Lesson #38: Cancer of Unknown Primary Site (CUPS)

One of the most basic tasks of any physician is to identify an abnormal lump, mass, or other physical abnormality, to make a diagnosis, and finally to track down the cause and extent of the lesion. Never is this more important and time-critical a task as when the lump or mass is suspected and subsequently discovered to be a malignancy. In this blog, I will describe those steps in the most expeditious guideline for evaluating a cancer of unknown primary site, as described by multiple national cancer organizations. Following these simple steps will not only provide the quickest diagnosis and treatment, but will also avoid denied imaging scans from radiology benefits managers.


Not all cancers that are diagnosed are cancers of unknown primary site. Most malignancies are found in an organ that is traditionally known to be the primary site for that cell type. For example, most adenocarcinomas found in the colon, pancreas, or breast are primary for those sites. CUPS are defined as a cancer found in an organ or lymph node NOT the customary primary site for that cell type. For example, an adenocarcinoma is not customarily found in the brain. If such a cancer is found in the brain, a search must be undertaken to find the primary site.

Two variants of Cancers of Unknown Primary Site

Metastatic melanoma is also considered a CUPS if a detailed skin and mucosal surface exam has failed to find a primary site.

CUPS may also apply to a pathologic bone fracture clearly due to metastatic cancer in a patient with no known previous cancer history.

Basic Work-up before using advanced imaging

The term CUPS may be applied whenever a biopsy is positive for a malignancy after completion of a history and physical exam (with rectal and pelvic exams) plus laboratory tests that do not point to the primary lesion.

If plain x-rays demonstrate bone lesions on suspicious for multiple myeloma, all electrophoresis and light chain tests must be completed before advanced imaging.

If the CUPS is a squamous cell carcinoma located in the chest or in lymph nodes above the clavicle, an additional detailed head and neck exam performed by a clinician skilled in laryngeal and pharyngeal examinations is indicated.

Clinical finding Recommended Imaging Study

Cancer found in a CT chest with contrast (71260) AND CT abdomen and pelvis with

lymph node or organ contrast (74177).

known not to be primary; CT neck with contrast (70491) if cervical or supraclavicular nodes

or if a subcutaneous cancer involvement.

of the skin is positive CT with contrast or MRI without and with contrast for any other

symptomatic site.

For females: Diagnostic mammography and full pelvic exam, if

mammogram is inconclusive and path is consistent with breast

primary, MRI bilateral (77049) may be requested.

Axillary adenocarcinoma Diagnostic mammogram and full pelvic exam (females) if

mammogram is inconclusive and path is consistent with breast

primary, MRI bilateral (77049) may be requested

If above are not diagnostic for primary site,

CT neck with contrast (70491), CT chest with contrast (71260) and

CT abdomen with contrast (74160)

CT with contrast or MRI without and with contrast for any other symptomatic site

If above studies have failed to PET scan or PET/CT (78815 or 78816)

provide diagnosis of primary cancer

Lesson: most cases of denied advanced imaging in the diagnosis of Cancer of Unknown Primary Site occur either because of the lack of documentation of a prior history, physical, and laboratory tests or because the ordering physician requests imaging with dual studies (without and with contrast) when merely a contrast CT is sufficient.

PET scan is a useful test but only if CT and MRI scans have failed to disclose the site of the primary cancer.