Useful information for Healthcare Professionals (HCP) to learn more about the basics of CUP (cancer of unknown primary) including epidemiology, pathogenesis, diagnostic work-up and therapeutic options of patients.

CUP Syndrome

In this section you can find useful information to learn more about the basics of CUP (cancer of unknown primary) including epidemiology, pathogenesis, diagnostic work-up and therapeutic options.


What is the definition of CUP?

CUP (cancer of unknown primary) syndrome is defined as a histologically and clinically verified cancer for which only metastases can be found at the time of diagnosis, but no primary tumour is detectable.1

CUP (cancer of unknown primary) syndrome is defined as a histologically and clinically verified cancer for which only metastases can be found at the time of diagnosis, but no primary tumour is detectable. – Liver metastasis – lung metastasis – unknown primary tumour.

How frequent is CUP?

CUP syndrome accounts for approximately 3–5% of all cancer cases.1,2

CUP syndrome accounts for approximately 3–5% of all cancer cases.

1. Fizazi K et al. Ann Oncol 2015; (26 suppl 5): v133–8.
2. Stella GM et al. J Transl Med 2012; 10: 12.


How might CUP develop?

There are various hypotheses on aetiology and pathogenesis. One tentative explanation for CUP is the “stem cell theory” of cancer.1–3 Asynchronous division of the premalignantly or malignantly transformed stem cells may produce daughter cells that do not grow locally but are able to metastasise. Given the favourable microenvironment of these metastases, these may spread to another site, even though no tumour develops in the tissue of origin.4 This hypothesis is supported by tumour genomics, with clonal evolution documented in various cancers (e.g., lung cancer).5

The “stem cell theory” of cancer: healthy stem cell -> normal DNA -> changed DNA -> premalignant/malignant stem cell -> uncontrolled cell growth -> haematogenous or lymphatic dissemination -> cancer of unknown primary.

1. Aktipis CA et al. Nat Rev Cancer 2013; 13: 883–92.
2. Visvader JE. Nature 2011; 469: 314–22.
3. Lee G et al. J Stem Cell Res Ther 2016; 6: 363.
4. López-Lázaro M. Oncoscience 2015; 2: 467–75.
5. Jamal-Hanjani M et al. N Engl J Med 2017; 376: 2109–21.

Risk factors

What are the potential risk factors for CUP?

Potential risk factors that support the development of CUP syndrome include:1-3

  • Diabetes mellitus
  • Smoking
  • Obesity
  • A positive family history of cancer
CUP syndrome risk factors: diabetes mellitus, smoking, obesity, positive family history of cancer.

1. Mnatsakanyan E et al. Cancer causes & control 2014; 25: 747–57.
2. Robert Koch Institut (2016) GEKID Publication. Available at: (last accessed March 2019).
3. Hemminki K et al. Int J Cancer 2015; 136: 246–47.

Clinical features

What are the clinical features of CUP syndrome?

CUP syndrome presents a complex disease picture. A variety of heterogeneous manifestations can be distinguished but none have been identified as exclusively specific to CUP syndrome.1-3

Common clinical symptoms associated with CUP: persistent pain in specific areas of the body, bowel and bladder dysfunction (e.g., abdomen, chest or skeleton), swollen lymph nodes (hard and painless), visible and palpable swellings and lumps, skin tumours, persistent cough and shortness of breath, bowel and bladder dysfunction, unexplained loss of appetite and weight loss, fatigue, recurrent fever and night sweats, unusual bleeding and discharge.

How is CUP syndrome categorised?

CUP has different subsets, identification of which can imply a specific treatment. Based on histology, there are 5 different subsets.4-6 

CUP syndrome – clinical features – 5 primary subsets: 29% undifferentiated or poorly differentiated adenocarcinomas, 5% squamous cell carcinomas, 5% undifferentiated neoplasms, 1% carcinomas with neuroendocrine differentiation, 60% well- and moderately-differentiated adenocarcinomas.

1. Unknown Primary: Symptoms and Signs. Available at: (last accessed March 2019).
2. Mayo Clinic Carcinoma of unknown primary. Available at: (last accessed March 2019).
3. The University of Texas MD Anderson Cancer Center. Cancer of Unknown Primary. Available at: (last accessed March 2019).
4. Stella GM et al. J Transl Med 2012; 10: 12.
5. Pavlidis N and Pentheroudakis G. Lancet 2012; 379: 1428–35.
6. Ettinger DS et al. NCCN Guidelines version 2.2019.


