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Intracranial involvement by Hodgkin disease is rare. We report a pediatric patient with Hodgkin disease who had intracranial disease at presentation. The patient was referred to our hospital with a suspicion of central nervous system tumor. Although the most common presenting feature of intracranial Hodgkin disease is cranial nerve palsy with brain parenchyma being the most common intracranial site of involvement, to our best knowledge no pediatric case of Hodgkin disease presented with isolated cavernous sinus syndrome reported. We report this rare case because of its unusual presentation, in which Hodgkin disease presented with cavernous sinus syndrome. Physicians should consider the probability of Hodgkin disease in children of all ages who present with cavernous sinus syndrome.

Cells from the involved spleens of 25 patients with Hodgkin's disease have been grown in long-term culture and compared with normal spleen macrophage cultures from control cases. The Hodgkin's spleen cell culture contained mono-, bi-, and multi-nucleate giant cells, many closely resembling Sternberg-Reed cells, which were adherent, phagocytically active and neoplastic by the dual criteria of aneuploidy and heterotransplantability. Lysozyme secretion was consistently observed in all Hodgkin's cultures tested. The giant cells possessed both Fc and complement (c3b) receptors, and lacked lymphocyte markers such as (c3b) receptors, surface IgM, and the capacity to form E-rosettes. Binucleate and multinucleate cells, as well as mononuclears, were capable of active DNA synthesis, and binuclear mitotic figures were observed. It is concluded that these cells are the in vitro descendants of the Sternberg-Reed and Hodgkin neoplastic cell population, and that they are derived from macrophages or closely related cells of the mononuclear phagocyte system.

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.

We studied the clinical and pathological features of six cases of non-Hodgkin's lymphoma (diffuse undifferentiated in four cases and diffuse histiocytic in two cases) occuring in patients treated for Hodgkin's disease. All six patients had received both radiation and chemotherapy. Abdominal or gastrointestinal involvement was present in five of the six cases. None of the patients had evidence of Hodgkin's disease when the diagnosis of non-Hodgkin's lymphoma was made. Five of the six patients were among a study group of 579 patients with Hodgkin's disease, prospectively followed since diagnosis. At 10 years the actuarial risk of development of non-Hodgkin's lymphoma in this study group is 4.4 per cent (1.2 to 15.0) (per cent probability with 95 per cent confidence limits) and is similar to that of developing acute leukemia: 2.0 per cent (0.3 to 12.9). Non-Hodgkin's lymphoma is a second tumor that may occur late in the course of patients treated for Hodgkin's disease--particularly in patients who have received both radiation therapy and chemotherapy. Like acute leukemia, non-Hodgkin's lymphoma may be another cancer that represents a substantial late risk of combined-modality therapy.

The proliferative response of T lymphocytes cultured with autologous non-T lymphocytes is known as the autologous mixed lymphocyte reaction (MLR). This reaction can be demonstrated reproducibly in healthy individuals and has been shown to generate specific cytotoxic T cells, as well as T cells that regulate antibody synthesis and cell-mediated immunity. In this study, we demonstrate that the autologous MLR is impaired or absent in most patients with Hodgkin's disease regardless of age, sex, pathologic stage, or histologic classification. In 64 patients, the mean autologous MLR was 3,084+/-1,878 cpm compared to 16,552+/-6,532 in 29 healthy donors. A defect in autologous MLR was observed in newly diagnosed patients before the initiation of therapy, but was also found in patients without evidence of recurrent disease up to 15 yr after treatment. These findings could not be explained by abnormal kinetics or poor viability of stimulator or responder cells. The possibility that suppressor cells are responsible for the reduction of T cell autoreactivity was examined by comparing the autologous MLR of a healthy HLA-identical sibling in the presence and absence of T or non-T cells of an affected sibling. No inhibitory effects were observed. Similarly, substitution of patient plasma for pooled AB serum failed to inhibit the autologous responses of normal donors. Increasing the number of responder T cells in the culture or removing adherent cells from the stimulator population enhanced autoreactivity in some patients, indicating that the defect is not absolute. In two families, T cells of healthy HLA-A, B, and DR-identical siblings of patients responded normally to the non-T cells of their affected siblings, whereas patients' T cells failed to respond both to their own stimulator cells and those of their healthy HLA-identical siblings. These data indicate that the impairment of autologous MLR in some patients is due to a reduction or dysfunction of responder T cell activity and not to a defect of autologous stimulator cells.

