Feasibility of a multimodal ¹⁸F-FDG-directed lymph node surgical excisional biopsy approach for appropriate diagnostic tissue sampling in patients with suspected lymphoma

For lymphoma patients, it is well recognized that ¹⁸F-FDG PET/CT imaging, in contrast to conventional anatomic imaging modalities (i.e., computed tomography, ultrasonography, or magnetic resonance imaging), allows for improved initial staging, treatment monitoring during therapy, restaging after completion of therapy, and detection of recurrent disease in the absence of any notably clinical and/or biochemical disease manifestations [1-13]. Along similar lines, ¹⁸F-FDG PET/CT imaging allows for the recognition of a lesser degree of disease burden than is detectable on conventional anatomic imaging modalities, thus creating a situation in which patients with suspected new or suspected recurrent lymphoma will less frequently present with palpable adenopathy on clinical examination. Surgical biopsy continues to represent the principal diagnostic pathway by which a definitive tissue diagnosis is confirmed in patients with suspected new or suspected recurrent lymphoma [14]. With the improved detection of more limited disease burden by ¹⁸F-FDG PET/CT imaging, which is more frequently associated with an inability to appreciate palpable adenopathy on clinical examination, the surgeon’s ability to successfully target the appropriate anatomical site of diagnostic tissue sampling for confirmation of the correct tissue diagnosis is made more challenging. Therefore, utilizing such innovative methodologies as a multimodal ¹⁸F-FDG-directed lymph node surgical excisional biopsy approach for guiding appropriate diagnostic tissue sampling of lymph nodes detected as ¹⁸F-FDG-avid lesions on diagnostic whole-body ¹⁸F-FDG PET/CT imaging can help the surgeon to maximize the likelihood of success in establishing the correct tissue diagnosis. Likewise, such methodologies have the potential for decreasing the degree of invasiveness as well as the degree of tissue disruption and tissue removal necessary for accomplishing successful tissue targeting.

Although we fully recognize that the current retrospective data analysis is based upon only 13 patients, the cases presented herein demonstrate that a multimodal ¹⁸F-FDG-directed lymph node surgical excisional biopsy approach for suspected lymphoma is technically feasible for guiding appropriate diagnostic tissue sampling of lymph nodes seen as ¹⁸F-FDG-avid lesions on diagnostic ¹⁸F-FDG PET/CT imaging, especially when such ¹⁸F-FDG-avid lesions are not easily appreciable as palpable adenopathy on clinical examination. Likewise, the conceptualization of this approach is well illustrated by the case presented in Figures 1 and 2. It is our belief that such a strategy can be best maximized when a multimodal imaging and detection approach is utilized involving perioperative patient and ex vivo surgical specimen ¹⁸F-FDG PET/CT imaging in combination with intraoperative ¹⁸F-FDG gamma probe detection. This line of reasoning has been validated by our group for a variety of disease-type-specific solid malignancies [16-18,33,35,36,38-41,43,44,46,47,52,61,69].

Along similar lines, three other groups of investigators have also previously described the successful utilization of commercially-available intraoperative hand-held gamma probe systems for ¹⁸F-FDG-directed lymph node surgical excisional biopsy in patients with suspected or documented lymphoma [27,31,50,67]. Gulec et al. described this technique in four patients in one report from 2006 [27] and in six patients in another report from 2007 [31]. Molina et al. described this technique in three patients in their report from 2009 [50]. Vos et al. described this technique in one patient in their report from 2012 [67]. However, none of these three other groups of investigators utilized perioperative patient and ex vivo surgical specimen ¹⁸F-FDG PET/CT imaging at the time of intraoperative ¹⁸F-FDG gamma probe detection, thus falling short of incorporating a multimodal approach to this sometimes challenging diagnostic dilemma.

