Association of Epstein-Barr virus genome with mixed cellularity and cellular phase nodular sclerosis Hodgkin's disease subtypes.

Association of Epstein-Barr virus (EBV) genome with Hodgkin's disease (HD) histological subtypes was investigated using the polymerase chain reaction (PCR). A highly significant association of EBV genome with the mixed cellularity (MC) subtype (10 positive out of 15 cases; 66%) was observed, suggesting a possible etiopathogenetic role of EBV in the induction of this subset. By contrast, a markedly lower frequency of association with EBV genome was found in nodular sclerosis (NS) (12 positive out of 46 cases; 26%) and in nodular lymphocytic predominance (NLP) (0 positive out of 5 cases) HD subtypes. In addition, in the NS series, the presence of EBV genome was mainly restricted to the 'cellular phase' NS subset. This finding strengthens the possibility, suggested by clinico-pathological features and survival rates, that 'cellular phase NS' is a disease more akin to MC than to typical NS HD.     

Distribution of T-lymphocyte subsets in Hodgkin's disease characterized by monoclonal antibodies.

Mononuclear-cell suspensions of lymph nodes, spleen and blood from 24 patients with active Hodgkin''s disease (HD) were studied for possible imbalance of T and B lymphocytes, and T-lymphocyte subsets, using monospecific anti-T antibodies and other reagents. A profile showing T-cell predominance was demonstrated in lymph nodes and blood, with total T-cells ranging from 50-70% of the cell count. As defined by monoclonal antibodies, 70-85 of the latter comprised the "inducer" subclass, the remainder being "suppressor" cells. There were no essential differences between histologically involved and uninvolved lymph nodes from HD patients, though total T-cell proportions were lower in "normal lymph node" controls. The profiles of spleens electively removed, as part of pre-treatment staging procedures, showed reduced total T-cell numbers, whether these were involved with HD or not. These differences are accounted for principally by fewer T "inducer" cells (24%, in spleen, v. 54% in involved lymph nodes and 47% in "normal" control nodes). Possible explanations for these findings are discussed. Our results demonstrate similar profiles in histologically diseased and normal tissue, rather than any clear imbalance of T-cell proportions which might explain the profound disturbances of T-cell function frequently demonstrated in vivo and in vitro.     

Variation in the frequency of Epstein-Barr virus-associated Hodgkin's disease with age.

A number of studies in developed countries have reported variation in the frequency of Epstein-Barr virus (EBV)-associated Hodgkin's disease (HD) with age. A 'three disease' model for HD that incorporates the EBV association, histological subtype of HD and age has recently been proposed. In this model, Hodgkin's disease of childhood and older adults is commonly EBV-associated and of mixed cellularity type, whereas young adult HD is generally not EBV-associated and is usually characterised by nodular sclerosis disease. A case series of HD diagnosed in the West Midlands between 1981 and 1997, inclusive, was used to investigate the applicability of the 'three disease' model. In situ hybridisation for the EBV early RNAs (EBERs) was used to determine the presence of EBV in the malignant Hodgkin/Reed-Sternberg cells. In contrast to the 'three disease' model, nodular sclerosis was the predominant subtype in each of the age groups within the case series. In addition, overall there was little variation in EBV-positive rates across the age ranges examined. However, when females were analysed separately, older women (45+ years) were significantly more likely to have EBV-positive disease than their younger counterparts (<45 years). In summary our results do not generally support the 'three disease' model.     

Inflammation and tissue repair markers distinguish the nodular sclerosis and mixed cellularity subtypes of classical Hodgkin's lymphoma

Background:

Classical Hodgkin''s lymphoma (cHL), although a malignant disease, has many features in common with an inflammatory condition. The aim of this study was to establish the molecular characteristics of the two most common cHL subtypes, nodular sclerosis (NS) and mixed cellularity (MC), based on molecular profiling and immunohistochemistry, with special reference to the inflammatory microenvironment.

Methods:

We analysed 44 gene expression profiles of cHL whole tumour tissues, 25 cases of NS and 19 cases of MC, using Affymetrix chip technology and immunohistochemistry.

