Clinical insights into duodenal-type follicular lymphoma: case series study

Abstract

In Asia, widespread early detection through endoscopic screening has resulted in higher diagnosis rates of asymptomatic duodenal-type follicular lymphoma (DFL). However, no standardized guidelines exist for diagnosing and managing DFL, and ongoing debates persist regarding the optimal treatment strategies. This retrospective observational study was conducted between February 2018 and July 2024. Endoscopic examination revealed small whitish nodular lesions in the second portion of the duodenum. Seven patients (58.0%) underwent involved-site radiation therapy. Two patients (17.0%) with stage IV disease underwent chemotherapy with rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Another two (17.0%) received chemotherapy with rituximab combined with cyclophosphamide, vincristine, and prednisone. One patient (8.0%) was treated with rituximab monotherapy. During a median follow-up of 30.2 months, no cases of disease progression were observed. Although radiation and chemotherapy are effective treatments, the slow progression of the disease may make a watch-and-wait strategy appropriate.

INTRODUCTION

Duodenal-type follicular lymphoma (DFL), a distinct variant of follicular lymphoma, was featured in the 2016 World Health Organization classification update.1 It is characterized by its localization to the small intestine, especially the second portion of the duodenum, and its indolent clinical course.2 A typical endoscopic finding is a whitish, multinodular mucosal or polypoid lesion measuring 1 to 5 mm.3 DFL shares immunophenotypic features with other follicular lymphomas, including the t(14;18)(q32;q21) translocation, while exhibiting unique pathological characteristics, such as a dendritic cell meshwork and low expression of CD10.4 Unlike most follicular lymphomas, DFL appears to have a distinct pathogenesis related to inflammation and antigen stimulation, sharing some similarities with mucosa-associated lymphoid tissue (MALT) lymphoma.5 A gene expression study showed that DFL shares characteristics with MALT and nodal follicular lymphoma. Specifically, genes such as DEG, CCL20, and MAdCAM-1 are upregulated in both MALT lymphoma and DFL, whereas protocadherin gamma subfamily genes are upregulated in both nodal follicular lymphoma and DFL.6

In Korea, the prevalence of asymptomatic DFL is notably higher than in many Western countries, primarily because of the widespread implementation of national screening programs. Specifically, national stomach cancer screenings conducted via esophagogastroduodenoscopy (EGD) have led to an increased detection of incidental duodenal lesions. Despite the growing recognition of DFL, no standardized guidelines exist for its diagnosis and management, leading to ongoing debate among clinicians. While some advocate for active treatment approaches, such as radiation or chemotherapy, others propose a “watch-and-wait” strategy given the indolent nature of the disease.2,7 Treatment decisions are primarily based on the characteristic clinical course of DFL, which is generally known for its slow progression. This has led some clinicians to prefer observation over immediate treatment.8 Currently, data on the natural course of DFL and the effectiveness of various treatment methods are lacking, making it challenging to establish optimal treatment strategies. This observational study aimed to analyze the clinical characteristics and outcomes of patients with DFL.

CASE REPORT

This retrospective observational study was conducted at Ewha Womans University Seoul Hospital. We included patients with histologically diagnosed follicular lymphoma involving the duodenum between February 2018 and July 2024 (Fig. 1).

Fig. 1.

Study flow chart.

An experienced pathologist (M.S.C.) reviewed all available hematoxylin and eosin-stained slides to select the most representative slide for immunohistochemical staining. Histopathological grading was performed according to the World Health Organization criteria. This study was reviewed and approved by the Institutional Review Board of Ewha Womans University Seoul Hospital (protocol number: 2024-08-011).

Twelve patients met the inclusion criteria, of whom 7 (58.3%) were women. The median patient age was 58 (range, 34–74) years. The initial clinical and histological characteristics are summarized in Table 1. Endoscopy revealed small whitish mucosal nodular lesions distributed in the second portion of the duodenum. Two patients had a whitish nodular mass measuring >20 mm in the same area. One patient had a hyperemic lymph node in the bowel mesentery, which was identified by FDG-PET/CT (Fig. 2). Another patient presented with hypermetabolic lymph nodes in the bilateral axilla, right common iliac, bilateral external iliac, and bilateral inguinal to the femoral regions (Fig. 3). Two patients had bone marrow involvement and were classified as having stage IV disease.

Table 1.

