Lymphoproliferative disorder during temozolomide therapy; a representative case of a formidable complication and management challenges

Abstract

Background: Lymphoproliferative disorder represents a heterogeneous clinicopathological spectrum characterized by uncontrolled proliferation of lymphocytes. Immunodeficiency is a major trigger of its development. While induction of immunodeficiency is a well-known adverse effect of temozolomide therapy, development of lymphoproliferative disorder following temozolomide therapy has not previously been described.

Case presentation: A patient with brainstem glioma developed constitutional symptoms, pancytopenia, splenomegaly and generalized lymphadenopathy during the 2nd cycle of maintenance therapy following induction therapy with temozolomide. Epstein-Barr virus-infected lymphocytes were observed histopathologically and "other iatrogenic immunodeficiency-associated lymphoproliferative disorder" (OIIA-LPD) was diagnosed. Although discontinuation of temozolomide led to rapid remission, relapse was observed 4 months later. CHOP chemotherapy was induced, resulting in secondary remission. Vigilant follow-up for another 14 months showed radiologically stable brainstem glioma and no further recurrence of OIIA-LPD.

Conclusions: This is the first report documenting OIIA-LPD during temozolomide administration. Timely diagnosis of the disease and discontinuation of the causative agent were considered to be the management of choice. Close monitoring for relapse should be continued. Finding a balance between glioma management and controlling the remission of OIIA-LPD remains to be clarified.

Keywords: Epstein-Barr virus; Glioma; Lymphoproliferative disorder; Temozolomide.

Fig. 1

The patient presented with high-intensity lesions on T2-weighted imaging of the pons (A). The lesion extended to the midbrain (B). The patient initially preferred to be followed-up at an outpatient clinic, during which time the lesion extended to the right middle cerebellar peduncle (C) and involved the midbrain and thalamus bilaterally (D)

Fig. 2

Stereotactic biopsy was performed, revealing diffuse infiltration of pleomorphic cells with nuclear atypia and eosinophilic cytoplasm (A). Immunohistochemical staining for R132H IDH1 yielded negative results (B). ATRX positivity was retained (C). Negative results were obtained for H3K27M (D). Sanger sequencing of the TERT promoter revealed C250T mutation (E). Methylation-specific polymerase chain reaction demonstrated unmethylated MGMT promoter. Results for the positive control, negative control, sample and blank are displayed from left to right (F). The samples derive from the same experiment and the gels and blots were processed in parallel. The diagnosis was glioblastoma, IDH-wildtype

Fig. 3

During the 2nd cycle of maintenance therapy following induction therapy with temozolomide, the patient experienced constitutional symptoms and cytopenia. Computed tomography showed systemic lymphadenopathy (A; arrowhead) and splenomegaly (B; asterisk). Positron emission tomography showed marked fluorodeoxyglucose-avid lymph nodes in the neck, axillae, mediastinum and para-aortic region (C)

Fig. 4

Histopathological investigation of an enlarged cervical lymph node revealed dense infiltration of lymphocytes, and the normal lymph node architecture was widely effaced (A). Infiltration of small to medium-sized lymphocytes, plasma cells and histiocytes was observed (B). Large, atypical lymphocytes with prominent nucleoli were sparsely observed. These large lymphocytes were positive for CD20 (C) and PAX5 (D). Epstein-Barr virus (EBV) DNA was confirmed by in-situ hybridization (E)

Fig. 5

OIIA-LPD is characterized by its association with immunosuppression, and regression after cessation of immunosuppressive agents. OIIA-LPD is occasionally associated with EBV infection, albeit not necessarily. This entity ranges from non-neoplastic lymphoid proliferation to malignant lymphoma (A). OIIA-LPD is mainly defined by its clinical pictures, whereas malignant lymphoma is predominantly defined pathologically and biologically (B)