The Role of Laparoscopy in Diffuse Large B-Cell Lymphoma with High 18F-Fluorodeoxyglucose Uptake Lymph Node in the Retroperitoneum After Chemotherapy

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and is the leading cause of lymphoma-related deaths globally [1,2]. The chemotherapy regimen of cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (known as R-CHOP), administered every 3 weeks for 8 cycles, has been the standard treatment plan for DLBCL. Patients who complete a course of chemotherapy and have a negative 18F-Fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG PET/CT) scan seem to be cured and do not require consolidative radiotherapy, even if the original tumor was large [3,4].

PET/CT is currently the standard imaging modality for staging and assessing responsiveness in all FDG-avid NHL, including DLBCL [5], and it is the best predictor of disease-free survival at the end of treatment [4]. PET/CT is used to evaluate remission after treatment completion in invasive NHL. Patients who have failed first-line treatment need to continue receiving PET/CT follow-up, confirm residual tumor activity, and consider performing pathological biopsy or receiving second-line treatment or salvage treatment [5,6]. PET scanning is highly sensitive. Negative scans have a high predictive value, ranging from 80% to 100%, while positive scans have a lower predictive value, varying from 50% to 100% [4,5]. However, lesions smaller than 6–8 mm may be overlooked due to their resolution being smaller than that of PET/CT. False-negative results can be caused by factors such as blood glucose levels and steroid use [5]. False-positive results can be caused by physiological high uptake, inflammation, and adrenal adenoma [7]. This suggests that patients with positive lesions based on PET/CT findings must be confirmed through biopsy or follow-up scans to exclude benign diseases or inflammation.

Excision biopsy is the standard method for lymphoma diagnosis. Core-needle biopsy (CNB) is widely used due to its low invasiveness and relatively high sensitivity. With progress made in detection methods such as B-ultrasound, CT, endoscopy, and the mature application of hydrodissection techniques, CNB can now reach almost all lymph nodes in the body relatively safely [8–10]. However, evaluating the overall structure of lymph nodes is crucial for distinguishing lymphoma from other diseases or determining the tissue subtypes of lymphoma. Complete lymph nodes can obtain sufficient tissue samples for various auxiliary tests, including cytogenetic analysis and flow cytometry [11]. Compared to excisional biopsy, the specimens obtained from CNB are relatively smaller, posing a huge challenge for pathologists in diagnosing and classifying diseases. Surgical procedures are mainly utilized for diagnosing lymphoma and alleviating lymphoma complications. Laparoscopy is very important in aiding the diagnosis of lymphoma [12]. Compared to CNB, laparoscopic biopsy offers the advantage of obtaining larger lymph node specimens and allows for the retrieval of multiple intact lymph nodes in a single procedure. The excellent visualization during laparoscopy minimizes the risk of injury to adjacent organs and vasculature. Furthermore, compared to open surgery, the laparoscopic approach is significantly less invasive, leading to enhanced postoperative recovery, superior cosmetic outcomes, and a reduced incidence of surgical complications. Consequently, the faster recovery and fewer complications often result in a shorter hospital stay for the patient.

The main objective of this study was to assess the value of diagnostic laparoscopic biopsy for high-FDG uptake solitary lesions in the mesenteric and retroperitoneal regions in patients with DLBCL in terms of remission duration. Five DLBCL patients who had received standard full-course chemotherapy were included. During the remission period, high-FDG uptake solitary lesions in the mesenteric and retroperitoneal regions were removed for biopsy under laparoscopic procedures. This minimally invasive approach can be used to evaluate efficacy and provide pathological evidence for subsequent treatment.

Case Report

Five patients were involved in this study. Figure 1 schematically depicts the screening flow and Table 1 summarizes the characteristics of these 5 patients. They were diagnosed with DLBCL and received standard chemotherapy from 2022 to 2023 in the First Affiliated Hospital of Zhejiang University School of Medicine. At the end of the treatment cycle, they underwent a PET/CT scan. The PET/CT showed that the FDG of the primary tumors was notably reduced, while high-FDG uptake lymph nodes were found in the abdominal cavity (Figure 2). The Deauville scores in these 5 patients ranged from 4 to 5. When a positive Deauville score was confirmed and the deep-seated intra-abdominal lymph nodes were deemed unsuitable for CNB, we opted for laparoscopic lymphadenectomy in these patients. The surgery was carried out by a gastrointestinal surgeon, and the postoperative pathological results were determined by professional pathologists. After the pathological results became clear, the hematologists formulated treatment plans for these patients.

