Expression of the c-Met oncogene by tumor cells predicts a favorable outcome in classical Hodgkin's lymphoma

Background

The c-Met signaling pathway regulates a variety of biological processes, including proliferation, survival and migration. Deregulated c-Met activation has been implicated in the pathogenesis and prognosis of many human malignancies. We studied the function and prognostic significance of c-Met and hepatocyte growth factor protein expression in patients with classical Hodgkin’s lymphoma.

Design and Methods

Expression of c-Met and its ligand, hepatocyte growth factor, were determined by immunohistochemistry. Prognostic values were defined in cohorts of German and Dutch patients with classical Hodgkin’s lymphoma. Functional studies were performed on Hodgkin’s lymphoma cell lines.

Results

Expression of c-Met was detected in the tumor cells of 52% (80/153) of the patients and expression of its ligand, hepatocyte growth factor, in 8% (10/121) of the patients. c-Met expression correlated with a 5-year freedom from tumor progression of 94%, whereas lack of expression correlated with a 5-year freedom from tumor progression of 73% (P<0.001) in the combined cohort. In multivariate analysis both c-Met (hazard ratio 5.0, 95% confidence interval 1.9–13.3, P<0.001) and stage (hazard ratio 2.8, 95% confidence interval 1.2–6.4, P=0.014) were independent predictors for freedom from tumor progression. In functional studies activation with hepatocyte growth factor did not affect cell growth, while the c-Met inhibitor SU11274 suppressed cell growth by inducing G2/M cell cycle arrest.

Conclusions

Although functional studies showed an oncogenic role of the hepatocyte growth factor/c-Met signaling pathway in cell cycle progression, expression of c-Met in tumor cells from patients with classical Hodgkin’s lymphoma strongly correlated with a favorable prognosis in two independent cohorts.     

Primary hepatic anaplastic large cell Ki‐1 non‐Hodgkin's lymphoma and hereditary hemochromatosis: a fortuitous association?1

Summary We report here a case of primary hepatic anaplastic large cell Ki‐1 non‐Hodgkin's lymphoma in a 60 year old patient followed for hereditary hemochromatosis.     

Adverse prognostic significance of CD20 positive Reed-Sternberg cells in classical Hodgkin's disease

The prognostic significance of CD20 positive classical Hodgkin's disease (cHD) is uncertain. All cHD cases referred to the Memorial Sloan-Kettering Cancer Center (MSKCC) were retrospectively identified (5/92-11/00); the samples were immunostained, and clinical data ascertained. Cases were re-reviewed without knowledge of clinical outcome. Univariate and multivariate analyses were performed 248 patients had cHD: 28 CD20(+) (11%); 220 CD20(-). All clinical characteristics were comparable except haemoglobin level at presentation. With a median follow-up of 29.2 months, significant prognostic factors in multivariate analysis were: CD20 positivity, elevated white blood cell count (WBC) and low absolute lymphocyte count for time-to treatment failure (TTF); and for overall survival (OS), CD20 positivity, elevated WBC count, bone marrow involvement and age >/=45 years. TTF was significantly poorer for ABVD-treated patients with CD20(+) cHD as compared with CD20(-) cHD. Among 167 patients treated at MSKCC, both TTF (P < 0.0001) and OS (P = 0.017) were significantly decreased in CD20(+) patients as compared with CD20(-) cHD. CD20(+) cHD is a poor prognostic factor for TTF and OS. All cHD cases should be immunophenotyped for CD20. A large prospective trial is needed to confirm these findings.     

Derangement of the T‐cell repertoire in patients with B‐cell non‐Hodgkin's lymphoma

Although a number of studies suggest that different immune pathways may play a role in the pathogenesis of non‐Hodgkin's lymphomas (NHL), the shape of the T‐cell compartment has been only superficially explored in these patients. In our study, we analyzed the peripheral T‐cell receptor (TCR) repertoire and the distribution of different T‐cell subsets – including regulatory T cells (Treg) – in 30 patients with NHL, by combining flow cytometry and spectratyping. We first demonstrated by flow cytometry an increased frequency of expanded T‐cell subpopulations expressing the same TCR beta variable (BV) subfamilies in CD8+ cells from NHL patients when compared with healthy controls, beside a higher frequency of Treg. Moreover, NHL patients were characterized by a higher percentage of BVs showing a skewed CDR3 profile both in CD4+ and CD8+ cells when analyzed by spectratyping. Our data suggest that the T‐cell branch of the immune system of patients with B‐cell NHL is deeply deranged, as witnessed by the increased degree of activation and skewing of their TCR repertoire along with the higher frequency of Treg.     

