Anti-amphiphysin antibody is a rare paraneoplastic autoantibody. A case of a 74-year-old man with anti-amphiphysin antibody and multiple symptoms, including bulbar palsy along with cerebellar ataxia, who responded to treatment with intravenous cyclophosphamide is reported. The patient presented with progressive unsteady gait and difficulty in swallowing food and water for three months. On admission, he had severe ataxia, downbeat and horizontal nystagmus, dysarthria, dysphagia, loss of tendon reflexes, and dysuria. Anti-amphiphysin antibodies were detected in the serum, resulting in the diagnosis of non-stiff anti-amphiphysin syndrome. No significant abnormalities were observed in imaging studies of the brain and the whole body. The patient was treated with high-dose intravenous immunoglobulin and steroids, yielding only slight improvement. After two courses of intravenous cyclophosphamide pulse therapy, his neurological symptoms, notably dysphagia and cerebellar ataxia, improved. Follow-up computed tomography and fluorodeoxyglucose-positron emission tomography/computed tomography showed enlarged mediastinal lymph nodes and hypermetabolic uptake of F-18 fluorodeoxyglucose six months after the onset of the neurological symptoms. Histological examination of a lymph node showed metastatic small cell lung cancer. This case highlights the efficacy of cyclophosphamide as second-line immunotherapy for anti-amphiphysin syndrome.

A 74-year-old man with no history of a major medical condition presented with left neck lymphadenopathy that slowly progressed over approximately 2 months. He reported no fever, night sweats, or weight loss. A physical examination revealed generalized lymph node swelling, including the bilateral neck, axillary, and inguinal lymph nodes. On laboratory examination, the complete blood count suggested mild thrombocytopenia at 14.1 ×104/μL. The results of a chemistry panel were normal, except for a lactate dehydrogenase level of 294 U/L, soluble interleukin-2 receptor level of 2140 U/mL, and hypergammaglobulinemia (IgG, IgA, and IgM levels were 2568, 236, and 547 mg/dL, respectively). Staging positron emission tomography/computed tomography (PET/CT) revealed hypermetabolic lymph nodes in the bilateral cervical, bilateral supraclavicular, paraaortic, and bilateral iliac regions. Moreover, hypermetabolic foci were detected in the mediastinum and spleen (Figure 1). Excisional biopsy of the left neck lymph node demonstrated that the lymph node architecture was affected by small to medium-sized lymphoid cells with a small number of interspersed large mono and binuclear atypical cells. Prominent vascularity and a variety of inflammatory cells were present in the background. On immunohistochemical analysis, large atypical cells were positive for CD30 and PAX5 (weak), and negative for CD15, CD20, and ALK. These results were consistent with the phenotype of Hodgkin and Reed/ Sternberg (HRS) cells. The small to medium-sized lymphoid cells exhibited a T follicular helper cell phenotype, and were positive for CD3, CD4, CD10, and PD-1. Both large mononuclear cells and lymphoid cells were negative on EBV-encoded small RNA1 in situ hybridization (EBER1ISH). The histopathological findings are shown in Figure 2. Rearrangements of the immunoglobulin heavy chain (IGH), T-cell receptor γ (TRG), and T-cell receptor β (TRB) were detected using DNA obtained from whole sections of paraffin-embedded specimens by polymerase chain reaction analysis using the BIOMED-2 protocol at SRL, Inc. (Tokyo, Japan).1 Although the diagnosis of AITL was made mainly based on the histopathological findings, it was difficult to differentiate HRS-like cells from true HRS cells. Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy was initiated. After the completion of six cycles of CHOP, restaging PET/CT demonstrated a complete metabolic response. AITL is a subtype of the second most common peripheral T-cell lymphoma, followed by peripheral T-cell lymphoma (PTCL), not otherwise specified.2 Due to the immunological dysfunctions associated with AITL, EBV-positive B lymphocytes can often expand. In rare cases, these reactive EBVpositive B lymphocytes are morphologically and immunophenotypically indistinguishable from true HRS cells. Therefore, they are termed HRS-like cells. HRS-like cells are often associated with EBV reactivation; however, EBVnegative HRS-like cells can exist.3 On the other hand, in rare instances, two distinct subtypes of malignant lymphomas develop simultaneously or serially in the same patient. Such lymphomas are referred to as composite lymphomas (CLs). CLs account for 1-4% of all malignant lymphomas.4 To date, eight cases of CL comprising classic Hodgkin lymphoma (HL) and PTCL have been reported. In three cases, HRS cells harbored EBV infection.5-7 On the other hand, five cases of CL constituting PTCL and HL with EBV negative-HRS cells have been reported.8 In general, IGH rearrangements are found in approximately 20% of AITL cases. However, B-cell clonality is likely in AITL cases with expanded EBV-infected B lymphocytes.9 In summary, when determining the diagnosis, it is challenging to distinguish HRS-like cells from true HRS cells. Furthermore, in the present case, EBV-negative large mononuclear cells and the detection of clonal IGH gene rearrangements without evidence of EBV reactivation made the diagnosis more difficult. We would like to ask experts about how to diagnose the present case.

A 68-year-old male presented with appetite loss and abdominal distention. The whole-body computed tomography scan revealed an ileocecal mass with a large amount of ascites, which was consistent with malignant lymphoma. Due to the worsening of his general condition following admission, he was intubated and admitted to the intensive care unit (ICU). In the ICU, we performed a core-needle biopsy (CNB) on the left peritoneal mass, the findings of which showed a pathological diffuse infiltration of CD20+ middle-sized lymphoid cells. After chemotherapy was initiated, the patient showed complete response, suggesting that CNB can be performed immediately and safely even on a critically ill patient.

Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) that is associated with elevated interleukin-6 (IL-6) expression, resistance to chemotherapy, and increased mortality. Although bevacizumab (Bev) is a widely used anti-angiogenic agent for EOC, the efficacy of Bev and the role of IL-6 in modulating angiogenesis in OCCC are unknown. We performed tube formation assays using human umbilical vein endothelial cells (HUVEC) cultured in OCCC cell-conditioned medium and using cells directly co-cultured with OCCC cells. We observed that IL-6 inhibition significantly mitigated the ability of Bev to impede tube formation in both cases. Furthermore, IL-6 blockade disrupted the anti-angiogenic efficacy of Bev and its concomitant anti-tumor activity. In addition, IL-6 inhibition resulted in a significant increase in angiopoietin-1 (Ang1) secretion and decreased vascular endothelial growth factor (VEGF) expression. Clinical specimens also exhibited this reciprocal relationship between IL-6 and Ang1 expression. Finally, depletion of Ang1 abrogated the effects of IL-6 inhibition on Bev activity, demonstrating that IL-6 supports the anti-angiogenic activity of Bev by suppressing Ang1 expression and promoting dependence on VEGF for angiogenesis. Altogether, our data suggest that OCCC tumors with high IL-6 levels are candidates for Bev therapy.