Gastric lymphoma presenting with predominant pancreatitis and cranial neuropathy: a rare clinical presentation—a case report

Introduction

Diffuse large B-cell lymphoma (DLBCL) is among the most prevalent histological subtypes of non-Hodgkin lymphoma (NHL), accounting for approximately 30% of newly diagnosed NHL cases annually. This aggressive form of B-cell lymphoma is characterized by considerable heterogeneity in its clinical presentation, histological features, and prognosis (1). However, high-grade B-cell lymphomas (HGBCL) account for approximately 2% of all NHLs, and patients with these neoplasms frequently exhibit refractoriness to standard therapy or experience relapse following treatment (2). Extra nodal NHL frequently involves the gastrointestinal tract, with the stomach being the most commonly affected site, followed by the small intestine and ileocecal region, while rectal involvement remains rare (3).

Primary gastric DLBCL (PG-DLBCL) generally manifests with symptoms such as abdominal pain, nausea, vomiting, gastrointestinal bleeding, and weight loss. However, the case discussed here is unusual as the patient with triple-hit HGBCL initially presented with pancreatitis, followed by the onset of multiple cranial neuropathies. The aim of this report was to raise awareness among clinicians regarding this condition. In cases of unexplained acute pancreatitis or multiple cranial neuropathies, PG-DLBCL should be considered as a differential diagnosis to reduce the risk of misdiagnosis or delayed diagnosis of this disease. We present this article in accordance with the CARE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-678/rc).

Case presentation

A 66-year-old Chinese female presented to Aerospace Center Hospital with a chief complaint of “intermittent abdominal pain over the past two weeks”. The patient described pain in the upper left abdomen, accompanied by nausea and fever, with a peak temperature of 38.0 ℃, occurring after the consumption of chicken. She denied having symptoms such as vomiting, jaundice, diarrhea, or melena, and reported no recent significant weight changes.

Her medical history included immune-related disorders, specifically primary immune thrombocytopenia and connective tissue disease diagnosed 18 years earlier, as well as Hashimoto’s thyroiditis diagnosed 7 years prior. There was no family history of malignancy, and she reported no known drug or food allergies. Additionally, she had no history of gallbladder inflammation, gallstones, abdominal trauma, smoking, or alcohol consumption.

On examination, the vital signs of the patient were stable, with no fever or palpable lymphadenopathy. Physical examination did not reveal any notable abnormalities. Laboratory tests revealed increased blood amylase (AMY: 204 U/L) and lipase (LIP: 330 U/L) levels, along with a mildly increased white blood cell count (WBC: 11.47×10⁹/L). Abdominal computed tomography (CT) demonstrated a distended pancreatic body and tail, with a blurred peripancreatic fat plane and multiple streaky opacities, though no significant dilation of the pancreatic duct was observed (Figure 1). The initial diagnosis was consistent with acute pancreatitis. The abdominal pain of the patient diminished after treatment with omeprazole and somatostatin, and subsequent tests indicated normalized AMY and LIP levels, indicating a favorable response to the therapeutic intervention.

Figure 1 Abdominal plain CT axial section shows a plump pancreatic body and tail with surrounding infiltration, indicative of inflammatory changes in the pancreas. CT, computed tomography.

Ten days later, the patient experienced a sudden onset of double vision, which was particularly noticeable when both eyes turned to the left. Physical examination revealed delayed direct and consensual pupillary light reflexes and impaired abduction of the left eye, while other neurological assessments were unremarkable. Cranial magnetic resonance imaging (MRI) identified scattered ischemic demyelinating lesions in the brain. Subsequently, the patient developed right eye motor disturbances, including ptosis and a complete inability to move the right eye in any direction. Involvement of cranial nerves, specifically the left abducens nerve and right oculomotor nerve, was suspected. Administration of medications aimed at improving nutrition and circulation resulted in significant improvement of these symptoms.

The patient gradually developed numbness and paralysis in the left facial region. A follow-up cranial MRI revealed abnormal signals in the left cavernous sinus, fullness of the pituitary gland, and demyelination changes in the white matter of the brain. A lumbar puncture indicated a mild elevation in mononuclear cells and protein levels in the cerebrospinal fluid, along with reduced glucose and chloride levels. The neurologist considered the possibility of multiple cranial neuropathies involving the left abducens, right oculomotor, and left facial nerves, potentially related to immunological abnormalities.

The patient began treatment with intravenous immunoglobulin (IVIG) at 20 g per day and methylprednisolone sodium succinate at 1 g per day, with the steroid dose being halved every three days. After 12 days of steroid therapy, the methylprednisolone dose was lowered to 60 mg daily, leading to partial improvement of symptoms. However, four days later, the patient experienced a worsening of nausea and vomiting. Laboratory tests revealed elevated inflammatory markers, including C-reactive protein, along with a recurrence of elevated pancreatic enzyme levels (AMY: 192 U/L, LIP: 388 U/L). In addition, the electrocardiogram (ECG) indicated sinus bradycardia, mild ST-T depression on V2–4 leads. Echocardiography revealed diffuse myocardial thickening, pericardial effusion, and decreased left ventricular diastolic function. After a consultation, the cardiologist considered the involvement of lymphoma in the heart leading to myocardial injury.