Enteroviral meningoencephalitis in a patient with non‐Hodgkin's lymphoma treated previously with rituximab

A 75‐year‐old man, with a long history of recurrent lymphoplasmacytoid lymphoma, presented with diffuse large‐cell lymphoma affecting adrenal glands and causing severe hypoadrenalism. The lymphoma responded to rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R‐CHOP) chemotherapy. Seven months postcompletion of chemotherapy, he developed signs of gastroenteritis and septicaemia. He deteriorated 24 h postadmission with a significant fall in Glasgow Coma Scale Score. Polymerase chain reaction testing of cerebrospinal fluid suggested enteroviral encephalitis. He responded symptomatically to intravenous immunogobulins. His immunoglobulin levels were monitored weekly and supplemented to maintain immunoglobulin G level at 10 g/l, but in spite of this, his neurological condition deteriorated and he died after 14 weeks. Rituximab can cause prolonged B‐cell deficiency. We speculate that profound immunosuppression induced by rituximab, together with previous chemotherapy, predisposed this patient to fatal enteroviral meningoencephalitis.     

Prevalence of hepatitis C virus and hepatitis G virus in patients with non‐Hodgkin's lymphoma

Hepatitis C virus (HCV) and hepatitis G virus (HGV) belong to the same family of flaviviridea. A causative role of HCV infection in the pathogenesis of non‐Hodgkin's lymphoma (NHL) has been discussed widely. Little is known about the possible association between NHL and HGV discovered recently. In this study, anti‐HCV and HGV‐RNA prevalence were investigated in a group of 70 patients with NHL. The results were compared to a control group of 70 age‐ and sex‐matched healthy subjects. One patient in each group (1.4%) was found to be anti‐HCV‐positive; the difference was not statistically significant (P > 0.05). Five subjects in the patient group (7.1%) were positive for HGV‐RNA, while a single subject was positive in the control group (1.4%); the difference was not statistically significant (P > 0.05). Odds ratios for anti‐HCV and HGV‐RNA were 1 and 5.30, respectively. Our findings suggest that neither HCV nor HGV are causative or contributing factors in the aetiopathogenesis of NHL.     

Accelerated hepatitis C virus replication with rituximab treatment in a non‐Hodgkin's lymphoma patient

The treatment of patients with non‐Hodgkin's lymphoma (NHL) may be complicated by concomitant chronic hepatitis C virus (HCV) infection. Recent data suggest that HCV may also be a contributing factor to the development of this disease. Although antiviral treatment has occasionally been reported to result in the regression of lymphoma in patients with HCV infection, the importance of the control of this infection on the prognosis of lymphoma needs to be defined. Here we report a patient with diffuse large B‐cell lymphoma who presented with a mass in her left breast. She had had HCV‐related liver cirrhosis for 6 years. She was given rituximab monotherapy for three consecutive weeks, but treatment had to be discontinued as a result of hematological toxicity. HCV viral load also increased, but then decreased gradually after rituximab was stopped. She could be given no further therapy. Six months later she presented with spinal involvement with infiltration of the cauda equina. Though cranial–spinal radiotherapy and steroids were started, she died shortly thereafter. Though rituximab is an invaluable drug in the treatment of B‐cell lymphomas, we believe that the use of such agents with potentially long‐lasting effects on B lymphocytes requires extended vigilance for accelerated replication of hepatitis B and C viruses.     

High tumour plasma cell infiltration reflects an important microenvironmental component in classic Hodgkin lymphoma linked to presence of B-symptoms

Plasma cells are important prognostic actors in different malignancies. The tumour microenvironmental composition in classic Hodgkin lymphoma (cHL) is a major prognostic key element; however, clinicopathological studies regarding plasma cells in cHL are lacking. The aim of this study was to investigate CD138+ (also termed SDC1+) plasma cell and IgG4 producing (IgG4+) plasma cells infiltration in the microenvironment of cHL. Immunohistochemistry with anti-CD138 and IgG4 antibodies was performed on diagnostic tumour biopsies from 124 patients with cHL, on tissue micro array (TMA). In 120 cases, CD138+ plasma cell-infiltration was associated with the presence of B-symptoms (P = 0·028) and advanced stage, IIB-IVB (P = 0·009). In multivariate analysis, CD138+ plasma cells correlated with eosinophil infiltration (P = 0·013). The subgroup of IgG4+ plasma cells was analysed in 122 cases and only correlated to CD138+ plasma cells (P = 0·004). Patients with high proportion of tumour infiltrating CD138+ plasma cells (defined as ≥10%), had a more inferior event-free survival (P = 0·007) and overall survival (P = 0·004) than patients with a low proportion of infiltrating CD138+ plasma cells (<10%), although significance was not maintained in multivariate analysis. In summary, a high proportion of tumour-associated plasma cells in cHL reflect an important component in the microenvironment of cHL.     