One hundred seventy-nine consecutive children with Hodgkin's disease seen at Stanford University Medical Center between the years 1961-1980 have been analyzed for survival and freedom-from-relapse as a function of clinical versus laparotomy staging as well as primary treatment modalities. Of laparotomy-staged patients, 86% are alive at 10 years after primary radiation with chemotherapy reserved for relapse, as compared with 90% managed by planned combined modality therapy (p = 0.62). Patients who were clinically staged and managed with primary radiation have only a 69% survival (p = 0.05). A favorable subgroup of patients with lymphocyte-predominant Hodgkin's disease experienced a low relapse rate regardless of primary treatment modality. Patterns of relapse in clinically staged patients reflect understaging, with most relapses in distant, nonirradiated sites, whereas the less frequent relapses in laparotomy-staged patients usually reflect regional recurrence. It is concluded that laparotomy staging is highly desirable to allow greatest flexibility in optimizing individual therapy. Routine combined modality treatment for all patients would overtreat certain favorable subgroups, who can be managed more conservatively as long as the information derived from surgical staging is available. For young children, in whom bone growth issues are paramount, combined modality treatment using low-dose radiation is recommended. For older children and adolescents, where concerns over chemotherapy-related leukemogenesis and infertility are more important than height considerations, radiation alone may be used for stages I-IIIA with equal overall success.

The phenotypic characteristics of a cloned giant cell line, SU/RH-HD-1, established from the spleen of a patient with Hodgkin's disease were studied. The cells grew slowly, adhered to the culture vessel surface, and had an elongated, irregular shape. After trypsinization, they became spherical and measured 30-100 micron in diameter. Although most cells were mononuclear, binucleated and multinucleated cells could be identified in expanded cultures. The cells phagocytized latex and ink particles and were nonspecific esterase-positive, but they did not secrete lysozyme. They were Epstein-Barr nuclear antigen-negative, and their culture fluid supernatants were devoid of reverse transcriptase activity. Electron microscopy revealed cells with a pronounced smooth endoplasmic reticulum, free ribosomes, some filaments, and mitochondria. Many 0.5- to 1.0-micron invaginations (pits) were seen along the cell membrane. Nucleoli were enlarged and prominent in the very heterochromatic nuclei. The SU/RH-HD-1 cells had 10- to 100-micron-long pseudopodia that were sometimes forked or branching, as well as multiple stress fibers. Electron microscopic appearance was suggestive of that of macrophages. This interpretation of the results was substantiated by monoclonal antibody studies, which revealed that the cells express antigenic determinants distinctive for cells of the monocyte-macrophage lineage and by functional studies demonstrating that the cells are capable of specific antigen presentation to immune T-cells. The SU/RH-HD-1 cells were aneuploid and could be cloned, first in liquid culture by limiting dilution and later in semisolid medium. It was likely that the SU/RH-HD-1 cells were derived from the neoplastic giant cell population in Hodgkin's disease and that they originated from cells of the mononuclear phagocyte-reticulum cell lineage.

Fifty-two patients 60 to 75 years of age were treated for Hodgkin's disease at Stanford University between 1968 and 1980. Adequate staging was defined as including a lymphogram and staging laparotomy for stage I to III and a positive bone marrow or liver biopsy or other evidence of diffuse involvement of extralymphatic tissues for stage IV. Adequate treatment was defined as subtotal lymphoid irradiation for pathologic stages I to IIA; total lymphoid irradiation for stages IIB to IIIA; and chemotherapy with or without irradiation for stages IIIB to IV. Twenty-four patients (46%) had advanced disease (IIIB to IV). Those patients who received appropriate treatment had a median survival of only 39 months. Of the 28 patients with limited disease (I to IIIA), 15 had laparotomy and adequate treatment. Thirteen did not have a laparotomy and 7 were treated with involved-field irradiation. The 5-year survival rate in the laparotomy-staged and adequately treated group was 86%, but in the clinically staged group, only 35% (p = 0.006).

