CORR Insights®: Does PET/CT Aid in Detecting Primary Carcinoma in Patients with Skeletal Metastases of Unknown Primary?

Where Are We Now?

Orthopaedic oncologists often are referred patients with skeletal lesions who do not have an underlying diagnosis; although uncommon, metastases from unknown primary tumors are not rare, as they account for approximately 3% to 5% of all adult malignancies [17]. These patients often undergo extensive testing in order to identify the primary tumor. One study of patients who underwent fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT in suspicious skeletal lesions [12] observed that 94% of patients also underwent one or more radiologic study other than PET/CT. A tremendous amount of resources, and potentially redundancy, is currently being invested in the workup of these patients.

The role of PET/CT in the diagnosis of skeletal lesions is evolving but remains undefined. One recent study [3] found the sensitivity, specificity rate and accuracy of PET/CT in detecting the primary tumor in carcinoma of unknown primary site as 84%, 78%, and 82%, respectively, which is consistent with the pooled sensitivity and specificity of 84% reported in a systemic review [9]. Looking specifically at bone metastasis, authors have previously reported no difference between standard techniques like computed tomography scans and FDG PET/CT [14]. In the current study [10], PET/CT again did not demonstrate clear benefit in detecting the primary site of suspicious bony lesions.

PET/CT scan is clearly not the panacea for the evaluation of suspected skeletal metastases. However, it does provide some valuable information that other modalities do not, including potentially differentiating benign bone lesions from malignant bone lesions via FDG uptake and/or SUVmax, potentially identifying ideal targets for biopsy based on FDG avidity, and providing whole-body imaging for disease extent in one study [3, 12, 16].

Where Do We Need To Go?

Redundant testing puts a financial strain on our patients and the healthcare system overall. Physicians are burdened with obtaining authorization for these multitude of tests while patients are burdened by the time and stress involved in obtaining multiple studies. PET/CT for unknown primaries is often used as a later option if traditional testing such as CT and/or bone scan is unrevealing [1]. In addition, obtaining both standard chest CT and PET for subcentimeter nodules may be unnecessary as PET/CT technology has evolved [2]. Is PET/CT best suited as a first-line single modality? Or perhaps PET/MRI and its lower radiation exposure is the more appropriate initial test? From a purely practical viewpoint, a standardized investigative algorithm for suspicious skeletal lesions with an unknown primary site is needed.

Improved prognosis and survival are seen with site/pathway-specific therapy compared to the empiric chemotherapy utilized for approximately 80% of patients with carcinoma of unknown primary site [5, 7]. While PET/CT has not proven to be superior to other modalities in detecting the primary site, the current study alluded to another role PET/CT may play regarding improving patient survival [10]. PET/CT is sensitive for detecting skeletal metastases, and in this study, the authors found 61 additional sites not otherwise detected by the authors’ standard algorithm [10]. Preliminary data suggest that survival may be improved with resection of oligometastatic disease in multiple carcinomas, not only renal cell carcinoma [4], but these resections carry additional morbidity for the patient, which may be acceptable if survival is improved. However, before an accurate determination can be made, we need to be certain of the oligometastatic status.

Speaking of accuracy, evolving immunohistochemistry and gene-expression profiling has improved the ability of pathologists to diagnose the tissue of origin from biopsy specimens (approximately 75% accuracy) [5, 8]. While current National Comprehensive Cancer Network Occult Primary Guidelines [11] do not recommend the routine use of gene-expression profiling for the identification of tissue of origin due to lack of robust data, PET/CT may aid in identifying the most-appropriate and safest site for biopsy. Determining how to combine the benefits of advanced imaging with new pathology techniques will streamline the work-up of patients who have metastatic carcinomas from an unknown primary tumor.

How Do We Get There?

The appropriate diagnostic algorithm for suspicious skeletal lesions is a balance between resource utilization and adequate evaluation. Such an initiative will likely require the coordination of the Musculoskeletal Tumor Society (MSTS) because the answer will only come from collaborative investigation.

Sarcoma surveillance strategies have been shown to have wide variation without high-quality evidence supporting the different protocols [6]. Fortunately, the Surveillance AFter Extremity Tumor surgerY (SAFETY) trial is a multi-institutional prospective, randomized trial under development that is investigating sarcoma surveillance [13]. While sarcoma surveillance remains a research priority for orthopaedic oncologists (and I applaud my colleagues for the SAFETY trial initiative), given the estimated 30,000 patients with carcinoma of unknown primary site that will be diagnosed in the United States in 2020 [15], a similar effort is warranted for metastatic bone disease. The potential impact on our patients and the healthcare system will be profound.

While a collaborative, prospective, randomized trial will provide the best evidence, valuable information on the topic can be obtained with proper registry data entry. With the forthcoming MSTS Registry, it will be important to capture appropriate data on the metastatic burden, the primary site, imaging modalities, and pathology/biopsy tissue to ascertain the answers to the evaluation and treatment of skeletal metastases.