The ability to successfully perform an ¹⁸F-FDG-directed lymph node surgical excisional biopsy procedure for suspected lymphoma is highly dependent upon the commercially-available intraoperative hand-held gamma probe that is used during such a surgical case. The most important performance parameters related to any given gamma detection probe system are generally thought to be: (1) overall sensitivity (i.e., efficiency); (2) spatial selectivity (i.e., radial sensitivity distribution); (3) spatial resolution (i.e., lateral sensitivity distribution); (4) energy resolution (i.e., spectral discrimination); and (5) contrast [46]. The most widely utilized commercially-available intraoperative hand-held gamma probes are generally designed for detecting radioisotopes of gamma-ray energies in the low-energy emission (0 keV to 150 keV) range and medium-energy emission (150 keV to 400 keV) range, thus allowing successful detection of radioisotopes such as: (1) technetium-99 m (^99mTc; 140 and 142 KeV; most commonly used for sentinel lymph node biopsy procedures and parathyroid surgery); (2) indium-111 (¹¹¹In; 171 and 247 KeV; used with octreotide to detect neuroendocrine tumors); (3) iodine-123 (¹²³I; 159 KeV; used with metaiodobenzylguanidine to detect neuroblastomas and pheochromocytomas); and (4) iodine-125 (¹²⁵I; 35 KeV; previously used with anti-TAG-72 monoclonal antibodies and anti-CEA monoclonal antibodies during radioimmunoguided surgery) [46,70].

However, most commercially-available intraoperative hand-held gamma probes are not specifically designed to directly or indirectly detect the resultant 511 KeV gamma emissions following positron annihilation emanating from higher energy gamma photon emitting/positron emitting radionuclides such as fluorine-18 (¹⁸F) or iodine-124 (¹²⁴I) [46,70]. Resultantly, there has been a recent appearance of commercially-available intraoperative hand-held gamma probes that are specifically intended for attempting to detect 511 KeV gamma emissions from higher energy gamma photon emitting/positron emitting radionuclides. These commercially-available intraoperative hand-held gamma probes have generally been designated as “PET” probes. The overall weight and physical size of any typical “PET” probe is generally a function of the degree of physical side shielding/collimation necessary to theoretically block adjacent background radiation, to limit the field of view, and to collimate the head of the probe, with the intention of limiting the area of tissue contributing to the probe count rate and of providing better spatial resolution between areas of tissue of differing radioactivity levels [46,70,78]. Attempts at improving the current “PET” probe design by further increasing physical side shielding/collimation or by increasing crystal diameter/thickness to capture a higher percentage of 511 KeV gamma emissions would only result in a “PET” probe configuration prohibitively large in physical size, heavy in weight, and which would be much more costly [46,70,78], thus representing significant obstacles to applying the currently commercially-available “PET” probes to the detection of ¹⁸F-FDG-avid tissues.

In order to attempt to bypass these physical barriers related to the degree of physical side shielding/collimation or crystal diameter/thickness in designing intraoperative hand-held gamma probes that are specifically intended for attempting to detect 511 KeV gamma emissions from higher energy gamma photon emitting/positron emitting radionuclides, engineering efforts have moved toward other directions for the adaptation of more novel “PET” probe designs that do not rely upon increasing physical side shielding/collimation or increasing crystal diameter/thickness. Examples of such alternative design concepts that can be adapted to “PET” probe design are secondary K-alpha x-ray fluorescence [70,78], active electronic collimation [28,54,58,60,67,79-81], and other crystal geometry designs using multiple small crystals with specific novel geometric configurations [82,83] for optimizing background rejection capabilities. These innovative alternative design schemas for detecting higher energy gamma photon emitting/positron emitting radionuclides, some of which have already been successfully applied to intraoperative hand-held gamma probe designs, are also the focus of current pre-clinical research that is actively looking at developing small platform, portable perioperative and intraoperative patient and ex vivo surgical specimen imaging devices with similar capabilities for detecting higher energy gamma photon emitting/positron emitting radionuclides. However, such small platform, portable perioperative and intraoperative patient and ex vivo surgical specimen imaging devices have not yet been fully realized or made commercially available for use in the clinical arena.