Phenotypic analysis of an established cell line derived from a patient with Hodgkin's disease (HD)

This report describes the phenotypic analysis of a cell line obtained from a female patient with the nodular sclerosing subtype of Hodgkin's disease (HD). The cell line has a neoplastic karyotype and is stable in culture in the absence of feeder layers or growth factors. Phenotypic analysis of this cell line shows that it cannot easily be characterized as either a lymphocyte, macrophage or granulocyte but resembles in its characteristics certain HD lines already described in the literature. The cell line carries the antigen defined by the Ki-1 monoclonal antibody, shows myeloid markers on a proportion of cells and has cytoplasmic UCH-T1.     

Hodgkin's disease in Hong Kong Chinese

A lower incidence of Hodgkin's disease in Orientals has been recognized. Although most Hong Kong Chinese came from the Guandong province of China, the incidence of Hodgkin's disease in Hong Kong Chinese is 9.2 per cent which is more comparable to the low figure of 6 per cent in Japan than the 32 per cent incidence in Guangdong. If this discrepancy in the ethnically similar populations is confirmed, other etiological or promoting factors must be considered. Ninety-two Hong Kong Chinese patients (54 males and 38 females) with Hodgkin's disease were reviewed. The median age was 34 years (range 5-79 years). The histology was lymphocyte predominant in nine (10 per cent), nodular sclerosing in 34 (37 per cent), mixed cellularity in 29 (31 per cent), lymphocyte depleted in nine (10 per cent) and unclassified in 11 (12 per cent). Seventeen per cent had stage Ia disease, 2 per cent Ib, 15 per cent IIa, 11 per cent IIb, 11 per cent IIIa, 9 per cent IIIb, 11 per cent IVa and 24 per cent IVb. Twenty-five of them (27 per cent) were staged by laparotomy. Twelve patients (13 per cent) had bulky disease. Identical to the pattern observed in Caucasians, our patients had an apparent biomodal age distribution, a male predominance and similar distribution of histological subtypes according to the Rye classification. The absence of an early peak in young adulthood and the lower incidence of the nodular sclerosing subtype reported in the Japanese was not observed in our patients. A variety of treatments were given to the 92 patients. Most of the patients with stage I-II disease received radiotherapy except for those with B symptoms, bulky disease or lymphocyte depleted histology, who received chemotherapy with or without radiotherapy. All patients with stage III-IV disease received chemotherapy with or without radiotherapy except for two patients with stage IIIa disease who had total nodal irradiation only. The multivariate analysis revealed that Ann Arbor staging was a significant independent factor determining the disease-free survival of patients in complete remission and the overall survival of all patients. Age was the other independent variable significantly determining the overall survival.     

Rearranging antigen-receptor genes in enriched Reed-Sternberg cell fractions of Hodgkin's disease

Molecular genetic analysis of rearranging antigen-receptor genes in non-Hodgkin's lymphomas has revealed the clonality and lineage in the majority of cases. In an analogous approach, we sought to apply gene rearrangement analysis to Hodgkin's disease to understand better the clonality and origin of this disorder. However, the putative neoplastic cell of Hodgkin's disease, the Reed-Sternberg cell and its variants, is extraordinarily rare in most cases of Hodgkin's disease. On the average, Reed-Sternberg cells and variants represent 0.1 per cent of total cell suspensions of nodular sclerosing Hodgkin's disease. As this frequency is below the minimum threshold of sensitivity of the Southern blot assay, we attempted to enrich for Reed-Sternberg cells before DNA extraction and analysis. Using either elutrition or Percoll density gradient centrifugation, we were able to enrich the percentage of Reed-Sternberg cells and variants to above 1 per cent in five cases of nodular sclerosing Hodgkin's disease. In three of these cases, immunoglobulin gene rearrangements were identified, but no T cell receptor gene rearrangements were seen. No rearrangements were detected in unseparated cells or in the Reed-Sternberg cell-depleted fractions. In addition, the L428 Hodgkin's disease cell line was found to have one rearranged and one deleted heavy-chain gene, a rearranged kappa gene, a rearranged lambda gene, and a single rearranged beta allele. No rearrangements of the T gamma gene were found in L428. Taken together, these findings indicate that clonal cell populations are present in Hodgkin's disease and suggest the possibility of a clonally expanded lymphoid cell in this disorder.     