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.

This paper presents a destillation of the authors' current views concerning the optimal management of Hodgkin's disease in relation to site(s) and stage of disease, constitutional symptoms, histopathology, and prior treatment, based on experience with a series of controlled clinical trials under way at Stanford University Medical Center since 1962.

Of 1360 consecutive patients with Hodgkin's disease treated at Stanford University, 1312 patients (96%) had complete remission, but 424 patients had a relapse. Fifty-five patients had relapses 36 months or more after completion of therapy. The actuarial risk of relapse in patients disease-free 3 years after therapy was 12.9%. The occurrence of late relapse was significantly related to stage I disease and nodular sclerosis histologic subtype. Late relapse was detected in 88% of patients by history, physical findings, or chest radiographs. Most patients with stage III and IV disease had late relapses in previously irradiated nodes or extranodally, but patients with stage I and II disease had late relapses primarily in unirradiated nodes. Disease-free survival after salvage therapy for late relapse was similar to that seen after treatment of earlier relapse. Prolonged surveillance of patients for late relapse is necessary after treatment of patients with Hodgkin's disease.

Nineteen children with Hodgkin's disease were immuized with dodecavalent pneumococcal vaccine; the efficacy of vaccination, the duration of response, and the significance of the time of immunization in relation to splenectomy and subsequent irradiation and chemotherapy were investigated. Eight children were immunized before splenectomy, and 11 were immunized after splenectomy, irradiation, and chemotherapy. All children were irradiated, and all but two received chemotherapy with MOPP (nitrogen mustard, vincristine sulfate, procarbazine, and prednisone). Sera were assayed for antibodies to the 12 polysaccharide types in the vaccine. The group of children immunized before splenectomy had a significant antibody response to 67% of the antigens tested, whereas the group immunized after splenectomy responded to 40% of the antigens (P less than 0.0001). The duration of response was variable. Pneumococcal vaccine was more likely to provoke an immunologic response if administered before splenectomy than if administered after splenectomy, irradiation, and chemotherapy; however, the response was not uniform. A response to one antigen did not necessarily imply a response to other antigens. In the absence of a readily available assay to determine a protective antibody response, one cannot rely on the vaccine as the sole means of preventing pneumococcal infections in asplenic children with Hodgkin's disease.

During the past decade at Stanford University Medical Center, in an attempt to protect ovarian function in young female patients irradiated for Hodgkin's disease, oophoropexy has been performed at the time of surgical staging. When pelvic irradiation is administered, a 10-cm thick lead block is used to shield the ovaries in the midline. With this technique, two-thirds of women have retained ovarian function, and nine women who underwent oophoropexy prior to high-dose pelvic irradiation have become pregnant. Six patients have given birth to eight babies. An additional two patients have had therapeutic abortions and one, a spontaneous abortion. The minimum radiation dose to the ovaries was 350 to 400 rads in 39 to 46 days. No abnormalities have been observed in the children; no ectopic pregnancies have occurred.

Between February 12, 1968 and August 17, 1977, 473 consecutive patients with Hodgkin's disease were entered into protocol studies at Stanford University Medical Center (SUMC). 242 of these 473 patients were pathological Stage I or II; 223 patients had disease above the diaphragm and 19 patients had disease confined below the diaphragm. When compared to patients with disease above the diaphragm, patients with Hodgkin's disease below the diaphragm were more frequently male (74% vs. 53%, p = 0.14), were on the average older (40 vs. 27, p less than .005) and more frequently had the histologic subtype of mixed cellularity (32% vs. 12%, p = .04). There was no difference in either survival or relapse-free survival between patients with Hodgkin's disease above the diaphragm and patients with disease below the diaphragm receiving similar treatment plans.

