Henry S. Kaplan

Non-hodgkin's lymphomas iv. clinicopathologic correlation in 405 cases

An analysis is presented of the histopathologic, clinical, and prognostic features in a series of 405 previously untreated patients with non‐Hodgkins lymphomas referred to Stanford University Medical Center between 1960 and 1971. All biopsies were histologically classified according to the criteria of Rappaport et al. and clinical extent of disease was thoroughly evaluated prior to treatment and staged according to the Ann Arbor Classification. Nodular lymphomas constituted 44% of the group and diffuse lymphomas 56%. Patients under the age of 35 years and those over 60 tended to have diffuse lymphomas. Although 39% of the patients had Stage IV disease at presentation, localized forms (Stage I, IE, II, IIE) were observed in 37%. Localized extralymphatic involvement occurred more often in patients with diffuse than nodular lymphomas (p < 0.001). Systemic symptoms occurred in 24% of patients with diffuse and 17% of those with nodular lymphomas; however, their presence did not adversely affect survival. Mediastinal adenopathy was noted in 24% of diffuse and 18% of nodular lymphomas (P = NS), and mediastinal “skipping” was observed in 20% of diffuse and 40% of nodular lymphomas (p < 0.05). By the criteria used, 81% of evaluable patients (Stages II through IIIE) with nodular lymphoma and 90% of those with diffuse lymphoma had contiguous sites of involvement (p = 0.07). Two frequently observed sites of initial extralymphatic involvement were bone marrow and gastrointestinal; the former was observed more often in advanced lymphocytic lymphomas, whether nodular or diffuse, and the latter in advanced, diffuse lymphomas. Actuarial survival correlated strongly with the histopathologic type of lymphoma; in each cellular category, patients with nodular lymphomas survived significantly longer than those with diffuse lymphomas (p < 0.05). Age at presentation also influenced survival in relation to certain histologic patterns. Patients with diffuse lymphocytic or mixed lymphomas who were less than 40 years of age had a worse prognosis than those over 40 (p = 0.02). In contrast, older patients with nodular lymphocytic and mixed lymphomas fared worse than those under 40 (p < 0.01). Patients with either initial bone marrow or gastrointestinal involvement survived longer if their lymphoma had a nodular pattern. It is concluded that histopathologic classification proposed by Rappaport et al. and the Ann Arbor Staging Classification are both useful guides to the management and prognosis of the non‐Hodgkins lymphomas.

The value of laparotomy and splenectomy in the staging of Hodgkin's disease.

Experience with 65 patients with biopsy‐proven Hodgkins disease who were subjected to laparotomy, splenectomy, liver biopsy, and para‐aortic lymph node biopsy is presented. There were no major complications. Histologic findings in the para‐aortic nodes, liver, and spleen are presented. A general correlation was observed between the occurrence of systemic symptoms and the extent of involvement below the diaphragm. There was no instance of liver involvement without concomitant splenic involvement. It is concluded that laparotomy with splenectomy is a valuable procedure for the more precise delineation of intra‐abdominal sites of involvement in Hodgkins disease prior to the initiation of extended field megavoltage radiation therapy with curative intent.

Female Reproductive Potential after Treatment for Hodgkin's Disease

Abstract The probability of maintaining ovarian function, becoming pregnant, and delivering a normal child is important to young women anticipating successful therapy for Hodgkins disease. In this study, reproductive function was retrospectively examined in 103 women 40 years old or younger who had undergone treatment for Hodgkins 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 Hodgkins disease have become pregnant and delivered phenotypically normal children. (N Engl J Med. 1981; 304:1377–82.)

Occurrence of Non-Hodgkin's Lymphoma after Therapy for Hodgkin's Disease

We studied the clinical and pathological features of six cases of non-Hodgkins lymphoma (diffuse undifferentiated in four cases and diffuse histiocytic in two cases) occuring in patients treated for Hodgkins 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 Hodgkins disease when the diagnosis of non-Hodgkins lymphoma was made. Five of the six patients were among a study group of 579 patients with Hodgkins disease, prospectively followed since diagnosis. At 10 years the actuarial risk of development of non-Hodgkins 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-Hodgkins lymphoma is a second tumor that may occur late in the course of patients treated for Hodgkins disease--particularly in patients who have received both radiation therapy and chemotherapy. Like acute leukemia, non-Hodgkins lymphoma may be another cancer that represents a substantial late risk of combined-modality therapy.