How is CUP diagnosed?

The heterogeneity of CUP syndrome makes diagnosis challenging. Although the prognosis for CUP patients is generally poor, the appropriate diagnostic work-up can help to identify patients who can have a favourable prognosis. This subset of patients receives a therapy according to the suggested site of tumour origin.1

CUP syndrome – diagnosis: initial diagnostic work-up: medical history and physical examination, blood tests, immunohistochemistry, CT scans of thorax/abdomen/pelvis, endoscopy, biopsy, histology -> initial diagnostic work-up completed – no primary site has been detected and confirmed -> secondary diagnostic work-up: histology, immunohistochemistry, imaging -> secondary diagnostic work-up completed – specific subsets identified, including those in the favourable prognosis subset.

What do guidelines recommend for CUP diagnosis?

The European Society of Medical Oncology (ESMO) recommends the following diagnostic work-up for suspected CUP patients:1

CUP syndrome – core diagnostic programme in all patients: specific history (previous tumours and surgeries, pain, abnormalities, excised nevi, [colon] adenomas, smoking); thorough general examination (skin, throat, breasts, prostate, rectum, testes, lymph nodes, ENT and gynaecological examination); full blood count, blood chemistry; abdominal, pelvic and chest CT; mammography in female patients; – programme in CUP subsets: breast MRI in female patients; determination of a-fetoprotein, HCG, CgA, PSA in male patients; endoscopy/ultrasound; CT/(FDG-)PET; octreoscan (somatostatin receptor scintigraphy) and CgA; – target groups: women with axillary lymph node metastases; men with NUT carcinoma, adenocarcinomatous bone metastases; depending on signs, symptoms and laboratory results; patients with cervical squamous cell carcinoma; patients with neuroendocrine tumours; CgA: chromogranin A; CT: computed tomography; ENT: ear, nose and throat; FDG: fluorodeoxyglucose; HCG: human chorionic gonadotropin; MRI: magnetic resonance imaging; NUT: nuclear protein in testis; PET: positron emission tomography; PSA: prostate specific antigen.

What is the role of molecular tumour profiling in CUP?

Molecular tumour profiling techniques, such as comprehensive genomic profiling (CGP) make it possible to identify clinically relevant alterations in CUP. Based on next-generation sequencing (NGS) technology, CGP detects both known and novel variants across the four main classes of genomic alterations in a large subset of cancer-related genes and identifies genomic signatures, i.e. tumour mutational burden (TMB) and microsatellite instability (MSI).2-7

Comprehensive genomic profiling – hybrid capture-based next-generation sequencing (NGS) identifies clinically relevant genomic alterations in a sample; – data aggregation and analysis allow translation of NGS information into actionable knowledge; – scientific/clinical expert review further aids clinical decision making; – a curated, quality-controlled report aims to help physicians identify targeted or immunotherapy treatment options.

Clinical practice example of CUP

A 53-year-old female patient presented with shortness of breath and a golf ball-sized subcutaneous mass in the right biceps with erythema of the overlying skin. PET and CT showed multiple metabolically active masses in both lungs.

Rather than subject the patient to the risk of a lung biopsy, it was decided to biopsy the skin lesion on the arm and perform CGP. Instead of the suspected lung cancer, CGP identified an EML4-ALK fusion alteration.8

CUP syndrome – clinical practice example of CUP – patient profile: female, 53 years old; never smoker; presents with worsening fatigue and severe exertional dyspnoea; – diagnostic work-up – physical examination: 3-cm hard, subcutaneous, proximal right upper extremity mass with erythematous discoloration of the overlying skin and lesions in the celiac nodal basin and the right upper arm; PET and CT imaging: multiple, metabolically active masses in the right and left lungs; brain MRI: 3-cm transcranial lesion in the left frontal bone (1.8 cm thick); – genomic profiling of biopsy identified an EML4-ALK fusion alteration; EML4 (exons 1–6); ALK (exons 20–29); CT: computed tomography: MRI: magnetic resonance imaging; PET: positron emission tomography.

1. Fizazi K et al. Ann Oncol 2015; (26 suppl 5): v133–8.
2. Frampton GM et al. Nat biotechnol 2013; 31: 1023–31.
3. He J et al. Blood 2016; 127: 3004–14.
4. Gagan J and van Allen EM. Genome Med 2015; 7: 80.
5. Rozenblum AB et al. J Thorac Oncol 2017; 12: 258–68.
6. Suh JH et al. Oncologist 2016; 21: 684–91.
7. NCCN Clinical Practice Guidelines in Oncology. Non-Small Lung Cancer. V.2.2019. Available at: (last accessed March 2019).
8. Chung J et al. Case Report Oncol 2014; 7: 628–82.