Fifteen pregnant women with Hodgkin's disease were followed. Five patients had irradiation, 1000 to 3000 rad to the neck, mediastinum, or both, during the second or third trimester with normal outcome of pregnancy. One patient had a spontaneous abortion in the first trimester after radiotherapy of 4400 rad to the breast, an estimated fetal dose of 9 rad. One patient who received chlorambucil throughout pregnancy delivered a normal infant. Six patients had therapeutic abortions; one had early induction of labor. In one patient previously treated for supradiaphragmatic Hodgkin's disease, detection of a supradiaphragmatic relapse was delayed because of pregnancy. We recommend abortion for patients who develop Hodgkin's disease early in pregnancy or who have received chemotherapy or irradiation during the first trimester. During the latter half of pregnancy, asymptomatic disease may be closely followed but early delivery is recommended. Supradiaphragmatic, symptomatic disease can be treated with modified irradiation. For subdiaphragmatic, symptomatic, or extranodal disease, single-agent chemotherapy may be preferable. Treatment requires individualization to insure that the patient will be cured and the fetus protected.

Eleven patients suspected of having tumor involving para-aortic lymph nodes were studied with the Varian 6 second whole body CT scanner. All patients had a pedal lymphangiogram; six were abnormal. In three of these six, CT provided clinically important information on the extent of disease which was not detectable by other radiographic studies. CT scanning improved on lymphangiographic interpretation when large bulky nodes were only partially filled and when whole chains of nodes failed to fill. In both situations, the enlarged paraaortic nodes were well delineated on CT. The internal architecture and morphological abnormalities of small well filled nodes were better portrayed by lymphangiography. In the four cases in which lymphangiograms were normal and the one case in which the lymphangiogram showed reactive hyperplasia, the CT scans were normal.

Three hundred eighteen patients with pathologic stage IA and IB, IIA and IIB, and IIIA Hodgkin's disease who entered into Stanford University Medical Center randomized trials comparing radiation therapy alone to radiation therapy plus six cycles of adjuvant chemotherapy were evaluated. Of these, 54 patients had extralymphatic (E) lesions. There were five relapses among these patients (9 percent), not different from the 37 relapses among the remaining 264 patients (14 percent) with Hodgkin's disease confined to the lymphatic system. Actuarial survival and freedom from relapse were not significantly different for patients with or without extralymphatic disease. The survival of patients with extralymphatic disease was similar whether they received radiation therapy alone or radiation therapy plus chemotherapy.

Between 1962 and 1972, 79 previously untreated children, aged 15 years and under, with biopsy-proven Hodgkin's disease were seen, evaluated, and treated at Standford University Medical Center. The 5-year actuarial survival for all patients was 89%; relapse-free survival was 66%. No relapse was seen following aggressive treatment with irradiation and MOPP chemotherapy. In patients who were pathologically staged, no relapse was seen beyond 2 years. Patients with mixed cellularity subtype fared surprisingly well as compared to those with the nodular sclerosing subtype. An analysis of the types of treatment administered and complications of therapy suggests that the major difference between children and adults with Hodgkin's disease is the potential for long-term sequelae resulting from aggressive treatment. In an attempt to maximize the quality of survival, a proposal is made for low-dose radiation and planned MOPP chemotherapy.

From July 1968 through December 1977, 171 previously untreated patients with pathological stage IIIA Hodgkin's disease were evaluated at Stanford University Medical Center. All patients underwent lymphography, staging laparotomy and splenectomy; 86 patients were treated with total lymphoid irradiation (mantle followed by inverted-Y) to 4400 rad. These patients received prophylactic irradiation to the preauricular region (3600 rad/4-5 wk.) if the high cervical lymph nodes were positive; the lung (1500 rad/4-5 wk.) if the ipsilateral pulmonary hilum was positive; and the liver (2200 rad/5-6 wk.) if the spleen was positive. Eighty-five patients were treated with total lymphoid irradiation followed by adjuvant chemotherapy-either nitrogen mustard, vincristine and procarbazine (MOP) or procarbazine, L-phenylalanine mustard, and vinblastine (PAVe). Five-year survival rates were not significantly different in the two groups (86% vs. 89%, P = .4); however, the five-year freedom from relapse rate was significantly better in the combined modality group (66% vs. 86%, P = .0026). Because of the success of MOP in the treatment of patients who had relapses after treatment with irradiation alone, the five-year freedom from second relapse rates in the two groups were not significantly different (85% vs. 88%, P = .8). Analysis of a large number of possible prognostic factors failed to identify any subgroup of patients whose survival was significantly improved by the use of adjuvant chemotherapy, including patients with "anatomic substage III2" (P = .52), clinical stage III (P = .26), unfavorable histology (P = .78), age greater than 39 yr. (P = .44), males (P = .55), and S- (P = .92). The most important factors indicating a benefit from adjuvant chemotherapy on survival were greater than or equal to 5 sites of involvement, including those above and below the diaphragm (P = .15) and extensive splenic involvement (more than four nodules detected in the splenectomy specimen) (P = .15). Possible explanations for these observations, which differ from those of series reported at other institutions, are discussed.

