Diffuse large B-cell lymphoma presenting as atypical foot pain: First reported case of primary cuboid bone involvement

1 Introduction

Primary bone lymphoma (PBL), first described by Oberling in 1928,¹ is a rare malignancy characterized by a malignant lymphoid infiltrate localized to the bone. This condition may present with or without cortical invasion or soft tissue involvement, but notably occurs in the absence of concurrent regional lymph node or distant organ involvement.^2,3 PBL constitutes a rare subset of lymphomas, representing approximately 5 % of primary bone tumors and 5–7% of extranodal lymphomas.^4,5 Among these, diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype, accounting for up to 90 % of PBL cases.^6,7 Involvement of bones in the foot is particularly rare, with limited case reports describing primary DLBCL in this region, predominantly affecting larger bones such as the calcaneus.^8–11

The presentation of DLBCL in the foot poses significant diagnostic challenges due to its nonspecific symptoms, which often mimic more common conditions such as gout, osteomyelitis, or other musculoskeletal disorders. Diagnostic complexity increases when malignancies, like PBL, involve smaller bones, such as the cuboid—a presentation not previously documented in the literature. The rarity of such cases underscores the importance of maintaining a broad differential diagnosis, particularly when conventional treatments fail to achieve expected outcomes.

This report describes the case of a 94-year-old male who presented with acute foot pain. Initially misdiagnosed as gout, subsequent investigations revealed DLBCL involving the cuboid bone. This case highlights the pivotal role of advanced imaging modalities and histopathological evaluation in establishing an accurate diagnosis and directing the management of rare oncologic conditions in atypical anatomical locations. This case highlights the importance of clinical vigilance and a systematic diagnostic approach for atypical foot pain, especially when standard treatments fail to provide symptom relief.

2 Case presentation

A 94-year-old male with a significant medical history of chronic kidney disease (CKD), glucose-6-phosphate dehydrogenase (G6PD) deficiency, hypertension, hyperlipidemia, hypothyroidism, osteoporosis, and a prior prostatectomy for prostate cancer presented with an acute onset of severe pain localized to his right midfoot. The pain was severe, significantly impairing ambulation. Physical examination revealed diffuse tenderness across the midfoot region, with no focal localization to a specific bone or joint, and a pes cavus foot structure. Initial foot and ankle radiographs demonstrated no abnormalities. Laboratory evaluations were notable for chronic anemia secondary to CKD and an elevated serum uric acid level of 8.0 mg/dL. Given the acute nature of the pain, combined with the patient's CKD and hyperuricemia, gout was initially suspected as a more common etiology. Treatment with a 5-day course of prednisone at a dose of 40 mg daily yielded partial symptomatic relief.

Despite corticosteroid therapy, the patient's pain persisted, prompting further investigation. The dual-energy computed tomography (DECT) scan, initially delayed for scheduling conflicts, was performed eight weeks later. The DECT scan ruled out gout by confirming the absence of characteristic urate deposits. Incidentally, it revealed a lytic lesion with endosteal scalloping in the cuboid bone, raising suspicion for a neoplastic process (Fig. 1A and B).

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Fig. 1 Sagittal (A) and Axial (B) CT Images of the Right Foot Sagittal (A) and axial (B) CT cuts showing a lytic lesion in the dorsolateral cuboid with endosteal scalloping, indicative of a neoplastic process.

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Following these findings, an MRI of the foot confirmed a lytic lesion with soft tissue involvement, raising strong concerns for malignancy (Fig. 2). Given the rarity of primary malignancies in the cuboid bone, metastatic disease from a primary cancer elsewhere was initially considered. A tumor marker workup was performed, revealing a mildly elevated carcinoembryonic antigen (CEA) level of 5.1 ng/mL, while alpha-fetoprotein (AFP) levels were negative. Prostate-specific antigen (PSA) was measured at 2.9 ng/mL, within the normal range, reducing the likelihood of prostate cancer recurrence or metastasis. Serum protein electrophoresis showed no evidence of monoclonal gammopathy, and beta-2 microglobulin levels were not significantly elevated, further lowering the suspicion of a plasma cell disorder or other hematologic malignancies.

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Fig. 2 Coronal STIR MRI of the Right Foot Coronal STIR MRI revealing a cuboid lesion with cortical thinning, focal cortical breakthrough, and mild peritumoral edema extending to adjacent bones and muscles, consistent with a locally aggressive process.

