To date, immunohistochemistry has largely focused on markers of cell type, as an aid to the diagnosis of specific tumours. More recently, it has been applied to a limited number of markers of cell proliferation, such as Ki-67 and PCNA, as prognostic factors in malignant tumours.
In addition to the above, Gown1 identifies emergent uses of immunohistochemistry, coining the term genogenic immunohistochemistry. These are:
Documentation of loss of expression of a protein due to specific mutations, usually truncation mutations.
Examples include:
Loss of expression of E-cadherin in lobular breast cancer, resulting in the loss of cellular cohesion. At least 23 different mutations of the E-cadherin gene have been identified: in other cases, transcription is impeded by methylation of the gene's promoter region. Similar inactivating mutations and loss of E-cadherin expression are to be found in lobular carcinoma in-situ but not in ductal carcinoma in in-situ or invasive ductal carcinoma.
Hereditary non-polyposis colon cancer arises because of mutations in genes for DNA repair, principally hMSH2 and hMLH1. The loss of these repair genes results in microsatellite instability. The lack of expression of hMSH2 or hMLH1 can be demonstrated immunohistochemically.
The t(2p23;5q35) translocation of anaplastic large cell lymphoma leading to the of the NPM/ALK fusion protein. This translocation in ALCL is associated with a significantly better survival. Other lymphomas with this translocation lack the typical morphology of ALCL, giving rise to the concept of an "ALKoma", defined not by morphology but by a specific mutation and fusion protein.
The overexpression of ALK due to an alternative translocation characterises neoplastic inflammatory myofibroblastic tumours and distinguishes them from reactive inflammatory pseudotumours.
Primitive neuroectodermal tumour/ Ewing's sarcoma has, in 90% of cases, a t(11;22)(q24;q12) translocation, resulting in a EWS/FLI-1 fusion gene and overexpression of the FLI-1 protein. Expression of FLI-1 differentiates PNET/EWS from other small blue round cell tumours.
WT-1 overexpression in desmoplastic small round cell tumour (DSRCT) is the result of a t(11;22)(p13;q12) translocation, resulting in an EWS/WT1 fusion protein, detectable immunohistochemically by antibodies directed against the C-terminal of WT-1.
Staining for promyelocytic leukemia (PML) protein will detect acute PML with t(15;17) because the microspeckled nuclear labeling pattern for PML-RARa is highly distinctive2.
Expression of c-kit (CD117) is highly characteristic of gastrointestinal stromal tumours. The drug STI571 blocks the kinase pocket of c-kit and is highly effective in the treatment of GISTs.
Identification of overexpression of the HER-2/neu protein to validate the use of trastuzumab (HerceptinTM) in the treatment of breast cancer patients. The HER-2/neu gene is overexpressed due to gene amplification.
There is the possibility that the molecular profiling of tumours, particularly where a large battery of genes needs to be tested, will be taken over by commercial enterprises, sidelining the surgical pathologist3.
References
1 A.M.Gown. Genogenic immunohistochemistry: a new era in diagnostic immunohistochemistry. Current Diagnostic Pathology 2002;8:193-200.
This page last revised 17.4.2006.
©SMUHT/PW Bishop