Although it's possible that the doctor has run every possible test and still can't locate the original cancer, there's also a chance he stopped short of conducting the full range of tests. These can include immunohistochemistry analysis, CT scans, MRIs and bone scans, blood tests for markers such as CA-125 (which suggests ovarian cancer) or PSA (which indicates prostate cancer), and examination with an electron microscope. Using a selection of these tests, he should at least be able to classify the type of cancer into one of three main types: squamous cell carcinoma; adenocarcinoma; or a catch-all known as "poorly differentiated malignant neoplasm." No matter what, though, a CUP diagnosis is a situation that calls for a second opinion, if for no other reason than to make sure all appropriate tests have been done.

Many people in this situation seek a second opinion from an oncologist but don't realize that a second opinion from a pathologist can also be extremely valuable. Since the treatment plan depends on what kind of cancer the patient has and how far it has spread, changes in the interpretation of the pathology can dramatically affect treatment and prognosis.

Start by obtaining a copy of the appropriate pathology report and cell slides from the doctor, and then seek out pathologists specializing in the type of cancer the doctor thinks she has. Some pathologists and clinics have a reputation for being especially good at decoding an unknown primary. One of the most respected is the Armed Forces Institute of Pathology (AFIP) in Washington, which offers the most advanced diagnostic and imaging techniques; others are available at major cancer centers such as the Dana-Farber Cancer Institute in Boston and the University of Texas's MD Anderson Cancer Center in Houston. You might even want to send slides to more than one pathologist -- in a case like this, the more information you have, the better off you are.