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These findings did not strongly suggest a carcinoma origin, redirecting the diagnostic focus toward alternative pathology. The absence of significant tumor marker elevation underscored the necessity of advanced imaging and histopathological confirmation. Whole-body PET/CT imaging subsequently revealed fluorodeoxyglucose (FDG) avid uptake confined to the cuboid bone (Fig. 3a), with no evidence of systemic or metastatic involvement. This critical finding confirmed the diagnosis of a primary malignant bone lesion and guided the decision for a targeted biopsy.

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Fig. 3a PET/CT of the Right Foot Axial PET/CT showing moderate to intense FDG activity in the cuboid lesion, consistent with high metabolic activity.

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A few days after the imaging studies, a CT-guided biopsy of the cuboid lesion was performed, and histopathological analysis confirmed a diagnosis of DLBCL, non-germinal center B-cell subtype (Fig. 4). Immunohistochemical staining demonstrated positivity for CD45, CD20, CD79a, BCL-6, and BCL-2, with a high proliferation index indicated by Ki-67 staining in approximately 70 % of the cells. Morphologically, the atypical lymphoid cells displayed medium to large size, irregular nuclei, and dispersed chromatin.

Fluorescence in situ hybridization (FISH) analysis identified BCL-6 rearrangement, a finding commonly associated with non-germinal center B-cell lymphoma. No MYC or BCL2 rearrangements were detected, effectively ruling out double-hit lymphoma. Notably, the patient did not report systemic B symptoms such as weight loss, night sweats, fever, or loss of appetite throughout the course of his illness.

Given the severity of the diagnosis and the potential for disease progression, the patient was admitted for inpatient oncologic management under the care of a multidisciplinary team (MDT) comprising specialists in hematology/oncology, infectious disease, nephrology, and orthopedic surgery. The team faced the dual challenge of delivering effective oncologic therapy while addressing the patient's advanced age, frailty, and renal insufficiency. Two weeks after the histopathology results, chemotherapy was initiated with Rituximab, Polatuzumab, and a reduced-intensity mini-CHP regimen (Cyclophosphamide, Doxorubicin, and Prednisone). During hospitalization, the patient developed MRSA cellulitis at the gluteal fold, necessitating the delay of subsequent chemotherapy to prioritize infection management. After infection resolution, further therapeutic adjustments were carefully evaluated to ensure patient safety and treatment effectiveness. Following the first sessions of chemotherapy, the patient experienced profound fatigue and increased infection risk due to immunosuppression, prompting concerns about the feasibility and tolerability of continuing systemic therapy.

Subsequently, two weeks after the initiation of treatment, whole-body PET/CT imaging demonstrated moderate to intense activity corresponding to the lytic lesion in the cuboid, consistent with persistent localized disease (Fig. 3b). Considering the combination of treatment-related complications and the PET/CT results, the MDT opted to transition to localized radiotherapy to minimize systemic toxicity while effectively targeting the disease. A total dose of 20 Gy (Gy) was delivered over five fractions of 4 Gy each, using a 3D conformal technique with an anterior-posterior/posterior-anterior (AP-PA) beam arrangement. Post-radiotherapy PET/CT demonstrated complete resolution of FDG activity in the cuboid bone (Fig. 3c), with this resolution achieved 11 weeks after the initiation of treatment. While long-term follow-up is ongoing, early clinical evaluations following radiotherapy showed significant pain reduction and no evidence of further disease progression, indicating a favorable response to this individualized treatment strategy.

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Fig. 3b Post-treatment PET/CT indicating partial response with reduced FDG activity in the cuboid.

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Fig. 3c Post-radiotherapy PET/CT demonstrating complete resolution of FDG activity, indicating radiological remission.

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Fig. 4 Histopathology and Immunohistochemical Stains of the Lymphoma A. H&E stained section shows medium to large-sized lymphoma cells (magnification X400). Immunohistochemical stains show that the lymphoma cells are positive for CD20 (B X200), BCL-6 (C X200), and MUM1 (D X200), while are negative for CD10 (E X200). The lymphoma cells exhibit a high proliferation index as shown by Ki-67 (F X200).

