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Uptake Patterns of Untreated Primary Gastrointestinal Extranodal Lymphomas on Initial Staging 18F-FDG PET/CT and Metabolic Tumor Parameters

Objective: Non-Hodgkin’s lymphomas arising from tissues other than primary lymphatic sites are classified as primary extranodal lymphomas (PEL). PELs of the gastrointestinal system (PGISL) originate from the lymphatic tissues within the gastrointestinal tract. The prognostic value of 18F-FDG PET/CT in lymphomas is high in terms of both overall survival (OS) and disease-free survival (DFS). Our aim was to investigate the uptake patterns and properties of low-grade and high-grade PGISL on primary staging 18F-FDG PET/CT, as well as the prognostic significance of metabolic tumor parameters in high grade PGISL. Methods: Thirty-nine patients with PGISL were enrolled in this retrospective cohort study between 2004-2015. Primary staging 18F-FDG PET/CT have been performed and quantitative parameters of SUVmax, SUVmean, metabolic tumor volume (MTV), total lesion glycolysis (TLG) have been calculated for all patients prior to treatment. Low-grade and high-grade PGISL were compared in terms of metabolic tumor parameters. Cox regression models were performed to determine factors that correlate with DFS in high-grade PGISL. Results: There were statistically significant differences between high-grade and low-grade PGISL in terms of SUVmax, SUVmean, MTV, TLG, recurrence, mortality, DFS and OS. None of the potential risk factors (sex, age, site, SUVmax, SUVmean, MTV, TLG) for recurrence and metastasis in high grade PGISL was identified as a risk factor on univariate and multivariate Cox regression analysis. Conclusion: Metabolic tumor parameters are not predictive markers in high-grade PGISL, especially in diffuse large B cell variant and primary gastric lymphoma. The first implications suggest they will not play a role in patient management.


Introduction
Non-Hodgkin's lymphomas (NHLs) arising from tissues other than primary lymphatic sites [lymph nodes (LNs), bone marrow, spleen, thymus and Waldeyer's ring of pharyngeal lymphatics] are classified as primary extranodal lymphoma (PEL) (1). Although PEL can be seen in almost any site, gastrointestinal system (GIS) is the most frequent site (2). Thus, PEL of the GIS (PGISL) is a NHL originating from lymphatic tissues of the gastrointestinal tract. The most commonly affected site is the stomach (50-60%) followed by the small intestine (approximately 30%), colon, very rarely pancreas and the liver (3). Approximately 1/2 to 2/3 of GIS NHLs are diffuse large B-cell (DLBC) lymphomas (1). Primary gastric lymphoma (PGL) constitutes less than 5% of all gastric neoplasms (4). It is the most common site in all PEL patients with an incidence of 4-20%, and a preponderance in men over the age of 50 (5). Histologically, PGL is predominantly high-grade, DLBC or low-grade mucosa-associated lymphoid tissue (MALT), also defined as extranodal marginal zone B cell lymphoma (6). MALT lymphoma is the most common variety in PGL (7). A heterogeneous group of lymphomas including MALT, DLBC, mantle cell (MC), Burkitt and T-cell affect the small bowel (7). Primary colon lymphoma has features similar to small bowel disease with wall thickening without obstruction (8). 30-50% of patients with small bowel lymphoma initially present with an abdominal emergency (9). The treatment of GIS lymphomas is controversial and depends on histologic type and disease stage (10). Although computed tomography (CT), 18-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) and 18 F-FDG PET/CT are used to stage PEL, CT is the most commonly used imaging modality for the management of patients with lymphomas (2). Most patients present with residual masses after treatment (11). A decrease in the size of a lymphomatous mass after treatment is considered as treatment response. However, a decrease in size on CT does not occur in case of fibrosis, necrosis and inflammation (11). Therefore, CT cannot differentiate residual disease from fibrosis. 18 F-FDG PET is a superior imaging technique that proved its utility especially in Oncology. It can display functional alterations that precede anatomical changes. Several limitations of CT in lymphomas can be overcome with 18 F-FDG PET. Besides, integration of CT to 18 F-FDG PET creates a superior imaging modality combining anatomical detail with functional information, which results in excellent accuracy and detection capability. With all these advantages, 18 F-FDG PET/CT is being widely used in the primary staging, evaluation of treatment response, and restaging of PGISL just like other types of HL and many NHL lymphomas. 18 F-FDG PET/CT also has a high prognostic value with respect to overall survival (OS) and disease-free survival (DFS). The semi-quantitative measurement of standardized uptake value (SUV) is an easy-to-calculate and noninvasive index reflecting 18 F-FDG metabolic rate. Its assessment has additional prognostic value in early response to treatment and long-term outcome in lymphoma patients and improves the prognostic value of the test manifestly as compared to visual analysis (12). Many studies have proven the effectiveness of 18 F-FDG PET/CT for primary staging, restaging and evaluation of treatment response in lymphomas (13). Despite the high incidence of PEL of the GIS, only a few studies with limited number of patients have been published in the literature on the use of 18 F-FDG PET/CT in the management of these patients (14). Moreover, to the best of our knowledge no prior studies have been published on metabolic tumor parameters in this selective subgroup of lymphoma. This study was conducted to investigate the usefulness of metabolic tumor indices on primary staging 18 F-FDG PET/CT for prognosis estimation in primary extranodal high-grade GIS lymphomas. We also studied the uptake patterns and properties of metabolic tumor parameters in different histological subtypes of PGISL.

