Diagnostic work-up of carcinoma of unknown primary: from immunohistochemistry to molecular profiling

Abstract

Carcinoma of unknown primary (CUP) remains a common and challenging clinical problem. The aim of diagnostic work-up in CUP is to classify as specifically as possible the cancer affecting the patient, according to the broad tumour type, subtype and, where possible, site of origin. This classification currently best predicts patient outcome and guides optimal treatment. a stepwise approach to diagnostic work-up is described. although pathology is based on morphology, the assessment of tissue-specific genes through immunohistochemistry (IHC) substantially helps tumour classification at each diagnostic step. For IHC in CUP, recent improvements include more standardised approaches and marker panels plus new markers. Tissue-specific genes are also being used in CUP work-up through molecular profiling. Large-scale profiles of hundreds of tumours of different types have been generated, compared and used to generate diagnostic algorithms. Commercial tests for CUP classification have been developed at the mRNa and microRNA and (miRNA) levels and validated in metastatic tumours and CUPs. While currently optimal pathology and IHC remain the 'gold standard' for CUP diagnostic work-up, and full clinical correlation is vital, the molecular tests appear to perform well: in the main diagnostic challenge of undifferentiated or poorly differentiated tumours, molecular profiling performs as well as or better than IHC.

Evaluation of the prognostic benefit of identifying the probable primary site in cancer of unknown primary

“…Consistent with previous studies (33)(34)(35), IHC screening was able to postulate probable primary sites in 59% (26/44) of confirmed CUP cases. Interestingly, the median survival of confirmed CUP patients with no probable primary site was higher than those with probable primary sites (figure 2).…”

Practical Applications in Immunohistochemistry: Carcinomas of Unknown Primary Site

“…There have been a number of recent publications advocating for the use of gene expression-based tests in the setting of CUP. [2][3][4] Both methodologies offer a similar range of accuracy in tumor classification (ranging from around 75% and greater); however, in our practice, gene expression-based tests are rarely used or required. Although the proposed algorithm of using gene expression profiling when the initial round of IHC panel is inconclusive may be a useful complement to IHC in some laboratories, in our practice, we often include an additional round of carefully selected and targeted IHC stains in such a scenario, which frequently leads to a diagnosis.…”

The Clinical Significance of Occult Gynecologic Primary Tumours in Metastatic Cancer

“…That scenario is a possibility because an indiscriminate approach of multiple ihc tests is currently not recommended. Such an approach frequently exhausts the biopsy specimen and often is not more revealing than a measured and rational stepwise approach 24,28 . Given our findings, oncologists and pathologists could ensure the selection of one or more proper ihc panels for women presenting with metastatic cancer of uncertain primary.…”

“…Thus, diagnostic tools that are more accurate are currently needed. For instance, gene expression profiling assays for the identification of primary tumours in metastatic cancer 6,[40][41][42][43][44][45][46] have recently emerged to complement traditional diagnostic procedures (for example, ihc analyses and computed tomography imaging) and are particularly useful when dealing with diagnostic difficulties 24,25,28 .…”