See also the separate article Carcinomatosis.

Most patients who have malignancy without an identifiable primary site have tumours derived from epithelial cells. Tumours derived from non-epithelial cells include melanoma, sarcoma, lymphoma and ovarian or testicular germ-cell tumours.

Epidemiology

• In England and Wales about 4% of patients with newly diagnosed cancer are found to have cancer without an identifiable primary site, despite exhaustive tests.¹
• A clear pathological diagnosis can be established in approximately 30% of cancers following a full and thorough assessment:²
  • The most common epithelial malignancies are lung (15%), pancreas (13%), colon/rectum (6%), kidney (5%) and breast (4%).
  • Sarcomas, melanomas and lymphomas each contribute 6-8%.
  • The remaining primary tumours include stomach (4%), ovary (3%), liver (3%), oesophagus (3%) and prostate (2%). A variety of other malignancies make up the other 22%.

Presentation

• Most patients present with advanced-stage cancers and therefore usually have symptoms of malaise, weakness, fatigue and weight loss.²
• Comprehensive history and physical examination are essential and should include breast, nodal areas, skin, genital, rectal and pelvic examination. Most patients present with areas affected in multiple visceral sites, especially lung, bone, lymph nodes and liver. Any investigations must be guided by reported symptoms and examination findings.

Investigations

Investigations should only be performed if:¹

• 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.
• The patient is prepared to accept treatment.

Initial investigations¹

• Initial investigations should include FBC (iron deficiency may indicate an occult gastrointestinal malignancy), renal function tests and electrolytes, LFTs, calcium, lactate dehydrogenase and urinalysis (microscopic haematuria may indicate genitourinary malignancy).
• CXR.
• Myeloma screen (when there are isolated or multiple lytic bone lesions).
• Symptom-directed endoscopy.
• Computed tomography (CT) scan of the chest, abdomen and pelvis.
• Prostate-specific antigen (PSA) in men.
• Cancer antigen 125 (CA-125) in women with peritoneal malignancy or ascites.
• Alpha-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) (particularly in the presence of midline nodal disease).
• 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.

Specialised tests¹

• Tumour markers should only be measured as follows:
  • AFP and hCG in presentations compatible with germ-cell tumours (particularly mediastinal and/or retroperitoneal masses and in young men).
  • AFP in presentations compatible with hepatocellular cancer.
  • PSA in presentations compatible with prostate cancer.
  • CA-125 in presentations compatible with ovarian cancer (including inguinal node, chest, pleural, peritoneal or retroperitoneal presentations). Carefully interpret the results because of limited test specificity.
• Upper and lower gastrointestinal endoscopy: carry out only if the symptoms, histology or radiology suggest a gastrointestinal primary tumour.
• Mammography: do not offer routinely unless clinical or pathological features are compatible with breast cancer.
• Breast MRI scan: refer patients with adenocarcinoma involving the axillary nodes to a breast cancer specialist team. If a primary tumour is not identified after standard breast investigations, consider dynamic contrast-enhanced breast MRI to identify lesions suitable for targeted biopsy.
• 18F-fluorodeoxyglucose positron emission tomography-CT (18F-FDG PET-CT) scan:
  • Offer to patients with cervical lymphadenopathy if a primary tumour is not identified on ear, nose and throat panendoscopy and radical treatment is an option.
  • Consider for patients with extra-cervical presentations.
• Immunohistochemistry:
  • Use a panel of antibodies: cytokeratin 7, cytokeratin 20, thyroid transcription factor-1, placental alkaline phosphatase, oestrogen receptor (women only) and PSA (men only) in patients with adenocarcinoma of unknown origin.
  • If a primary tumour is not identified, use additional immunohistochemistry, guided by the results of the panel of antibodies and the clinical picture.
• Flexible bronchoscopy and video-assisted thoracoscopic surgery (VATS): when percutaneous biopsy is unsuitable or inappropriate for intrapulmonary nodules of probable metastatic origin, offer:
  • Flexible bronchoscopy with biopsy, brushings and washings, even when there is no endobronchial or central nodal disease on imaging.
  • Exploration with VATS - only after a negative bronchoscopic procedure.
• Histology to investigate malignant peritoneal disease: obtain a tissue sample for histology in patients with ascites, if technically possible.
• Gene-expression-based profiling should not be used to identify primary tumours.

