Rare Sinonasal Case of IRF4 -Rearranged Large B-Cell Lymphoma Mimicking Chronic Sinusitis

Abstract

Large B-cell lymphoma (LBCL) with IRF4/MUM1 rearrangement is a rare and newly recognized entity predominantly involving Waldeyer’s ring of lymphoid tissue in the oropharynx. Unusual clinical presentations can result in delayed diagnosis of LBCL with IRF4 rearrangement, resulting in increased patient morbidity. We present a case involving a pregnant woman with a frontal sinus swelling and clinical diagnosis of chronic sinusitis and possible Pott’s puffy tumor. An endoscopic procedure and subsequent histologic examination revealed diffuse LBCL with diffuse IRF4/MUM1 staining, supported by fluorescence in situ hybridization analysis showing an IRF4 locus rearrangement at 6p25.3. Subsequent imaging revealed metastatic disease to cervical, thoracic, and lumbar spinal regions. This case highlights the importance of consideration of lymphomas in patients who may clinically appear to have non-neoplastic disease, especially in the head and neck regions.

Introduction

Hematologic malignancies, while relatively uncommon, represent the second most frequent type of malignancy in the head and neck region. ¹ B-cell lymphomas, in turn, represent the majority of lymphomas that occur in the head and neck. Patients typically present with enlargement of cervical lymph nodes and tonsils (Waldeyer’s ring, in the oropharynx), and less commonly with systemic symptoms such as night sweats, weight loss, fever, and fatigue. Large B-cell lymphoma (LBCL) with IRF4/MUM1 rearrangement is a newly described entity characterized by large, atypical lymphocytes exhibiting strong immunohistochemical expression of IRF4/MUM1, and commonly translocation involving IRF4 and IgH upon fluorescence in situ hybridization. The median age of patients at the time of presentation is in the second decade of life, with most patients diagnosed at less than 18 years old. ² LBCL with IRF4 rearrangement is generally responsive to immunochemotherapy. We present the case of a 39-year-old pregnant female referred for frontal sinus swelling and non-resolved chronic sinusitis. She was found to have metastatic LBCL with IRF4 rearrangement. We report this case to highlight the importance of including lymphomas in the differential diagnoses of disorders of the head and neck, especially in patients with unusual clinical presentations.

Case Presentation

A 39-year-old pregnant woman at 31 weeks and 5 days of gestation with a history of Crohn’s disease was referred for evaluation of persistent, nonresolving chronic frontal sinusitis. No nasal polyps were present. Despite completing 2 courses of antibiotics with only transient symptomatic relief, her condition worsened. She also underwent balloon sinuplasty, which failed to alleviate her symptoms. Daily use of intranasal fluticasone (Flonase^®, Haleon) and saline irrigation provided no improvement. Notably, she had previously experienced right upper quadrant pain radiating to the back, which had been attributed to pregnancy-related changes. One month prior to presentation, she developed visual disturbances and headaches, prompting magnetic resonance imaging (MRI) of the brain, which revealed right frontal lobe edema and left frontal sinus opacification.

At the time of evaluation, she denied headache, vision changes, epistaxis, nasal discharge, and lymphadenopathy. Physical examination was notable only for 2 areas of palpable edema on the central forehead without overlying warmth, erythema, or tenderness. Bony prominences and sinuses were non-tender to palpation. Laboratory studies were significant for neutrophilic leukocytosis (white blood cell: 18.55 × 10⁹/L) and mild anemia (Hgb: 11.3 g/dL). A noncontrast brain MRI study demonstrated intracranial extension of bifrontal sinusitis with mass effect on the right frontal lobe and focal leftward deviation of the falx cerebri. Associated findings on MRI included bifrontal osteomyelitis, subdural empyema, and a bilateral subcutaneous scalp abscess extending along the frontal bone (Figure 1).

Figure 1.

(A) Sagittal T1 and (B) axial T2 views of MRI of the brain showing intracranial extension of a process centered in the sinuses (green arrow), overlying the right frontal lobe with regional mass effect (white arrow) on underlying cerebral parenchyma and leftward deviation of the falx focally (blue arrow). A subcutaneous scalp abscess courses along the frontal bone (orange arrow) and extends bilaterally. MRI, magnetic resonance imaging.

The patient underwent endoscopic bilateral frontal sinusotomy, anterior ethmoidectomy, and septoplasty. Intraoperatively, a left septal deviation and dishwater-like fluid within the left frontal sinus were noted. Pale, edematous tissue was observed in bilateral frontal recesses, but no discrete masses or purulent collections were identified. Cultures of the fluid were negative for bacterial (aerobic and anaerobic) and fungal organisms. Human immunodeficiency virus testing was negative, and there was no evidence of peripheral lymphadenopathy or hepatosplenomegaly.