Mantle irradiation in Hodgkin's disease. An analysis of technique, tumor eradication, and complications†

Analysis of the treatment and follow‐up records of 377 Hodgkins 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%), Lhermittes 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.

Central Nervous System Involvement in non-Hodgkin 's Lymphoma: An Analysis of 105 Cases

Records of 105 patients with central nervous system (CNS) lymphoma were analyzed in order to better define the incidence, setting, and management of CNS lymphoma and the role for CNS prophylaxis. Survival was best for patients under 30 years of age treated with whole‐brain irradiation and intrathecal (IT) chemotherapy whose CNS involvement was an isolated event (median survival time, 1.8 years). Survival was worst for patients over 30 years of age whose CNS invasion occurred at a time of progressive systemic lymphoma (median time ten weeks if treated with whole‐brain irradiation with or without IT chemotherapy). The risk of CNS invasion was greatest for those with lymphoblastic lymphoma. Among patients with Stage IIE, III, or IV histiocytic lymphoma, the risk of CNS involvement was greatest for those with progressive or relapsing disease or involvement of the testes, peripheral blood, or epidural space of the spinal cord.

Leukemogenic Activity of Filtrates from Radiation-Induced Lymphoid Tumors of Mice

Cell-free filtrates of x-ray-induced lymphoid tumors of strain C57BL/ Ka mice have elicited, on injection into newborn isologous hosts, a lymphoma incidence of 15 to 19 percent. In control mice of the same subline, the incidence of spontaneous lymphoma is about 1 percent. No leukemogenic activity could be detected in filtrates from thymi harvested at 2 to 32 days following completion of x-ray treatment. Activity was evident at 64 days and was perhaps somewhat greater at 128 days. Serial cell-free passage of filtrates in newborn F1 hybrid mice resulted in a marked increase in lymphoma incidence (69 percent), coupled with a shortening of the median latency. Supplementary x-irradiation failed to enhance the activity of filtrates after neonatal injection.

The Radical Radiotherapy of Regionally Localized Hodgkin's Disease

Hodgkins disease has long been a subject of controversy focused variously on its essential nature (neoplasia vs. infection), its site of origin (unifocal vs. multicentric or systemic), its histologic classification, and its optimal treatment (14) . It is therefore ironic that one of the few aspects concerning which there has been rather wide agreement is its prognosis. The concept of Hodgkins disease as an inexorably fatal condition has taken firm hold, so much so that it is actually defined in one recent textbook on the pathology of lymphoid tumors (21) as a “progressive condition leading inevitably to death.” If one were to accept such a definition at its face value, the advent of a curative form of therapy would presumably require a change in the diagnosis! This hopeless attitude, which seems philosophically linked to the view that the disease makes its first appearance in multicentric or disseminated foci, is responsible for the fact that the established approach to treatment has been palliative (23...

Impaired Lymphocyte Function in Untreated Hodgkin's Disease

Abstract To provide a rapid and quantitative in vitro method for assessing cellular immunoresponsiveness in Hodgkins disease, we measured protein synthesis by lymphocytes stimulated by phytohemagglutinin. The function of peripheral blood lymphocytes from 44 untreated patients with Hodgkins disease was investigated and compared with that of lymphocytes from 37 normal persons. A phytohemagglutinin dose-dependent defect in lymphocyte stimulation was detectable in Hodgkins disease, even in patients with limited disease (Stages I and II). The defect was more pronounced in patients with more extensive disease (Stages III and IV). The lymphocytes of patients in continuous remission for two to eight years after intensive megavoltage radiotherapy also exhibited severely impaired responses. (N Engl J Med 290:181–186, 1974)

Long term effects of radiation of T and B lymphocytes in peripheral blood of patients with Hodgkin's disease.

Total lymphocyte counts, and the percentage of T and B lymphocytes and monocytes in untreated patients with Hodgkins 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 Hodgkins 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.