It certainly is not about the winner’s cup for the best oncologist out there when the colleagues are talking about CUP (Cancer of Unknown Primary). Most of the time a frown appears on the face because nobody really knows how he should treat a CUP patient. There is only little to be found in scientific literature about the metastasizing cancer with a primary growth that cannot be found any more.
Jo Symons for example was such a patient. The New York Times reported about her destiny a while ago. She had adenoids in her neck, on her chest and her lymph nodes. The 46 year old graphic designer died without any physician ever finding out where the tumor originally started growing. During the last 8 months prior to her death they changed chemotherapy three times because it was supposed to defeat first an ovarial-, then a mamma- and last but not least a pancreas carcinoma.
Metastases already in the diagnosis
A CUP is not as rare as you would want think in a medicine availing over imaging with extremely high solution and diagnostic abilities for uncountable cancer markers. In two to five percent of all newly diagnosed cancer cases the search for the primary tumor is in vain at first. An atypical metastasizing pattern distinguishes the “man in the shadow” of all tumors already during diagnosis. Just recently, a Swedish working group reported about epidemiologic data covering the past five decades. This data shows a permanent increase of particularly adenocarcinomas of unknown origin in patient above their fifties until their late nineties. Prognoses for those patients are bad. Only every fifth patient lives for more than one year after the diagnosis was made. Among those, younger patients have better chances to survive the cancer in the long run.
Oncologists have been discussing for a long time, whether we are talking about an own species of tumor type here, different from other known types of cancer by their pattern and whether known and well characterized tissue growths have changed strongly during their spreading. In CUP cases, the primary tumor might be so small that it cannot be discovered with regular imaging technologies such as CT, ultrasound, MRI or PET any more. A strong local immune system might have participated in the original growth’s dissolving in thin air. But it also might be that epithelium cells have removed from their original place and then transformed into malign cells independently.
Daughters inhibit growth of parents
As early as in the seventies of the last century, researchers observed in mice that metastases inhibit the primary tumor. Daughter growths of a transplanted bronchial carcinoma inhibited the growth of subcutaneously applied samples of the primary tumor. The French Eludie Fabre observed a regression of the primary tumor in human patients suffering from testicular tumors while the metastases spread unimpaired.
And if you do not know which tumor you are looking at it becomes difficult to decide on treatment options. Hence there is no standard regime against CUP. Taxan and platinum derivates with remission rates of 20 to 40 percent seem to be the most promising. But second-line therapies are nearly always a failure.
Is there any hope left beyond the 1:5 chance for patients who got the diagnosis “CUP”? Not always this diagnosis is final. In ten to twenty percent of all CUPs the primary tumor shows up during the course of the disease.
Coincidence determines whether the chemotherapy works or not
More than half of all unknown cancer cases are being resolved during autopsy, mainly lung- or pancreas carcinomas followed by liver, bile duct and colon are the original location of the tumors. A range of tumor markers which is permanently growing allows histologists to take more and more CUPS out of the dark of their origin. Oncologists and pathologists in the cancer department are now getting support from geneticists as well. Microarray tests allow the comparison of genetic expression profiles of defined tumor species with the sample in question.
Now three commercial testing systems enable to identify many unknown growths after all. For example “CupPrint” compares 495 genes, the “TissueOfOrigin”-test even 1500. Two more recent studies published in the Journal of Clinical Oncology show the advantage in characterization of formalin-fixed tissue samples bedded in paraffin. In about 84 patients, more than 80 percent of the known tumors revealed their correct origin. CupPrint delivered a result for 22 unknown adenocarcinomas. A newer test characterizing the tumor by PCR succeeded in 60 percent after all. The potential tumor type remained consistent within the course of disease and therapy responds most of the time. But the costs of about 3,000 Dollars are relatively high for an elaborate analysis which limits the genetic test to cases where all other tools of the pathologists fail.
Only few studies have put CUP in the crosshairs with a prospective approach so far. But this would be the only way to clear for example whether an elaborate RNA test would influence the therapy thus prolonging the survival time significantly – and thereby justify itself. The activation patterns of the genes are far from being a guarantee for a successful therapy. A recent “Nature”-article of Harvard scientists attempts to prove that random protein variability of tumor cell is responsible for success or failure of chemotherapy independent from a switched-on genes.
Not only physicians and researchers toil with CUP. Only little of the industry’s money flows into resolving unknown tumor objects. If you would like to learn about CUP and don’t want to dig yourself through years of Medline issues, you can visit Jo’s Friends in the internet. Jo Symons might have lost her personal fight against an unknown enemy but her husband John Symons brings together experts, affected people and sponsors to snatch the mask off the CUPs’ “man in the shadow”.