Nodular histiocytic lymphoma, emphasizing results of stage I disease treated by radiotherapy. A report of the Japan Lymphoma Radiation Therapy Study Group (JLRTG)

The records of 49 patients with nodular histiocytic lymphomas (NH) who were treated from 1972 to 1985 in hospitals belonging to the JLRTG were retrospectively reviewed. The actuarial survival rate and relapse-free survival rate of all patients after 5 years were 55.0 and 51.3%, respectively. Twenty-one patients with stage I disease had a significantly better survival rate than did 12 patients with stage II disease (P less than 0.01). Without combination chemotherapy, all 15 patients with stage I NH treated by radiation therapy were in complete remission, and 14 of them remained alive and well. Among these 15 patients, no difference in relapse was observed between patients who received involved field irradiation (1 of 6) and those who received extended field irradiation (2 of 9). Patients with stage II or more NH should be treated with intensive chemotherapy and radiotherapy, as are patients with diffuse histiocytic lymphoma (DH). However, involved field radiotherapy with careful follow-up observation may be the treatment of choice for patients with stage I NH, provided their tumors are not bulky.     

Testicular seminoma. Results of the Yale University experience, 1964-1984

Eighty-three testicular seminoma patients were treated with radiation therapy from 1964 through 1984. Seventy-nine (95%) of the 83 patients had early disease that included 61 Stage I, 15 Stage IIA (pelvic or paraaortic lymph node involvement less than or equal to 5 cm), and 3 Stage IIB (pelvic or paraaortic lymph node involvement greater than 5 cm) patients. The 15-year actuarial survival for this group of Stage I and II patients was 95% (+/- 5%). Stage I patients were treated with a mean paraaortic/pelvic dose of 2924 cGy and only one patient developed recurrent disease. This recurrence was at the margin of the radiation field and probably represents a marginal miss. The Stage IIA patients were treated with slightly higher doses (mean, 3335 cGY) to the paraaortic/pelvic region and there were no recurrences. The three Stage IIB patients received tumor doses of 3245 cGy, 4090 cGy, and 4500 cGy, respectively, and there were no recurrences. Low dose prophylactic mediastinal and supraclavicular irradiation (mean, 2320 cGy) was used in 17 (94%) of the 18 Stage II patients and there were no mediastinal or supraclavicular recurrences. Four patients presented with advanced disease (one Stage III, three Stage IV) and the only disease-free survivor was treated with cisplatinum-based combination chemotherapy and radiation therapy. Three patients developed minor complications from the radiation therapy: one patient had persistent scrotal and leg edema and two patients treated with prophylactic mediastinal irradiation had chronic low leukocyte counts. Two of the 79 Stage I and II patients developed a second malignancy: one had bronchogenic carcinoma at the margin of a mediastinal field, and one had diffuse histiocytic lymphoma both in and out of the radiation therapy fields. The 15-year actuarial probability of developing a second malignancy was 3.3%. Radiation therapy after operation is a successful treatment option for most patients with Stage I and II seminoma.     

Extended field irradiation in the treatment of patients with cervical carcinoma involving biopsy proven para-aortic nodes

Between November 1974 and November 1979, 15 patients with cervical carcinoma were treated with extended field irradiation for biopsy proven para-aortic lymph node (PALN) metastases. Treatment consisted of pelvic and para-aortic irradiation at a daily dose of 180 to 200 rad per day, delivering 4000 to 6000 rad to the pelvis and 4000 to 5000 rad to the para-aortic nodes. One or two intracavitary insertions each delivered an additional 2000 to 3500 rad to point A. The three year actual disease free survival for the 12 patients with Stage I and II disease was 50%. All six survivors remain alive without evidence of disease for 41 to 93 months, with a mean and median follow-up of 65 months. All patients dying of disease did so within 26 months, all but one dying within one year. All patients with Stage III and IV are dead of disease. Pelvic disease was controlled in 11 of 12 patients with Stage I or II disease, and in one of the three patients with Stage III and IV disease. There was no clinical indication of failure in the PALN in any patient. Nine patients failed with disseminated disease. Three of 15 patients (20%) suffered serious treatment-related complications. Two of these were attributed to the pelvic irradiation, with one patient requiring a colostomy. Thus, complications resulting from the extended field irradiation were seen in only one patient (6.7%). There was no treatment related mortality. Extended field irradiation can lead to a 50% survival in patients with Stage I and II cervical carcinoma and PALN metastases, a survival comparable to that reported in patients with involved pelvic nodes.     