Immunogenotyping in Hodgkin's disease

This review presents and discusses the immunogenotypic findings in 112 cases of Hodgkin's disease (HD) and eight Hodgkin's cell lines. Clonal rearrangements of the T cell receptor gamma and beta chain, as well as immunoglobulin heavy and light chain genes, are detected in the majority of nodular sclerosis and lymphocytic depletion subtypes. Together with the recent immunophenotypic data, these findings are in favour of the view that HD is a disease of activated lymphoid cells. Further investigations will be necessary to characterize the morphology and immunophenotype of the clonally rearranged cell population which seems not to be confined to the Sternberg-Reed and Hodgkin cell in every case. Prospective clinical studies including the genotype of HD cases have to be done in order to address the question of whether or not distinctive immunogenotypic profiles correlate with the clinical course of this lymphoproliferative disorder.     

Radiotherapy for Hodgkin's disease in pregnancy

Hodgkin's disease diagnosed during pregnancy poses a dilemma as there are risks of abortion and fetal malformation with the use of radiotherapy and chemotherapy. A patient with Hodgkin's disease during pregnancy treated with radiotherapy is presented.     

In vitro analysis of cell populations involved in Hodgkin's disease lesions and in the characteristic T cell immunodeficiency

Hodgkin's disease (HD) is an aggressive human lymphoproliferative disease that displays a curious pleomorphic histopathologic appearance unlike that of any of the common non-Hodgkin's lymphomas (NHL). Although the bizarre giant cells of the HD lesion, the Reed-Sternberg cells (RSC) and mononuclear variant Hodgkin's cells (HC), have been considered to be malignant cells, little objective evidence supports this conclusion. We have studied the proliferative characteristics of T cell as well as RSC and HC-enriched populations from HD lesions, and found the majority of the proliferative activity in the T cell populations. RSC-enriched populations not only showed little spontaneous proliferation, but also did not respond to a variety of cytokine growth factors in vitro, suggesting that these cell populations are not actively growing cells. Further molecular studies to identify possible monoclonal T or B cell populations in HD lesions, using a TCR beta chain probe and IgH probes respectively on Southern blot analysis, revealed no evidence of monoclonal lymphoid cell populations. Additional studies on the characteristic T cell immunodeficiency in HD were also undertaken. Our previous studies had associated a decrement in IL-2 production with this defect. Our studies now show that an intrinsic T cell abnormality exists when HD patients' T cells are stimulated with agonistic MAb that can optimally activate and stimulate IL-2 production in normal control T cells.     

Residual mediastinal widening following therapy in Hodgkin's disease

The chest radiograms (CXR) of 102 patients with Hodgkin's disease presenting with mediastinal involvement at diagnosis were reviewed to assess the incidence and relevance of residual mediastinal abnormalities after therapy. All patients had completed planned treatment and had no evidence of persisting extramediastinum disease at restaging. Thirty-nine cases (38 per cent) showed residual mediastinal widening at the end of therapy (minimal changes in nine and measurable changes in 30 cases). Neither presenting features nor treatment modality correlated with residual mediastinal mass on chest X-ray. The isolated intrathoracic relapse rate was 11 per cent for patients with normal mediastinum following therapy, as compared with 20.5 per cent for those with residual widening; this difference did not reach statistical significance (p = 0.3). The persistence of mediastinal abnormalities was associated with a trend towards a higher risk of intrathoracic relapse for patients with initial bulky disease (p less than 0.05) and for those with B symptoms (p = 0.07). Using thoracic CT scan for restaging (56 patients), the residual mediastinum rate rose to 70 per cent; the predictability of local relapse with this procedure was not greater than with conventional X-ray study.     

A review and interpretation of cytogenetic abnormalities identified in Hodgkin's disease

The nature of the cell which gives origin to Hodgkin's disease remains unclear after years of intensive investigation. Cytogenetic data, which are very scarce in Hodgkin's disease, could contribute information which might help elucidate this problem. Review of our own data and others shows that the most frequent abnormalities in this disorder involve chromosomes 14q in 35 per cent of cases, 11q in 32 per cent, 6q in 32 per cent, and 8q in 18 per cent. The most common breakpoint in chromosome 14 occurred at 14q32 where the IgH chain genes reside thus suggesting that in these cases the cell of origin might be a B lymphocyte. The 11q and 6q structural abnormality have also been frequently seen in lymphoid disorders such as ALL and large cell lymphoma. Of interest also is the fact that in a certain type of childhood pre-B cell acute lymphoblastic leukemia which shows cytogenetic abnormalities on 11q23, aberrant myeloid and monocytic markers are seen. This suggests that in Hodgkin's disease a similar phenomenon might occur which could help to explain why the Reed-Sternberg cell expresses myeloid-monocytic antigens such as Leu M-1.     