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3 Discussion

The presentation of DLBCL in the cuboid bone is exceedingly rare, with no previously documented cases in the literature to our knowledge. PBL typically involves larger skeletal structures, such as the femur, pelvis, or spine, making its occurrence in smaller foot bones an uncommon phenomenon.¹² Beal et al. reported that PBL accounts for approximately 5 % of all non-Hodgkin lymphomas,¹³ with only a small proportion affecting the bones of the foot.¹⁴ The rarity of foot involvement often causes diagnostic delays, as malignancy is typically not prioritized in the differential diagnosis of atypical foot pain. This case highlights the importance of considering a broad differential diagnosis, especially when initial treatments fail.

The initial presentation mimicked gout, and the absence of systemic symptoms of lymphoma—such as fever, night sweats, or weight loss—or any other symptoms aside from foot pain added to the diagnostic complexity. The absence of hallmark signs delayed diagnosis, requiring advanced imaging for further evaluation. DECT was instrumental as the first study to identify pathology, excluding gout and revealing the lytic lesion. This critical finding prompted further investigation with MRI and PET/CT, which confirmed localized malignancy and ruled out systemic disease. Together, these imaging modalities refined the diagnostic pathway and guided the subsequent therapeutic strategy. Furthermore, a CT-guided biopsy of the lesion provided histopathological confirmation of DLBCL.

The successful management of this patient highlights the essential role of MDT in balancing oncologic treatment with patient safety in elderly, frail patients. The team initially employed reduced-intensity chemotherapy with Rituximab, Polatuzumab, and mini-CHP to balance efficacy with tolerability, guided by evidence supporting reduced-dose chemotherapy regimens in older patients.¹⁵ However, the patient experienced profound fatigue and an increased risk of complications, including MRSA cellulitis, after initiation of chemotherapy. This led the MDT to reassess the treatment strategy, prioritizing infection management before proceeding. Guided by PET/CT findings and the patient's intolerance to chemotherapy, the MDT transitioned to localized radiotherapy as a pragmatic alternative to systemic therapy, aiming to minimize systemic toxicity while maintaining disease control. Post-treatment PET/CT demonstrated resolution of FDG activity in the cuboid bone, indicating radiologic remission.

In the current literature, the only other documented case of lymphoma involving the cuboid bone is a report by Allman, which described metastatic non-Hodgkin lymphoma in the setting of Waldenström macroglobulinemia.¹⁶ Unlike Allman's case of secondary bone involvement, our case represents the first reported instance of primary bone lymphoma in the cuboid. Both cases underscore the potential for lymphoma to manifest in smaller bones like the cuboid, highlighting the importance of including lymphoma in the differential diagnosis of atypical foot pain, especially after more common conditions such as gout have been excluded.

4 Conclusion

This case represents the first reported instance of primary DLBCL in the cuboid bone, marking a significant contribution to the understanding of rare malignancies in atypical locations. It underscores the essential role of integrative, multidisciplinary, and adaptive care in managing complex oncologic cases. The patient's journey highlights the necessity of tailoring diagnostic and therapeutic strategies to individual clinical circumstances, particularly when balancing frailty, comorbidities, and the risks of systemic treatment. This case further highlights the importance of advanced imaging modalities and multidisciplinary collaboration in achieving optimal patient outcomes. Future research is essential to refine diagnostic and therapeutic pathways for rare oncologic conditions, enhancing the ability to deliver precise and effective care in similarly challenging scenarios.

CRediT authorship contribution statement

Moamen Elhaddad: Lead author, Conceptualization, Writing – original draft, coordinated contributions from co-authors. Alexander Carrillo-Kashani: Contributed to clinical case management and provided critical input on the manuscript revisions. Jacob Stibelman: Assisted with imaging interpretation and provided technical insights for the manuscript. Karina Tavakalyan: Provided surgical expertise and contributed to the discussion of management approaches. Hongyu Ni: Conducted and interpreted the histopathological, Formal analysis, contributing to the discussion of pathology findings. B. David Massaband: Senior author and residency program director, Supervision, provided final manuscript review for intellectual rigor and journal compliance.

Patient consent

Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.

Institutional ethical committee approval

Institutional ethical approval was not required for this case report as per the committee's guidelines. However, the case complies with all ethical standards for human study reporting.

Funding/sponsorship statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.