Staging laparotomy, consisting of splenectomy and biopsies of liver, lymph nodes, and bone marrow, is a very useful adjunct in the workup of a patient with Hodgkin's disease. In this series of 400 patients, 1 percent required reoperations for complication, 3.7 percent had major complications, and 14 percent had minor complications from the operation. Further evidence of Hodgkin's disease was discovered in 42 percent of the cases and a change from the clinical to the pathologic stage occurred in 27.5 percent of these cases. The surgeon's task in the treatment of Hodgkin's disease and other malignant diseases is to document and mark the areas of involvement so that accurate and appropriate therapy can be given, while minimizing morbidity and mortality.

Patients with Hodgkin's disease often manifest impairment of cell-mediated immune responses in both in vivo and in vitro tests, as well as a markedly decreased percentage of E rosette-forming (T) lymphocytes in the peripheral blood. This report describes the inhibition of E-rosette formation by normal peripheral blood lymphocytes after incubation with extracts prepared from the spleens of patients with Hodgkin's disease. Such extracts also depressed E-rosette formation by the peripheral blood lymphocytes of patients with Hodgkin's disease after those cells had been restored to normal function by prior incubation in foetal calf serum. Similarly prepared extracts from the spleens of normal donors had no immunodepressive effect. The E-rosette inhibitory substance in the Hodgkin's disease spleen extracts was found to be a complex containing beta-lipoprotein, C-reactive protein, and C1q.

A total of 440 previously untreated patients with Hodgkin's disease have been treated on randomized clinical trials at Stanford University, testing the value of combined modality therapy. A group of 244 patients with stages I, II and III were treated between 1968 with radiotherapy alone or combined with adjuvant MOPP chemotherapy. The adjuvant MOPP significantly improves the initial freedom from relapse (FFR) duration but improvement in survival is only minimal and not yet significant. The ability to induce a second durable remission after initial treatment failure results in freedom from second relapse rates (FF2dR) which more closely parallel survival figures than FFR. Adjuvant MOPP cannot yet be recommended as a routine adjuvant in the radiation maanagement of Hodgkin's disease. A pilot trial of the role of radiation therapy in the chemotherapy management of stage IV patients does not indicate an advantage of the irradiation. Preliminary analyses of new treatment programs in 163 patients with all stages of disease treated between 1974--1977 indicate improved survival and FFR rates, the majority of patients receiving combined modality therapy. Only three patients have died and nine patients have relapsed during the three year period of these new trials.

The evolution of our concepts concerning the fundamental nature and natural history of Hodgkin's disease is reviewed. Recent evidence establishes that it is indeed a malignant neoplasm, albeit a curious one, the giant cells of which display aneuploid karyotypes, often with marker chromosomes indicating their clonal derivation, and the functional and surface marker properties of cells of the mononuclear phagocyte series. The disease tends initially to spread by contiguity from one lymph node chain to others with which direct lymphatic channel communications exist. Essentially all patients, even those with limited disease, have some degree of impairment of cell-mediated immunity, apparently due to inhibition of T-lymphocyte function. Lymphangiography, computed tomography, and laparotomy with splenectomy have greatly improved the accuracy of clinical staging. Total lymphoid megavoltage radiotherapy and/or multidrug combination chemotherapy now permit the eradiction of disease of all stages, resulting in a dramatic improvement in prognosis and an increasing frequency of permanent cure of this once inevitably fatal condition.