Results:

In the NS subtype, 152 genes showed a significantly higher expression, including genes involved in extracellular matrix (ECM) remodelling and ECM deposition similar to wound healing. Among these were SPARC, CTSK and COLI. Immunohistochemistry revealed that the NS-related genes were mainly expressed by macrophages and fibroblasts. Fifty-three genes had a higher expression in the MC subtype, including several inflammation-related genes, such as C1Qα, C1Qβ and CXCL9. In MC tissues, the C1Q subunits were mainly expressed by infiltrating macrophages.

Conclusions and interpretations:

We suggest that the identified subtype-specific genes could reflect different phases of wound healing. Our study underlines the potential function of infiltrating macrophages in shaping the cHL tumour microenvironment.     

The occurrence and management of esophageal fistulas resulting from Hodgkin's disease.

At their radiation therapy (RT) department, the authors saw a young woman with an esophageal fistula from Hodgkin's disease that was not responsive to chemotherapy; this prompted a review of the literature concerning such patients. Twenty-two patients with Hodgkin's disease and esophageal fistula were found to have been reported previously. Most patients had active disease at the fistula site, and most who were treated with RT or chemotherapy had prompt fistula closure. Fistula formation as a complication of RT for Hodgkin's disease was found to be an extremely unusual occurrence.     

Hodgkin's disease in AIDS complex patients. Report of four cases and tissue immunologic marker studies

Hodgkin's disease developed in four homosexual men with prodromal manifestations associated with the Acquired Immune Deficiency Syndrome (AIDS) (generalized lymphadenopathy in three and persistent diarrhea, fever, and weight loss in one). All had inversion of the peripheral blood helper-to-suppressor T-cell ratio. The presentations with Hodgkin's disease were atypical with advanced disease (Stage IIIB or IV) in three of four patients and marrow involvement at diagnosis in two. Response to therapy was poor. Immunopathologic studies on the Hodgkin's disease tissue were performed in two patients. In contrast to Hodgkin's disease in non-AIDS risk patients, the Hodgkin's disease tissue in these patients demonstrated severe depletion of helper T-lymphocytes with a predominance of suppressor cells (tissue helper-to-suppressor cell ratio of 0.19 and 0.33, respectively, on immunoperoxidase-stained preparations). In contrast, in five cases of Hodgkin's disease from non-AIDS risk individuals, the lymphocytes population consisted predominantly of helper T-lymphocytes (median tissue helper-to-suppressor cell ratio 3.15, range 2.12-7.77). Homosexual men with AIDS risk factors are at risk for the development of Hodgkin's disease. Hodgkin's disease in these patients may be atypical with severe depletion of helper T-lymphocytes and a predominance of suppressor cells. The lack of an appropriate T-cell immunologic response may contribute to the poor prognosis observed in these patients.     

Human immunodeficiency virus-related lymphoreticular malignancies and peripheral neurologic disease. A report of four cases

The most common human immunodeficiency virus-related (HIV) malignancies to date include Kaposi's sarcoma and the high-grade non-Hodgkin's lymphomas. There also appears to be an association between HIV and an aggressive form of Hodgkin's disease. In addition, there is a spectrum of HIV-related central and peripheral neurologic syndromes. This article documents four patients with HIV-associated lymphoma who presented with peripheral neurologic syndromes as part of their neoplastic process. Autopsy results obtained from two of these patients showed direct nerve infiltration by lymphoma. All patients had an elevated serum lactate dehydrogenase (LDH). It is recommended that HIV-related lymphoma be considered in a high-risk patient who presents with a peripheral neurologic syndrome especially if there is an elevated serum LDH.     

Risk patterns of Hodgkin's disease in Los Angeles vary by cell type.

Over the period 1972-1985, 2729 cases of Hodgkin's disease were diagnosed in Los Angeles County, and 2492 were subclassified using the Rye classification. The occurrence of these cases was examined in relation to age, sex, race, place of birth, social class, occupation, and year of diagnosis. The pattern of nodular sclerosis occurrence conformed to expectations, supporting the polio model of etiology for this subtype. However, the risk pattern of mixed cell disease was quite distinct from that of nodular sclerosis, suggesting that the two may not share a common etiology. The pattern of lymphocyte predominance in Hodgkin's disease, with a special prominence in younger blacks, resembled neither that of nodular sclerosis nor that of mixed cell disease. The cases of lymphocyte-depletion Hodgkin's disease showed no distinctive epidemiological features, and its continued classification with nodular sclerosis and/or mixed cellularity can be justified solely by histological or biological evidence.     