Differential diagnosis

An apparent metastasis may be an unusual primary tumour.¹

Management¹

• All patients with possible malignancy of unknown primary origin should be referred immediately with a rapid referral pathway so that all patients are assessed within 2 weeks of referral.
• Patients should be referred to the specialist clinic for the specific tumour type if and when the primary malignancy is identified.

Service provision¹

• The National Institute for Health and Clinical Excellence (NICE) has recommended that every hospital with a cancer centre or unit should establish a carcinoma of unknown primary (CUP) team, and ensure that patients have access to the team when malignancy of undefined primary origin (MUPO) is diagnosed.
• The team should consist of an oncologist, a palliative-care physician and a CUP specialist nurse or key worker as a minimum, and should have a named lead clinician.

Radical treatment

Presentations that may benefit from radical treatment:

• Upper- or mid-neck squamous cell carcinoma: refer to a head and neck multidisciplinary team.
• Adenocarcinoma involving the axillary nodes: refer to a breast cancer multidisciplinary team.
• Squamous cell carcinoma confined to the inguinal nodes: refer to a specialist surgeon in an appropriate multidisciplinary team to consider curative treatment. If the disease is operable, offer:
  • Superficial lymphadenectomy and consider post-lymphadenectomy radiotherapy (if there are risk factors for residual disease, e.g. multiple involved nodes or extracapsular spread); or
  • Simple excision of clinically involved nodes, followed by radiotherapy.
• Solitary metastasis in the liver, brain, bone, skin or lung: refer to the appropriate multidisciplinary team to consider radical local treatment.

Chemotherapy for confirmed CUP origin

• Offer chemotherapy directed at a specific treatable syndrome if patients have clinical and/or laboratory features of a specific treatable syndrome and adequate performance status.
• If patients do not have clinical features of a specific treatable syndrome, tell them about the potential benefits and risks of chemotherapy.
• Offer patients the opportunity to enter clinical trials. If chemotherapy is offered outside clinical trials, when deciding which treatment to use, take into account the clinical and pathological characteristics of the tumour and the toxicity profile of the drugs, their ease of administration and response rate.

Multiple metastases including brain involvement¹

• After initial and special investigations, refer patients with apparent brain metastases as the only sign of malignant disease to a neuro-oncology multidisciplinary team.
• Do not offer chemotherapy except as part of a controlled clinical trial.
• Inform patients and carers that there is no evidence that any treatment offers improved survival and there is limited evidence that surgery and/or whole brain radiotherapy improves neurological symptoms.

Palliative care

See the separate articles Palliative Care, Terminal Care, Looking After People With Cancer, Helping Patients Face Death and Dying, Prescribing in Palliative and Terminal Care, Pain Control in Terminal Care, Nausea and Vomiting in Palliative Care.

Prognosis²

• Median survival ranges from 11 weeks to 11 months. The 5-year overall survival rate is about 11%.
• The prognosis for patients with multiple organ involvement and poor performance status is very poor with a median survival of 3-4 months. The 1-year survival rate is less than 15% and the 5-year survival is 5-10%.
• Male sex, multiple brain metastases, pleural/lung involvement, liver involvement, adrenal involvement, and adenocarcinoma histology have an unfavourable prognosis.
• Lymph node involvement and neuro-endocrine histology are associated with a more favourable prognosis.

Document references

1. Metastatic malignant disease of unknown primary origin, NICE Clinical Guideline (July 2010); Diagnosis and management of metastatic malignant disease of unknown primary origin
2. Tan WW et al; Metastatic Cancer, Unknown Primary Site, eMedicine, Mar 2009

Internet and further reading

• Carcinoma of Unknown Primary Treatment, National Cancer Institute (US)

Acknowledgements