Tumor-infiltrating macrophages correlate with adverse prognosis and Epstein-Barr virus status in classical Hodgkin's lymphoma

Background

Classical Hodgkin’s lymphoma is characterized by a minority of neoplastic cells surrounded by a heterogeneous background population of non-neoplastic cells including lymphoma-associated macrophages. High levels of expression of both the monocyte/macrophage lineage-associated antigens CD68 and CD163 have been suggested to have pro-tumor effects. The aim of our study was to correlate expression of CD68 and CD163 with the clinico-pathological features and prognosis of a cohort of patients with previously untreated Hodgkin’s lymphoma.

Design and Methods

A tissue microarray was constructed from paraffin-embedded tumor tissues from 288 cases of classical Hodgkin’s lymphoma. CD68 and CD163 expression was assessed immunohistochemically and the degree of macrophage infiltration within the tumor was scored using point grid counting. Clinical data were obtained from clinical records.

Results

The patients’ median age was 37 years (range, 6–86 years). The male to female ratio was 1.2. In classical Hodgkin’s lymphoma (n = 288) high CD68 and CD163 expression correlated, at the univariate level, with poorer overall survival (P=0.002 and P=0.03, respectively) and event-free survival (P=0.03 and P=0.04, respectively). At the multivariate level, high CD68 expression remained significantly predictive of overall survival (P=0.004). In addition, we demonstrated that both high CD68 and CD163 expression were associated with the presence of Epstein-Barr virus in the neoplastic cells (P=0.001 and P=0.0002, respectively).

Conclusions

In classical Hodgkin’s lymphoma, high expression of the macrophage/monocyte-related antigens CD68 and CD163 correlates with adverse outcome and with the presence of Epstein-Barr virus in the tumor cell population.     

Secondary amyloidosis causing nephrotic syndrome in a patient with non‐Hodgkin's lymphoma: quite a rare diagnosis

Secondary amyloidosis is usually a complication of chronic inflammation. Amyloidosis cases during the course of non‐Hodgkin's lymphoma (NHL) are usually of AL‐type, only one NHL patient with secondary amyloidosis has been reported. Our 79‐year‐old male patient visited us with multiple lymphadenopathies, and he was diagnosed with nodal marginal zone B‐cell lymphoma. After four cycles of combined chemotherapy; his urea, creatinine levels started to increase and he developed nephrotic‐range proteinuria. His rectal biopsy demonstrated amyloid deposition in submucosal vessel walls. The patient has been under hemodialysis for 10 months and his lymphoma is still in partial remission. We presented this case because it is the second NHL patient who developed secondary amyloidosis during his disease course.     

Combination of 177Lu‐lilotomab with rituximab significantly improves the therapeutic outcome in preclinical models of non‐Hodgkin's lymphoma

Objectives

To investigate the therapeutic potential of the next‐generation anti‐CD37 radioimmunoconjugate ¹⁷⁷Lu‐lilotomab satetraxetan (¹⁷⁷Lu‐lilotomab) in combination with the anti‐CD20 antibody rituximab for treatment of mice with non‐Hodgkin's lymphoma (NHL) xenografts.

Methods

Nude mice with subcutaneous (s.c.) Burkitt's lymphoma Daudi xenografts and SCID mice intravenously (i.v.) injected with Mantle cell lymphoma Rec‐1 cells were treated with either ¹⁷⁷Lu‐lilotomab or rituximab alone or with the combination of both treatments. Tumour volume, body weight, blood counts and clinical status were monitored. CD20 expression was measured using flow cytometry with fluorescence‐labelled rituximab.

Results

The combination of ¹⁷⁷Lu‐lilotomab and rituximab was synergistic for treatment of nude mice with s.c. Daudi xenografts while it was additive for treatment of SCID mice with i.v. injected Rec‐1 cells. Binding of rituximab to NHL cells in‐vitro was increased by pretreatment with ¹⁷⁷Lu‐lilotomab.

