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Review
. 2023 Dec;42(4):1189-1200.
doi: 10.1007/s10555-023-10101-6. Epub 2023 Jul 3.

Carcinoma of unknown primary (CUP): an update for histopathologists

Katie Beauchamp  1 , Bruce Moran  2 , Timothy O'Brien  3 , Donal Brennan  4   5 , John Crown  6 , Kieran Sheahan  2 , Maura Bríd Cotter  2
Affiliations
Review

Carcinoma of unknown primary (CUP): an update for histopathologists

Katie Beauchamp et al. Cancer Metastasis Rev. 2023 Dec.

Abstract

Carcinoma of unknown primary (CUP) is a heterogeneous group of metastatic cancers in which the site of origin is not identifiable. These carcinomas have a poor outcome due to their late presentation with metastatic disease, difficulty in identifying the origin and delay in treatment. The aim of the pathologist is to broadly classify and subtype the cancer and, where possible, to confirm the likely primary site as this information best predicts patient outcome and guides treatment. In this review, we provide histopathologists with diagnostic practice points which contribute to identifying the primary origin in such cases. We present the current clinical evaluation and management from the point of view of the oncologist. We discuss the role of the pathologist in the diagnostic pathway including the control of pre-analytical conditions, assessment of sample adequacy, diagnosis of cancer including diagnostic pitfalls, and evaluation of prognostic and predictive markers. An integrated diagnostic report is ideal in cases of CUP, with results discussed at a forum such as a molecular tumour board and matched with targeted treatment. This highly specialized evolving area ultimately leads to personalized oncology and potentially improved outcomes for patients.

Keywords: Carcinoma of unknown primary; Immunohistochemistry; Metastatic; Molecular pathology; Morphology; Pitfalls.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Examples of antibody cocktails a TTF-1/Napsin A in the lung tumour, b P63/34BE12 and AMACR in the prostate, and c P63 and CK5/6 in the skin
Fig. 2
Fig. 2
Careful morphological analysis performed on H&E can differentiate an a adenocarcinoma with a glandular growth pattern from non-carcinoma tumour subtypes like b a lymphoma composed of dyscohesive sheets of neoplastic cells within minimal cytoplasm, c a melanoma comprising sheets of epithelioid cells with abundant cytoplasm and prominent nucleoli, and d a sarcoma with spindled morphology
Fig. 3
Fig. 3
Metastatic epithelioid angiosarcoma. a Low power view and b high power view of skin H&E showing an epithelioid tumour with vasoformative foci. c Strong AE1/3 expression. d Strong nuclear ERG expression
Fig. 4
Fig. 4
Illustrative case of metastatic CUP. A Low power glandular morphology. B High power poorly differentiated. C CK7 positive. D CK20 positive. E Gata 3 positive. F TTF1 negative. G CDX2 negative. H PSA negative
See this image and copyright information in PMC

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