Hodgkin's disease and AIDS. Twenty-three new cases and a review of the literature

Despite numerous reports suggesting an association of Hodgkin's disease (HD) with the acquired immunodeficiency syndrome (AIDS), HD in an individual seropositive for the human immunodeficiency virus (HIV) still is not considered a criterion for the diagnosis of AIDS. The authors report 23 new cases of HD in individuals at risk for AIDS and review the literature. As a group, individuals at risk for AIDS who develop HD have a more aggressive form of the illness (82% with stage III or IV), have or develop AIDS-related opportunistic infections (54%), second neoplasms (10%), and /or profound cytopenias (32%), and 85 to 90% are HIV positive when tested. More than two thirds die within 1 year of the diagnosis of HD. The authors conclude that HIV infection alters the clinical course of HD, that advanced or high-grade HD in HIV-infected individuals should be considered indicative of AIDS, and all patients with HD should be tested for HIV.     

Hodgkin's disease and non-Hodgkin's lymphoma containing Reed-Sternberg-like giant cells in Taiwan. A clinicopathologic analysis of 50 cases.

Hodgkin's disease (HD) is uncommon in Taiwan. In reviewing the clinicopathologic features of 50 cases, the authors found that the diagnosis of HD was complicated with non-Hodgkin's lymphoma (NHL). Fourteen cases were reclassified as NHL containing Reed-Sternberg (RS) giant cells, mostly peripheral T-cell lymphoma (PTL), and 34 cases as classic HD, which included 8 cases of lymphocyte predominance, 10 of nodular sclerosis, 12 of mixed cellularity, and 4 of lymphocyte depletion. For cases of HD, there was a bimodal age-incidence distribution with peaks at the third and fifth decades; 61.8% manifested Stage B symptoms and 80.6% had Stage III/IV disease. The group of patients with NHL, compared with those with classic HD, was found to be older (mean age, 41.4 years versus 33.1 years; P less than 0.05), to have more extranodal disease (35.7% versus 8.8%, P less than 0.05), less complete remission rate (25% versus 67.9%, P less than 0.05), and shorter median survival (29 months versus 90 months). Most of the NHL patients originally were diagnosed as having atypical or unclassified HD. Thus, the authors conclude that the previous observation of a predominance of mixed cellularity HD in Asian regions may be attributable to the inclusion of PTL, which may mimic HD in histology. Because there is a marked difference in clinical behavior and prognosis, it is important to distinguish between HD and NHL containing RS giant cells in an area with a high incidence of PTL.     

Intracranial Hodgkin's disease. A report of 12 cases and review of the literature

Intracranial involvement by Hodgkin's disease is rare. Of the 30 previously reported cases, in many of which central nervous system (CNS) disease was documented postmortem, no associated risk factors have been elucidated, and response to treatment has been poor. This report cites 12 additional cases treated at the Stanford University Medical Center, five of whom have enjoyed prolonged freedom from intracranial relapse.     

Hepatocellular carcinoma with sarcomatous change. Clinicopathologic and immunohistochemical studies of 14 autopsy cases

Among 355 autopsy cases of hepatocellular carcinoma (HCC), 14 cases exhibited sarcomatous appearance (incidence, 3.9%). A clinicopathologic study was performed in these 14 cases, and the immunohistochemical localization of keratin (KRT), vimentin (VMT), albumin (ALB), fibrinogen (FBG) and alpha-fetoprotein (AFP) was also examined using the avidin-biotin complex method. Clinically, the HCCs with sarcomatous appearance were characterized by negative or low serum AFP levels and high incidence of extrahepatic metastasis. Grossly they were of infiltrative, mixed expansive and infiltrative, and pedunculated types. Histologically, the tumor consisted mainly of spindle-shaped cells and partly of multinucleated cells, and showed a sinusoidal growth pattern at the tumor-nontumor boundary. Immunohistochemically, tumor cells in the regions showing sarcomatous appearance were frequently found to be positive to KRT and VMT, whereas the percentage of positivity to ALB, FBG, and AFP were not significantly different from those in ordinary HCC. These results strongly suggest that the lesion showing sarcomatous appearance represents the sarcomatous change of HCC rather than being regarded as the complication of HCC and sarcoma.     

