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ECR 2019 / C-2849
PET CT in Carcinoma of unknown primary. Is it all about finding the primary ?
Congress: ECR 2019
Poster No.: C-2849
Type: Educational Exhibit
Keywords: Tissue characterisation, Metastases, Cancer, Diagnostic procedure, PET-CT, Oncology, Nuclear medicine, Molecular imaging
Authors: R. N. Jayan1, L. O'Mahony1, E. Mulvihill1, R. A. fernando2, N. Seshadri2, R. S. Dwarkanath2, E. Ahmed1; 1Liverpool/UK, 2Liverpool /UK


Definition and epidemiology


Carcinoma of unknown primary (CUP) represents a heterogeneous group of metastatic malignancies for which no primary tumour site can be identified after diagnostic work-up. 'Provisional CUP' is defined as patients with metastatic malignancy of proven epithelial, neuro-endocrine or undifferentiated lineage after initial but not exhaustive investigations. 'Confirmed CUP' can be diagnosed after all investigations are complete. In contrast, malignancy of undefined primary Origin (MUO) is a patient who presents with suspected metastatic malignancy, identified on clinical examination or by imaging, without an obvious primary site.


In the U.K, the incidence of CUP is approximately 9000 cases per year.  CUP comprises 2% of all new cancer cases, making it the 15th most common cancer in the U.K. It is, however, the 5th most common cause of cancer death, accounting for 6% of all cancer deaths.1


Diagnostic work-up

The initial diagnostic phase should be comprehensive but tailored to the patient and their presenting clinical features. NICE guidelines on MUO recommend the following2:

  • Comprehensive history and physical examination including breast, nodal areas, skin, genital, rectal and pelvic examination 
  • Full blood count; urea, electrolytes and creatinine; liver function tests; calcium; urinalysis; lactate dehydrogenase 
  • Myeloma screen – if multiple lytic bone lesions 
  • Symptom-directed endoscopy 
  • Computed tomography (CT) scan of the chest, abdomen and pelvis 
  • Testicular ultrasound in men with presentations compatible with germ-cell tumours 
  • Biopsy and standard histological examination, with immunohistochemistry where necessary, to distinguish carcinoma from other malignant diagnoses

Tumour markers should be taken only in those with certain clinical features suggestive of a particular malignancy, including prostate specific antigen (PSA), cancer antigen 125 (Ca125), alpha-foetoprotein (AFP) and beta human chorionic gonadotrophin (bHCG). Summarised below:


Tumour marker

Associated malignancy




Prostate cancer

Male sex


Epithelial ovarian tumours, primary peritoneal carcinoma

Women with ascites, inguinal node, chest, pleural, peritoneal or retroperitoneal malignancy


Germ cell tumours of ovaries and testes

Midline nodal disease, mediastinal &/or retroperitoneal masses in young male


Hepatocellular carcinoma

Liver mass


Germ cell tumours (choriocarcinoma) of testes, choriocarcinoma of uterus

Midline nodal disease, mediastinal &/or retroperitoneal masses in young male


Conventional CT imaging is widely available and may be sufficient in locating a primary tumour, however, it has limitations. CT only detects anatomical abnormalities and does not detect functionally active disease. It can have poor contrast resolution in some structures where the surrounding density is similar to the tumour. This is particularly problematic with small lesions and non-enhancing lesions in normal structures, which may be missed.


Prognostic categorisation of patients with MUO is an important part of the diagnostic work-up. Certain clinical presentations are associated with a more favourable outcome, including those with limited or oligometastatic disease and malignancies where there is a specific treatment available, often having the potential for an excellent outcome3. These include:

  • Melanoma
  • Lymphoma
  • Sarcoma
  • Germ cell tumours
  • Neuroendocrine tumours

Unfavourable subsets would include MUO presenting with either widespread early involvement, rapid progression or displaying aggressive biological and clinical behaviour.


Additional imaging with PET-CT

The question of who should have additional imaging is often discussed in the CUP multidisciplinary team (MDT) meeting and a knowledge of other available imaging techniques is important for any radiologist involved in the care of these patients. NICE guidelines suggest offering PET-CT to patients with provisional CUP presenting with cervical lymphadenopathy with no primary tumour identified on ear, nose and throat panendoscopy where radical treatment is a potential option. In presentations of extra-cervical malignancy with unknown primary, PET-CT should be considered following discussion at the CUP MDT2.


One of the most widely used radiopharmaceutical in PET-CT is  18F-Fluorodeoxyglucose (18F-FDG). However, other radiopharmaceuticals are available depending on the primary tumour in question. Gallium 68-DOTANOC is a somatostatin analogue used with PET for suspected neuro-endocrine tumours. Gallium-68 labelled prostate specific membrane antigen (68Ga-PSMA) is a newer PET tracer used for suspected prostate cancer. 


Other factors to consider before performing PET-CT and any other specialised investigations in accordance with NICE guidance are:

  1. The results are likely to affect a treatment decision
  2. The patient understands why the investigations are being carried out
  3. The patient understands the potential benefits and risks of investigation and treatment
  4. The patient is prepared to accept treatment

Are there other questions that PET-CT can answer that will influence patient management?


The described benefits of PET-CT to date have mainly been centred around searching for a primary tumour site and the detection rate using PET-CT has been reported to be around 40%4,5,6. We propose that in addition to locating the primary, PET-CT can provide additional information that can significantly influence patient management.


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