Effect of Clinical, Endoscopic, Radiological Findings, and Complications on Survival in Patients with Primary Gastrointestinal Lymphoma

Background: The purpose of this study was to evaluate the clinical, endoscopic, and radiological characteristics, complications, survival outcomes, and prognostic factors of patients with primary gastrointestinal lymphoma. Methods: This study retrospectively analyzed the demographic, laboratory, endoscopic, and radiological characteristics and treatment outcomes of 43 patients with newly diagnosed primary gastrointestinal lymphoma. Results: The median age was 62 years (range: 26-83). The primary lesion location was the gastric in 33 (77%) patients and the intestinal in 10 (23%) patients. The most common lesions were the corpus (33%) and corpus + antrum (24%) in primary gastric lymphoma and the ileum (60%) in primary intestinal lymphoma. The most common endoscopic findings were diffuse infiltrative lesion (23%) and mass-forming (33%), while the most common computed tomography finding was wall thickening (53%). Wall thickening and mass-forming at computed tomography were greater in primary intestinal lymphoma than in primary gastric lymphoma (P = .034). Complications were observed in 9 (21%) patients and 13 (31%) patients who underwent surgery. Complication and surgery rates were higher in primary intestinal lymphoma than in primary gastric lymphoma (P = .003 and P = .014, respectively). Five-year overall survival and 5-year event-free survival rates were 75% and 72%, respectively. Univariate analysis showed that intestinal involvement, advanced clinical stage, a high International Prognostic Index score, mass-forming and wall thickening at computed tomography, extranodal involvement, and complication were found to adversely affect survival. Multivariate analysis revealed that intestinal involvement and a high International Prognostic Index score were independent prognostic factors for overall survival and event-free survival. Conclusion: Patients with primary gastrointestinal lymphoma with intestinal involvement and high International Prognostic Index score should be followed closely.


INTRODUCTION
Primary gastrointestinal lymphoma (PGIL) is a malignancy derived from the gastrointestinal tract and spreads primarily through neighboring lymph node invasion. 1,2 It constitutes 30%-40% of extranodal lymphomas and 1%-4% of malignant gastrointestinal tract tumors. 3,4 Monoclonal proliferation developing as a result of antigenic stimulation and recurring inflammation plays a key role in the pathogenesis. 1,2 Some possible risk factors such as Helicobacter pylori (HP), human immunodeficiency virus, and Epstein-Barr virus infection, celiac disease, autoimmune diseases, immunosuppressive drugs, and inflammatory bowel diseases are involved in the etiology. 1,5 Primary gastrointestinal lymphoma is most frequently seen in the gastric, followed by ileocecal region, small bowel, and colon in the gastrointestinal tract. 6,7 Histologically, diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma are most common, while follicular lymphoma (FL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), enteropathy-associated T-cell lymphoma, and post-transplant lymphoproliferative disease are less common. 8,9 Endoscopic biopsies from the region with lymphoma involvement in the gastrointestinal tract are required for diagnosis. 10 Computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasonography, or 18 F-fluorodeoxyglucose positron emission tomography are used to assess the spread of the disease. 11 Treatment options include HP eradication therapy, immunotherapy, chemotherapy, surgery, and radiotherapy, although the optimal treatment for PGIL still remains controversial. 12 Life-threatening complications such as perforation, bleeding, and obstruction can also be seen during the course of the disease. 13 Although the medical literature contains studies concerning PGIL, the number of studies evaluating the relationship between endoscopic and radiological findings, complications, and survival is limited. The purpose of this study was to evaluate the clinical, endoscopic, and radiological characteristics, complications, survival outcomes, and prognostic factors of patients with PGIL.

MATERIALS AND METHODS Patient Selection
This study was carried out on patients with newly diagnosed PGIL between January 2006 and August 2020 at the Karadeniz Technical University Medical Faculty. Diagnosis of PGIL was based on Dawson standards. 14 Patients younger than 18 years of age were excluded from this study. Demographic data, laboratory, endoscopic, and radiological findings, complications, treatments, and responses were collected retrospectively from our hospital's electronic data record system. Since this article is a retrospective study, informed consent was not obtained from the patients. Approval for the study was granted by the ethic committee of Karadeniz Technical University Medical Faculty under protocol no. 2021/92.

Diagnostic Procedure
Esophagogastroduodenoscopy, ileocolonoscopy, or surgical resection when clinical presentations did not permit endoscopic procedures were performed based on the sites of lymphoma involvement in the gastrointestinal tract. Preparates from tissue samples obtained from endoscopic biopsy and/or surgical resection were stained with hematoxylin-eosin and were assessed using immunohistochemical methods (CD20 and CD3 routinely for all patients and CD5, CD10, CD23, CD15, CD30, terminal deoxynucleotidyl transferase [tdt], cyclin D1, Bcl-2, Bcl-6, c-myc, p53, Ki-67, and immunoglobulin light chain [κ, λ] for selected patients). In line with the World Health Organization 2016 Lymphoma Classification, MALT lymphoma, FL, and MCL were classified as low-grade lymphomas and DLBCL, BL, lymphoblastic lymphoma, and T-cell lymphoma as high-grade lymphomas. 15 Pathological lesions detected during endoscopic procedures were defined as superficial, diffuse infiltrative, ulcer, or mass-forming. Computed tomography findings were defined as normal, wall thickening, or mass-forming.

