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Hodgkin’s Lymphoma: A Case Study with Nystagmus and Diplopia

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Hodgkin’s Lymphoma: A Case Study with Nystagmus and Diplopia


Paraneoplastic neurologic syndromes (PNS) are uncommon but important clinical situations caused by cancer, but not a direct result of tumor invasion. As compared to solid tumors, the chances of association of PNS with lymphomas are quite low. However, Hodgkin’s and non-Hodgkin’s lymphomas, neuroblastoma, testicular cancer, and some gynecological malignancies show definite PNS.

Paraneoplastic cerebellar degeneration (PCD), one of the most common PNS, represents a heterogeneous group that differs in clinical features, prognosis, and associated tumor and antibody. The association of Hodgkin’s lymphoma (HL) with PCD was first described in the mid 1960s and subsequently antibodies against cerebellar Purkinje cells (anti-Tr or PCA-Tr) were identified. Anti-Tr antibodies show a unique staining pattern characterized by punctate immunoreactivity in both the dendritic tree and soma of cerebellar Purkinje cells but not in their axons. Recently, Delta/Notch-like epidermal growth factor-related receptor (DNER) was identified as the target antigen of anti-Tr antigen.

PCDs associated with Hodgkin’s lymphoma often show serologic detection of antibodies against DNER antigen.  Unlike the popular belief, ectopic expression of onco-neural DNER antigen by Reed-Sternberg (RS) cells play a marginal role in pathogenesis of these neurologic syndromes, says the recent studies.

A 2003 study by Bernal et al. confirmed the  strong association between anti-Tr antibodies and PCD associated with HD; 1 out of 15 HL patients in the study demonstrated antibody positivity for DNER antigen at  the level of RS cells. They also reported that anti-Tr antibodies from different patients can recognize similar epitopes.

CASE REPORT: Hodgkin’s Lymphoma With Diplopia and Nystagmus

A 38-year-old male was presented with left supraclavicular adenopathy. An excisional node biopsy revealed effacement of lymph node architecture. The presence of various neoplastic cells with morphologic and phenotypic features (e (PAX5-, CD15+, CD30+, LCA-, EBV-) of Hodgkin and Reed-Sternberg (RS) cells. Cytoplasmic expression of the DNER antigen was strong in these cells.

After staging, a nodular sclerosis variant of stage III disease classical Hodgkin’s Lymphoma (cHL), was diagnosed. The patient developed gaze-evoked diplopia, and paroxysmal frontal pain. Cerebrospinal fluid (CSF) examination revealed 108 mononuclear cells/mmc, which was then confirmed using cytospin. CSF flow cytometry showed 92% of the cellular elements to be CD3+ T lymphocytes, with minimal non–clonal, CD20+ B lymphocyte cells. Isoelectric focusing analysis was normal with no oligoclonal IgG bands. Similarly, gadolinium-enhanced brain MRI also showed normal results. In the next few days diplopia became spontaneous, right-beat nystagmus appeared, and a minimal VII right cranial nerve deficit was also reported.

Since microbiologic and virologic CSF evaluation confirmed lymphocytic pleocytosis and detected HHV-7 DNA (40 copies/mL), the researchers searched for onconeural antibodies. Subsequent indirect immunofluorescence and immunoblot techniques confirmed serum anti–DNER antibodies.

Following Graus criteria and HL-associated PCD diagnosis, the patient was given ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine) for a total of 6 cycles. The neurologic symptoms gradually improved; spontaneous nystagmus disappeared, paroxysmal frontal pain episodes reduced and VII cranial nerve deficit resolved.

Final re-evaluation in November 2020, revealed complete remission with minimal gaze-evoked diplopia; serum anti–DNER antibodies were found negative. A follow-up MRI showed moderate enlargement of pericerebellar CSF spaces.


  • Formaldehyde fixation and paraffin embedding (FFPE) was used for histologic examination.
  • Hematoxylin, eosin, and Giemsa stains were used for morphological evaluation.
  • Automated platform Dako Omnis Envision Flex was used to perform immunohistochemical analysis.
  • CD20, CD79a, CD3, CD5, LCA/CD45, PAX5, CD30, CD15, LMP1, CD68/PGM1, and
    DNER were used as biomarkers for the analysis.
  • A polyclonal antibody (Abcam) was used for DNER immunostaining.
  • A high pH buffer solution was used to mediate heat-induced antigen retrieval.
  • Paraffin-embedded cerebellum sections were used as the control for testing Cytoplasmic positivity for DNER.


There are several significant differences in PNSs when occurring in association with non–Hodgkin’s lymphomas and Hodgkin’s lymphoma. PCD is a classic and best-characterized PNS. The pathological remark of PCD is the destruction of cerebellar Purkinje cells by onconeural antibodies. Many patients with PCD and HL have anti-neuronal antibodies in their serum and/or CSF. PCD develops either as part of a severe case of encephalomyelitis, e.g., in patients with anti-Hu antibodies, or as an isolated syndrome, e.g., in patients with anti-Yo, anti-Ri, or anti-Tr antibodies. Therefore, this case report is of great significance in understanding the correlation between HL and anti–Tr antibodies associated with PCD. It also reinforces the fact that the missing link in PCD development could lie in the expression of antigens that are common between the neoplastic cell and the nervous tissue.

Recent data show that the enhanced expression of marker proteins is of clinical significance. For example, anti–Hu in SCLC, anti–Yo in ovarian cancer, anti–amphiphysin in breast cancer. Literature reviews also showed that the ectopic expression of DNER antigen plays an extremely marginal role in the anti–Tr syndrome associated with HL.

The clinical and pathologic features of Hodgkin’s lymphoma reflect an abnormal immune response resulting from a variety of cytokines by the malignant Reed-Sternberg (RS) cells or surrounding tissues. Previous studies reported numerous cHL cases characterized by the expression of the tumor necrosis factor receptor (TNFR) family and its ligands, as well as an over/underproduction of Th2 cytokines and chemokines. This also underlines the complexity and peculiarity of the HL tumor microenvironment.

Increasing evidence suggests that the immune evasion and immune modulation strategies of RS cells contribute to tumor development. Therefore, it is also important to explore the link between the presence of anti-DNER antibody-associated PCDs and class II HLA molecules on RS cells.


The presence of serum anti–DNER antibodies is closely associated with ectopic expression of the same antigen by neoplastic cells.

Given the complexity of the neoplastic microenvironment, the precise mechanisms and pathways involved in the pathogenesis of PCD need to be explored in greater depth.


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