ALK (lung)

ALK is a protein, 200 kDa, a transmembrane receptor tyrosin kinase, presumably receptor for the growth factor pleiotrophin. In normal tissues, ALK protein is expressed only few cells within the developing and mature nervous system (glial cells, neurons, endothelial cells and pericytes) (11-13). The ALK gene was discovered in the late 1980s, when it was noted that CD30+ anaplastic large cell lymphomas (ALCLs) may be associated with a balanced (2;5)(p23;q35) chromosomal translocation in some cases (1-5). Subsequently, cloning of the chromosomal breakpoints identified ALK gene, which was located at chromosome 2p23, and NPM (encoding ubiquitously expressed nucleophosmin), located at 5q35 (6). The resulting NPM-ALK hybrid protein (also known as p80) contains 40% of the amino-terminal portion of NPM linked to the entire cytoplasmic domain of ALK (7-10).

The t(2;5) translocation that involves the ALK gene accounts for about 80% of the ALCL cases (14) (Fig. 1). In the remaining cases, other variant rearrangements involving ALK gene are seen, including t(1;2)(q21;p23), inversion 2(p23;q35), t(2;3)(p23;q21), t(2;17)(p23;q23), and t(X;2)(q11-12;p23). In these uncommon rearrangements ALK gene is juxtaposed to TPM3, encoding a nonmuscle tropomyosin; TFG (TRCK fusion gene), encoding a polypeptide with a predicted coiled:coiled domain; ATIC, which encodes an enzyme, 5-aminoimidazole-4-carboximide-1-ß-D-ribonucleotide transformylase/inosine monophosphate cyclohydrolase, that participates in purine metabolism; CLTC, encoding the clathrin heavy-chain gene; or MSN, encoding moesin, a member of the protein 4.1 family of membrane-associated polypeptides(15-20). ALK gene is translocated not only in ALCL, but also in inflammatory myofibroblastic tumor. Tropomyosin 4 and RANBP2 genes were found involved only in inflammatory myofibroblastic tumor, nucleophosmin and TRCK fusion gene in ALCL only, while tropomyosin 3, and clathrin heavy chain genes were found involved in rare cases of both ALCL and inflammatory myofibroblastic tumors (27,28). ALK has also been detected by immunohistochemistry in some sarcomas, particularly rhabdomyosarcoma (29). However, in most of the soft tissue tumors, except the inflammatory myofibroblastic tumors, it displayed merely low-level expression. It has also been described in some cases of neuroblastoma (30). ALK1 can also be expressed in diffuse large B cell lymphoma (DLBCL). These are unique DLBCL with monomorphic large immunoblast-like cells, containing large central nucleoli, which tend to invade lymphatic sinuses. Superficially they resemble anaplastic large cell lymphoma (ALCL) but they lack CD30. These lymphomas express epithelial membrane antigen (as do ALCL), but also contain cytoplasmic IgA (31). In contrast, CD30-positive DLBCL are ALK1-negative. ALK-positive ALCL usually present in young men, presenting with advanced disease (stage III or IV), are commonly associated with fever, and there is extra nodal involvement. However, they respond well to chemotherapy and have a favourable outcome (24,25). Interestingly, ALK-positive ALCL are consistently BCL2-negative (26).

The main application is classification of malignant lymphomas, viz. identification of ALCL. Furthermore ALK is important for the identification of inflammatory myofibroblastic tumors.

Appendix is recommendable as positive and negative external tissue control, in which ganglion cells of the myenteric plexus and dispersed axons must show an at least weak to moderate staining reaction and no staining should be seen in smooth muscle cells and epithelium.
Lung adenocarcinomas with and without ALK translocation can be applied as supplemental external positive and negative tissue control and are crucial at the validation/verification phase of the IHC methods. The ALK status of all the included positive and negative tissue controls must be confirmed by FISH in the validation process. 
ALCLs will typically express a too high level of antigen and cannot be recommended as the only positive tissue control for lu-ALK.

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