NCCN Occult Primary Guidelines Update

Cancers of unknown primary (CUP) affect between 3% and 5% of all patients with cancer. At the National Comprehensive Cancer Network (NCCN) 15th Annual Meeting, David Ettinger, MD, The Sidney Kimmel Comprehensive Cancer Center at John's Hopkins, and Charles Handorf, MD, PhD, University of Tennessee Cancer Institute, presented updates to the NCCN Occult Primary Guidelines. Because CUP can be difficult to treat, Ettinger stressed the importance of “ruling out potentially curable cancers, including thyroid, breast, ovarian, prostate, and germ cell.” In addition, he noted that “as more effective therapies, which produce a 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 type.”

One of the changes to the guidelines was the inclusion of PET/CT scanning as an initial evaluation option. While the recommendation is a class 2B, meaning a consensus of the NCCN panel was not reached but there was no major disagreement, Ettinger noted “PET/CT may be useful because it may show you a site to biopsy.” In addition, the updated guidelines include core needle biopsy as the preferred biopsy method.

Handorf discussed the pathology evaluation of tumors, noting that clinicians “need to think about efficiency of care.” One of the slides he presented showed the costs of using typical pathologic evaluation methods, including routine light microscopic evaluation at between $10 and $100, immunohisochemical evaluation at between $100 and $1000, and molecular profiling at more than $1000. Handorf noted that it is easy to see how these costs can add up, and he cautioned the findings may not help improve the care of the patient, stating “pathology evaluation is pointless unless fully integrated with clinical management to provide the best possible outcomes.” The guidelines maintain hematoxylin and eosin staining as the gold standard, as it will identify most tumors (75%-85%). Handorf noted that those that are unidentified and require further workup are generally well differentiated adenocarcinoma (60%), poorly differentiated carcinoma and adenocarcinoma (29%), squamous cell carcinoma (5%), poorly differentiated malignant neoplasm (5%), and neuroendocrine carcinoma (1%). Because new markers are constantly being introduced, Handorf warned that the guidelines can only remain general and “do not serve as a cookbook,” a theme that surfaced throughout the meeting. Handorf noted “the ultimate diagnostic usefulness of immunohistochemistry in a given case is inversely proportional to how much it is being relied upon to make the diagnosis.” He also noted that while molecular diagnostics for CUP will find a growing place in cancer diagnostics, inclusion in future NCCN guidelines will depend on relevance demonstrated as clinical effectiveness and efficiency.

Several changes were made to the NCCN guidelines on the workup and treatment of CUP lesions. For masses that are located in the retroperitoneum, upper endoscopy was added as an additional workup option, whereas upper and lower endoscopy was added for liver masses. If additional workup of inguinal nodes is needed, proctoscopy can be considered if clinically indicated; cytoscopy was removed as an option. The panel also clarified their stance regarding the use of mammography, which now indicates if a mammogram and breast ultrasound is negative, but there is histopathologic evidence of breast cancer, breast magnetic resonance imaging is indicated. The panel also recommends that clinicians consider surgery for patients with lung nodules that are considered resectable.

Since the majority of CUPs are adenocarcinomas, Ettinger briefly outlined these tumors, indicating that well-differentiated adenocarcinomas usually occur in the elderly, involve multiple metastatic sites such as the liver and lungs, respond poorly to treatment, and have a median survival of 3 to 4 months. He noted, “we are dealing largely with an incurable disease and we are seeking to prolong life.” When it comes to poorly differentiated carcinomas (with or withour adenocarcinomatosis differentiation), these tumors generally affect younger patients, have a short duration of symptoms, often grow rapidly, and there is generally involvement of the mediastinum, retroperitoneum, and lymph nodes; however, because some of these patients have highly responsive neoplasms, the guidelines recommend an empiric trial of cisplatin/etoposide (plus bleomycin) in these patients. They also call for considering chemotherapy in symptomatic patients with a performance status of 1 or 2 or asymptomatic patients with an aggressive cancer, and to base the chemotherapy regimen to be used on the histologic type. Further, neuroendocrine tumor regimens were replaced with links to appropriate NCCN guidelines: NCCN Small Cell Lung Guidelines for poorly differentiated or small cell subtype other than lung neuroendocrine tumors and NCCN Neuroendocrine Tumors Guidelines-Carcinoid Tumors for moderate and well-differentiated neuroendocrine tumors.

Regarding follow-up of patients with occult primaries that are not being actively treated, the guidelines recommend taking a thorough history and conducting a physical examination every 3 to 6 months for the first 3 years, then as indicated; conducting diagnostic tests based on symptomatology; and providing psychosocial support. The NCCN’s Occult Primary Panel’s future plans include obtaining some biopsy specimens for genetic/DNA profiling, conducting phase II studies of targeted agents in previously treated patients, and to find ways to personalize medicine for patients with CUP.

To review the full NCCN Guidelines, including Occult Primary, visit the NCCN website.