181 children with Hodgkin's disease were analyzed with respect to the occurrence of herpes zoster and varicella (HZ-V) infections, possible contributing factors, and prognostic significance. The overall frequency of HZ-V was 34.8%. The occurrence in stage I was significantly lower than in other stages. Previous splenectomy was not found to increase significantly the risk of infection. High-risk patients were those receiving extensive radiotherapy plus combination chemotherapy; 56% developed HZ-V infections in this group. The frequency with extensive field radiotherapy alone was 23.8%. 80% of infections occurred during the first year after completion of treatment. Their occurrence was not a poor prognostic sign in terms of relapse or fatality, even when occurring late. The high frequency of disseminated infection (27%) with its subsequent morbidity should lead toward a better understanding of the immunologic deficiencies in these patients and the possible role of prophylactic measures, in patients undergoing extensive radiotherapy in combination with multiagent chemotherapy.

An analysis of complications of therapy requires long-term and frequent followup. Reported here is a review of 179 consecutive children with Hodgkin's disease from Stanford University Medical Center who were seen, treated, and followed over a 20-year period. Complications of treatment are related to the extent of disease and the aggressiveness of therapy. Severe complications from radiotherapy are associated with high-dose, extended-field treatment in preadolescent children. Severe chemotherapy-associated complications include immunosuppression, sterility, and secondary oncogenesis. As cure rates are increasingly optimistic among children with Hodgkin's disease, successful treatment with minimal morbidity remains our greatest challenge. Therapy programs require continual refinement utilizing assessment of short- and long-term side effects of treatment.

Total lymphocyte counts, and the percentage of T and B lymphocytes and monocytes in untreated patients with Hodgkin's disease were not significantly different from those observed in normal donors. At the completion of radiotherapy, the mean total lymphocyte count of 503/mm3 was 4 SD below the mean for normal controls. Although a group of 26 patients in continuous complete remission from 12 to 111 mo after radiation treatment regained normal total numbers of lymphocytes and monocytes, they exhibited a striking T lymphocytopenia and B lymphocytosis. Concomitantly, there was a significant increase of null (neither T nor B) lymphocytes. The response of peripheral blood lymphocytes to phytohemagglutinin, concanavalin A, and tetanus toxoid before treatment was significantly impaired. 1-10 yr after completion of treatment there seemed to be little or no recovery of these responses. The capacity of peripheral blood lymphocytes to respond to allo-antigens on foreign lymphocytes in vitro (mixed lymphocyte reaction) was normal in nine untreated patients. However, the mixed lymphocyte reaction was markedly impaired during the first 2 yr after treatment. There was a partial and progressive restoration of the mixed lymphocyte reaction during the next 3 yr, and normal responses were observed in patients in continuous complete remission for 5 yr or more. The in vivo response to dinitrochlorobenzene was also examined. 88% (15/17) of patients initially sensitive to dinitrochlorobenzene were anergic to the allergen at the completion of a course of radiotherapy, but nine of these regained their hypersensitivity response during the 1st yr after treatment. This data suggests that there is a sustained alteration in both the number and function of circulating T cells after radiation therapy in patients with Hodgkin's disease which may persist for as long as 10 yr after treatment. The restoration of cell mediated immune functions after radiotherapy is time dependent and its kinetics may differ for various T-cell functions. The implications of these findings with respect to the state of immunological competence after radiotherapy are discussed.

At Stanford University, between 1968 and 1978, 230 patients with pathologic stage I--II Hodgkin's disease were treated on prospective clinical trials with either irradiation alone or irradiation followed by 6 cycles of adjuvant combination chemotherapy. The actuarial survival at 10 yr was 84% for patients in either treatment group. Freedom from relapse at 10 yr was 77% among patients treated with irradiation alone and 84% after treatment with combined modality therapy [p(Gehan) = 0.09]. Freedom from second relapse at 10 yr was 89% and 94%, respectively [p(Gehan) = 0.56]. Several prognostic factors were evaluated in order to identify patients at high risk for relapse or with poor ultimate survival after initial treatment with irradiation alone. Systemic symptoms, histologic subtype, age, and limited extranodal involvement (E-lesions) did not affect the prognosis of patients and failed to identify patients whose survival could be improved by the routine use of combined modality therapy. Patients with large mediastinal masses (mediastinal mass ratio greater than or equal to 1/3) had a significantly poorer freedom from relapse when treated with irradiation alone than when treated initially with combined modality therapy [45% versus 81% at 10 yr, p(Gehan) = 0.03). The 10-yr survival of these patients, however, was not significantly different (84% versus 74%). The implications of these observations on the management of patient with early stage Hodgkin's disease are discussed.