Prognostic factors in Hodgkin's disease.

The clinical records and treatment results of 163 patients with Hodgkin's disease, who were seen at Ellis Fischel State Cancer Hospital (EFSCH) between 1940 and 1971, were reviewed and analyzed. More than 200 clinical and histological variables were recorded for each case of Hodgkin's disease, including details of radiotherapy and chemotherapy. Statistical studies were carried out in order to evaluate the independent prognosis significance of each of these factors. All of the lesions were reclassified according to the Lukes proposal which was modified and recommended at the 1965 Rye classification (except for hepatomegaly which was included in Stage IV). This is a retrospective study, and the modern techniques of staging were rarely used in pretreatment studies (since 1965, only ten patients have had an abdominal exploration). The basic work-up consisted of a complete blood count, urinalysis, blood type, chest X ray, and EKG. Lymphangiogram and radioisotope liver scans were used on less than 10% of the patients. About 30% of the patients had gastrointestinal X rays and 70% had IVP. Bone marrow biopsies -- the majority of which were done by needle aspiration -- were obtained for approximatley 50% of the patients. Clinical stage, histological type, and presence of absence of systemic symptoms appeared to be themost significant prognostic factors. The classification of systemic symptoms according to the criteria of either the Rye or Ann Arbor conferences showed no particular difference in determining the survival rate. Among the systemic symptoms, fever appeared to be the most important for survival rate. Survival rates were higher in nonanemic and nonlymphocytopenic patients. Eosinophilia, blood group, and Rh factor had no prognostic significance. The relapse-free interval was an important indicator of long-term prognosis. The unfavorable influence of relapse in ultimate prognosis was clearly seen; however, the extent of the relapse site was shown to have no significant influence on survival.     

Isolation of activated ras transforming genes from two patients with Hodgkin's disease

Despite impressive advances in the clinical management of Hodgkin's disease, little is known about its cellular origin or the mechanism(s) of "Hodgkinogenesis." Recent findings that certain human cellular oncogenes can cause malignant transformation suggest that aberrant activation of these genes may play a role in carcinogenesis. To determine if such genes are operative in Hodgkin's cells, we isolated DNA from splenic nodules of three patients with nodular sclerosis Hodgkin's disease and tested its ability to transform mouse NIH 3T3 cells, the standard assay for oncogene-mediated malignant transformation. Transformed cells containing human DNA were obtained from two patients. DNA from these primary transformants yielded secondary transformants of NIH 3T3 fibroblasts; one also transformed normal mouse bone marrow macrophages, a cell type probably related to the Hodgkin's cell. When analyzed by Southern blot methods for homology with closed oncogene probes, the transforming genes from both patients had homology with N-ras. The homology and size of the restriction fragments were similar to those of transforming genes isolated from patients with acute nonlymphocytic leukemias. The presence of the same activated oncogene in tumor tissue from two different patients suggests that it may play an important role in Hodgkinogenesis.     

Trends in mortality from Hodgkin's disease in western and eastern Europe

Hodgkin's disease mortality rates steadily declined by about 75% between the late 1960's and the late 1990's in the current European Union countries and the USA, and Japan. Eastern European countries, however, showed only an approximately 40% decline between the late 1960's and the early 1990's, and no further fall thereafter.     

Lymphocyte predominant Hodgkin's disease: clinical presentation and results of treatment

