rapid turnaround. (2) Also, FISH and PCR assays are useful to confirm that the rearrangements actually involve the RUNX1/RUNX1T1 (AML1ETO) and CBFB/MYH11 genes in t(8; 21) and inv(16), respectively, as inv(16) may be cryptic by conventional cytogenetics. (15) In addition, some studies (16) have reported that some AMLs, which appear to be associated with t(8; 21) or inv(16) but with slightly different breakpoints or deletion of genetic material, may in fact involve other genes that may not have the same positive impact on prognosis. Certain secondary cytogenetic abnormalities are frequently encountered in patients with CBF AML. Those who harbor t(8; 21) display loss of a sex chromosome (Y or X) and/or deletions of the long arm of chromosome 9, del(9q). In contrast, patients harboring inv(16) occasionally demonstrate trisomy 22, as well as trisomy of chromosomes 8 and 21. (10,11,17,18) Recently published reports have generated an interest in testing for KIT gene mutations. The KIT gene encodes a tyrosine kinase receptor involved in signaling pathways related to cell proliferation and survival. These mutations generally result in a gain of function and the encoded protein is constitutively activated in the absence of its natural ligand, thereby promoting leukemia cell proliferation and survival. (2) KIT mutations occur in 20% to 25% of t(8; 21) cases and in approximately 30% of cases with inv(16). (19) In the future, the promising treatment with tyrosine kinase inhibitors might mandate screening for KIT mutations in these subgroups of patients with AML. Also, mutations of KRAS or NRAS are reported in up to 30% of pediatric CBF-associated leukemias. (20)


In general, CBF AMLs are considered to have a favorable prognosis when compared with other AML subtypes or with cytogenetically normal AML. (21) In both subtypes, after standard induction therapy with cytarabine and anthracyclines, complete remission can be achieved in approximately 90% of the patient population. (10,11,17) The CALGB study (22) found that treatment with high-dose cytarabine has a better outcome than treatment with intermediate- or low-dose cytarabine. In addition to the drug dose, the number of chemotherapy courses also plays a significant role in the outcome. Patients who receive 3 or 4 courses of high-dose cytarabine have a better outcome than those receiving only a single course. (23) Marcucci et al (10) reported that 50% of patients with CBF AML have long-term survival when repetitive cycles of high-dose cytarabine are used as postremission therapy. For both subtypes of CBF AML, patients have a high complete remission rate with long-term, disease-free survival when treated with high-dose cytarabine in the consolidation phase. (24,25) Treatment of CBF AML with fludarabine and Ara-C (FA) or with FA plus granulocyte colony-stimulating factor (FLAG) is more promising than the standard 3 plus 7 anthracycline/cytarabine (Ara-C) combination, since the former is associated with a better event-free survival. (26) The relapse and survival curves for t(8; 21) and inv(16) AML are similar in most studies; however, occasional studies have noted that patients with t(8; 21) have significantly shorter survival times after relapse than patients with inv(16), and is related to a lower response to salvage treatment in patients with t(8; 21). (10,11,17,21)





Most clinical studies have found that the CBF AML group is associated with a better complete remission (CR) rate, overall survival (OS), and lower relapse risk (RR) than patients with cytogenetically normal AML. In 1 clinical study, the CBF AML group had a CR of 72%, RR of 56%, and OS of 34% at 5 years, while the cytogenetically normal AML group in the same study had a CR of 63%, RR of 78%, and OS of 15% at 5 years. This improvement in CR and OS is seen in other studies; hence, the inclusion of CBF AML in the current WHO classification as a "good prognosis" AML. (25,27)

For patients harboring inv(16), achieving a negative RT-PCR status after remission-induction chemotherapy might require several months. The risk of relapse is higher in patients with a demonstrable fusion transcript by RT-PCR during remission. Also, the relapse risk increases for those who do not achieve a negative status within the first 9 to 12 months. For t(8; 21) AML, the fusion transcript has been detected for up to 10 years in patients with complete remission. (2) Therefore, the detection of low-level minimal residual disease with a very high-sensitivity RT-PCR assay may not differentiate those patients with a higher risk for relapse. Patients whose fusion transcript level is persistently high and those whose minimal residual disease status changes from negative to positive are at higher risk of relapse.