Materials and Methods
Thirty-nine patients with PGISL (only stage 1-2 disease) from 2004 to 2015 were enrolled in this retrospective cohort study. The cases were histopathologically proven by excisional biopsy. The study was conducted at the Nuclear Medicine Department of a training and research hospital of a medical school. Primary staging 18 F-FDG PET or 18 F-FDG PET/CT have been performed for all patients prior to treatment. Disseminated nodal disease secondarily involving GIS and Hodgkin lymphoma (HL) with GIS involvement were excluded. Patients who didn't have primary staging 18 F-FDG PET/CT and inadequate followup were also not included. Involvement of GIS as the predominant site with a few minor draining LNs only were also categorized as PGISL and included in the study. These patients were treated and followed up by the Medical Oncology Department of our hospital. CD20 (+) cases were treated by R-CHOP protocol (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone), while CD20 (-) cases received CHOP. The patients were followed by clinical history, physical examination, lactate dehydrogenase and sedimentation rate measurement, complete blood count, liver function tests, CT and/or 18 F-FDG PET/CT. Information and data were obtained from clinic follow-up files, radiation therapy records, physician records of other departments at our hospital or personal contact with the patients on telephone.

F-FDG PET/CT Imaging Protocol
Patients fasted for 6 hours and their blood glucose level had to be under 150 mg/dL before the injection of an activity of 370-555 MBq of 18 F-FDG according to patient's weight. Image acquisitions were performed 1 hour later with an integrated PET/CT scanner (Discovery 690-GE Healthcare). Unenhanced low dose CT and PET emission data were acquired from mid-thigh to the vertex of the skull in supine position with the arms raised over head. CT data was obtained by automated dose modulation of 120 kVp (maximal 100 mA), collimation of 64×0.625 mm, measured field of view (FOV) of 50 cm, noise index of 20% and reconstructed to images of 0.625 mm transverse pixel size and 3.75 mm slice thickness. PET data was acquired in 3D mode with scan duration of 2 min per bed position and an axial FOV of 153 mm. The emission data was corrected in a standardized way (random, scatter and attenuation) and iteratively reconstructed (matrix size 256×256, Fourier rebinning, VUE Point FX [3D] with 3 iterations, 18 subsets).

Visual and Quantitative Interpretation
Quantitative PET/CT parameters used in the study include maximum standardized uptake value (SUV max ), average standardized uptake value (SUV mean ), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). They were calculated according to a standard protocol on a dedicated workstation (Volumetrix for PET/CT and AW volume share 4.5, GE Healthcare, Waukesha, WI, USA). SUV max and SUV mean corrected for body weight were computed by standard methods from the activity at the most intense voxel in three-dimensional tumor region from the transaxial whole body images on attenuation-corrected PET/CT images. MTV (cm 3 ) was measured with semiautomatic PET analysis software using an automatic isocontour threshold method based on a theory of being greater than 42% of the SUV max value within the tumor. TLG values were calculated by multiplying MTV and SUV mean . The corresponding CT scan of lesions were used as a guideline to demarcate them if their boundaries were difficult to define for the calculation of SUV max (15). We retrospectively examined demographic characteristics, clinical findings, histology, clinical stage, response to treatment and outcome of the patients. OS was defined as the interval between diagnosis and death of any cause including ones other than the disease itself or until last follow-up. DFS was defined as the interval between diagnosis to detection of relapse or until last follow-up. Informed consent was waived due to the retrospective design of the study using records, documents and data of patients referred to our clinic for the test. Ann-Arbor staging system and definitions were used in this study. The study was approved by The study was approved by a Gülhane were performed for the evaluation of factors impacting recurrence. The variables having a value of p<0.5 were further included into multivariate analysis. ROC curve was drawn to evaluate the diagnostic value of SUV max , SUV mean , MTV and TLG. They were dichotomized by splitting into two groups according to ROC curve. Kaplan-Meier method with log-rank test was used to compare DFS times of metabolic tumor parameters. The study was approved by our Institutional Review Board.

