General
- Much info came from Balestrino 2020 and NICE 2010
- As a histologically confirmed metastatic cancer for which clinicians are unable to identify a primary tumour source after the diagnostic workup.
Definition
- Malignancy of undefined primary origin (MUO)
- Metastatic malignancy identified on the basis of a limited number of tests, without an obvious primary site, before comprehensive investigation.
- Provisional carcinoma of unknown primary origin (provisional CUP)
- Metastatic epithelial or neuro-endocrine malignancy identified on the basis of histology or cytology, with no primary site detected despite a selected initial screen of investigations, before specialist review and possible further specialised investigations.
- Confirmed carcinoma of unknown primary origin (confirmed CUP)
- Metastatic epithelial or neuro-endocrine malignancy identified on the basis of final histology, with no primary site detected despite a selected initial screen of investigations, specialist review, and further specialised investigations as appropriate.
Investigation
- When to and not to investigate
- Do not offer further investigations to identify the primary site of origin of the malignancy to patients who are unfit for treatment.
- Perform investigations only if:
- The results are likely to affect a treatment decision
- The patient understands why the investigations are being carried out
- The patient understands the potential benefits and risks of investigation and treatment and
- The patient is prepared to accept treatment.
- History
- Physical examination including
- Breast,
- Nodal areas,
- Skin,
- Genital,
- Rectal
- Pelvic
- Blds
- Full blood count;
- Urea,
- Electrolytes and creatinine;
- Liver function tests;
- Calcium;
- Urinalysis;
- Lactate dehydrogenase
- Myeloma screen (when there are isolated or multiple lytic bone lesions)
- Prostate-specific antigen (PSA) in men
- Tumour markers
- Do not measure tumour markers during diagnosis except for:
- AFP and hCG
- Presentations compatible with germ-cell tumours
- Mediastinal and/or retroperitoneal masses and in young men
- AFP
- Presentations compatible with hepatocellular cancer.
- PSA
- Presentations compatible with prostate cancer.
- CA125
- Women with presentations compatible with ovarian cancer (including those with inguinal node, chest, pleural, peritoneal or retroperitoneal presentations).
- Carefully interpret the results because of limited test specificity.
- Symptom-directed endoscopy
- Do not carry out upper or lower gastrointestinal (GI) endoscopy in patients with MUO unless the symptoms, histology or radiology suggest a GI primary tumour.
- Radiological
- CXR
- CT TAP
- Mammography
- Do not offer mammography routinely to women presenting with MUO, unless clinical or pathological features are compatible with breast cancer.
- Testicular ultrasound in men with presentations compatible with germ-cell tumours
Contrast-enhanced computed tomography (CT) scan | Can be performed in emergency, no contraindications (except pregnancy and allergy to contrast medium). Allows visualization of acute bleeding. Less sensitive than MRI (especially for lesions in the posterior fossa, multiple punctate metastases and for leptomeningeal metastases) |
Contrast-enhanced magnetic resonance (MRI) | Higher resolution than CT scan; needs patient's collaboration (not suitable in case of psychomotor agitation, claustrophobia). Contraindicated in patients with medical devices that are not compatible (some types of pacemaker, metallic implants, etc.) and if there are contraindications to the contrast medium (allergy, risk of nephrogenic systemic fibrosis, etc.). |
Diffusion-weighted (DW)-MRI | Useful in differential diagnosis with abscesses: diffusion usually restricted in abscesses and unrestricted in BM. Exception: mucinous BM can show restricted diffusion |
Gradient echo/other susceptibility-weighted images (SWI) | Useful for the identification of hemosiderin and other blood breakdown products. May improve detection of haemorrhagic BM. |
Perfusion MRI - cerebral blood volumes (CBVs) | Peri-tumoral CBV lower in BM than in malignant gliomas, while higher in BM than in abscesses |
MRI spectroscopy (MRS) | Lower choline/creatinine ratios in BM compared to high grade gliomas. |
18F-fluordesoxyglucose (FDG)-Positron emission tomography (PET) | Lower sensitivity and specificity than MRI in the detection of BMs. Does not provide enough information for differential diagnosis. Whole body FDG-PET useful to identify the primary tumour or other metastasis (see main text). |
- Biopsy
N342. retrospective CUP vs non CUP
- Reference: DAmbrosio 2007.pdf
- Survival was not statistically different between patients with an undiagnosed primary (UDP) lesion and those with a diagnosed primary (DP) tumor (6 months)
- 36% survival was not affected by the eventual identification of the primary disease
- Delaying therapeutic intervention in pursuit of a primary diagnosis may not be appropriate.
- Prognostic factors for the overall population included
- Treatment
- Treatment modality was the most significant independent variable affecting survival in patients with brain metastases
- Age < 65 years
- Discharge status
- Absence of systemic metastasis
- Asymptomatic cerebral metastasis
Management
- NICE 2010
- Multiple metastases including brain involvement
- Not offer chemotherapy to patients with brain metastases of unknown primary origin except as part of a controlled clinical trial.
- Inform patients with brain metastases of unknown primary origin and their carers that there is no evidence that any treatment offers improved survival and there is limited evidence of improvement in neurological symptoms with surgery and/or whole brain radiotherapy.
- Surgery
- Aim
- For tissue diagnosis,
- Symptomatic relief,
- Significant difference in prognosis between complete and incomplete resection
- SRS
- Advantage
- Can be performed even in elderly patients
- Can be used in those who are not amenable to surgery
- WBRT
- Some benefit in survival
- This benefit has no different if WBRT was short-course radiotherapy (RT) (20 Gy in 5 fractions) with extended regimen
- Chemotherapy
- Systemic chemotherapy with conventional agents in BM-CUP does not achieve a long-term benefit and the overall survival is estimated to reach 12.3% after 2 years, 6.6% after 3, and 0% after 5
- Systemic medical therapies
Outcome
- Most patients died due to extracranial progression, rather than intracranial progression
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