From Biology to Diagnosis and Treatment: The Ariadne's Thread in Cancer of Unknown Primary

Sep 24, 2026

Cancer of unknown primary (CUP) is a heterogeneous group of malignancies in which the primary site cannot be identified at diagnosis despite extensive workup. CUP represents about 1–3% of human cancers and is stratified into two prognostic subsets based on initial clinicopathologic features. Diagnosis relies on medical history, examination, histopathology with algorithmic immunohistochemistry, and CT imaging of the chest, abdomen, and pelvis, while molecularly guided strategies are still evolving. This review synthesizes current advances from biology and profiling to classification, diagnostic pathways, and treatment approaches.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Keywords

1. Introduction

Diagnostic layer and initial workup

Emerging diagnostic modalities

Prognostic subsets and treatment approaches

Review From Biology to Diagnosis and Treatment: The Ariadne's Thread in Cancer of Unknown Primary Beatrice Gadiel Mathew 1, Fine Aliyuda 1, Denis Taiwo 1, Kehinde Adekeye 1, Godwin Agada 1, Elisabet Sanchez 1, Aruni Ghose 1,2,3, Elie Rassy 4 and Stergios Boussios 1,5,6,7, * Citation: Mathew, B.G.; Aliyuda, F.; Taiwo, D.; Adekeye, K.; Agada, G.; Sanchez, E.; Ghose, A.; Rassy, E.; Boussios, S. From Biology to Diagnosis and Treatment: The Ariadne's Thread in Cancer of Unknown Primary. Int. J. Mol. Sci. 2023, 24, 5588. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms24065588](10.3390/ijms24065588) Academic Editor: Alfred King-Yin Lam Received: 7 February 2023 Revised: 10 March 2023 Accepted: 13 March 2023 Published: 15 March 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK 2 Department of Medical Oncology, Mount Vernon Cancer Centre, East and North Hertfordshire NHS Trust, London HA6 2RN, UK 3 Department of Medical Oncology, Barts Cancer Centre, St. Bartholomew's Hospital, Barts Health NHS Trust, London EC1A 7BE, UK 4 Department of Medical Oncology, Institut Gustave Roussy, 94805 Villejuif, France 5 King's College London, Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, London SE1 9RT, UK 6 Kent Medway Medical School, University of Kent, Canterbury CT2 7LX, UK 7 AELIA Organization, 9th Km Thessaloniki—Thermi, 57001 Thessaloniki, Greece * Correspondence: stergios.boussios@nhs.net or [stergios.boussios@kcl.ac.uk or](stergios.boussios@kcl.ac.uk or) [s.boussios@kent.ac.uk](s.boussios@kent.ac.uk) [Abstract:](Abstract: Cancer of unknown primary)[ Cancer of unknown primary](Abstract: Cancer of unknown primary) ([CUP](CUP)) [encloses a group of heterogeneous tumours](encloses a group of heterogeneous tumours), [the pri](the pri) mary sites for which cannot be identiﬁed at the time of diagnosis, despite extensive investigations. CUP has always posed major challenges both in its diagnosis and management, leading to the hypothesis that it is rather a distinct entity with speciﬁc genetic and phenotypic aberrations, considering the regression or dormancy of the primary tumour; the development of early, uncommon systemic metastases; and the resistance to therapy. Patients with CUP account for 1–3% of all human malignancies and can be categorised into two prognostic subsets according to their clinicopathologic characteristics at presentation. The diagnosis of CUP mainly depends on the standard evaluation comprising a thorough medical history; complete physical examination; histopathologic morphology and algorithmic immunohistochemistry assessment; and CT scan of the chest, abdomen, and pelvis. However, physicians and patients do not fare well with these criteria and often perform additional time-consuming evaluations to identify the primary tumour site to guide treatment decisions. The development of molecularly guided diagnostic strategies has emerged to complement traditional procedures but has been disappointing thus far. In this review, we present the latest data on CUP regarding the biology, molecular proﬁling, classiﬁcation, diagnostic workup, and treatment. Keywords: cancer of unknown primary (CUP); biology; molecular profiling; classification; diagnosis; treatment 1. Introduction Cancer of unknown primary origin (CUP) is a diverse category of cancers with varying clinical and histological characteristics for which no original tumour site has been identiﬁed despite a thorough diagnostic workup [1] . It is the seventh to the eighth most

FAQs

What is cancer of unknown primary (CUP)?

CUP refers to cancers where the primary tumor site cannot be identified at diagnosis despite extensive investigation. It is a heterogeneous group with distinct clinical and histological features.

How is CUP diagnosed in standard practice?

Standard evaluation includes thorough medical history and physical examination, histopathologic morphology with algorithmic immunohistochemistry, and CT imaging of the chest, abdomen, and pelvis. Biopsy of the most accessible lesion is also part of the workup.

What are the main diagnostic and treatment challenges in CUP?

Patients often need additional, time-consuming evaluations to find the primary site, and conventional molecularly guided diagnostic strategies have been disappointing so far. CUP is commonly managed using prognostic stratification and—when appropriate—empirical chemotherapy for unfavourable groups.

Sep 24, 2026

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