Conclusions

Treatment of mice with NHL xenografts with ¹⁷⁷Lu‐lilotomab synergistically increased tumour suppression of subsequent anti‐CD20 immunotherapy and improved survival. If the same effect is confirmed in a recently started clinical study, it could change the way radioimmunotherapy and CD20 immunotherapy would be used in the future.

     

Tandem high-dose chemotherapy and autologous stem cell transplantation in refractory/relapsed Hodgkin's lymphoma: a monocenter prospective study

We designed a prospective study to evaluate the feasibility and efficacy of tandem high-dose chemotherapy (HDCT) in the treatment of refractory or relapsed Hodgkin's lymphoma (HL). Thirty-two patients were treated with salvage chemotherapy (IGEV, ifosfamide, gemcitabine, and vinorelbine) and chemo-sensitive patients received a first HDCT course with melphalan 200 mg/m(2) (MEL200) and a second BEAM course. The median time interval between the two HDCT courses was 66 days. The median number of reinfused CD34(+) cells was 4.7 x 10(6)/kg after MEL200 and 5.8 x 10(6)/kg after BEAM. The hematological reconstitution after both HDCT courses did not differ. No grade III or IV renal, hepatic, lung, cardiac, and neurological toxicity was observed. Severe (grade III and IV) oral mucositis was the most prominent complication affecting 60 and 50% of patients after MEL200 and BEAM, respectively. Fever of unknown origin occurred in 65 and 70% of patients after MEL200 and BEAM, respectively. One patient died from septic shock during the aplasia period following BEAM. In an intention-to-treat analysis, the overall response rate increased after each stage of protocol, ranging from 47% to 65% and 75% after IGEV, MEL200, and BEAM, respectively. Tandem HDCT is feasible and effective in patients with relapsed or refractory HL.     

Pulmonary manifestations of peripheral T‐cell lymphoma: case report and review of the literature

Introduction: Peripheral T‐cell lymphomas (PTCL) represent approximately 10% of non‐Hodgkin's lymphomas. Pulmonary involvement is an uncommon manifestation of this heterogeneous group of malignancies. Methods: Report of a case. Results: This case report describes a 75‐year‐old man with fever, weight loss, anemia, enlargement of spleen and liver, atypical lymphocytes and pulmonary nodules. Lung biopsy showed lymphocytic infiltration of the lung parenchyma. T‐cell receptor gamma gene rearrangement by polymerase chain reaction confirmed the diagnosis of peripheral T‐cell lymphoma. Unfortunately, the patient died because of refractory and aggressive disease. Conclusion: Pulmonary and pleural involvement are seen in patients with PTCL and usually carry a poor prognosis. The subject of pulmonary involvement in peripheral T‐cell lymphoma is discussed. Please cite this paper as: Vahid B, Machare‐Delgado E and Marik PB. Pulmonary manifestations of peripheral T‐cell lymphoma: case report and review of the literature. The Clinical Respiratory Journal 2007; 1:114–117.     

Ki-67 expression level,histological subtype,and the International Prognostic Index as outcome predictors in mantle cell lymphoma

OBJECTIVES: Mantle cell lymphoma (MCL) is characterised by translocation t(11;14) (q13;q32) leading to rearrangement of bcl1/CCND1 and overexpression of the cell-cycle regulatory protein cyclin D1. We assessed the significance of the cell proliferation rate as an outcome predictor with the five components of the International Prognostic Index (IPI) and the histological subtypes of MCL. PATIENTS AND METHODS: The hospital case records and histopathological material of 127 patients diagnosed with MCL in a single centre were reviewed. The cell proliferation rate was assessed by Ki-67 immunostaining and mitosis counting. Cox's multivariate regression model was used in multivariate survival analyses. The median follow-up time was 87 months. RESULTS: The mantle zone/nodular subtype of the common variant (19%) was associated with median survival of 70 months, the diffuse subtype of the common variant (64%) of 35 months, and the blastoid subtype (17%) of 11 months (P < 0.001). Patients with Ki-67 expression in > or = 26% (the upper tertile) of the lymphoma cells had median survival of only 13 months as compared with 45 months in the rest of the patients (P < 0.001). In a multivariate analysis high Ki-67 expression, Ann Arbor stage III-IV, and age over 60 yr had independent influence on survival, whereas serum lactate dehydrogenase level, the number of extranodal disease sites, and performance status did not. CONCLUSIONS: The IPI may not be an optimal tool for outcome prediction in MCL, and a better prognostic index may be obtained by including Ki-67 expression and possibly the histological subtype in the index.