Cancer of Unknown Primary Site

SUMMARY:Carcinoma of Unknown Primary Site (CUPS) is a heterogeneous clinical pathologic syndrome for which the anatomical site of origin of the primary tumor is clinically undetectable. CUPS accounts for approximately 2% of all advanced malignances annually. The American Cancer Society estimates that about 31,430 cases of Cancer of Unknown Primary site will be diagnosed in 2014 in the United States. The pathobiology of tumors from unknown primary sites is similar to those with detectable primary tumors and therefore may respond to therapies similar to those with easily detectable primary tumors. Historically, the treatment approach for patients with CUPS included broad spectrum empiric chemotherapy. Histological evaluation of the biopsy tissue alone has been the standard practice for decades. With the availability of gene expression profiling assays and advances in ImmunoHistoChemistry staining as well as imaging technology, predicting the tissue of origin of the primary tumor and tailoring therapy accordingly, has improved overall survival in this patient population. Evaluation of a patient with CUPS starts with gathering and incorporating medical information which includes the patient’s gender, medical history, clinical findings and sites of metastases. A CT scan of the chest, abdomen and pelvis with IV and oral contrast is recommended, although PET (Positron Emission Tomography) or an MRI can be performed in those with renal insufficiency or iodine allergy. PET scan is recommended for those with cervical lymphadenopathy with squamous histology, to help determine the extent of the disease and treatment planning for radiation. PET imaging is also helpful for patients with solitary metastases before locoregional therapies are planned, as well as assessing response in patients with predominantly bone only disease. In women presenting with isolated axillary lymphadenopathy, adenocarcinoma histology, negative mammograms and ultrasound, MRI of the breasts is indicated. With the exception of those patients with CUPS who present with cervical lymphadenopathy, diagnostic procedures such as bronchoscopy, EGD and colonoscopy are not recommended in asymptomatic patients. Tumor markers in general do not have diagnostic value in patients with CUPS although they could be utilized to monitor response to treatment. However, PSA when elevated in a male with adenocarcinoma and osteoblastic metastases, is suggestive of a prostate primary. Similarly an elevated Beta HCG and AFP in a patient with undifferentiated or poorly differentiated carcinoma, is suggestive of an extragonadal germ cell tumor and an elevated AFP is also helpful in making a diagnosis of Hepatoma. Approximately 60% of the patients with CUPS have well or moderately differentiated adenocarcinoma on light microscopy, 30% have poorly differentiated carcinoma or adenocarcinoma, 5% have poorly differentiated or undifferentiated malignancy and 5% have squamous cell carcinoma. Following histological evaluation on light microscopy, the biopsy specimen is further tested using ImmunoHistoChemical stains, using peroxidase labeled antibodies against tumor specific antigens, taking advantage of the similarities in the tumor profiles of primary and metastatic malignancies. After delineating a tumor as carcinoma, lymphoma, sarcoma or melanoma, additional IHC testing can help identify tumors such as a lung primary (postive Thyroid Transcription Factor 1-TTF1and positive CytoKeratin 7- CK7), lower gastrointestinal cancers (positive CK20, positive CDX2 and negative CK7) or a breast primary (positive CK7 and positive Mammaglobin). Tissue-of-Origin molecular profiling is based on the principle that in patients with CUPS, molecular signatures of metastatic tumors are similar to their primary tumor. Tissue-of-Origin molecular profiling is performed using tools such as DNA microarray, quantitative real time polymerase chain reaction assay (rt-PCR) or assays based on messenger RNA (mRNA) or microRNA. These tests are cost-effective and 70% – 90% accurate. This study can be performed on formalin-fixed samples as well as samples from fine needle aspiration. Even though platinum based chemotherapy has been the default regimen for patients with CUPS, histological evaluation of biopsy tissue by light microscopy, IHC testing and molecular profiling assay may complement each other and help guide the Health Care Provider to select site specific therapy. The survival outcomes of CUPS patients with a Tissue-of-Origin molecularly diagnosed profile are comparable to those with similar type advanced cancer with a known primary. The authors concluded that with additional molecular insights into tumor biology and availability of newer therapeutic agents, patients with CUPS and known primary tumors may eventually be treated alike. Varadhachary, GR and Raber, MN. N Engl J Med 2014; 371:757-765