Metastases in the Absence of a Primary Tumor: Advances in the Diagnosis and Treatment of CUP Syndrome

Abstract

Introduction: The term cancer of unknown primary site (CUP) syndrome is used to describe malignancies in which a complete diagnostic work-up detects metastases in the absence of an identifiable primary tumor.

Methods: Based on a selective literature review, national and international guidelines, and the experience of the "Arbeitskreis CUP-Syndrom der Arbeitsgemeinschaft Internistische Onkologie der Deutschen Krebsgesellschaft" (CUP Syndrome Committee of the Medical Oncology Joint Working Group of the German Cancer Society), developments in the diagnosis and treatment of CUP syndrome are reported.

Results: Most patients diagnosed with CUP have an unfavorable prognosis, with a life expectancy of less than 12 months. Nevertheless, it is important to identify subsets of patients in whom specific treatment offers the chance of long-term survival or even full recovery.

Discussion: Only rigorous further development of diagnostic tools and treatment protocols will enable an improvement of the poor prognosis of patients with CUP syndrome. Specific molecular treatment strategies have shown promising results.

Keywords: CUP syndrome; diagnosis; metastasis; molecular medicine; treatment success.

Figure 1

Identified primary tumors in patients with CUP syndrome. The frequencies in the illustration are based on historical data (6, 7) and have been compiled from several dissection studies

Figure 2

Algorithm for the histological and immunohistological investigation of tumor manifestations with unknown primary tumor. The probable diagnosis is gradually approached using the immunohistological profile. There are additional marker profiles for the subgroups of specific tumors, but these will not be discussed in this review. The diagnoses are given in regular typeface, the immunohistological markers are given in bold (e18).

Figure 3

Investigation of a patient with CUP syndrome using the PET/CT hybrid technique. The images are from a 42-year old male patient with a history of smoking, who first visited his GP with swelling of the cervical lymph nodes and left hematothorax. Extirpation of a cervical lymph node gave the histological diagnosis of squamous cell carcinoma. The tumor cells were TTF1-positive in immunohistology. The PET/CT investigation found multiple mediastinal lymph node metastases—right intraclavicular and paraaortic at the level of the celiac trunk—, also suspected pleural carcinosis. The present findings indicate a primary tumor in the left lung, even though this could not be directly identified. With the kind approval of Professor Uwe Haberkorn MD, Department of Nuclear Medicine, Heidelberg University

Figure 4

Principle of gene expression analyses with microarrays in patients with CUP syndrome. Biopsies are taken of metastases in patients with known primary tumors (patient 1) and tumor manifestations of CUP patients (patient 2). RNA is then extracted from tumor tissue. Using microarray technology, a specific gene expression profile can be prepared from the RNA from each tumor. With the help of statistical methods, a comparison can be made between the gene expression patterns in patients with CUP syndrome and patients with known primary tumors. In the present example, patient 1 would be assigned to the same group as patient 2. It is possible that studies of this sort may lead to changes in therapy.