In the case reported here the patient presented with Stage IVB mixed cellularity Hodgkin's disease was complicated by massive splenomegaly, bone marrow infiltration with Hodgkin's disease, and severe pancytopenia. The pancytopenia was reversed by glucocorticosteroid therapy but recurred when steroids were tapered. Reinstitution of steroids resulted in recovery of peripheral blood counts, allowing administration of full-dose combination chemotherapy leading to a complete clinical remission and obviating the need for emergency splenectomy.

We previously reported a patients who developed fulminant pneumococcal sepsis 12 years after successful treatment for Hodgkin's disease, which included splenic irradiation. We have since evaluated splenic size and function in 25 patients who had received splenic irradiation 5 to 16 years previously either for Hodgkin's disease (n = 19) or non-Hodgkin's lymphoma (n = 6). Mean maximum splenic diameter as measured on a 99mTc-sulfur colloid liver-spleen scan was 6.2 cm in the irradiated group and 9.7 cm in a control group (p less than 0.001). The mean percentage of erythrocytes containing pits when observed with interference phase microscopy was 13.0% in the irradiated group, which was significantly different (p less than 0.001) from the levels found in each of the control groups: normal subjects, 0.9%; unstaged and untreated lymphoma patients, 0.6%; and patients after splenectomy, 33.7%. Patients who have had splenic irradiation should be considered at risk of developing overwhelming pneumococcal sepsis.

Analysis of the treatment and follow-up records of 377 Hodgkin's disease patients who received mantle irradiation but no planned chemotherapy reveals an overall supradiaphragmatic relapse rate of 21%. Complications of treatment included symptomatic pulmonary radiation reaction (20%), pericarditis (13%), Lhermitte's sign (15%), and thyroid dysfunction (13%). The addition of a subcarinal block after 2500 to 3500 rads and the use of the thin lung block technique in selected patients have reduced the incidence of pulmonary and pericardial complications to less than 5% without sacrificing local control. Further modifications in technique and treatment policy are discussed in terms of improving the therapeutic ratio.

In order to assess its potential uses in the staging and treatment planning of lymphoma, CT was performed in 27 newly diagnosed, previously untreated patients with Hodgkin's disease or non-Hodgkin's lymphoma; 18 staging laparotomies provided pathologic correlations. CT detected and defined disease in areas not well evaluated by conventional techniques (high para-aortic, mesenteric, splenic hilar nodes). CT interpretation of splenic size and weight correlated well with splenic weight confirmed at pathology. Nodules were identified in several spleens containing foci of lymphoma.

Thyroid function was measured in 119 children, 16 years of age or less, after radiotherapy (XRT) for Hodgkin's disease. Thyroid abnormalities developed in 4 of 24 children (17%) who received 2600 rad or less, and in 74 of 95 children (78%) who received greater than 2600 rad to the cervical area, including the thyroid. The abnormality in all but three (one with hyperthyroidism and two with thyroid nodules) included the development of elevated levels of thyroid stimulating hormone (TSH). Age, sex, and administration of chemotherapy were not significant factors in the development of thyroid dysfunction. All children had lymphangiograms (LAG) and no time relationship was noted between thyroid dysfunction and LAG-XRT interval. The mean interval from radiotherapy to documented thyroid dysfunction was 18 months in the low-dose group and 31 months in the high-dose group, with most patients becoming abnormal within 3 to 5 years. Of interest was a spontaneous return of TSH to within normal limits in 20 children and substantial improvement in another 7. This study confirms the occurrence of dose-related occult hypothyroidism in children following external irradiation of the neck.

