Despite extensive clinical and pathologic evaluation, the anatomical primary site is not found in 2% to 4% of patients who present with advanced cancer annually. The inability to identify the primary site leads to a diagnosis of occult primary malignancy or carcinoma of unknown primary (CUP).1,2

Prognosis is poor for patients diagnosed with CUP: median survival is 6 to 9 months.1,2  For this reason, current efforts are centered on detecting the primary tumor, including the use of molecular profiling, so that appropriate therapy can be administered.

“As more effective therapies, which produce significant, good quality-of-life and long-term survival in patients with epithelial tumors are developed, it will be important to identify the specific tumor,” David S. Ettinger, MD, FACP, FCCP, Chair of the NCCN Occult Primary Panel, told

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“At the present time, you would not want to miss a diagnosis of thyroid, breast, ovarian, prostate cancer as well as germ cell tumors because of the effective treatments available,” added Dr. Ettinger, who is also the Alex Grass Professor of Oncology at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.

This is especially important for the 20% of patients deemed to be in a “favorable subset,” based on standard clinical and pathologic features. For the 80% of patients in the “unfavorable subset,” median survival following treatment with broad-spectrum empiric chemotherapy, the standard for most patients for the past 15 years, is 9 months.2

What Sets CUP Apart?

Characteristics of tumors comprising CUP are early dissemination, aggressiveness, and unpredictability of metastatic pattern.The tumors have a wide variety of clinical presentations, with more than 50% of patients having multiple sites of involvement. Common sites include the liver, lungs, bones, and lymph nodes.Sites of metastasis, which are not specific enough to identify the tissue of origin, may provide clues for additional testing: for example, colorectal tumors metastasized to liver/peritoneal cavity and kidney malignancies metastasized to nodes/bone/lung.2

Autopsy studies have revealed small, clinically undetectable primary tumor sites in approximately 75% of patients. Most patients with CUP have carcinoma; adenocarcinomas are the most common histology.2

“The taxonomy and management of carcinoma of unknown primary has matured over the past decade with the use of sophisticated imaging and pathologic tools,” Gauri R. Varadhachary, MD, of The University of Texas MD Anderson Cancer Center, Houston TX, noted in an article in Clinical Cancer Research. “In the era of tailored therapeutics, this presents both an opportunity and a challenge.”3

For example, Dr. Ettinger said that “studies comparing performance of immunohistochemistry (IHC) and gene expression profiling (GEP) all suggest a role for the use of GEP in the assignment of primary sites to CUP.”

“Use of GEP, in selected cases, may direct therapy to improve outcomes,” he added. “IHC and GEP should be used in a complementary fashion to diagnose CUP when the diagnostic conclusion is likely to lead to specific or improved therapeutic choices. IHC, however, should be considered as the first line of diagnosis.”

Evaluating Approaches to Profile CUP at the Molecular Level

Recently, John D. Hainsworth, MD, of Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN, reported in the Journal of Clinical Oncology results of the first large prospective evaluation, to their knowledge, “of molecular profiling in the clinical management of patients with CUP.” The primary end point was the percentage of patients who had a tissue of origin successfully predicted by the assay.4

The trial used a 92-gene molecular profiling reverse transcriptase-polymerase chain reaction (RT-PCR) assay (CancerTYPE ID®, bioTheranostics, Inc., San Diego, CA) on tumor biopsies from patients with newly diagnosed CUP to predict tissue of origin. “Patients who were treatment candidates received standard site-specific first-line therapy,” the authors reported.