What is the prognosis for CUP patients?

Only 15–20% of patients with CUP have a favourable prognosis based on their clinicopathological classification. These patients have chemosensitive and potentially curable tumours and can achieve long-term disease control with a multidisciplinary approach.1

The majority of CUP patients (80–85%) have a poor prognosis, meaning that treatment response is poor and median overall survival is generally less than one year.1

Prognosis for CUP patients: 15–20% favourable prognosis cases – patients with chemosensitive and potentially curable tumours who can experience long-term disease control –> treated similary to patients with equivalent primary tumour which has metastasised; – 80–85% poor prognosis cases – patients whose disease has modest sensitivity to therapy and have a median overall survival of < 1 year -> palliative chemotherapy.

Survival rate of CUP patients of poor-prognosis subset

The survival rates for patients with poor prognosis are low:2

  • 1 year: 38%
  • 5 years: 10%
  • 10 years: 8%
CUP syndrome – Minnie Pearl Cancer Research Network: CUP patients treated in phase II studies; N = 396; median survival of 9.1 months; 1 year: 38%; 5 years: 10%; 10 years: 8%.

1. Fizazi K et al. Ann Oncol 2015; (26 suppl 5): v133–8.
2. Greco FA and Hainsworth JD (2011) Cancer of unknown primary site, DeVita VT Jr., Hellman S, Rosenberg SA (eds) Cancer: Principles and Practice of Oncology (9th ed) Philadelphia, PA, JB Lippincott: 2033–51.


How is CUP clinically managed?

Treatment should be tailored to the individual patient according to the clinicopathological characteristics and its subsequent prognostic classification. The 15–20% of CUP patients with a favourable prognosis should be treated similarly to patients with metastases from equivalent known primary tumours. Patients with unfavourable risk profiles currently have a poor prognosis despite treatment with different chemotherapy combinations in clinical trials.1

The figure shows a proposal for clinical management of patients with CUP, including assignment to defined subsets, exclusion of non-CUP neoplasms and the use of prognostic parameters:1

Patient with CUP – treatment: strong suspicion of primary tumour (IHC, molecular testing) with potential specific treatment: bone metastases from prostate cancer; breast, ovaries, lungs, renal, colorectal; –> exclusion of non-CUP neoplasms: non-epithelial tumour; extragonadal germ cell tumours; – site specific treatment – CUP with favourable risk profile: women with peritoneal carcinosis (ACUP); men with ACUP with axillary lymph node involvement; squamous cell carcinoma with cervical lymph node involvement; neuroendocrine CUP; CUP with single organ manifestation; undifferentiated NUT midline carcinoma; colorectal-like CUP (IHC/molecular profile); prostate cancer-like CUP; ACUP: adenocarcinoma of unknown primary; ECOG: Eastern Cooperative Oncology Group; IHC: immunohistochemistry; LDH: lactate dehydrogenase; NUT: nuclear protein in testis; OS: overall survival; PS: performance status. Modified from Fizazi, K., et al.

Evolving treatment options for CUP patients

In recent years platinum-based chemotherapy has been supplemented by two additional options as shown in the image on the right.2-9

Evolving treatment options for CUP patients – option 1: treatment based on potentially identifying the tissue of origin; gene expression and epigenetic profiling can be used to potentially identify the tissue of origin; tumour type-specific therapy might improve overall survival; – option 2: treatment based on genomic alterations regardless of the tissue of origin; genomic profiling can identify clinically relevant genomic alterations and direct new treatment options in patients with CUP; the majority of CUP samples have at least one genomic alteration that is potentially targetable.

1. Fizazi K et al. Ann Oncol 2015; (26 suppl 5): v133–8.
2. Hainsworth JD and Greco FA. ASCO educational book 2018.
3. Moran S et al. Lancet Oncol 2016; 17: 1386–95.
4. Greco FA et al. Ann Oncol 2012; 23: 298–304.
5. Ross JS et al. JAMA Oncol 2015; 1: 40–9.
6. Subbiah IM et al. Oncoscience 2017; 4: 47–56.
7. Varghese AM et al. Ann Oncol 2017; 28: 3015–21.
8. Kato S et al. Cancer Res 2017; 77: 4238–46.
9. Krämer A et al. J Clin Oncol 2018; 36: 15_suppl e24162.