Malignant lymphoma of the uterine cervix

Three patients with primary malignant lymphoma of the uterine cervix are reported and the literature is reviewed. All of the patients in the current cases presented with irregular menstruation. Two patients were found to have diffuse histiocytic lymphoma, and one patient had diffuse mixed lymphoma. Histologic diagnosis was confirmed by outside expert pathologists in all cases. In spite of locally advanced disease according to FIGO's classification (Stage IVA-2 and Stage IIB-1), they responded well to external irradiation, and had control of tumor within the pelvis. All are alive at 13, 7, and 3 years, respectively, after the completion of irradiation. One patient developed disseminated disease 4.25 years after the completion of external irradiation, but was successfully treated with combination chemotherapy for 2 years, and is alive at 6.75 years after the completion of chemotherapy without disease. Review of the other 21 cases reported in the literature reveals that 14 were free of disease after treatment. The importance of distinguishing malignant lymphoma from undifferentiated carcinoma or sarcoma is emphasized since cervical malignant lymphoma can be successfully treated with irradiation in spite of locally advanced disease.     

Combined modality therapy for stage I-II large cell lymphoma

Between January 1978 and December 1986, 94 patients with Stage I-II large cell lymphoma were evaluated at Stanford University Medical Center and treated with a combination of chemotherapy (CTX) and irradiation (XRT). The predominant histology was diffuse large cell (78), followed by immunoblastic (7), follicular large cell (6), and diffuse mixed small and large cell lymphoma (3). Twenty-three patients had Stage I and 71 had Stage II disease. Fifty-one had extranodal involvement (13 IE, 38 IIE), and 11 had B symptoms (2 IB, 9 IIB). Lymphoma was supradiaphragmatic in 58 patients, infradiaphragmatic in 21, and only in extranodal sites in 15. Patients received either involved (81) or extended (13) field XRT with a median dose of 40 Gy and combination CTX with 2 to 9 cycles (median 6) of either CHOP (68), M-BACOD (8), C-MOPP (8), MACOP-B (4), or other (6). Seventy-two patients remain with no evidence of disease, 21 are dead with disease, and one suffered an intercurrent death. Among the 19 patients who relapsed, there were six failures within the XRT field only, two within and outside the XRT field, and 11 outside of the XRT fields only. Actuarial survival and freedom from relapse (FFR) for the entire population were 74% and 72% at 5-years, respectively (33 month median follow-up). Stage I patients achieved 81% survival and 78% FFR, and Stage II patients had 72% survival and 70% FFR. In univariate and multivariate analyses, a favorable outcome was associated with the CTX-XRT-CTX sequence of therapy (p = 0.001), low LDH (p = 0.01), and small tumor bulk (p = 0.04). There were no relapses or deaths among the 21 patients receiving the "sandwich" sequence (CTX-XRT-CTX) of therapy. This series may serve as a comparison with single modality treatment programs for localized large cell lymphoma using either XRT or CTX alone.     

Results of radiotherapy in control of stage I and II non-Hodgkin's lymphoma.

We retrospectively analyzed 114 patients with non-Hodgkin's lymphoma, clinical stages I and II, classified by the criteria of Rappaport and treated by radiotherapy alone. Of 84 patients classifiable, one-third were nodular and two-thirds diffuse lymphomas. Berkson-Gage actuarial and relapse-free survivals were determined for these two groups and for subgroups stratified by histology, stage, and by presence or absence of extranodal disease. Five year relapse-free and overall survivals were 83% and 100%, respectively, for the nodular group and 37% and 59% for the diffuse group. Extranodal involvement was less frequent in the nodular (19%) than in the diffuse (52%) group, where it was associated with Stage IE disease and increased relapse-free and actuarial survival. Histopathological subtype in the diffuse group (histiocytic versus combined lymphocytic poorly differentiated and mixed lymphocytic-histiocytic) did not influence survival. Extranodal involvement and stage I disease were associated with better survival in the diffuse histiocytic group. Successful radiotherapy for all stages of disease, all histologies, was not correlated with extended versus involved fields, and 89% of the relapses in the entire series were by wide dissemination.     