The records of 59 patients with lymphocyte predominant Hodgkin's disease (LPHD) evaluated and treated at Stanford University Medical Center between 1963 and 1983 were reviewed. Of these 59 patients, 92% are alive at 10 years following treatment, 78% are relapse-free, and none have died of Hodgkin's disease. Compared with the other histologic subtypes of Hodgkin's disease, LPHD presents more frequently as stage I or II disease (78% vs. 55%) and less frequently with constitutional symptoms (7% vs. 32%). Despite these factors, there is no statistically significant difference in either survival or freedom-from-relapse (FFR) between the histologic subtypes when comparisons are made on a stage-for-stage basis. Analysis of sites of presentation and relapse reveals that LPHD rarely involves intrathoracic structures. Patients with C.S. I disease presenting in inguinofemoral or high cervical lymph nodes do not require staging laparotomy as none of these patients were upstaged by surgery. Patients with stage I disease involving high cervical lymph nodes may be treated with limited field irradiation employing fields no more extensive than a mantle and Waldeyer's ring field, as no relapses have been seen in such patients treated in this fashion. Although limited field irradiation was used successfully for LPHD presenting in other localized sites, inadequate patient numbers preclude assessment of this treatment for those clinical presentations.     

An unusual site of presentation for Hodgkin's disease in the middle ear

We are presenting a case history of a patient with advanced Hodgkin's disease, who had secondary involvement of his middle ear. To our knowledge this is the first case report of such clinical presentation where radiation therapy was of good help for bringing about symptomatic relief. Possible routes of spread are discussed and the literature is reviewed.     

Increased levels of circulating interleukin-6 in patients with Hodgkin's disease.

Expression of interleukin-6 (IL-6) and IL-6 receptors has been demonstrated in Hodgkin and Reed-Sternberg (H and RS) cells in vitro and in vivo. In order to evaluate the clinical significance of IL-6 serum levels in patients with Hodgkin's disease (HD), we tested the sera of 56 untreated patients with HD by means of a sensitive sandwich ELISA. While IL-6 was only rarely detectable in healthy controls or patients with non-Hodgkin's lymphoma, 32 of 56 patients (57 per cent) had detectable IL-6 levels (range 12-32 pg/ml). The rates of detectable IL-6 levels and the median levels were not correlated with age, sex, histological subtype, stage or the presence of B-symptoms, nor with any of a wide spectrum of laboratory parameters tested, including erythrocyte sedimentation rate, total leukocyte and lymphocyte counts, serum levels of soluble CD8, CD25 or CD30. The rates of complete remissions and freedom from treatment failure were not different in IL-6-negative and IL-6-positive patients. Except in one of 23 follow-up sera taken after therapy, IL-6 was no longer detectable even for patients who suffered from progressing disease, suggesting that the neoplastic H and RS cells are not the major source of circulating IL-6.     

Treatment selection for stage IIIA Hodgkin's disease patients

Two treatment policies for the therapy of patients with Stage IIIA Hodgkin's disease are compared. From 1969-1976, 49 newly diagnosed and pathologically staged IIIA patients received total nodal irradiation (TNI) alone (no liver irradiation). Although actuarial survival was 80% at 5 years and 68% at 10 years, actuarial freedom from relapse was only 38% at 5 years. Accordingly, a new treatment policy was instituted in 1976. Patients with either CS IIIA disease, multiple splenic nodules, IIIA with a large mediastinal mass or III2, received combined modality therapy (combination chemotherapy and irradiation). All others received TNI. Thirty-six patients have been treated under the new program. The actuarial survival is 90% at 5 years and the relapse-free survival is 87%, suggesting the superiority of this approach.     

Prognostic factors in decision-making in the clinical management of Hodgkin's disease

At the beginning of this conference, Dr Ford asked whether or not Hodgkin's disease was a malignancy. Most physicians would agree that, regardless of whether this question can be answered on a molecular level, Hodgkin's disease certainly behaves like a malignancy, and clinically fits criteria necessary to call it one. It grows without control locally, comprising vital organs. It 'metastasizes', infiltrates organs, and causes organ dysfunction. Patients afflicted with the disease have a shortened life span without proper therapy, as demonstrated by DeVita in his original publication describing the benefits of MOPP chemotherapy (nitrogen mustard, vincristine, procarbazine, prednisone) (DeVita et al., 1970). However, it can progress very slowly, with 50 per cent of untreated patients with stage III or IV disease dead at one year, but 10 to 15 per cent alive at five years. Therefore, in its clinical behaviour, Hodgkin's disease certainly qualifies as a malignant disorder, despite the fact that we do not have the molecular means of calling it one.     