International patterns in the occurrence of Hodgkin's disease in children and young adult males

It was reported over 20 years ago that there were distinct age-specific patterns of Hodgkin's disease incidence in countries with different levels of economic development, and that there was an inverse relationship between the incidence of Hodgkin's disease in children and young adults within countries. Such observations were important, leading to hypotheses on the possibly infectious aetiology of the disease. Since the initial report, diverging trends in the incidence of Hodgkin's disease in children and young adults have been observed, and data from a much larger number of countries and cancer registries have become available. This led us to reassess international age-related incidence patterns of Hodgkin's disease occurrence. Recent data show distinct differences in age-specific Hodgkin's disease incidence patterns in different geographic regions. In general, the United States (US) and European countries had the pattern of low childhood rates and high young adulthood rates. However, countries which are not part of the European Union (EU), mainly Baltic states and countries of central and eastern Europe, showed a variant of this pattern: similarly high young adult rates, but rates in children higher than those in the US and EU. Incidence-rate patterns for Latin American countries differed from those previously observed, with a shift towards patterns observed in more economically developed countries. Analysis of incidence data from earlier sources dating back to 1963 confirmed the original finding of an inverse association in incidence rates (c. 1963-1967) using a selected group of cancer registries, but not when all data were considered. This association has become weaker over the past 20 years. Using current incidence rates (1983-1987), no association between Hodgkin's disease rates in children aged 5 to 14 years (as well as 0 to 9 years) and young adults (20 to 34 years) was found. © 1995 Wiley-Liss, Inc.     

The immunophenotype of Reed-Sternberg cells. A study of 50 cases of Hodgkin's disease using fixed frozen tissues

The authors analyzed 50 cases of Hodgkin's disease (HD) with a panel of antibodies which detect B-cell and T-cell specific markers and activation antigens using a sensitive immunocytochemical technique and paraformaldehyde-lysine-periodate (PLP) fixed-frozen tissues. In 60% of cases either T-cell or B-cell specific antigens were detected on Reed-Sternberg (RS) cells. Most T-cell cases were of nodular sclerosing (NS) and mixed cellularity (MC) type (65% and 30%, respectively) and most B-cell cases were either of NS or lymphocyte predominant (LP) type (55% and 45%, respectively). Leukocyte common antigen (LCA) was usually negative on RS cells in NS, but was present in approximately 50% of the cases of MC and LP types. Almost all cases were positive for the CD30 antigen (Ki-1). Most cases were also positive for CD15 (LeuM1) with the exception of the LP type. Activation antigens (Ia, CD25, T9) were expressed in a high proportion of cases regardless of subtype. The results suggest that most cases of HD are histogenetically derived from activated T-cells or B-cells.     

In situ expression of the IL-1-alpha and TNF-alpha genes by Reed-Sternberg cells in Hodgkin's disease.

The histopathologic pattern of tissues involved by Hodgkin's disease (HD) suggests excessive activation of environmental cells by cytokines released by Hodgkin-Reed-Sternberg (HRS) cells, which are considered as the neoplastic component of HD lesions. This hypothesis has been supported by many studies performed in vitro using HD cell lines. In this study, we have tried to demonstrate the cytokine-producing cells in an environment as close as possible to the in vivo conditions, using in situ hybridization onto frozen sections of HD samples. [35S]-labelled single-stranded RNA probes were prepared by transcribing human cDNA fragments of the TNF-alpha and IL-1 alpha genes subcloned into appropriate vectors. A total of 19 specimens of HD lesions, including 7 cases of nodular sclerosing (NS) type and 12 cases of mixed cellularity (MC), were tested with both types of probes. Clinical stages included stage I (6 cases), stage II (4 cases), stage III (6 cases) and stage IV (3 cases). TNF-alpha and/or IL-1 alpha expression was observed in 12 among 19 HD cases. However, neither the histological type nor the clinical status of the patients was correlated with the profile of cytokine secretion. Most of the cytokine-producing cells could be identified as HRS cells due to their morphological appearance. In 3 cases, simultaneous analysis by immunohistochemistry and in situ hybridization showed that IL-1 alpha/TNF-alpha mRNA-producing cells simultaneously expressed the CD30 antigen, thereby confirming the HRS nature of these cells.