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Diagnostics of CUP

As a starting point, it is always recommended to do a medical work-up to identify a potentially curable cancer, or to diagnose as accurately as possible in order to influence the choice of treatment (4, 5, 6).

The definition of this disease group indicates that tests have already been performed, for example, blood tests as well as histological and radiological examinations.

For rapid disease progression and poor health status, a time-demanding search for the primary tumor is not indicated, if palliative supportive care is the only treatment alternative.

Localization of metastatic lymph nodes may indicate where the primary tumor originated. Some examples may be:

  • Metastatic tumors to the neck often originate from the head/neck area. 
  • Breast cancer should be considered in middle-aged women with axillary tumors,.
  • For metastatic tumors in the groin, the primary tumor may have originated from the anus or gynecological area.
  • Spreading to retroperitoneal lymph nodes may originate from prostate, testicular, or ovarian cancer.
  • Thyroid, breast, or prostate cancer should be considered for bone metastasis. 
  • Lymphoma should be considered for lymph node metastases.
  • For metastasis in the lungs or liver, the primary tumor can originate from any location.

 Medical work-up

These examinations should be performed at minimum:

  • Thorough anamnesis (including possible risk factors, as well as examination regarding any possibly removed moles)
  • Clinical examination (including head/neck, rectal exploration, and breast palpation)
  • Histology assessment including relevant immunohistochemical panels (3)
  • Laboratory testing (standard hematology and biochemistry)
  • CT thorax/abdomen/pelvis, mammography for women

If the histological assessment and/or clinical examination points in a certain direction, this may be conclusive evidence for choice of radiological and other diagnostic procedures. Additional examinations including MRI (including breast MRI in women with axilary node metastsis), skeletal scintigraphy, ultrasound (especially of testicles in young men) and PET should be performed based on individual assessments, but are not performed routinely. Endoscopy and gynecological examination should also be considered.

Applicable tumor markers in serum include alpha-fetoprotein (AFP), human choriongonadotropin (hCG), chromogranin A and PSA to exclude extragonadal germinal cell tumors, neuroendocrine tumors and prostate cancer. CEA and CA125  are relatively unspecific markers for adenocarcinomas and will rarely be of value, but may point in the direction of ovarial/germinal cell cancer in women with abdominal or mediastinal metastases. 

For suspicion of a primary tumor in the head/neck, the following is also performed:

  • Ear/nose/throat exam including nasoscopy, epipharyngoscopy, and flexible laryngoscopy
  • Fine needle cytology, possibly biopsy. If a biopsy is necessary, an incision should be made such that the scar can be removed in a later lymph node resection. 
Evaluation of general health condition (WHO PS status) and LD level are of significance in determining a prognosis. WHO class 0-1 and normal LD indicate a relatively good prognosis, which should benefit from combination chemotherapy.

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