Document Type : Original Research


Dept. of Pathology, Firouzgar Hospital, Tehran University of Medical Sciences, Tehran, Iran


Background & Objectives: Anaplastic lymphoma Kinase (ALK) is a receptor tyrosine kinase involved in the genesis of several human cancers. ALK was initially identified because of its involvement in anaplastic large cell lymphoma (ALCL). ALK is believed to foster tumorigenesis following activation by autocrine and/or paracrine growth loops. Studies reveal that the presence of anti-ALK antibodies may be relevant to the relatively good prognosis. Therapeutic approaches consisting of gene therapy and immunotherapy targeting this molecule hold promise.
Material & Methods: We examined a number of human breast cancers to see if ALK is expressed in this tumor and studied its relation with type of carcinoma and its grade, tumor size, presence of necrosis, vascular invasion , skin involvement, lymph node metastasis and patient’s age. 
Result: 100 patients were enrolled with mean age of 50.2 ± 12.5 years. The histological phenotypes of the breast cancers studied included Invasive Ductal Carcinoma, Invasive Lobular Carcinoma and Medullary Carcinoma. ALK expression was evaluated by immunohistochemistry which was positive in 47 cases (47%). No statistically significant relationship is found between the above mentioned parameters except for tumor size and ALK expression. (P< 0.01)


  1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2(9):533-43.
  2. Ebrahimi M, Najafi M,Harirchi I,Jarrahi AM,Mohagheghi A,Mousavi SM. Breast cancer in Iran, an epidemiological review. Breast J 2007; 13(4):383-91.
  3.  Perez-Pinera P, Chang Y, Astudillo A, Mortimer J, Deuel TF. Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer. Biochem  Biophys Res Commun 2007;358(2):399-403.
  4.  Pulford K, Morris SW, Turturro F. Anaplastic Lymphoma Kinase Proteins in Growth Control and Cancer. J Cell Physiol 2004; 199(3):330-58.
  5.  Morris SW, Kirstein MN, Valentine MB, Dittmer K, Shapiro DN, Look AT, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1995; 267(5196):316-7.
  6.  Le Beau MM, Bitter MA, Larson RA, Doane LA, Ellis ED, Franklin WA, et al . The t(2;5)(p23;q35): a recurring chromosomal abnormality in Ki-1-positive anaplastic large cell lymphoma. Leukemia 1989; 3(12):866-70.
  7.  Dirks WG, Fähnrich S, Lis Y, Becker E, MacLeod RA, Drexler HG. Expretion and Functional Analysis of anaplastic lymphoma kinase (ALK) Gene in Tumor Cell Lines. Int J Cancer 2002; 100(1):49-56.
  8.  Li R, Morris SW. Development of anaplastic lymphoma kinase (ALK) small-molecule inhibitors for cancer therapy. Med Res Rev 2008;28(3):372-412.
  9.  Pillay K, Govender D, Chetty R. ALK protein expression in rhabdomyosarcomas. Histopathology 2002; 41(5):461-7.
  10.  Lamant L, Pulford K, Bischof D, Morris SW, Mason DY, Delsol G, et al. Expression of the ALK tyrosine kinase gene in neuroblastoma. Am J Pathol 2000; 156(5):1711-21.
  11.  Li XQ, Hisaoka M, Shi DR, Zhu XZ, Hashimoto H. Expression of anaplastic lymphoma kinase in soft tissue tumors: an immunohistochemical and molecular study of 249 cases. Hum Pathol 2004; 35(6):711-21.
  12.  Powers C, Aigner A, Stoica GE, McDonnell K, Wellstein A. Pleiotrophin signaling through anaplastic lymphoma kinase is rate limiting for glioblastoma growth. J Biol Chem 2002; 277(16):14153-8.
  13.  Dirks WG, Fähnrich S, Lis Y, Becker E, MacLeod RA, Drexler HG. Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines. Int J Cancer 2002; 100(1):49-56.
  14.  Pulford K, Lamant L, Espinos E, Jiang Q, Xue L, Turturro F, et al. The emerging normal and disease-related roles of anaplastic lymphoma kinase. Cell Mol Life Sci 2004; 61(23):2939-53.
  15.  Tuma RS. ALK gene amplified in most inflammatory breast cancers. J Natl Cancer Inst 2012; 104(2):87-8.
  16.  Pulford K, Falini B, Banham AH, Codrington D, Roberton H, Hatton C, et al. Immune response to the ALK oncogenic tyrosine kinase in patients with anaplastic large-cell lymphoma. Blood 2000; 96(4):1605-7.
  17.   Piva R, Chiarle R, Manazza AD, Taulli R, Simmons W, Ambrogio C, et al.  Ablation of oncogenic ALK is a viable therapeutic approach for anaplastic large-cell lymphomas. Blood 2006; 107(2):689-97.
  18.  Cheng M, Quail MR, Gingrich DE, Ott GR, Lu L, Wan W, et al. CEP-28122, a Highly Potent and Selective Orally Active Inhibitor of Anaplastic Lymphoma Kinase with Antitumor Activity in Experimental Models of Human Cancers. Mol Cancer Ther 2012;11(3):670-9.
  19.  Deng X, Wang J, Zhang J, Sim T, Kim ND, Sasaki T, et al. Discovery of 3,5-Diamino-1,2,4-triazole Ureas as Potent Anaplastic Lymphoma Kinase Inhibitors. ACS Med Chem Lett 2011;2(5):379-384.
  20.  Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR,  et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large cell lymphoma. Mol Cancer Ther 2007;6(12 Pt 1):3314-22.
  21.  Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem 2011;54(18):6342-63.
  22.  Morris SW, Naeve C, Mathew P, James PL, Kirstein MN, Cui X, et al. ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkins lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). Oncogene 1997;14(18):2175-88.
  23.  Gambacorti-Passerini C, Messa C, Pogliani EM. Crizotinib in Anaplastic Large-Cell Lymphoma. N Eng J Med 2011;364(8) ):775-6.
  24.  Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small cell lung cancer. N Eng J Med 2010;363(18):1693-703.
  25.  Falini B, Pileri S, Zinzani PL, Carbone A, Zagonel V, Wolf-Peeters C, et al. ALK+ lymphoma : clinico-patholoical finding and outcome. Blood 1999;93(8):2697-706.
  26.  Mossé YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 2008;455(7215):930-5.
  27.  Passoni L, Longo L, Collini P, Coluccia AM, Bozzi F, Podda M, et al. Mutation-Independent Anaplastic Lymphoma Kinase Overexpression in Poor Prognosis Neuroblastoma  Patients. Cancer Res 2009;69(18):7338-46 .
  28.  Rodig SJ, Mino-Kenudson M, Dacic S, Yeap BY, Shaw A, Barletta JA, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the Western populations. Clin Cancer Res 2009;15(16):5216-23.
  29.  Bagci O, Tumer S, Olgun N, Altungoz O. Copy number status and mutation analyses of anaplastic lymphoma kinase (ALK) gene in 90 sporadic neuroblastoma tumors. Cancer Lett. 2012;317(1):72-7.
  30. Paik JH, Choe G, Kim H, Choe JY, Lee HJ, Lee CT, et al.Screening of anaplastic lymphoma kinase rearrangement by immunohistochemistry in non-small cell lung cancer: correlation with fluorescence in situ hybridization. J Thorac Oncol 2011;6(3):466-72.