Gastrointestinal lymphoma in Chinese: a retrospective analysis

Eighty-four Chinese patients with gastrointestinal lymphoma were reviewed. There were 45 gastric and 39 intestinal lymphomas. The median age was 45 years and the male to female ratio 1.14:1. Diffuse histiocytic (60 per cent) or diffuse large cell (53.5 per cent) lymphoma comprised a majority of the cases. A high incidence of gastrointestinal bleeding at presentation was observed in our patients. According to a modified staging classification, a larger proportion of patients with intestinal lymphoma had advanced disease (Stage III and IV) than those with gastric lymphoma (82 per cent versus 55 per cent, p less than 0.02) and gastric lymphoma carried a better prognosis. The modified staging classification used in this study appeared to stratify better the patients into 2 sub-groups of localized (Stage I and II) and advanced (Stage III and IV) disease, which correlated very well with the prognosis. Good treatment results were obtained following intensive therapy in our patients with localized disease (Stage I and II). The poorer treatment results of patients with advanced disease (Stage III and IV) call for better chemotherapy regimens and earlier diagnosis. Surgical resection of the primary gastrointestinal lesion is recommended to prevent haemorrhage and perforation following chemotherapy, which occurred in 38 per cent of our patients whose gastrointestinal lesions were not resected.     

Differences in age and sex distributions among patients with non-Hodgkin's lymphoma.

The records of a group of 337 adult patients with non-Hodgkin's lymphoma seen at the Stanford University Medical Center, Division of Oncology were examined for relationships between stage and histopathological classification and simple demographic characteristics. Patients with Stages I and II of disease and diffuse varieties of lymphoma were found to be younger than patients in other categories. An excess of male patients was noted particularly in younger patients with diffuse lymphoma and Stages I and II of disease. Male patients with Stages I and II disease were noted to be bimodally distributed with respect to age, with peak number of patients in the fourth and sixth decades. This was particularly apparent among patients with diffuse histiocytic lymphoma. The implications of these findings are discussed.     

Prognostic factors in non-Hodgkin's lymphoma

The results obtained with the various types of treatment in non-Hodgkin's lymphoma are reviewed and the data from the recent EORTC trials are summarized. In patients with Stage I follicular histology, regional radiotherapy (RT) alone gives excellent results. The long-term relapse-free survival (RFS) is high and relapsing patients can be rescued by aggressive combination chemotherapy; initial chemotherapy with CVP improves RFS but not total survival (TS). In patients with Stage I diffuse histology, the long-term survival is less satisfactory. CVP chemotherapy does not improve either RFS or TS; therefore if adjuvant chemotherapy is justified, it should be more aggressive than CVP. In patients with Stage II follicular type, regional radiotherapy alone gives good results. The addition of abdominal bath irradiation to regional RT increases RFS but not TS. After relapse, patients can be rescued by combination chemotherapy. In patients with Stage II diffuse histology, extended RT followed by CVP gives poor results and RT should be combined with more aggressive combination CT; the preliminary results of an integrated alternating regimen being excellent. In patients with Stage III and IV follicular type, the 8 year TS of patients treated with combination CT regimen (CHVP) followed by localized irradiation is approximately 55%, however the indications for the various types of treatment are still unclear. In patients with diffuse Stage III and IV, the results obtained with a combination CT regimen (CHVP) are still unsatisfactory, but are better in patients treated by a more aggressive CT regimen (CHVP-Bleo-VCR). Therefore aggressive CT associated with localized irradiation appears to be the best treatment. Further research should aim to identify the optimal combination CT regimen. In patients with high grade lymphomas who have relapsed the use of bone marrow autografts will be investigated. The present data show that besides histological type and age, the main prognostic factor is total tumor body burden as assessed by clinical stage, number of involved lymph node areas, and bulk of the disease. The study of the biological characteristics of the disease may provide more powerful prognostic indicators.     