Compared to other cytogenetic AML subgroups, CBF AML is considered a more favorable subset of AML. Risk-adapted stratification is used that is based on the genetic makeup of individual cases. Although partial deletion of chromosome 9, del(9q), was considered to be an unfavorable prognostic factor, recent multicenter studies (11,28) have failed to show any prognostic impact of del(9q) on complete remission and relapse-free survival. Patients with inv(16) and 1 or more secondary chromosome abnormalities, especially trisomy 22, had a lower risk of relapse than those with inv(16) solely. (10) Patients with CBF AML and mutations in the KIT gene (exon 17) have a higher risk of relapse. (19) The mechanism underlying KIT gene mutations that adversely affects the prognosis involves phosphorylation of the KIT receptor after physiologic binding of KIT ligand, which activates downstream pathways supporting cell proliferation and survival. (29) KIT mutations represent not only a prognostic indicator but also a potential therapeutic target for the tyrosine kinase inhibitors (Table 2). The CALGB study (10) showed that for patients with t(8; 21), race was an important prognostic factor. Induction chemotherapy had a lower risk of failure among the white population than the nonwhite population. Also, secondary cytogenetic abnormalities had less prognostic impact on the white patients than the nonwhite patients. In contrast, for inv(16), race did not have any prognostic impact. Gene expression profiling has helped to derive other genetic prognostic factors. A recent study by Bullinger et al (30) showed the role played by deregulated MAPK and JNK pathways as prognosticators. Nucleophosmin and Fmslike tyrosine kinase 3/internal tandem duplication without wild-type allele have only been rarely reported with CBF AML, and hence their prognostic value for this subset of AML remains unclear. (31)


Core-binding factor AML occurs owing to disruption of genes encoding different subunits of CBF, essential genes for hematopoietic cell differentiation. In the WHO classification, this distinct subset of leukemia is categorized as AML with recurrent genetic abnormalities. Identification of the cytogenetic fusion transcripts is considered diagnostic of acute leukemia, even when the blast count is less than 20%. The myeloid blasts in t(8; 21) AML are large, with abundant basophilic cytoplasm, with perinuclear hofs, occasional to numerous azurophilic granules, and blunted Auer rods. Generally, inv(16) AML is characterized by myelomonocytic blast differentiation and an increased eosinophil count, with eosinophil precursors demonstrating variable numbers of large, purple-violet cytoplasmic granules. In patients with CBF AML, a higher relapse risk is observed when mutations in the KIT gene (exon 17) are present. For CBF AML, induction therapy with fludarabine and Ara-C (FA) or FA plus granulocyte colony-stimulating factor (FLAG) is associated with a better event-free survival than the standard 3 plus 7 anthracycline/cytarabine (Ara-C) combination. Core-binding factor AML carries a better prognosis than cytogenetically normal AML or other subtypes of AML.


(1.) Arber D, Vardiman J, Brunning R, et al. Acute myeloid leukemia with recurrent genetic abnormalities. In: Swerlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:110-123. World Health Organization Classification of Tumours; vol 2.

(2.) Marcucci G. Core binding factor acute myeloid leukemia. Clin Adv Hematol Oncol. 2006; 4(5):339-341.

(3.) Rowley J. Identification of a translocation with quinacrine fluorescence in a patient with acute leukemia. Ann Genet. 1973; 16(2):109-112.

(4.) Le Beau MM, Larson RA, Bitter MA, et al. Association of an inversion of chromosome 16 with abnormal marrow eosinophils in acute myelomonocytic leukemia: a unique cytogenetic-clinicopathological association. N Engl J Med. 1983; 309(11):630-636.

(5.) Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer. 2002; 2(7):502-513.

(6.) Paschka P. Core binding factor acute myeloid leukemia. Semin Oncol. 2008; 35(4):410-117.

(7.) Downing JR. The core-binding factor leukemias: lessons learned from murine models. Curr Opin Genet Dev. 2003; 13(1):48-54.

(8.) Yokomizo T, Ogawa M, Osato M, et al. Requirement of Runx1/AML1/ PEBP2alphaB for the generation of haematopoietic cells from endothelial cells. Genes Cells. 2001; 6(1):13-23.

(9.) van Dongen JJ, Macintyre EA, Gabert JA, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease: report of the BIOMED-1 Concerted Action--investigation of minimal residual disease in acute leukemia. Leukemia. 1999; 13(12):1901-1928.

(10.) Marcucci G, Mrozek K, Ruppert AS, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8; 21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. J Clin Oncol. 2005; 23(24):5705-5717.

(11.) Appelbaum FR, Kopecky KJ, Tallman MS, et al. The clinical spectrum of adult acute myeloid leukaemia associated with core binding factor translocations. Br J Haematol. 2006; 135(2):165-173.

(12.) Yin CC, Medeiros LJ, Bueso-Ramos CE. Recent advances in the diagnosis and classification of myeloid neoplasms--comments on the 2008 WHO classification. Int J Lab Hematol. 2010; 32(5):461-476.

(13.) Huret JL. inv(16)(p13q22), t(16; 16)(p13; q22), del(16)(q22). Atlas Genet Cytogenet Oncol Haematol. 1997; 1(2):81-82.

(14.) Gustafson SA, Lin P, Chen SS, et al. Therapy-related acute myeloid leukemia with t(8; 21) (q22; q22) shares many features with de novo acute myeloid leukemia with t(8; 21)(q22; q22) but does not have a favorable outcome. Am J Clin Pathol. 2009; 131(5):647-655.

(15.) Merchant SH, Haines S, Hall B, et al. Fluorescence in situ hybridization identifies cryptic t(16; 16)(p13; q22) masked by del(16)(q22) in a case of AML-M4 Eo. J Mol Diagn. 2004; 6(3):271-274.

