Abstract
Immunohistochemistry has become an essential ancillary examination for the identification and classification of carcinomas of unknown primary site (CUPs). Over the last decade, the diagnostic accuracy of organ- or tumour-specific immunomarkers and the clinical validation of effective immunohistochemical panels has improved significantly. When dealing with small sample sizes, diagnostic accuracy is crucial, particularly in the current era of targeted molecular and immune-based therapies. Effective systematic use of appropriate immunohistochemical panels enables accurate classification of most of the undifferentiated carcinomas as well as careful preservation of tissues for potential molecular or other ancillary tests. This review discusses the algorithmic approach to the diagnosis of CUPs using CK7 and CK20 staining patterns. It outlines the most frequently used tissue-specific antibodies, provides some pitfalls essential in avoiding potential diagnostic errors and discusses the complementary tools, such as molecular tumour profiling and mutation-specific antibodies, for the improvement of diagnosis and prediction of the treatment response.
Highlights
In the absence of an identifiable primary tumour site, despite extensive multidisciplinary investigations, carcinomas of unknown primary site (CUPs) are characterized as metastatic carcinomas [1]
Its expression is maintained in almost all adenocarcinomas of the appendix and in over 85% of colon adenocarcinomas [29]
PAX8 is a sensitive but not very specific marker, its expression has been observed in carcinomas of renal, thyroid, ovarian, endometrial, or uterine origin (Figure 8) [21]
Summary
In the absence of an identifiable primary tumour site, despite extensive multidisciplinary investigations, carcinomas of unknown primary site (CUPs) are characterized as metastatic carcinomas [1]. When dealing with a CK7−/CK20+ CUPs of non-Lieberkhunian morphology, the first aetiology to be considered is a colorectal origin corresponding most often to a poorly differentiated adenocarcinoma (Figure 4) [7] In these undifferentiated forms, CK20 is often only focally positive, whereas medullary or undifferentiated carcinomas of colorectal origin frequently have a CK7−/CK20− phenotype. The specificity of S100P is limited as many neoplasms demonstrate positive expression, including pancreatic, gallbladder, digestive, bladder and pulmonary adenocarcinomas [51] Their routine use is limited by their restricted availability in pathology laboratories. PAX8 is a sensitive but not very specific marker, its expression has been observed in carcinomas of renal, thyroid, ovarian, endometrial, or uterine origin (Figure 8) [21]. The tissue material used for diagnosis and phenotyping should be used sparingly if a molecular analysis is expected
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