Histiocytic lymphoma presenting with portal hypertension and bleeding esophageal varices: a case report

An unusual case of histiocytic lymphoma presenting with portal hypertension and bleeding esophageal varices is reported. Laparotomy revealed bulky nodal disease in the portahepatis compressing the portal vein, common bile duct, hepatic artery, and cystic duct. Liver was free of tumor, and there was no evidence of extra-abdominal disease. Radiation therapy to the right upper quadrant of the abdomen produced a transient remission for one month, followed by relapse in mediastinum and both lung hilae.     

Rosette and blastogenesis inhibition by plasma from Hodgkin's disease and other malignancies. Positive correlation in State I and II Hodgkin's disease

The simultaneous presence of both rosette- and mitogen-induced blastogenesis inhibitors was measured in the plasma from 29 patients with active Hodgkin's disease, 21 patients with advanced lung cancer, nine patients with diffuse histiocytic lymphoma, 25 patients with non-Hodgkin's lymphoma, and 17 patients with a variety of solid tumors. Only patients with active Hodgkin's disease consistently demonstrated factors which interfered with both rosetting and mitogenesis when normal allogeneic cells were utilized. While a similar proportion of patients with early and late Hodgkin's disease possessed plasma which could inhibit both tests, a significant correlation between these tests was observed only in Stage I and II disease. Varying degrees of inhibition of these tests was also observed when plasmas from patients with other malignancies were tested. Both lung cancer and histiocytic lymphoma plasma contained a factor which was capable of significantly inhibiting in the rosette assay when compared to normal human serum. Plasma from these patients also demonstrated inhibition of blastogenesis, but unlike Hodgkin's disease, no correlation between these activities could be demonstrated. Neither patients with diffuse or nodular lymphocytic lymphoma nor patients with solid tumors had significant plasma inhibition in either assay.     

Localized non-Hodgkin's lymphoma of the breast

Chart review identified 18 patients seen at Memorial Hospital from 1970 to 1984 with primary non-Hodgkin's lymphoma localized to the breast. Sixteen involved the breast alone (Stage IE), whereas two also involved ipsilateral axillary lymph nodes (Stage IIE). None had B symptoms. Histologic subtypes included 11 diffuse histiocytic, 4 diffuse poorly differentiated, 2 diffuse mixed and one nodular mixed. Thirteen patients (72%) are alive with 55 months median follow-up (11 months-14 years). Three patients died with recurrent disease at less than 2 years, one recurred at 4 years and died 6 years after diagnosis, and one died at 30 months without clinical evidence of disease. Seven (39%) have remained continuously disease-free (11 months-11 years; median, 54 months). Of the clinical Stage I patients, 1 of 3 treated with mastectomy alone recurred in the scar, whereas 1 of 12 treated with irradiation alone recurred locally. Thus, radiation therapy alone achieved good local control, although distant relapses remain a problem in these clinically staged patients. Overall, the outcome of clinically localized non-Hodgkin's lymphoma of the breast is similar to that for localized lymphoma in other sites.     

Radiation therapy treatment of stage I and II extranodal non-Hodgkin's lymphoma of the head and neck

We have reviewed the records of 76 patients with Stage I or II extranodal non-Hodgkin's lymphoma who were referred to the Division of Radiation Oncology, Mallinckrodt Institute of Radiology, during the years 1964 through 1974. The histologic slides were reviewed in the 67 cases in which they were available. Forty-three percent of Ann Arbor Stage I and II patients relapsed after primary radiation treatment.Seventy-three percent of these failed in sites distant from the irradiated volume. Failures in the treated volume were infrequent (7%) except in those patients presenting with primary lesions of the brain (4/5). Those patients presenting with lesions of Waldeyer's ring experienced a decrease in survival with increasing tumor size. Because of the high rate of failure in distant sites with tumors in the lingual and palatine tonsils, we are recommending the study of adjuvant chemotherapy in these cases, after primary radiation treatment.     

CVP-remission-maintenance in stage I or II non-Hodgkin's lymphomas: preliminary results of a randomized study.

