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Tissue of Origin Test

The identity of most tumors can be accurately determined using histologic, clinical, and radiographic findings. However, when tumors are poorly differentiated or metastatic with no clear primary, identifying the tissue of origin may be difficult. The Tissue of Origin Test (Pathwork® Diagnostics, CA, USA) is a molecular diagnostic test that was developed to assist in the diagnosis of metastatic, poorly differentiated, and undifferentiated cancer.

The Tissue of Origin Test is based on an Affymetrix microarray. It compares the expression for 2000 genes in a patient's tumor with a panel of 15 known tumor types that were diagnosed according to current clinical and pathological practice (bladder, breast, colorectal, gastric, testicular germ cell, kidney, hepatocellular, non-small-cell lung, non-Hodgkin's lymphoma, melanoma, ovarian, pancreatic, prostate, thyroid and sarcoma). These 15 tumor types represent 90% of all cancers. The test provides a similarity score for each of the 15 tumor types included in the assay. The Tissue of Origin Test received US FDA marketing clearance for the testing of formalin-fixed, paraffin-embedded (FFPE) tumor samples in June 2010.

Tissue must be sent by the referring pathologist to a central laboratory to obtain this testing. Tumor RNA is isolated, amplified and reverse transcribed to generate biotinylated cDNA, which is then hybridized to a microarray. The microarray is scanned to acquire signal intensity. A computer algorithm quantifies the similarity between RNA expression patterns of the unknown specimen and the 15 known tumor types. Each specimen produces 15 similarity scores, ranging from 0 (very low similarity) to 100 (very high similarity), that sum to 100. The highest similarity score indicates the most likely primary site.  A similarity score ≤5 rules out a tissue type as the likely primary site with greater than 99% likelihood.  If no similarity score is ≥20, the accuracy of the top score is not assured and therefore not reported. In published studies, as many as one fourth of samples have yielded indeterminate scores.

Studies indicate that the Tissue of Origin Test has the potential to result in a change in diagnosis and revision of treatment plan for approximately four-fifths of cases submitted for analysis.  Rather than being considered the final diagnosis, the prediction of the Tissue of Origin Test should be integrated with other information such as clinical history, imaging data, histology and immunohistochemistry to arrive at a final diagnostic consensus of tissue origin.  So far, not studies have demonstrated whether tissue of origin identification in cancer with unresolved tumors improves treatment outcomes.

Currently, the National Comprehensive Cancer Network (NCCN)'s panel on occult cancer does not recommend the use of any gene-expression profiling product as part of routine evaluation. However, some experts suggest that gene-expression profiling assays are an emerging diagnostic tool that will eventually be included in guidelines.

Pathwork Diagnostics ceased operations on April 2, 2013.

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