Staging and Prognosis
Primary gastrointestinal lymphoma staging was performed using the Lugano International Conference classification based on physical examination, laboratory findings (complete blood count, lactate dehydrogenase [LDH], albumin, erythrocyte sedimentation rate [ESR]), imaging techniques (posteroanterior x-ray and neck-thoracicabdominal-pelvic CT), and bone marrow biopsy. 16 Stage I and stage II were defined as early stage and stage IV as advanced stage. Patients were also classified as low risk (scores 0-1), low-moderate risk (score 2), moderatehigh risk (score 3), or high risk (scores 4-5) based on the International Prognostic Index (IPI). 17

Treatment and Response Evaluation
The patients received the following chemotherapy protocols: R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone) for DLBCL, HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) for BL, R-CHOP, R-COP (rituximab-cyclophosphamide, doxorubicin, and prednisone), and R alone for MALT lymphoma, R-CHOP for MCL. Patients with MALT lymphoma also received HP eradication therapy. Patients with relapse and refractory were given high-dose chemotherapy. Surgical procedures were performed for diagnosis or complications. Responses to treatment were defined using the Lugano classification

The Relationship Between the Primary Lesion Location and Clinical, Endoscopic, and Radiological Findings
No difference was determined between PGL and PIL in terms of age, gender, or laboratory tests. Eight (24%) patients were low-grade lymphoma and 25 (76%) patients were high-grade in PGL, while 1 (10%) patient was low-grade lymphoma and 9 (90%) patients were high-grade in PIL. Twenty-seven (82%) patients were early stage and 6 (18%) patients were advanced stage in PGL, while 5 (50%) patients were early stage and 5 (50%) patients were advanced stage PIL. Twenty-seven (82%)  patients were in the ≤2 IPI score and 6 (18%) patients were in the ≥3 IPI score in PGL, while 5 (50%) patients were in the ≤2 IPI score and 5 (50%) patients were in the ≥3 IPI score in PIL. Extranodal involvement was present in 5 (15%) patients in PGL and in 5 (50%) patients in PIL. No statistically significant difference was observed between PGL and PIL in terms of lymphoma grade, stage, IPI score, or extranodal involvement. Complications developed in 3 (9%) patients in PGL and in 6 (60%) patients in PIL. Surgery was performed on 3 (9%) patients in PGL and on 5 (50%) patients in PIL. Complication and surgery rates were significantly higher in PIL than PGL (P = .003 and P = .014, respectively) ( Table 3).
Endoscopic images were viewed superficial, ulcer, or diffuse infiltrative lesion in 18 (67%) patients and massforming in 9 (33%) patients in PGL, while superficial, ulcer, or diffuse infiltrative lesion was seen in 2 (29%) patients and mass-forming in 5 (71%) patients in PIL. But endoscopic findings were not significantly different between the 2 groups.
Computed tomography detected wall thickening or massforming in 19 (58%) patients in PGL, while no abnormal findings showed in 14 (42%) in PGL. Wall thickening or mass-forming were detected in 10 (100%) patients in PIL. Computed tomography findings of wall thickening or mass-forming were significantly more common in PIL than in PGL (P = .034).  Figure 1).
Significant independent prognostic factors for better OS and EFS were primary lesion location and IPI score at multivariate analysis. The risk of mortality in patients with PIL was approximately 8.5 times higher than in patients with PGL. Also, the risk of mortality was approximately 9.5 times higher in patients with high IPI scores than low IPI scores (Table 4).  immunoproliferative small intestinal disease is high. 21 This variation between societies may be due to geographical changes in infections, autoimmune diseases, and environmental factors. 19 In the present study, similarly to Western societies, gastric involvement was detected at a rate of 77% and intestinal involvement at 33%.
While the most frequently involved region in patients with PGL is the corpus or the fundus, in patients with PIL is the ileum. 5  Superficial, ulcer, diffuse infiltrative, and mass lesions can be seen on the endoscopic images of patients with PGIL. Wall thickening or mass is detected in 85% of cases at abdominal CT. 12 In the present study, superficial, ulcer, or diffuse infiltrative lesions were more frequent on the endoscopic images from patients with PGL, while mass lesions were more common in patients with PIL, but the difference was not statistically significant.
Wall thickening or mass-forming was more frequently detected at CT in patients with PIL than in those with PGL. Complications such as obstruction and perforation are more frequently seen in patients with PGIL presenting with mass lesions, especially those with intestinal involvement, and this increases surgical requirements. Li et al 13 reported that complications were more common in patients with intestinal involvement compared to those with gastric involvement (28.6% and 10.8%, respectively). Complication development and surgery requirement rates were also higher in PIL compared to PGL in the present study. Surgery requirements associated with severe complications in patients with PGIL have been reported at less than 5%. 24 In contrast to the previous literature, however, emergency surgery due to complication development was performed on 12% of patients enrolled in the present study. It should be remembered that the risk of complications, and therefore surgery requirements, may be higher in patients with PIL in particular, due to the bowel wall being thinner and the greater frequency of mass lesions.  13 reported performance status, LDH levels, and histological type as independent prognostic risk factors in patients with PGIL. In the present study, primary lesion location, stage, IPI, extranodal involvement, mass and wall thickening at CT, and complications emerged as associated with survival at univariate analysis. But only primary lesion location and IPI are independent risk factors in the multivariate analysis.
The most important limitations of our study are that it is a retrospective study and the number of cases is low. Other limitations are the lack of endoscopy reports for some patients. In addition, it was also not possible to evaluate the HP eradication therapy results due to HP not having been diagnosed in some patients.