The effect of adjuvant combination chemotherapy when given to non-laparotomized patients in remission after radiotherapy in stage I or II non-Hodgkin's lymphoma was studied in a prospective randomized multicenter study. Locally extended field radiotherapy was given to a target absorbed dose of 40 Gy in 20 fractions. Fifty-five patients who were in complete remission 6 weeks after conclusion of radiotherapy were randomized to either no further therapy or to 9 cycles of CVP (cyclophosphamide + vincristine + prednisolone). The relapse-free survival at 30 months was 41% for patients without and 86% for patients with adjuvant chemotherapy (p = 0.02). The survival was the same for both treatment arms, being 90% at 30 months. Fifteen patients have relapsed, 14 of them with extensions and 1 with a recurrence within the radiation target volume. Analysis of subgroups showed that adjuvant chemotherapy in the present series significantly prolonged the relapse-free survival in diffuse histiocytic lymphoma.     

Radiation therapy of Waldeyer's ring lymphoma

Forty-nine patients with biopsy-proven Waldeyer's ring lymphoma were treated with radiation therapy between 1968 and 1979; 45 to 50 Gy were given to Waldeyer's ring structures with a 5- to 10-Gy boost to the primary site. Uninvolved low cervical nodes received 40 to 50 Gy. Chemotherapy was reserved for treatment failures. Actuarial 5-year survival was 53%, disease-free survival was 48%, and local control was 98%. Patients with Stage I disease fared better than patients with Stage II disease, and unilateral adenopathy conferred a better prognosis than bilateral adenopathy. When classified by the Rappaport system, nodular lymphomas had a better prognosis than diffuse lymphomas, and of the diffuse lymphomas, histiocytic lymphoma was a more lethal disease than lymphocytic lymphoma. Patients with diffuse undifferentiated lymphomas in the Rappaport system, or high-grade lymphomas in the Working Formulation, fared poorly. Most relapses were systemic, and actuarial 5-year survival after salvage was only 20%. A logical approach to the treatment of this disease can be based on these prognostic features.     

Survival of patients with localized histiocytic lymphoma.

Twenty of 65 patients with diffuse histiocytic lymphoma were identified by staging laparotomy as being in pathologic stages (PS) I, I(E), II, II(E). Six of the 20 patients were treated with total nodal, 10 with extended mantle, and four with involved-field radiotherapy. The survival rate and relapse-free survival at five years were 71% and 78%, respectively. All relapses occurred within the first year and were confined to patients with PS II disease and four or more sites of involvement. Accurate pathologic staging identifies patients who are potentially curable with radiotherapy. Further studies are required to determine the treatment necessary to achieve cure in PS II patients with more than four sites of involvement.     

Improved survival following combined radiation therapy and chemotherapy for unfavorable prognosis stage I-II non-Hodgkin's lymphomas

A retrospective analysis of 144 patients with stage I-II non-Hodgkin's lymphoma (NHL) treated between June 1968 and December 1980 was performed. Patients were staged by bone marrow biopsy, chest radiography, blood chemistries, and either bipedal lymphangiography, computerized axial tomography, or surgical exploration of the abdomen. Patients were subclassified by extent of disease; minimal disease was defined as less than 10 cm and involved one or two contiguous sites, while patients with disease exceeding these limitations were considered to have extended stage I-II disease. Treatment consisted of radiation therapy (RT) alone in 74 patients and 70 patients were treated with chemotherapy with or without RT. Combination chemotherapy in patients with diffuse undifferentiated (DU) or diffuse histiocytic (DH) lymphoma resulted in a significantly higher 6-year survival as compared to patients treated with RT alone. For minimal disease DU/DH patients, the 6-year survival with chemotherapy +/- RT was 96% as compared to 61% with RT alone (P = .03). For extended disease DU/DH patients the 6-year survival with chemotherapy +/- RT was 56% as compared with 18% with RT alone (P = .003). This survival advantage from the initial use of chemotherapy was not seen in any of the other histologic subgroups.     

