Reed-Sternberg cell-derived lymphotoxin-α activates endothelial cells to enhance T-cell recruitment in classical Hodgkin lymphoma.

It is known that cells within the inflammatory background in classical Hodgkin lymphoma (cHL) provide signals essential for the continual survival of the neoplastic Hodgkin and Reed-Sternberg (HRS) cells. However, the mechanisms underlying the recruitment of this inflammatory infiltrate into the involved lymph nodes are less well understood. In this study, we show in vitro that HRS cells secrete lymphotoxin-α (LTα) which acts on endothelial cells to upregulate the expression of adhesion molecules that are important for T cell recruitment. LTα also enhances the expression of hyaluronan which preferentially contributes to the recruitment of CD4(+) CD45RA(+) naïve T cells under in vitro defined flow conditions. Enhanced expression of LTα in HRS cells and tissue stroma; and hyaluronan on endothelial cells are readily detected in involved lymph nodes from cHL patients. Our study also shows that although NF-κB and AP-1 are involved, the cyclooxygenase (COX) pathway is the dominant regulator of LTα production in HRS cells. Using pharmacological inhibitors, our data suggest that activity of COX1, but not of COX2, directly regulates the expression of nuclear c-Fos in HRS cells. Our findings suggest that HRS cell-derived LTα is an important mediator that contributes to T cell recruitment into lesional lymph nodes in cHL.

Epstein-Barr virus infection correlates with the expression of COX-2, p16(INK4A) and p53 in classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL), a germinal-center related B cell neoplasm in almost all cases, is characterized by scarcity of the neoplastic Hodgkin/Reed-Sternberg (H/RS) cells. Epstein-Barr virus (EBV) has been shown to affect cell cycle and regulation of apoptosis. In total, 95 cases of cHL were studied. Five-micrometer sections were prepared and stained with hematoxylin and eosin and immunohistochemical streptavidin-biotin methods for EBV-LMP-1, COX-2, p53, p16, ki-67 and cleaved caspase-3. In-situ hybridization for EBV encoded RNA was used to confirm the detection of EBV in H/RS. There were 49 nodular sclerosis, 32 mixed cellularity, 8 lymphocyte-rich, and 6 lymphocyte-depleted subtypes in this series of cases. EBV, COX-2, p16(INK4A) and p53 were detected in 55% (52/95), 64% (61/95), 62% (59/95), and 65% (62/95) of the cases respectively. EBV was detected in 62% (38/61), 70% (41/59), and 69% (43/62) of COX2, p16 and p53 positive cases respectively. On the other hand, EBV-non-infected cases of cHL are associated with 59% (20/34), 69% (25/36), and 73% (24/33) of COX2, p16 and p53 negative cases respectively. In conclusion, EBV infection is associated with the expression of COX-2, p16(INK4A) and p53. EBV might be the dominant factor in determining the expression of these three proteins.

Lymphoplasmacytic lymphoma-Waldenström macroglobulinemia: an unusual presentation in ovaries, fallopian tubes and uterine cervix.

Lymphoplasmacytic lymphoma is an indolent malignancy of B cells and plasma cells. The disease presents in the adults with bone marrow and lymph nodes involvement. Extranodal involvement is rare but has been reported in spleen and liver. Herein, we present a case of a 50-year-old woman who underwent hysterectomy and salpingo-oophorectomy for irregular uterine bleeding. Histologic examination of uterine cervix, uterine walls and fallopian tubes reveal dense lymphoplasmacytic infiltrate that was most pronounced in ovaries. This is the first case report on lymphoplasmacytic lymphoma-Waldenström macroglobulinemia initially presenting and secondarily involving both ovaries and other gynecological organs.

Expression of CD137 on Hodgkin and Reed-Sternberg cells inhibits T-cell activation by eliminating CD137 ligand expression.

Hodgkin lymphoma is caused by a minority population of malignant Hodgkin and Reed-Sternberg (HRS) cells that recruit an abundance of inflammatory cells. The long-term survival of HRS cells among the vast majority of immune cells indicates that they have developed potent immune escape mechanisms. We report that the TNF receptor family member CD137 (TNFRSF9) is expressed on HRS cells, while normal B cells, from which HRS cells are most often derived, do not express CD137. In 48 of 53 cases of classical Hodgkin lymphoma, CD137 was detected on HRS cells. Ectopically expressed CD137 transferred by trogocytosis from HRS cells to neighboring HRS and antigen-presenting cells, which constitutively express the CD137 ligand (CD137L and TNFSF9), became associated with CD137L and the CD137-CD137L complex was internalized. Disappearance of CD137L from the surface of HRS and antigen-presenting cells led to reduced costimulation of T cells through CD137, reducing IFN-γ release and proliferation. Our results reveal a new regulatory mechanism for CD137L expression that mediates immune escape by HRS cells, and they identify CD137 as a candidate target for immunotherapy of Hodgkin lymphoma.

Expression of Epstein-Barr virus in Hodgkin lymphoma in a population of United Arab Emirates nationals.