Additionally, the patient demonstrated multisystem abnormalities, such as elevated liver enzymes [alanine aminotransferase (ALT: 64 U/L), gamma-glutamyl transferase (GGT): 117 IU/L], increased cardiac injury markers (troponin and B-type natriuretic peptide), immune system abnormalities (elevated thyroglobulin antibody, positive ANA, and anti-Ro-52 antibody), and coagulation abnormalities (shortened activated partial thromboplastin time and elevated D-dimer levels). Follow-up abdominal contrast-enhanced CT and MRI revealed progression of the thickening and infiltration in the pancreatic tail, multiple liver lesions, and diffuse thickening of the gastric wall. Notably, an irregular mass with indistinct borders, closely associated with the pancreatic tail, was identified as enlarged left adrenal gland with uneven reinforcement and a central necrotic area (Figure 2).

Figure 2 Abdominal contrast-enhanced MRI examination. (A) Enhanced coronal view shows diffuse thickening of the gastric wall with mild enhancement, and an irregular mass with close and ill-defined boundaries in the lower part, adjacent to the pancreatic tail. (B) DWI sequence reveals a nodular peripheral area of high signal intensity in the left lobe of the liver, accompanied by diffuse thickening of the gastric wall with increased DWI signal. (C) DWI sequence displays a nodular area of high signal intensity in the right lobe of the liver. (D) The T2-weighted imaging sequence illustrates a nodular area of high signal intensity in the right lobe of the liver with clear borders. DWI, diffusion weighted imaging; MRI, magnetic resonance imaging.

Subsequent gastroscopy revealed circumferential congestion and erosion within the gastric body (Figure 3). Histopathological examination of the biopsy confirmed the presence of invasive B-cell lymphoma in the gastric body (Figure 4). Immunohistochemical analysis demonstrated that the staining of PAX-5 and CD20 was strongly positive: CD20 showed strong and diffuse membrane staining, with a positive rate of ≥90% (covering almost all tumor cells); PAX5 showed strong and diffuse nuclear staining, with positive rate of ≥90%, consistent with the B-cell lineage of the tumor cells. Both stainings were clear and specific, with no non-specific background staining, and the positive staining for P53, CD20, PAX-5, Bcl-2, Bcl-6, MUM-1, Ki-67 (70%), c-Myc, and Vimentin, while CD5, CK, EBER, CD3 and CD10 staining were negative. This immunophenotype is consistent with triple-hit HGBCL, as it exhibits high proliferation activity (high Ki-67) and co-expression of B-cell markers (CD20, PAX-5) and oncoproteins (c-Myc, Bcl-2, Bcl-6) corresponding to the rearranged genes. Additionally, a rapid urease test for Helicobacter pylori infection yielded a negative result. Fluorescent in situ hybridization (FISH): MYC, BCL2 and BCL6 gene rearrangements were all positive. For FISH methods/thresholds: we used commercially available dual-fusion probe kits (Abbott Laboratories, USA) targeting MYC (8q24), BCL2 (18q21), and BCL6 (3q27). At least 200 interphase cells were counted per probe. A rearrangement was considered positive if ≥10% of the counted cells showed fusion signals (for MYC and BCL2) or split signals (for BCL6). Bone marrow puncture and biopsy: the proliferation of bone marrow nucleated cells was extremely active, and a large number of abnormal lymphocytes could be seen, accounting for about 45% of the bone marrow nucleated cells. Cytochemical staining: peroxidase staining was negative, and glycogen staining was positive in some cells.

Figure 3 Gastroscopic findings. Endoscopic view of the gastric body showing diffuse, circumferential mucosal changes characterized by pronounced congestion, edema, and superficial erosions, suggestive of infiltrative disease.

Figure 4 Histopathological examination of gastric biopsy (hematoxylin and eosin stain, 400× magnification). The gastric mucosa is effaced by a dense, diffuse infiltrate of large, atypical lymphoid cells (representative cells indicated by arrows). These cells exhibit vesicular chromatin, prominent nucleoli, and a high nuclear-to-cytoplasmic ratio, consistent with high-grade B-cell lymphoma. Scale bar: 50 µm.

The patient initially presented with pancreatitis, which later progressed to involve multiple organ systems, including cranial neuropathy, liver lesions, myocardial injury, and adrenal gland abnormalities. Finally, there was a definitive diagnosis of non-germinal center primary gastric HGBCL (triple-hit HGBCL), stage IV based on the Ann Arbor classification, with an International Prognostic Index (IPI) score of 4.