One hundred twenty-one patients with newly diagnosed, previously untreated Hodgkin disease underwent abdominal and pelvic computed tomographic (CT) scanning and bipedal lymphography. These studies were followed by staging laparotomy, which included biopsy of the liver, retroperitoneal and mesenteric lymph nodes, and splenectomy. Correlation of the results of the imaging studies with the histopathologic diagnoses revealed a small--but significant--increased accuracy of lymphography compared with CT in assessing the retroperitoneal lymph nodes. The theoretical advantages of CT scanning in detecting lymphomatous deposits in lymph nodes about the celiac axis and the mesentery, or in the liver and spleen, were not confirmed. In part this was due to the relative incidence and the small size of individual lesions at these sites in patients with Hodgkin disease at the time of initial diagnosis and staging.

The probability of maintaining ovarian function, becoming pregnant, and delivering a normal child is important to young women anticipating successful therapy for Hodgkin's disease. In this study, reproductive function was retrospectively examined in 103 women 40 years old or younger who had undergone treatment for Hodgkin's disease with total-lymphoid irradiation (TLI) alone, combination chemotherapy, or combined TLI and chemotherapy. Infertility was directly related to gonadal exposure to therapy and to age at treatment. Twenty women became pregnant after receiving total-nodal irradiation or combination chemotherapy or both. No fetal wastage occurred, and no birth defects were seen in the 24 infants born to these women. Even after intensive treatment programs, women successfully treated for Hodgkin's disease have become pregnant and delivered phenotypically normal children.

Two hundred forty-three consecutive patients with Hodgkin's disease who relapsed after an initial course of treatment at the Stanford University Division of Radiation Therapy underwent subsequent systematic evaluation and retreatment. An analysis of the influence of numerous parameters, including sex, histopathology, original stage, relapse site, and original and second therapy, on actuarial survival and on relapse-free survival was undertaken. Most relapses (87%) occurred within 3 years of the initial treatment course. The 5-year relapse-free survival measured from the time of second treatment increased from 14% before to 39% after the introduction of multiple agent chemotherapy (MOPP) for relapsing disease. Patients treated with MOPP chemotherapy for nodal relapses showed increased subsequent relapse-free survival (61%) when compared with patients treated only with radiotherapy for nodal relapses. Based on the combined findings of this analysis, recommendations are made regarding the management of patients with Hodgkin's disease who have suffered a relapse.

Three patients (two female and one male), who had received mantle irradiation for Hodgkin's disease eight, ten, and twelve years previously, developed papillary thyroid carcinoma. The radiation doses to the necks overlying the site of thyroid cancers were 3000, 4000, and 4100 rads, respectively. It has been stated that there is no risk of developing thyroid cancer with such high doses of external irradiation but apparently this complication will be encountered in a small number of patients.

The pretreatment roentgenographic evaluation of 105 consecutive patients less than 16 years of age with Hodgkin's disease was reviewed. The patients were divided into groups aged 1-10 years (37%) and 11-15 years (63%). All patients had chest roentgenograms, of which 36% were abnormal in the younger group and 77% abnormal in the older group. Full-lung tomography was helpful only when the chest film was abnormal or equivocal. Foot lymphography was performed in 103 patients with 20% positive for Hodgkin's disease. Lymphographic-histologic correlation was 98% in the 62 patients undergoing laparotomy. Routine skeletal surveys, as well as examinations of the urinary tract and gastrointestinal tract, were not rewarding.

This is a summary report of the Stanford randomized clinical trials of the management of Hodgkin's disease, initiated in 1962. There have been four major changes in the treatment protocols during this 22 year period. Between 1962-67, 132 patients with CS I, II and III disease were enrolled on various radiation trials. Between 1968-74, 367 patients were enrolled on studies primarily evaluating the role of adjuvant MOPP chemotherapy. Between 1974-80, variations in the chemotherapy regimen and the sequences of the combined modality programs were studied. The current studies, initiated in 1980, have enrolled 102 patients, and test a new mild adjuvant chemotherapy, VBM, (vinblastine, bleomycin and methotrexate) and utilizes ABVD in combined modality and alternating regimens. During the two decades of these studies, involving more than 800 patients, the initial remission rate and duration and the survival of all patients treated have progressively improved.