Hodgkin lymphoma (HL) shows wide geographic variation in histological subtypes and in its association with the Epstein-Barr virus (EBV). HL has three main epidemiological patterns (I, II and III). Type I pattern, which is prevalent in developing countries, shows a relatively high incidence in male children, a low incidence in the third decade and a second peak of high incidence in older age groups. Type III, which is usually seen in developed countries, is characterised by a low rate in children and a pronounced initial peak in young adults. The third pattern (Type II), which is described in many Asian countries, is intermediate and reflects a transition between types I and III. In this pattern there is both a childhood and a third decade peak. The proportion of EBV positive HL is low in industrialised countries, high in non-industrialised countries and intermediate in early-industrialised countries. Reports from the Arabian Gulf and Middle East are few. The aim of this study is to determine the epidemiology of HL in a population of United Arab Emirates (UAE) nationals, an early industrialised country in the Arabian Gulf, and to delineate the extent of its association with EBV. In total, 88 cases of HL were diagnosed in native patients during the period 1988 through 2004 at Tawam hospital. Forty-five paraffin blocks were available for this study. Five-micrometer sections were prepared and stained with hematoxylin and eosin and the immunohistochemical streptavidin-biotin methods for CD45, CD3, CD20, CD15 and CD30. Other sections were examined for the presence of EBV using the immunohistochemical streptavidin-biotin method for the latent membrane protein 1 and in situ hybridisation for EBV encoded RNA to determine the prevalence of EBV in Hodgkin cells and its possible role in the pathogenesis of HL. Nodular sclerosis (NS) subtype was the most common type of HL among UAE nationals followed by mixed cellularity (MC), lymphocytic predominant (LP), unclassified, lymphocytic depletion (LD) and lymphocyte rich (LR) subtypes, respectively. EBV was seen in 17 of 45 (38%) cases of HL and was predominately seen in the MC subtype followed by NS, LD and LR subtypes, respectively. EBV was more frequently expressed in HL in the pediatric age group than the adult age group. These data indicate that the epidemiology of HL in a native population of the UAE is suggestive of a type II epidemiologic pattern in terms of age distribution, and histopathologic subtypes, whereas the frequency of EBV expression is more suggestive of a type III epidemiologic pattern. The significant association between EBV and HL that we have found further strengthens the suggestion that all cases of HL should be assessed for EBV status, because its presence may have a significant impact on prognosis and response to therapy.

Strongyloides hyper-infection causing life-threatening gastrointestinal bleeding.

A 55-year old male patient was diagnosed with strongy-loides hyper-infection with stool analysis and intestinal biopsy shortly after his chemotherapy for myeloma. He was commenced on albendazole anthelmintic therapy. After initiation of the treatment he suffered life-threatening gastrointestinal (GI) bleeding. Repeated endoscopies showed diffuse multi-focal intestinal bleeding. The patient required huge amounts of red blood cells and plasma transfusions and correction of haemostasis with recombinant activated factor VII. Abdominal aorto-angiography showed numerous micro-aneurysms ('berry aneurysms') in the superior and inferior mesenteric arteries' territories. While the biopsy taken prior to the treatment with albendazole did not show evidence of vasculitis, the biopsy taken after initiation of therapy revealed leukoclastic aggregations around the vessels. These findings suggest that, in addition to direct destruction of the mucosa, vasculitis could be an important additive factor causing the massive GI bleeding during the anthelmintic treatment. This might result from substances released by the worms that have been killed with anthelmintic therapy. Current guidelines advise steroids to be tapered and stopped in case of systematic parasitic infections as they might reduce immunity and precipitate parasitic hyper-infection. In our opinion, steroid therapy might be of value in the management of strongyloides hyper-infection related vasculitis, in addition to the anthelmintic treatment. Indeed, steroid therapy of vasculitis with other means of supportive care resulted in cessation of the bleeding and recovery of the patient.

[Life-threatening gastrointestinal bleeding related to the treatment of strongyloidiasis hyperinfection in an immunocompromised patient]. / Eletet veszélyeztetó gastrointestinalis vérzés strongyloides hiperinfekció kezelése kapcsán immunszupprimált betegben.

The clinical course and sequel of the life-threatening gastrointestinal (GI) bleeding during the treatment of strongyloides helmintic hyperinfection induced by immunosuppression in a patient with multiple myeloma is presented. A 55-year old male patient was diagnosed with strongyloides infection with stool analysis and intestinal biopsy shortly after his combined chemotherapy for myeloma. He was commenced on albendazole anthelmintic therapy. However, after initiation of the treatment he suffered life-threatening GI bleeding. Repeated endoscopies, including intraoperative enteroscopy, concluded to diffuse multifocal intestinal bleeding. The patient required huge amounts of red blood cells and plasma transfusions and correction of haemostasis with recombinant activated factor VII. Abdominal aorto-angiography showed numerous microaneurysms ("berry aneurysms") in the superior and inferior mesenteric arteries' territories. While the biopsy taken prior to the treatment with albendazole did not show evidence of vasculitis, the biopsy taken after initiation of therapy revealed leukoclastic aggregations around the vessels which was also consistent with vasculitis. These findings suggest that--in addition to direct destruction of the mucosa-vasculitis could be an important additive factor to the massive GI bleeding during the anthelmintic treatment. This might result from substances released by the worms that have been killed with anthelmintic drugs. Current guidelines advise steroids to be tapered and stopped in case of systematic parasitic infections as they reduce immunity and precipitate parasitic hyperinfection. In our pinion, steroid therapy might be of value in the management of strongyloides hyperinfection related vasculitis--in addition to the specific anthelmintic treatment. Indeed, steroid therapy of vasculitis with other means of supportive care yielded in sequel of the bleeding and in recovery of the patient.