Recurrent Marginal Zone Lymphoma with Bone Marrow Involvement Detected by F-FDG PET/CT and Biopsy: A Diagnostic Challenge

Introduction

Marginal zone lymphoma makes up 7% of all lymphomas and is a B-cell non-Hodgkin lymphoma that first infiltrates the outer zone of follicles and slowly spreads centrally into the perifollicular mantle zone and germinal center [1,2]. While clinical presentation, blood tests, and radiological findings are all essential to the diagnostic process, marginal zone lymphoma, as with any other type of lymphoma, can be confirmed histopathologically through the biopsy of suspected tissues [1]. It is classified into 4 stages according to the Ann Arbor staging system [2]. Possible treatment includes watch and wait, radiotherapy, immunochemotherapy, and target therapy, as well as the antibiotic eradication of Helicobacter pylori (HP), since chronic HP infections can also lead to marginal zone lymphoma [2,3]. The prognosis can be determined according to the mucosa-associated lymphoid tissue (MALT) international prognostic index (IPI) and depends on how many risk factors the patient has [4].

Fluorine-18-fluorodeoxyglucose (18F-FDG) uptake in positron emission tomography/computed tomography (PET/CT) reflects the level of cellular metabolism of glucose in the tissues and is therefore a useful tool for diagnosing and monitoring malignant diseases, as cancer cells generally have a higher glucose consumption than normal cells [5]. The brighter the signal, the higher the glucose intake [5]. Malignant infiltration in bone marrow is often demonstrated as simultaneous focal or asymmetric hot spots in PET/CT with a high maximum standardized uptake value (SUVmax) of 18F-FDG [6,7].

Challenges in diagnosing lymphoma through 18F-FDG uptake in PET/CT have also been documented in other case reports: one reports a patient with Hodgkin disease and diffuse low 18F-FDG bone marrow uptake (BMU) without definite bone marrow infiltration [8], while the other describes marginal zone lymphoma with focal 18F-FDG uptake in lymph nodes [9].

This report is of a 74-year-old man presenting with anemia and a diagnosis of recurrent marginal zone lymphoma with bone marrow involvement identified with 18F-FDG PET/CT imaging and biopsy.

Case Report

In July 2011, a 64-year-old man with anemia (hemoglobin [Hb]: 37 g/L) and body weight loss of 7 kg in 1 month was diagnosed with marginal zone lymphoma, stage III, through lymph node biopsy. With no response to initial treatment via HP eradication, he received 6 cycles of cyclophosphamide, oncovin, and prednisolone (COP) in 5 months. He went into complete remission in April 2012, and Hb was restored to 120 g/L. For the next decade, he received regular follow-ups and was not administered drugs for chronic disease or hematopoietic cytokines (such as granulocyte colony-stimulating factor or erythropoietin). Hb levels remained within normal range, and he also remained completely asymptomatic.

During a routine check-up in October 2021, anemia (Hb: 65 g/L, white blood cell count: 4.53×109/L, platelet count: 293×109/L) was noted. Recurrent disease was then pathologically established through excisional biopsy of one of multiple abdominal subcutaneous nodules, with histopathological features corresponding to those of the marginal zone lymphoma from July 2011. 18F-FDG PET/CT (Figure 1A) and maximum intensity projection (MIP) (Figure 1B) images displayed diffuse, homogeneously distributed low 18F-FDG BMU, while bone marrow involvement (BMI) was subsequently confirmed by bone marrow biopsy, which revealed hypercellularity with diffuse infiltration of lymphoma cells (Figures 2, 3).

The patient received 6 cycles of combination therapy with reduced dosage of bendamustine, lenalidomide, and rituximab for the next 7 months [10]. Complete remission was achieved in June 2022, as depicted by subtle 18F-FDG BMU in PET/CT (Figure 4A) and MIP (Figure 4B), as well as negative histo-pathological results from bone marrow re-biopsy, which revealed normocellular hematopoietic cells without pathological evidence of lymphoma cell involvement (Figures 5, 6). Furthermore, normal hemogram, as well as an improvement in performance status from Eastern Cooperative Oncology Group (ECOG) 3 to ECOG 1, has been recorded since February 2022.

Discussion

Ambiguous lesions with low 18F-FDG SUV in PET/CT are generally categorized as benign processes. As opposed to higher BMU with a focal or asymmetric pattern, which is almost always associated with myeloproliferative disorders and malignant diseases, leading causes of diffuse homogeneous low 18F-FDG BMU in PET/CT most commonly reflect hyperplastic bone marrow status and include long-standing anemia, administration of hematopoietic cytokines, and inflammation [7,8,11,12]. Large-scale clinical analyses suggest that malignancy is usually first considered when SUVmax is above 6.560 [6], while SUVmax >10 implies a higher likelihood for aggressive non-Hodgkin lymphoma [13].

This case report serves as a warning that we must be alert to potential malignant BMI even with the concurrence of diffuse homogeneous low 18F-FDG BMU in PET/CT images and enhanced bone marrow hematopoietic conditions, such as insufficient peripheral circulating blood cells or the administration of hematopoietic cytokines. Although peculiar lesions may be distinguished as malignant or benign based on their standardized uptake value (SUV) in PET/CT, pathological evaluation cannot always be categorically omitted.

In other words, based on the statistics, the possibility of malignant BMI in diffuse homogeneous low 18F-FDG BMU in PET/ CT is not always taken into account at first [14–16]. However, we reported pathologically established bone marrow malignancy in what was expected to be a benign case, with recurrent diffuse BMI of lymphoma cells. The resolution of diffuse homogeneous 18F-FDG BMU in PET/CT and negative pathological results in bone marrow after treatment illustrate malignancy-free status, with a normal hemogram that reflects recovery of hematopoiesis from suppressed status due to malignant BMI.

We compared our case with 2 similar previous case reports. The first is a 2003 case report of a patient with Hodgkin disease who also had diffuse low 18F-FDG BMU that was otherwise only seen in conditions with increased marrow hematopoiesis [8]. Unlike in our patient, however, the diagnosis was not pathologically proven through bone marrow biopsy [8], which meant that bone marrow involvement could not be confirmed. The second case report, in 2023 described a patient, diagnosed with marginal zone lymphoma through the biopsy of a subcutaneous nodule, whose PET/CT images showed localized enhanced signal of 18F-FDG in lymph nodes [9]. The focally increased up-take could be interpreted as a possible characteristic of malignancy, although definite pathological disease staging was not possible [9]. In contrast, the PET/CT images in our case displayed an evenly distributed, mild 18F-FDG uptake in bone marrow throughout the whole body, a feature commonly and arbitrarily only associated with benign diseases. Our case is unique in that the patient’s diagnosis, which was fully expected to be benign based on the radiological findings, was in the end pathologically proven to be malignant. In our presented case, the correlation between the patient’s diffuse homogeneous low 18F-FDG bone marrow uptake in PET/CT and positive bone marrow involvement was not only confirmed before treatment, but also validated again after treatment through the resolution of diffuse BMU and negative bone marrow biopsy. The confirmed malignant diagnosis and resulting effective treatment emphasizes our message that the surveillance of pathological bone marrow status is always warranted even if signs and symptoms imply otherwise.

Conclusions

This report has highlighted the importance of follow-up for patients with low-grade lymphoma, including marginal zone lymphoma, and supports the diagnostic role of 18F-FDG PET/ CT imaging and the pathological verification in identifying malignant involvement in bone marrow.