Following confirmation of the diagnosis via gastric endoscopic pathology, the patient was treated with R-CHOP chemotherapy, comprising rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. Additionally, intrathecal dexamethasone and cytarabine were administered to treat multiple cranial neuropathies and to prevent central nervous system involvement by the lymphoma.

Treatment outcome and prognosis of the patient

Following the administration of the R-CHOP chemotherapy regimen, the patient experienced bone marrow suppression on the fourth day, which led to the development of leukopenia. This immunosuppressed state was complicated by a pulmonary infection, and blood cultures revealed a multi-drug-resistant Klebsiella pneumoniae infection. Despite the initiation of antibiotic therapy, the condition of the patient continued to deteriorate. On the 11th day after chemotherapy, she developed septic shock and subsequently succumbed to the complications.

Ethical consideration

All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine (No. 2024-097). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Primary gastric HGBCL is a common form of primary extra nodal NHL (PE-NHL) (4). Its clinical manifestations often lack specificity and may involve multiple organ systems, increasing the risk of misdiagnosis. HGBCL with MYC, BCL2 and BCL6 rearrangements constitutes a distinct clinicopathological entity characterized by aggressive behavior, inherent resistance to conventional immunochemotherapy, and suboptimal clinical outcomes (5). This case concerns a 66-year-old female who initially presented with abdominal pain and was diagnosed with pancreatitis. As the disease progressed, she developed multiple cranial nerve symptoms, including the involvement of the abducens, oculomotor, and facial nerves. Despite receiving nutritional and circulatory support, symptom improvement was limited. Subsequent neurological symptoms included abnormal sensation on the left side of the face and facial muscle paralysis, which revealed partial response to treatment with IVIG and corticosteroids. Further evaluations revealed multi-system involvement, including pericardial effusion, elevated cardiac enzymes, hepatic lesions, and adrenal lesions, with enhanced CT imaging revealing gastric wall thickening. The differential diagnosis included autoimmune diseases and lymphoma. Gastroscopy ultimately confirmed gastric triple-hit HGBCL, with local invasion by the lymphoma contributing to the development of pancreatitis, and lymphoma-induced immune dysfunction causing polyneuritis. This case depicts the diagnostic complexity and challenges encountered in such presentations, highlighting the need for heightened clinical awareness when encountering patients with atypical symptoms and multi-system involvement to reduce the risk of misdiagnosis.

Tumors are an uncommon cause of pancreatitis, with pancreatic lymphoma representing less than 0.5% of all pancreatic tumors. Cases of pancreatitis resulting from primary or secondary lymphoma account for approximately 1–2% of acute pancreatitis cases (6). The occurrence of pancreatitis due to local invasion by gastric lymphoma is even rarer. For example, Raj et al. described a 54-year-old female who presented with acute-onset pancreatitis; gastroscopy identified thickened gastric folds in the fundus, and histopathological analysis confirmed a diagnosis of PG-DLBCL (7). The condition of the patient responded favorably to chemotherapy, leading to remission. In the current case of PG-DLBCL, imaging studies demonstrated diffuse gastric wall thickening along with an irregular mass located at the gastric fundus, which was closely associated with the pancreatic tail and had indistinct borders. This raised the possibility of direct invasion by the gastric tumor into the pancreas, leading to pancreatitis—a presentation similar to the case reported by Raj et al. (7). Here, pancreatitis likely represents a manifestation of local invasion by PG-DLBCL and serves as an initial clinical indicator of the underlying lymphoma. However, the patient was diagnosed with diffuse large B lymphoma without a biopsy of the pancreas, and no autopsy was performed after death, so there is no conclusive evidence of a direct link between pancreatitis and lymphoma.

Lymphoma frequently involves multiple organ systems whereas cranial nerve damage is relatively rare. Reports indicate that such neurological manifestations usually arise from direct infiltration by lymphoma cells, leading to nerve injury. For instance, Hammond et al. documented an 80-year-old male who developed progressive unilateral cranial nerve paralysis over a year (8). Enhanced MRI of the head and neck identified an enhancing lesion around the left infraorbital nerve and a dumbbell-shaped mass in the cerebellopontine angle. A biopsy confirmed the diagnosis of NHL, which manifested as Garcin syndrome secondary to the lymphoma. Similarly, Amo et al. described a 75-year-old male with facial hemiplegia, sensory disturbances, and cutaneous involvement (9). Initially diagnosed with unexplained facial paralysis, further histological examination revealed DLBCL, with muscle biopsy revealing extensive destruction of facial muscle tissue by lymphoma cells.

