NPM / ALK, p80

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) translocation, 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 a domain of the ALK protein. ALK-11 is a rabbit polyclonal anti-human antibody against the ALK protein⁴. ALK-1, ALKc and p80 all react with both normal ALK and the NPM-ALK fusion protein.

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.

anaplastic large cell lymphoma	85% (180/213, 39/736), 43/6710, 60/10011
new subtype large B-cell lymphoma	8/8
T-cell lymphoma	0/35
B-cell lymphoma	0/100
Hodgkin's disease	0/80, negative6, 0/63 (31 nodular sclerosing, 32 mixed cellularity)10
Lymphomatoid papulosis	0/8
Inflammatory myofibroblastic tumour	44/734, 4/108
reactive lymphoid tissue	negative5
alveolar rhabdomyosarcoma	14/317, 4/16 (distinctive dot-like positivity. includes staining in 6/9 of solid alveolar pattern)8
embryonal rhabdomyosarcoma	6/407
mixed alvoelar / embryonal rhabdomyosarcoma	1/47
pleomorphic rhabdomyosarcoma	1/67
unclassified rhabdomyosarcoma	1/27, 2/158
rhabdomyosarcomatous component of mixed Mullerian tumour	4/167
leiomyosarcoma	1/108
MPNST	4/108
malignant fibrous histiocytoma	1/118

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 ALCL have a better survival than ALK-negative nodal ALCL^2,9

• 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

This page last revised 10.1.2004.

©SMUHT/PW Bishop