Histological examination revealed reactive ciliated pseudostratified columnar epithelium overlying diffuse infiltrates of large atypical lymphoid cells exhibiting high nuclear-to-cytoplasmic ratios, round to irregular nuclear contours, conspicuous nucleoli, and mitoses (Figure 2A and B). The background cells consisted of scattered mature lymphocytes, eosinophils, and apoptotic bodies. The neoplastic cells expressed CD20, PAX5, CD10, BCL6, IRF4/MUM1 (strong and diffuse), CD45, and a high proliferative index of 70% to 80% was identified (Figure 2C-F). The atypical cells were negative for desmin, AE1/AE3, Cyclin D1, SOX10, CD3, CD5, CD23, CD30, BCL-2, and EBV by in situ hybridization. Fluorescence in situ hybridization studies revealed an IRF4 locus rearrangement at 6p25.3, confirming a diagnosis of LBCL with IRF4 rearrangement (LBCL-IRF4).

Figure 2.

(A) Low power and (B) high power histologic images of a diffuse infiltrate by large, atypical lymphoid cells with a high nuclear-to-cytoplasmic ratio, irregular and vesicular nuclei, and a moderate amount of cytoplasm. Atypical mitoses and apoptotic bodies are appreciated (hematoxylin and eosin, 100× and 500× oil, respectively). Immunohistochemical stains for (C) CD20, (D) MIB-1, (E) BCL-6, and (F) IRF4/MUM1 show diffuse positivity in tumor cells (100×).

Subsequently, full-body imaging was performed and showed metastases to the cervical, thoracic, and lumbar spine. The patient underwent induction of labor and parturition prior to initiating chemotherapy. She received 6 cycles of MR-CHOP (high-dose methotrexate, rituximab, cyclophosphamide, doxorubicin, and vincristine) with intrathecal cytarabine and Cyberknife intensity-modulated radiation therapy to the frontal sinus and T7-T12. At the 2-year follow-up visit, the patient continued to show no evidence of disease.

Discussion

LBCLs comprise a category of non-Hodgkin lymphomas characterized by heterogeneous morphology and molecular phenotype. Lymphomas account for approximately 5% to 11% of all sinonasal malignancies.^1,2 In Western countries, LBCLs are the most common lymphomas affecting the head and neck, whereas NK/T-cell lymphomas are more prevalent in Asian and Hispanic populations. Within the sinonasal tract, the maxillary sinus is the most commonly affected site for LBCLs.^1,3 The differential diagnoses include other types of aggressive B-cell lymphomas, such as diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, pediatric-type follicular lymphoma, blastoid mantle cell lymphoma, and plasmablastic lymphoma.

Sinonasal LBCLs usually present with nonspecific clinical symptoms, unfortunately leading to diagnostic delay in a significant number of cases. Patients may present after local extension of the malignancy. B symptoms (fever, night sweats, and weight loss) are generally absent in localized sinonasal LBCLs. Imaging is crucial for diagnosis and assessing disease extent. MRI is superior to computed tomography (CT) in visualizing soft tissue involvement and is particularly useful in evaluating sinonasal LBCLs. On the other hand, CT is preferred for assessing bony erosion. Positron emission tomography-CT plays a pivotal role in staging by identifying potential metastases. Endoscopically, sinonasal LBCLs appear as soft tissue masses that may be obscured by overlying inflammation, mimicking other conditions such as granulomatosis with polyangiitis. ³

Histologically, LBCLs are characterized by diffuse proliferation of centroblasts and, less commonly, immunoblasts/plasmablasts, and may exhibit areas of necrosis. ² Neoplastic cells typically display significant cytologic atypia, manifesting as hyperchromasia, cleaved or angulated nuclei, atypical mitoses, and, generally, there is no vascular invasion. ³ Immunophenotypically, these cells express pan-B-cell markers including CD19, PAX5, BOB1, OCT2, and CD20, while lacking expression of T-cell markers such as CD3, CD4, CD5, and CD8. The proliferative index is usually high, ranging from 60% to 90%.^2,3

LBCLs are commonly classified using the Hans algorithm into activated B-cell, germinal center B-cell (GCB), and unclassified subtypes. ⁴ Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) is a rare subtype of DLBCL, recently recognized as a distinct entity in both the World Health Organization (fifth edition) and the international consensus classification of lymphoid neoplasms. It is a GCB-type LBCL defined by the t(6;14)(p25.3;q32) translocation involving IGH::IRF4.^2,5 The most common anatomic sites include Waldeyer’s ring, tonsils, cervical lymph nodes, and sometimes the gastrointestinal tract. ⁶ Management typically involves standard chemoimmunotherapy (e.g., R-CHOP or rituximab, cyclophosphamide, doxorubicin, and vincristine). Predominantly affecting children and young adults, LBCL-IRF4 is associated with a favorable prognosis. ⁷

This case highlights the biological diversity within LBCLs and emphasizes the importance of including them in the differential diagnosis for patients presenting with nonspecific sinonasal symptoms. We also report this case to draw attention to the uncommon occurrence of LBCL with IRF4 rearrangement in the sinonasal region, which is a rare presentation of a diffuse LBCL.