From electrophysiological studies, we discovered peripheral cranial nerve paralysis involving the left facial and trigeminal nerves. Phuljhele et al. reported a case of a 76-year-old male who was initially diagnosed with optic perineuritis, which progressed to central retinal vein occlusion, and was eventually diagnosed with optic nerve lymphoma secondary to PG-DLBCL (10).

In the present case, the patient exhibited bilateral cranial nerve involvement, specifically affecting the left abducens and facial nerves, as well as the right oculomotor nerve, throughout the progression of the disease. Although cranial MRI did not reveal direct evidence of lymphoma invasion into the nerves, treatment with corticosteroids and IVIG led to an improvement in the cranial nerve dysfunction. Considering the cranial nerve involvement cannot be ruled out due to patients’ immunological abnormalities, we hereby make the following responses and analysis after in-depth consideration.

• Timeline of disease progression. The patient was first diagnosed with primary gastric DLBCL, and then developed the symptoms of multiple cranial nerve involvement, such as visual abnormalities and eye movement disorders. As a systemic disease, lymphoma can cause immune disorders through a variety of mechanisms, which is closely related to the occurrence of multi-cranial nerve symptoms. However, the patient’s previous immune-related diseases were in a relatively stable state over a long period of time without obvious neurological symptoms.
• Analysis of cranial MRI. The cranial MRI showed abnormal signals in the left cavernous sinus. In general, if the lymphoma directly invasions the cranial nerves, neuromorphic changes should be visible on imaging, such as nerve thickening, strengthening, and other signs of direct involvement. However, in this case, except for the abnormal signal of cavernous sinus, there were no imageological features indicating direct invasion of cranial nerves, so the possibility of direct invasion of cranial nerves by lymphoma can be basically ruled out. In the case of nerve injury caused by connective tissue disease, MRI often shows changes related to vasculitis in the brain parenchyma, such as multiple cerebral infarction, white matter lesions, or abnormal enhancement of the pia, but MRI in this case did not show these features. For thyroid disease, although thyroid dysfunction can affect the nervous system, there are generally no specific changes in the cavernous sinus region on MRI images, and the manifestations of cavernous sinus lesions in this patient are not consistent with the imaging characteristics of cranial nerve injury caused by thyroid disease. Therefore, the comprehensive analysis of the head MRI report can exclude the possibility of cranial nerve injury caused by direct invasion of previous diseases (connective tissue disease, thyroid disease) and lymphoma.
• Analysis of disease characteristics. Lumbar puncture revealed slightly elevated levels of monocytes and proteins, and decreased levels of glucose and chloride in cerebrospinal fluid (CSF). These CSF changes were more consistent with meningeal invasion of lymphomas or involvement of meninges in lymphoma-induced immune responses, rather than the CSF manifestations commonly seen in primary immune thrombocytopenia, connective tissue disease, and Hashimoto’s thyroiditis. In addition, primary immune thrombocytopenia mainly affects the hemostatic function of the blood system, and usually does not directly invade the cranial nerves. Although connective tissue disease can involve the nervous system, it is usually accompanied by typical symptoms of multi-system damage such as skin and joint, and this patient has no related manifestations. Hashimoto’s thyroiditis usually results in abnormal thyroid function and rarely leads directly to multi-cranial neuropathy.
• Autoantibodies. Although the patient has elevated thyroglobulin antibodies, positive ANA, and positive anti-RO-52 antibodies, these antibody positives do not necessarily mean that they directly caused the current cranial nerve involvement. In patients with lymphoma, the immune system is stimulated by the tumor and abnormal levels of various autoantibodies can occur. Therefore, these antibody positivity may be a concomitant phenomenon of immune dysregulation induced by lymphoma, rather than a direct cause of multi-cranial nerve involvement.

Although we believed that lymphoma-induced immune dysregulation was the primary cause of multiple cranial nerve involvement, we fully recognized that the patient’s complex medical history increased the difficulty of the diagnosis. In order to further improve the study, we will elaborate the complexity of the etiology of multi-cranial nerve involvement in a more comprehensive way in the “Discussion” section of this paper, clearly pointing out that the potential influence of previous immune-related diseases on the disease cannot be completely excluded, and conduct in-depth analysis and discussion on the possibility of multi-cranial nerve involvement caused by different etiologies.

Conclusions

In conclusion, this report describes a rare presentation of an older patient who initially manifested with pancreatitis, later developing multiple cranial nerve deficits, and was ultimately diagnosed with triple-hit HGBCL. The diagnosis incorporated the possibility of local tumor invasion leading to pancreatitis and immune-mediated mechanisms contributing to multi-cranial nerve impairment. The diagnostic and therapeutic journey of the patient was notably complex, highlighting the importance for clinicians to maintain a high index of suspicion for lymphoma in patients presenting with atypical symptoms and multi-system involvement, thereby reducing the risk of misdiagnosis and oversight.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-678/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-678/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-678/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine (No. 2024-097). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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