Characteristics of patients and treatment outcomes for duodenal follicular lymphoma

Case	1	2	3	4	5	6	7	8	9	10	11	12
Sex	Female	Male	Female	Male	Male	Female	Female	Female	Female	Male	Male	Female
Age at diagnosis (yr)	50	57	67	37	45	74	72	55	74	60	34	69
Symptoms	None	None	None	None	None	None	None	None	None	None	None	None
Endoscopic finding	Multiple white nodular lesions at the second portion of the duodenum	70-mm-sized whitish nodular mass at the second portion of the duodenum	Multiple white nodular lesions near the AoV	Multiple white nodular lesions at the second portion of the duodenum	Multiple white nodular lesions at the second portion of the duodenum	Multiple white nodular lesions at the second portion of the duodenum	Multiple white nodular lesions at the second portion of the duodenum	Multiple white nodular lesions near the AoV	20-mm-sized flat white nodular mass at the second portion of the duodenum	Multiple white nodular lesions at the second portion of the duodenum	Multiple white nodular lesions at the second portion of the duodenum	Multiple white nodular lesions at the second portion of the duodenum
Lugano stage	Stage IV	Stage I	Stage IV	Stage I	Stage I	Stage I	Stage I	Stage II1	Stage I	Stage I	Stage I	Stage I
Follow-up duration (mo)	61.5	19.6	44.5	19.6	12.6	27.6	30.5	7.6	19.6	10.6	8.5	100.5
Treatment	R-CHOP, R maintenance	ISRT, 27 Gy/15 Fx	R-CHOP, R maintenance	ISRT, 24 Gy/12 Fx	ISRT, 27 Gy/15 Fx	ISRT, 30.6 Gy/17 Fx	ISRT, 30.6 Gy/17 Fx	R-CVP	R-CVP	ISRT, 24 Gy/12 Fx	Rituximab	ISRT, 30 Gy/15 Fx
Current status	CR	CR	CR	CR	CR	CR	CR	Ongoing chemotherapy	CR	CR	Ongoing chemotherapy	CR

AoV, ampulla of Vater; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; ISRT, involved-site radiation therapy; Gy, gray; Fx, fraction; R-CVP, rituximab, cyclophosphamide, vincristine, prednisolone; CR, clinical remission.

Fig. 2.

Endoscopic, radiological, and pathological findings of case no. 1. (A) Multiple white nodular lesions are observed near the ampulla of Vater. (B) A hypermetabolic lymph node is identified in the bowel mesentery, just above the aortic bifurcation (arrow). (C) Pathological findings show neoplastic follicles in the duodenal mucosa (hematoxylin and eosin stain, ×50) and immunohistochemical staining positive for CD21, positive for BCL-2, and with a low Ki-67 proliferation index (immunohistochemistry, ×50).

Fig. 3.

Endoscopic, radiological, and pathological findings of case no. 3. (A) Multiple white polypoid mucosal lesions, approximately 0.2 cm in size, are observed in the second portion of the duodenum. (B) Abdominal computed tomography reveals lymph node enlargement in the right common iliac and right inguinal areas (arrow). (C) Hypermetabolic lymph nodes are noted in the bilateral axilla, right common iliac, bilateral external iliac, and bilateral inguinal to femoral areas (arrow). (D) Pathological findings show neoplastic follicles in the duodenal mucosa (hematoxylin and eosin stain, ×50) and immunohistochemical staining positive for CD21, diffusely positive for BCL-2, and with a low Ki-67 proliferation index (immunohistochemistry, ×50).

The patients were followed for a median duration of 30.2 (range, 7.6–100.5) months. The clinical outcomes according to treatment are summarized in Table 1. Involved-site radiation therapy (ISRT) at doses of 24.0 to 30.6 Gy across 12 to 17 fractions was administered to seven patients (58.3%), all of whom achieved complete remission. Two patients (16.7%) diagnosed with stage IV disease underwent 6 cycles of chemotherapy consisting of rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) (rituximab 375 mg/m²+cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m², and prednisone 60 mg/m² every 3 weeks), followed by maintenance rituximab therapy at 375 mg/m² weekly. Two patients (16.7%) received 6 cycles of R-CVP chemotherapy (rituximab 375 mg/m²+cyclophosphamide 750 mg/m², vincristine 1.4 mg/m², and prednisone 60 mg/m² every 3 weeks). One patient (8.3%) underwent 4 cycles of rituximab monotherapy (375 mg/m² weekly). No recurrence or progression to systemic nodal involvement was observed during follow-up.

DISCUSSION

This study examined the clinical features, treatment, and outcomes of 12 patients with DFL. Most patients had localized disease, whereas two presented with bone marrow involvement. ISRT was effective in achieving complete remission in more than half of the cases, whereas chemotherapy was used in advanced stages. No recurrence or systemic progression was observed during the follow-up.

