NPM / ALK, p80, Anaplastic Lymphoma Kinase

The ALK protein is probably a tyrosine kinase receptor for the growth factor pleiotrophin3. The normal ALK protein is 200kD6. The majority of anaplastic large cell lymphomas are associated with the t(2;5)(p23;q35) translocation13, which results in the fusion of the cell cycle regulating nucleolar protein nucleophosmin (NPM) with the anaplastic lymphoma kinase (ALK), producing an 80 kD chimeric protein6, consisting of the N-terminal portion of the NPM protein joined to the entire cytoplasmic domain of the ALK protein11. The antibody ALK1 recognises an intracellular domain of the ALK protein14. ALK-1, ALKc and p80 all react with both normal ALK and the NPM-ALK fusion protein. ALK-11 is a rabbit polyclonal anti-human antibody against the ALK protein4.

Immunohistochemical expression

• It is expressed in normal tissues during embryogenesis7.

• The only staining in normal adult tissues is in scattered glial cells, neurones and endothelial cells of the central nervous system6, where it is weak and only seen in frozen sections

• The pattern of positivity depends on the buffer used. Citrate buffer results in nuclear, nucleolar and cytoplasmic staining. EDTA gives stronger nuclear and weaker cytoplasmic staining. Malignant cells expressing the NPM-ALK hybrid show nuclear, nucleolar and cytoplasmic staining. Those expressing the full length ALK receptor show cytoplasmic but not nuclear or nucleolar staining.

Positivity for ALK in Inflammatory myofibroblastic tumour and rhabdomyosarcoma is associated with extra copies of 2p23 and ALK break-apart or ALK/NPM fusion, as demonstrated by FISH8.

Diagnostic utility

• differentiation of anaplastic large cell lymphoma from Hodgkin's disease

• detection of anaplastic large cell lymphoma in bone marrow

• ALK-positive nodal anaplastic large cell lymphoma have a better survival than anaplastic large cell lymphoma-negative nodal ALCL2,9

• identification of inflammatory myofibroblastic tumours.

References

1 Delsol G, New antibodies and new applications of old antibodies in the diagnosis of hematolymphoid neoplasms. In Immunohistochemistry Long Course, Nice, October 18-23, 1998.

2 ten Berge, R. L., Snijdewint, F. G., von Mensdorff-Pouilly, S. MUC1 (EMA) is preferentially expressed by ALK positive anaplastic large cell lymphoma, in the normally glycosylated or only partly hypoglycosylated form. J Clin Pathol 2001;54:933-939. FULL TEXT

3 Stoica, G. E., Kuo, A., Aigner, A. Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin. J Biol Chem 2001;276:16772-9. FULL TEXT

4 Cook, J. R., Dehner, L. P., Collins, M. H., Ma, Z., Morris, S. W., Coffin, C. M., Hill, D. A. Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study. Am J Surg Pathol 2001;25:1364-1371.

5 Christie Problems in Tumour Patholgy, 7.6.2002.

6 Pulford, K., Lamant, L., Morris, S. W. et al. Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. Blood 1997;89:1394-404.

7 Pillay, K., D. Govender, et al. (2002). "ALK protein expression in rhabdomyosarcomas." Histopathology 41(5): 461-7. (Initialy published as Pillay K, Bickhoo A, Govender D, Chetty R. ALK protein expression in rhabdomyosarcomas. Pathological Society July 2002, abstract 171.)

8 Cessna, M. H., H. Zhou, et al. (2002). "Expression of ALK1 and p80 in inflammatory myofibroblastic tumor and its mesenchymal mimics: a study of 135 cases." Mod Pathol 15(9): 931-8. (Initially published as Coffin CM et al. Expression of ALK 1 and p80 in inflammatory myofibroblastic tumour and its mimics. A study of 135 cases. Mod Pathol 2001;14:10A.)

9 Cataldo KA, Jalal SM, Law ME, et al. Detection of t(2;5) in anaplastic large cell lymphoma: comparison of immunohistochemical studies, FISH, and RT-PCR in paraffin-embedded tissue. Am J Surg Pathol 1999; 23:1386-92

10 Nakamura S, Shiota M, Nakagawa A, et al. Anaplastic large cell lymphoma: a distinct molecular pathologic entity: a reappraisal with special reference to p80(NPM/ALK) expression. Am J Surg Pathol 1997; 21:1420-32

11 Falini B, Bigerna B, Fizzotti M, et al. ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum. Am J Pathol 1998; 153:875-86

12 Hutchison RE, Banki K, Shuster JJ, et al. Use of an anti-ALK antibody in the characterization of anaplastic large-cell lymphoma of childhood. Ann Oncol 1997; 8 Suppl 1:37-42

13 Lamant L, Meggetto F, al Saati T, et al. High incidence of the t(2;5)(p23;q35) translocation in anaplastic large cell lymphoma and its lack of detection in Hodgkin's disease. Comparison of cytogenetic analysis, reverse transcriptase-polymerase chain reaction, and P-80 immunostaining. Blood 1996; 87:284-91

14 Delsol G, Lamant L, Mariame B et al.  A new subtype of large B-cell lymphoma expressing the ALK kinase and lacking the 2;5 translocation.   Blood 1997;89:1483-90. FULL TEXT

15 De Paepe P, Baens M, van Krieken H, et al. ALK activation by the CLTC-ALK fusion is a recurrent event in large B-cell lymphoma. Blood 2003; 102:2638-41 FULL TEXT

16 Gascoyne RD, Lamant L, Martin-Subero JI, et al. ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases. Blood 2003; 102:2568-73 FULL TEXT

17 Coffin CM, Hornick JL,Fletcher CD Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol 2007; 31:509-20

This page last revised 30.4.2007.

©SMUHT/PW Bishop