(16.) Jiao B, Wu CF, Liang Y, et al. AML1-ETO9a is correlated with C-KIT overexpression/mutations and indicates poor disease outcome in t(8; 21) acute myeloid leukemia-M2. Leukemia. 2009; 23(9):1598-1604.

(17.) Schlenk RF, Benner A, Krauter J, et al. Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol. 2004; 22(18):3741-3750.

(18.) Delaunay J, Vey N, Leblanc T, et al. Prognosis of inv(16)/t(16; 16) acute myeloid leukemia (AML): a survey of 110 cases from the French AML Intergroup. Blood. 2003; 102(2):462-469.

(19.) Paschka P, Marcucci G, Ruppert AS, et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8; 21): a Cancer and Leukemia Group B Study. J Clin Oncol. 2006; 24(24):3904-3911.

(20.) Goemans BF, Zwaan CM, Miller M, et al. Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia. 2005; 19(9):1536-1542.

(21.) Dombret H, Preudhomme C, Boissel N. Core binding factor acute myeloid leukemia (CBF-AML): is high-dose Ara-C (HDAC) consolidation as effective as you think? Curr Opin Hematol. 2009; 16(2):92-97.

(22.) Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia: Cancer and Leukemia Group B. N Engl J Med. 1994; 331(14):896-903.

(23.) Byrd JC, Dodge RK, Carroll A, et al. Patients with t(8; 21)(q22; q22) and acute myeloid leukemia have superior failure-free and overall survival when repetitive cycles of high-dose cytarabine are administered. J Clin Oncol. 1999; 17(12):3767-3775.

(24.) Bloomfield CD, Lawrence D, Byrd JC, et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res. 1998; 58(18):4173-4179.

(25.) Grimwade D, Walker H, Oliver F, et al. The importance of diagnostic cytogenetics on outcomein AML: analysis of 1, 612 patients entered into the MRC AML 10 trial--The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood. 1998; 92(7):2322-2333.

(26.) Borthakur G, Kantarjian H, Wang X, et al. Treatment of core-binding-factor in acute myelogenous leukemia with fludarabine, cytarabine, and granulocyte colony-stimulating factor results in improved event-free survival. Cancer. 2008; 113(11):3181-3185.

(27.) Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood. 2001; 98(5):13121320.

(28.) Schoch C, Haase D, Haferlach T, et al. Fifty-one patients with acute myeloid leukemia and translocation t(8; 21)(q22; q22): an additional deletion in 9q is an adverse prognostic factor. Leukemia. 1996; 10(8):1288-1295.

(29.) Lennartsson J, Jelacic T, Linnekin D, et al. Normal and oncogenic forms of the receptor tyrosine kinase kit. Stem Cells. 2005; 23(1):16-43.

(30.) Bullinger L, Rucker FG, Kurz S, et al. Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia. Blood. 2007; 110(4):1291-1300.

(31.) Verschraegen CF, Vasuratna A, Edwards C, et al. Clinicopathologic analysis of mullerian adenosarcoma: the M. D. Anderson Cancer Center experience. Oncol Rep. 1998; 5(4):939-944.

Nikhil A. Sangle, MD, FRCPath; Sherrie L. Perkins, MD, PhD

Accepted for publication October 26, 2010.

From the Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, and ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Nikhil A. Sangle, MD, FRCPath, Department of Pathology, University of Utah Health Sciences Center, 50 N Medical Dr, Salt Lake City, Utah 84132 (e-mail:
Table 1. Morphologic Features of t(8;21) and inv(16) Acute
Myeloid Leukemia

t(8;21) inv(16)

* Large myeloid blasts with * Variable number of eosinophils
abundant basophilic cytoplasm

* Numerous azurophilic granules * All stages of eosinophilic

* Perinuclear clearing or hofs * Immature purple-violet
 cytoplasmic granules

* Occasional blasts containing * Mainly evident at the
Auer rods promyelocyte and myelocyte stages

Table 2. Important Prognostic Factors for t(8;21) and inv(16) Acute
Myeloid Leukemia

t(8;21) inv(16)

* KIT gene mutation (exon 17) * KIT gene mutation (exon 17)
adversely affects the prognosis adversely affects the prognosis

* Prognostic significance of * Patients with trisomy 22 have
del(9q) is debatable a lower risk of relapse
COPYRIGHT 2011 College of American Pathologists
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2011 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Sangle, Nikhil A.; Perkins, Sherrie L.
Publication:Archives of Pathology & Laboratory Medicine
Date:Nov 1, 2011
Previous Article:Nuclear protein in testis midline carcinomas: a lethal and underrecognized entity.
Next Article:Human epidermal growth factor receptor 2 testing in gastroesophageal cancer: correlation between immunohistochemistry and fluorescence in situ...

Terms of use | Copyright © 2017 Farlex, Inc. | Feedback | For webmasters