Two patients with diffuse large B-cell lymphoma appeared to have beaten their cancer, only to develop sudden, devastating neurological symptoms months later. In both cases, positron emission tomography combined with computed tomography revealed intense fluorodeoxyglucose uptake along nerve tissue, pointing to neurolymphomatosis, an extremely rare condition in which neoplastic lymphoma cells directly infiltrate nerve tissue. Because of the locations of the abnormalities, biopsies could not be taken, and clinicians had to rely on imaging, the clinical course and laboratory tests to reach a final diagnosis. Both patients died shortly after the examinations, underlining the poor prognosis associated with this rare manifestation of lymphoma.
The two cases are described in a report published in EJNMMI Reports by a team led by Febby Hutomo and Marcel P. M. Stokkel. The report documents how diffuse large B-cell lymphoma, the most prevalent subtype of lymphoid neoplasm, can return not in lymph nodes or other commonly involved organs but in the peripheral and central nervous system. Diffuse large B-cell lymphoma accounts for around 40 percent of all non-Hodgkin lymphomas worldwide, and it most commonly presents with involvement of the lymph nodes, liver, spleen and bone marrow. Involvement of other organs occurs with much lower incidence rates, which makes neurological relapse of this kind exceptionally difficult to anticipate and diagnose.
Neurolymphomatosis is characterized by direct infiltration of the endoneurium, the innermost connective tissue layer of a nerve, by neoplastic lymphoma cells. The condition must be distinguished from direct compression of nerves caused by adjacent lymphadenopathy or extranodal lymphomatous masses, as well as from paraneoplastic neuropathies, in which nerve damage arises as an indirect immune-mediated effect of the cancer rather than from actual tumor infiltration. In neurolymphomatosis, the peripheral nerve, cranial nerve, plexus or a combination of these structures is found to be the most predominant site of involvement.
Diagnosis of this entity is complicated by a fundamental clinical dilemma. Histologic confirmation of lymphoma cells in nerve tissue remains the gold standard, but obtaining such a biopsy is often not feasible because of the potential for irreversible damage to the peripheral nerve. This is precisely what happened in both reported cases. In the absence of tissue, fluorodeoxyglucose PET/CT becomes the central diagnostic tool. In many guidelines, FDG PET/CT is already recommended for staging diffuse large B-cell lymphoma, and it has high diagnostic value in assessing bone marrow involvement, where focal increased FDG uptake is regarded as more sensitive than bone marrow biopsy to detect infiltration, with high specificity.
The first patient was a 55-year-old man diagnosed with the activated B-cell like subtype of diffuse large B-cell lymphoma in December 2022. He underwent a total of six courses of R-CHOP chemotherapy in 2023, and follow-up CT scanning and blood tests in July 2023 revealed a complete response as the optimal therapy result. In December 2025, however, he presented again with sudden blindness of his right eye and weakness of his right arm, four days before the PET/CT scan. He had no history of trauma or infection. An orbital CT performed in December 2025 demonstrated diffuse thickening of the right optic nerve, prompting referral to the Nuclear Medicine Department for restaging with PET/CT imaging.
The PET/CT, performed with contrast-enhanced CT, showed high FDG uptake with thickening of the right optic nerve behind the right orbit. In addition, intense uptake was seen in a major part of the right brachial plexus and the right sciatic nerve. Focal lesions with high FDG avidity were also found in the liver and the fourth right rib. No other pathological FDG uptake was noted throughout his body, and in particular there was none in the lymph nodes, spleen or bone marrow. The imaging findings were concluded to be indicative of diffuse large B-cell lymphoma with peripheral neurolymphomatosis. Because of the localizations, biopsies from these sites were not possible. Laboratory tests revealed a high lactate dehydrogenase level of 1280 units per liter, but no signs of infection.