Malignant lymphoma of the thyroid gland

We reviewed the records of 20 patients with malignant lymphoma presenting in the thyroid gland who were seen at The Princess Margaret Hospital between 1958 and 1977. The disease predominantly affected females of an older age group and clinically was characterized by a rapidly enlarging neck mass associated with obstructive symptoms. Seventeen of the patients (85 %) had histiocytic lymphoma. Eighteen patients (90 %) either were clinically Stage IE or Stage HE disease (Ann Arbor classification). All patients were treated with radiotherapy. Adjuvant chemotherapy was used in only three patients. Overall survival rate at 5 years was 35%. All recurrences but one occurred within 6 months. Survival rate at 5 years from time of recurrence was 7%. Postmortem examination of eight patients showed widespread lymphoma in all; the lung, G.I. tract, liver and kidney were the most frequently affected distant sites. The long term survival group (A) was composed of three patients with Stage I and four with Stage II disease. The failure group (B) included live patients with Stage I, six with Stage II and two with Stage IV disease. Group A patients had “localized” disease and all but two patients received radiation treatment to the neck and mediastinum. Group B patients with Stage I disease received radiation to the neck only and none survived 5 years. All six Stage II patients in group B (five patients with “extensive” disease and one with “localized” disease) received radiation to the neck only; none survived 5 years. We conclude that radiotherapy to the neck and mediastinum is an adequate form of treatment in patients with lymphoma of the thyroid gland with Stage I or localized Stage II disease. More advanced disease should be managed with radiation and chemotherapy.     

Involved field radiotherapy or chemotherapy in the management of stage I nodal intermediate grade non-Hodgkin's lymphoma

Early stage intermediate grade non-Hodgkin's lymphoma (NHL) is frequently treated with chemotherapy alone or in conjunction with radiotherapy. We have managed clinical Stage I nodal, intermediate grade NHL with involved field radiotherapy alone for non-bulky (less than 5 cm post-surgery) disease or combination chemotherapy alone for more bulky disease. Forty-three patients were treated between 1978 and 1989. Of the 30 patients with non-bulky disease treated with radiotherapy, 29 (97%) achieved complete remission (CR). Thirteen (42%) patients relapsed after radiotherapy and ten of these achieved a further CR (durable in eight) following salvage chemotherapy. Eleven patients with bulky disease received combination chemotherapy with nine (82%) attaining CR (durable in eight). Two patients with bulky disease received radiotherapy-both achieved CR, but have relapsed and died of lymphoma. Overall actuarial 5 year survival for the total group is 77% with a median follow-up of 30 months (range 3-119 months). The 5 year actuarial survival for the 30 patients with non-bulky disease treated with radiotherapy is 86% at a median follow-up of 39 months (range 8-119 months). The 4 year actuarial survival of the 11 patients treated with chemotherapy is 60% with a median follow-up of 25 months (range 3-55 months). We conclude that involved field radiotherapy alone is efficacious for clinical stage I patients with non-bulky nodal intermediate grade NHL and that patients relapsing after radiotherapy are adequately salvaged by chemotherapy. Patients with bulky disease have an inferior survival and should receive combination chemotherapy.     

Long-term survival of patients with localized diffuse histiocytic lymphoma

From January 1970 to March 1981, localized diffuse histiocytic lymphoma (DHL) was identified in 31 patients by exploratory laparotomy and splenectomy (pathologic stage I, 17 patients; pathologic stage II, 14 patients) at the University of Chicago. The median follow-up time was 72 months. All patients were previously untreated and received radiation therapy as their primary treatment modality. Chemotherapy was administered only at the time of relapse. All but two patients achieved a complete remission (CR) with radiation therapy. The actuarial disease-free survival for patients with stage I disease is 94% at 5 years and 72% at 10 years. For stage II disease, the disease-free survival is 56% at 5 years and 31% at 10 years. The difference in the disease-free survival between stage I and II is statistically significant (P = .02). The survival at 10 years is 70% for stage I disease and 46% for stage II disease. Five patients had documented relapses (four had stage II disease). Only two of those who relapsed achieved a second CR with salvage chemotherapy. Our data show an excellent outcome in patients with pathologic stage I disease, indicating that a high percentage of these cases can be cured with radiotherapy alone. Patients with clinical stage II disease might be served better with chemotherapy.