DFL typically presents as well-circumscribed germinal centers filled with centrocytes and few centroblasts, without tingible body macrophages or mantle zones.9 The neoplastic cells express markers such as CD20, BCL-6, BCL-2, and BACH2, similar to low-grade nodal follicular lymphoma, but lack CD5, BCL-1, MUM-1, Blimp-1, and T-cell markers, and have a low Ki-67 proliferation rate.10 Additionally, DFL displays distinct CD21 and CD23 expression patterns compared with nodal and extranodal follicular lymphomas, such as those found in the colon and stomach.11 A recent study reported that low-grade follicular lymphoma cases showed a homogenous CD21 expression pattern, while advanced-grade cases had predominantly peripheral, weak central CD21 expression. Therefore, a thorough pathological evaluation is crucial for the accurate diagnosis of duodenal follicular lymphoma, as its histological and immunophenotypic features are key to distinguishing it from other types of follicular lymphomas and determining its grade.

In this study, all patients diagnosed with DFL received active treatment, such as radiation therapy (RT) or chemotherapy, with none managed using the watch-and-wait strategy.12 This was based on several considerations. First, most patients expressed significant anxiety upon receiving a cancer diagnosis and preferred active treatment, despite the indolent nature of the disease. Second, under our institution’s multidisciplinary care policy, most patients consulted hematologists. Based on the clinical judgment that the long-term natural course of DFL may vary among individuals, early treatment was recommended. A recent retrospective study conducted in Korea evaluated the role and clinical significance of video capsule endoscopy (VCE) in patients with DFL. Notably, lesion extension beyond the duodenum was observed in ten patients (66.7%). Among them, one patient was managed with an observation strategy, while the remaining nine patients received systemic chemotherapy. Of the eight patients who did not undergo VCE, seven received RT, and one was observed without treatment. Based on the findings of this recent study, and for similar clinical considerations, we also chose to implement active intervention in most of our patients.13 However, the “watch-and-wait” approach has been considered a valid option, particularly for asymptomatic patients without systemic involvement.14 The long-term outcomes of patients with primary intestinal follicular lymphoma treated with the watch-and-wait strategy were examined in Japan.15 In this study, 124 out of 248 patients with gastrointestinal follicular lymphoma had localized disease, and 73 of them were managed without initial treatment. Over a mean follow-up period of 8.3 years, spontaneous remission occurred in approximately 16% of patients. Given patient preferences, multidisciplinary recommendations, and limited long-term data in Korea, active treatment is favored in most early-stage DFL cases.

RT is a well-established treatment for DFL, and several reports support its efficacy. A retrospective study was conducted on 20 patients treated with RT alone between 2008 and 2017, most of whom had stage I and low-grade disease.16 The study used 24 Gy in 12 fractions for 17 patients and 30.6 to 36 Gy in 18 fractions for three patients, achieving a complete remission rate of 95%. Similarly, in this study, more than half of the patients received ISRT, all of whom achieved a complete remission. However, 85.2% (46 of 54) of patients with DFL in the descending duodenum were reported to have lesions in the distal small intestine, mainly in the jejunum.17 ISRT has reduced the radiation field compared with the broader regional fields used in the past.18 Despite this, RT to the duodenum still carries the risk of damaging nearby organs, particularly the pancreas. Although DFL generally has a favorable prognosis, some cases may undergo histological transformation into aggressive lymphoma, mainly diffuse large B-cell lymphoma.19 It is crucial to identify high-risk patients who may require aggressive chemotherapy at diagnosis. According to the 2024 National Comprehensive Cancer Network guidelines, the first-line chemotherapy for patients with advanced stage III–IV disease includes the following20: (1) bendamustine plus rituximab, (2) R-CHOP, (3) R-CVP, (4) obinutuzumab-based regimens, and (5) lenalidomide plus rituximab. Supporting this, a recent multicenter retrospective study reported that, during a follow-up period of 0.9 to 7.1 years, six out of 73 patients with primary intestinal follicular lymphoma experienced disease progression. Among them, one received RT for mesenteric lymphadenopathy, and the remaining five received systemic chemotherapy.15

In conclusion, DFL generally follows a slow, indolent course, particularly in cases confined to the duodenum. Although ISRT has been effective in achieving remission, its efficacy may be limited when lesions extend beyond the duodenum to areas such as the jejunum or distal small intestine. Additionally, despite the reduction in the radiation field size with ISRT, the risk of damage to adjacent organs, such as the pancreas, remains. This highlights the need for precise staging and careful treatment planning to optimize outcomes while minimizing toxicity.