The patient was put on second-line chemotherapy including methotrexate, cytarabine and rituximab. After two cycles his symptoms resolved and his lactate dehydrogenase level almost immediately dropped to normal, at 100 units per liter. During this chemotherapy course, however, he showed a sudden onset of symptoms of infection, with fever confirmed by a C-reactive protein level of 21 milligrams per liter and rapidly increasing leukocyte counts. At that time, imaging, including any assessment of treatment response, was no longer possible due to the rapid deterioration of his clinical condition. Despite the fact that all clinical symptoms related to recurrent lymphoma with peripheral neurolymphomatosis had resolved, the patient passed away due to an uncontrollable septic shock.
The second patient was a 48-year-old woman who presented in September 2025 with a large mass in the left submandibular region. Biopsy revealed diffuse large B-cell lymphoma of the activated B-cell like subtype, and a course of three cycles of R-CHOP chemotherapy was started in October 2025. An interim PET/CT in January 2026 showed a complete response, and despite side-effects it was decided to continue with another three cycles of chemotherapy. In March 2026, she presented with sudden inferior paraplegia, two days before the PET/CT, and she also reported urinary and fecal incontinence one day before the scan. She had no history of trauma or infection and was referred for restaging with FDG PET/CT imaging.
Her PET/CT revealed high diffuse FDG uptake bilaterally in the cerebellum and in the spinal cord, ranging from the level of the first cervical vertebra to the tenth thoracic vertebra. Remarkably, the uptake of FDG in her brain was diminished. A distended bladder with hydronephrosis and stasis of activity was also seen, but without any FDG-avid lesion. No other pathological FDG uptake was noted in other parts of her body, especially not in the lymph nodes, spleen or bone marrow. Follow-up laboratory tests revealed a high lactate dehydrogenase level of 1276 units per liter, indicative of recurrent lymphoma. A biopsy was scheduled, but the patient passed away two days after the PET/CT. The ultimate diagnosis was an aggressive form of recurrent diffuse large B-cell lymphoma with central neurolymphomatosis.
The authors acknowledge that the lack of histological confirmation of recurrent disease is a limitation of both cases, but a biopsy was not possible given the localization of disease and the patients’ conditions. The final diagnoses rested on imaging, clinical course and elevated lactate dehydrogenase levels. The cases highlight neurolymphomatosis as a rare involvement of lymphoma with a poor prognosis, and they show that when biopsy and histological evaluation are not possible, clinicians must rely on other diagnostic techniques such as FDG PET/CT. The report notes that MRI neurography has been described in the literature as having comparable diagnostic yield and can be regarded as a good alternative. Rapid progression or therapy-related side-effects, such as infection, in recurrent lymphoma associated with neurolymphomatosis are usually prognostic indicators, and severely diminished brain uptake of FDG is regarded as a prognostic factor derived from the PET/CT. Several studies have also shown that neurolymphomatosis within the nervous system is a poor prognostic factor in non-Hodgkin lymphoma, with primary neurolymphomatosis generally having a better prognosis than secondary neurolymphomatosis arising from systemic lymphoma, with reported overall median survival times of 15.0 months and 10.0 months respectively.
Subject of Research: PET/CT diagnosis of rare central and peripheral neurolymphomatosis in two patients with diffuse large B-cell lymphoma
Article Title: Central and peripheral Neurolymphomatosis, a rare involvement of DLBCL on PET/CT
Article References: Hutomo, F., Mulyanto, I. D., Indrawati, H., Christina, E., Celine, E., & Stokkel, M. P. M. (2026). Central and peripheral Neurolymphomatosis, a rare involvement of DLBCL on PET/CT. EJNMMI Reports, 10(1), Article 46. https://doi.org/10.1186/s41824-026-00335-2
Image Credits: AI Generated
DOI: 10.1186/s41824-026-00335-2
Keywords: neurolymphomatosis, DLBCL, PET/CT, FDG uptake, non-Hodgkin lymphoma, R-CHOP, brachial plexus, spinal cord, lactate dehydrogenase, prognosis, case report, nuclear medicine
News Source: Nathaniel Bowman. (November 6, 2026). PET/CT Reveals Rare Lymphoma Spread Into Nerves in Two Fatal DLBCL Cases. Scienmag.
