How can I differentiate between CUP and other malignancies in a patient with metastatic disease and no identifiable primary site?

To differentiate cancer of unknown primary origin (CUP) from other malignancies in a patient presenting with metastatic disease and no identifiable primary site, a structured diagnostic approach is essential. Initially, comprehensive clinical assessment including detailed history, physical examination (with attention to breast, nodal areas, skin, genital, rectal, and pelvic regions), and basic laboratory tests (full blood count, liver and renal function, calcium, urinalysis, lactate dehydrogenase) should be performed to identify any clues to the primary site or alternative diagnoses such as lymphoma or melanoma ¹.

Imaging with chest X-ray and computed tomography (CT) scans of the chest, abdomen, and pelvis is recommended to detect possible primary tumours or metastatic patterns suggestive of specific cancers ¹. Symptom-directed endoscopy and tumour marker tests (e.g., PSA in men, CA125 in women with peritoneal disease, AFP and hCG in suspected germ-cell tumours) should be selectively used based on clinical presentation to avoid unnecessary investigations ¹.

Histological examination of biopsy samples with immunohistochemistry is critical to distinguish carcinoma from other malignancies and to classify tumour type. A panel of antibodies including cytokeratin 7, cytokeratin 20, thyroid transcription factor-1, placental alkaline phosphatase, oestrogen receptor (in women), and PSA (in men) helps refine the diagnosis and may suggest a likely primary site or tumour lineage [1, (Beauchamp et al., 2023)].

If no primary site is identified after initial investigations and specialist review, the diagnosis of provisional CUP is made. Further specialised investigations, including positron emission tomography–computed tomography (PET-CT), may be considered especially in cases such as cervical lymphadenopathy without identified primary, to improve detection of occult primaries ¹. Molecular diagnostic tests and genomic profiling are emerging tools that can assist in identifying tissue of origin but are not yet universally standardised [1, (Beauchamp et al., 2023)].

Importantly, differentiation from other malignancies such as lymphoma, melanoma, sarcoma, or germ-cell tumours is based on histopathology and clinical features, as these have distinct treatment pathways regardless of primary site identification [1, (Zaun et al., 2018)].

In summary, differentiating CUP from other malignancies involves a stepwise approach integrating clinical, radiological, pathological, and selective molecular investigations to exclude identifiable primaries and non-epithelial cancers, thereby confirming CUP diagnosis [1, (Pentheroudakis et al., 2007); (Beauchamp et al., 2023)].