Results
There were 23 DLBC lymphomas (59%), 12 MALT lymphomas (31%), 2 T-cell lymphomas (5%), one MC lymphoma and one Burkitt lymphoma in the study. Totally, we had 26 high-grade PGISL (67%) and 13 lowgrade PGISL (33%). Twenty-eight of the patients were male (72%) and 11 were female (28%). Mean age of the patients was 57±15 years (21-87 years). The site distribution amongst these 39 patients was as follows: 23 PGL (59%) (Figure 1), 7 small bowel (18%), 7 primary colon lymphoma (18%), one primary pancreas lymphoma, and one primary liver lymphoma. Thirty-four out of 39 (87%) cases had stage 1, while 5 (13%) had stage 2 disease. Patient characteristics and demographic findings, clinic-pathologic features and follow-up data of high-grade and low-grade PGISL are presented in Table 1 and Table 2. There were statistically significant differences between high-grade and low-grade PGISL in terms of SUV max , SUV mean , MTV, TLG, recurrence, mortality, DFS and OS. The comparison of high-grade and low-grade PGISL features is shown in Table 3. Univariate Cox regression was performed for all potential risk factors (sex, age, site, SUV max , SUV mean , MTV, TLG) impacting recurrence and/or metastasis (met/rec). Site, SUV max , SUV mean , was determined as statistically significant on univariate analysis. The results of univariate Cox regression analysis are shown in Table 4. Factors with p<0.5 on univariate analysis (sex, age, SUV max , SUV mean , and site) were evaluated further with multivariate model. Only sex remained statistically significant on multivariate analysis (p=0.037). Within the group of patients with high-grade PGISL, 8 patients (31%) died and 9 patients (34.5%) developed met/rec during follow-up. Four patients died of causes other than the disease (cardiovascular events, cerebrovascular diseases, aging, etc). Four patients died of disease related reasons (extensive metastasis and related complications). OS at the 5 th year was 77%, and 73% at the 10 th year. The average time to detection of met/rec was 12.6 months (4-22). DFS was 80.5% and 65% at the first and second years, respectively. ROC curve was drawn to evaluate the diagnostic value of SUV max , SUV mean , MTV and TLG in high-grade PGISL ( Figure 2). Survival graphics of high-grade PGISL-DLBC variant obtained by univariate Cox regression analysis was plotted. Metabolic tumor parameters were Alagöz et al. 18 Figure 3. The sensitivity and specificity rates of SUV max SUV mean , MTV, and TLG according to cut-off values for high-grade PGISL are represented in Table 5.

Discussion
18 F-FDG PET/CT was performed in 447 patients with NHL during the study period in our department. The incidence of PGISL in our study group is 8.7% (39/447), evidently under the rates reported in the literature due to our selective population. The peak incidence is in the 6 th -7 th decades with a male predominance (16). The mean age of our group was 57 years with a male preponderance, in line with the literature. The risk of NHL is higher in men than in women, but there are certain types of NHL that are more common in women (16). However, there are no studies that have identified sex as a risk factor in the literature. We found that sex was the only factor affecting recurrence on multivariate analysis. Although female sex was the only risk factor for recurrence in our study, we attribute this finding to the insufficient sampling number, and thus believe this finding might not be clinically important.
Gastrointestinal tract is the most common extranodal site of NHL (17). The stomach is the most frequently involved (60-74% of cases) site, followed by the duodenum and small bowel (10-20%), ileocecal region (7-10%), and colon (<10%) (18). Our results are consistent with these reports, except that the colon was affected in a greater percentage of patients (equal to small intestine involvement) than previous studies. The stomach is the most common site of primary GIS lymphoma, and gastric MALT lymphoma is the most common type (7). In our study, 39% of gastric   Our incidence of gastric DLBC was markedly higher than gastric MALToma. This result is in contrast to the literature. MALT, DLBC, MC, Burkitt and T cell can all be seen in the small bowel and colon. The most common variant was DLBC (59%) in our patients followed by MALT (31%). These   findings are also completely in agreement with previous reports. Primary hepatic lymphoma (PHL) is very rare and up to date, only about 300 cases were published in the literature. Of all PELs, only 0.4% occurs in the liver (9). The most common variant in the liver is DLBC, accounting in one study for 71% of all cases (19). Our sole PHL patient was a DLBC subtype with poor prognosis (recurred at the 13 th , died at the 21 st month). Primary pancreatic lymphoma (PPL) is defined as an extranodal lymphoma arising in the pancreas with the bulk of the tumor localized to the pancreas. PPL is a very rare disease, accounting for less than 0.5% of pancreatic tumors (20). The only case with PPL in our study was a DLBC variant and his clinical course was fatal with high metabolic parameters (recurred at the 9 th , died at the 17 th month).
There is a correlation between 18 F-FDG uptake and histologic grade of lymphoma, since rapidly proliferating lymphoma cells have a high metabolic rate and aggressive subtypes of NHL take up high levels of 18   The authors declared that this study received no financial support.