Bone involvement in Hodgkin's disease

Bone involvement in Hodgkin's disease is uncommon and seldom encountered at initial diagnosis. Seven cases with osseous involvement were identified from a series of 147 patients with Hodgkin's disease treated at Auckland Hospital from 1980 to 1988. Only one patient was found to have bone lesions at the time of initial presentation. Two patients had multiple lesions and 5 had a solitary lesion. Sites of involvement included the spine, pelvis, femur, humerus, ribs, sternum, scapula and base of skull. Six patients had nodular sclerosing histology and one had mixed cellularity disease. All 7 patients were treated with systemic chemotherapy for their advanced disease, and 5 patients needed local radiotherapy to sites of bone involvement. The radiation dosage schedules were individualized, ranging from 30 Gy to 40 Gy, using either a 6 MeV linear accelerator or cobalt machine. At the time of analysis of this study, 4 patients were in complete remission, 2 patients completed chemotherapy with good response and only 1 patient died of disseminated disease. The current review has demonstrated an encouraging response to treatment and good long term control. We believe that combined-modality therapy is effective in the treatment of osseous involvement in Hodgkin's disease.     

Second primary malignant neoplasms in patients treated for Hodgkin's disease at St Bartholomew's Hospital

The incidence of second malignant neoplasms (SMN's) was investigated in a group of 529 patients with Hodgkin's Disease (HD) treated at St Bartholomew's Hospital (SBH). SMN's were seen in 27 of these patients giving an incidence rate three and a half times that expected in an age and sex matched normal population (p = much less than 0.001). The incidence rate was higher in those receiving multiple chemotherapy and radiotherapy for relapsed HD compared with those receiving primary radiotherapy, chemotherapy or chemotherapy with adjuvant radiotherapy (p = 0.02). However, the increased incidence rate in those patients treated with chemotherapy on relapse, may reflect in part a delayed effect of their primary therapy, since the incidence rate in the primary treatment group only becomes significantly raised after six years. When allowance was made for this delay the difference between the two groups was no longer significant. The incidence rates for Non-Hodgkin's Lymphoma (NHL) and myelogenous leukaemia were 32 and 57 times those expected, compared with only two and a half times the expected rate for non-haematological SMN's (p = much less than 0.001). The four acute myeloid leukaemias (AML) all occurred within five years of treatment compared to wide-ranging intervals between treatment and occurrence of SMN in the other groups. The increased incidence of NHL may be an alternative expression of lymphoid abnormality rather than a treatment-related occurrence. Multiple SMN's were diagnosed in three patients. This represented a highly significant (p = much less than 0.001) increase over the expected incidence of multiple neoplasia in the general population. Several factors may contribute to the development of SMN's in HD, including an inherent disposition of HD itself. The time-dependent incidence pattern of SMN's with a delay followed by an increased incidence rate, suggests that treatment plays a key role. It is not yet clear whether more intensive, or multiple treatments add to the risk accrued for the initial treatment.     

Unilateral and bilateral breast cancer in women surviving pediatric Hodgkin's disease

PURPOSE: To define demographic and therapeutic associations with the risk of breast cancer in children treated for Hodgkin's disease (HD), particularly the frequency and interval to the development of contralateral breast cancer. METHODS AND MATERIALS: All 398 female patients (<19 years) treated for HD in five institutions during the accrual period were evaluated. Mean follow-up was 16.9 years. The standardized incidence ratio (SIR) was calculated as the ratio of the observed number of cases to the expected number of cases, estimated using age-matched controls from the Surveillance, Epidemiology, and End Results database. RESULTS: A total of 29 women developed breast cancer (25 invasive, 4 ductal carcinoma in situ; SIR, 37.25; 95% confidence interval, 24.96-53.64). Time to diagnosis was 9.4 to 36.1 years. Cumulative incidence was 24% at 30 years. Ten patients (34%) had bilateral disease (9 metachronous, 1 synchronous). The interval to contralateral breast cancer was 12 to 34 months. On univariate analysis, significant variables included stage of HD, mantle radiation dose, pelvic radiation (protective), and follow-up time. On multivariate analysis, early stage and older age at diagnosis of HD (12 years) were significant predictors of secondary breast cancer. CONCLUSIONS: Women surviving pediatric HD were found to have a 37-fold increase in the risk of breast cancer and a high likelihood of rapidly developing bilateral disease. Early-stage HD and age greater than 12 years at diagnosis of HD were independent risk factors. Higher radiation doses may augment risk, and pelvic radiation may be protective. Breast cancer screening methodology and frequency, plus the role of prophylaxis in patients with unilateral disease, require definition.