The lymph nodes with suspicious tumor activity shown on PET/CT were successfully removed. Clear visualization of the surgical field and sufficient sampling volume contributed to the definitive diagnosis (Figures 3, 4). The laparoscopic procedures lasted between 49 minutes and 2 hours 47 minutes (median: 1 hour 51 minutes). One to 6 lymph nodes (median: 1 node) were retrieved. The mean postoperative hospital stay was 3.6 days (range: 3–4 days). All patients recovered uneventfully without major complications. The histological manifestations of 4 patients were inflammatory, and that of 1 patient showed tumor activity. For 2 of the patients without tumor activity, chemotherapy or drug treatment was not continued, and only regular ultrasound or CT follow-up was carried out. So far, no tumor recurrence has been found. Following laparoscopic surgery, pathological examination revealed no evidence of residual tumor activity. However, extensive areas of high FDG uptake were observed in the mesenteric regions. After hematology consultation, the possibility of occult tumor activity in these hypermetabolic regions could not be definitively excluded. Consequently, the 2 patients received subsequent therapy: one underwent lenalidomide monotherapy, while the other completed 4 cycles of R-GemOxD (Rituximab + Gemcitabine + Oxaliplatin + Dexamethasone) chemotherapy. Post-chemotherapy PET/CT surveillance demonstrated persistent FDG avidity without significant resolution. Chemotherapy was therefore discontinued, and both patients remain recurrence-free during follow-up, suggesting the absence of viable malignancy and indicating that further chemotherapy was unwarranted. Additionally, for patients with extensive lesions, we recommend expanding intraoperative lymph node sampling during laparoscopic procedures. This approach enhances diagnostic accuracy by reducing sampling bias and may prevent unnecessary postoperative chemotherapy. One patient with definite tumor activity was receiving chemotherapy with the R-GemOxD regimen. All 4 patients with pathologically negative results have been followed for over 2 years and have remained free of tumor recurrence. The patient with a pathologically positive result has been followed for more than 1.5 years and continues to receive treatment. Currently, for patients undergoing EOT-PET screening with intra-abdominal lesions scoring Deauville 4–5, laparoscopic biopsy surgery is performed when clinically feasible. Postoperative diagnostic evaluation is rigorously conducted, and standardized management protocols are implemented.

Discussion

Surgical intervention is an effective option for diagnosing and staging lymphoma, as well as managing complications such as hemorrhage, perforation, and obstruction [13]. However, with advancing understanding of the disease and developments in imaging, staging and diagnosis no longer rely solely on surgical approaches. For patients who must undergo surgery, combination chemotherapy is more effective than surgery alone [14]. Currently, chemotherapy and radiotherapy play a dominant role in the treatment of lymphoma, with chemotherapy alone capable of curing most patients with DLBCL [15]. PET/CT is now a mature and widely used modality for evaluating treatment response in lymphoma. Growing evidence supports its pivotal role in the staging and response assessment of both HL and NHL. Following first-line treatment, patients assessed with an EoT-PET DS of 1–3 are considered PET-negative, while those with a DS of 4–5 are considered positive [16,17]. Similar to interim PET, EoT-PET exhibits a high negative predictive value (NPV), but its positive predictive value (PPV) is variable. The DS 1–3 vs 4–5 cut-off demonstrates higher sensitivity and NPV, but lower specificity and PPV [16]. At the 2.5-year timepoint, the PPV of PET non-complete response (non-CR) for overall survival (OS) was 43.2%, while the NPV of PET-CR for OS was 92.9% [18]. However, Heiko Schöder’s study failed to demonstrate a statistically significant association between EoT-PET and patient clinical outcomes [17]. In one study, PET was positive in 21/65 patients (32.3%) after 4 cycles of R-CHOP chemotherapy; biopsy confirmation revealed that 19/21 (90.5%) were false positives, with pathology confirming that the majority of positive uptake was due to inflammation [16].

For patients with a positive PET-CT finding, pathological confirmation or continuation of chemotherapy is required [5,6]. Currently, CNB is the most commonly used method. Among the 5 patients selected in our study, the FDG-avid lymph nodes were all located intra-abdominally. Their considerable depth, interference from bowel gas, and proximity to other organs and blood vessels made CNB sampling challenging. CNB success is more reliant on the operator’s clinical experience. If the needle samples necrotic tissue within the tumor, it can lead to inconclusive results or even necessitate a repeat biopsy [19]. Furthermore, CNB typically yields relatively small tissue samples. In a clinical study encompassing 1000 patients, the average CNB specimen length was 32 mm, with an average volume of 185 mm3 [20]. Compared to complete lymph node excision, CNB provided a definitive diagnosis in 92.3% of cases, while surgical excision achieved this in 98.1% of cases. The discordant referral diagnosis rate was 23.1% for CNB, higher than the 21.2% rate for surgical excision. Diagnostically, CNB resulted in more non-definitive diagnoses, including unclassifiable lymphomas or ambiguous diagnoses falling between reactive lesions and lymphoma [19,21]. Additionally, from the perspective of disease research and development, while CNB provides adequate material for immediate clinical management, it often fails to yield sufficient material for today’s expanding genomic studies. It is particularly inadequate to support high-throughput sequencing based on tumor tissue, which is crucial for fundamental biology research, understanding treatment response, developing targeted therapies, and improving patient prognosis [22].

Conclusions

Laparoscopic surgery enables the clear excision of suspicious retroperitoneal lymph nodes for pathological biopsy. Consequently, it holds the promise of serving as a complementary approach to CNB for elucidating the tumor activity of retroperitoneal lymph nodes with high FDG uptake in lymphoma patients after chemotherapy. Currently, there is no standardized approach for biopsy or optimal timing of laparoscopy in patients with intra-abdominal FDG-avid lymph nodes (Deauville score 4–5) following chemotherapy. Prospective trials are needed to address this.