Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03.

PURPOSE: To assess the efficacy of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy in patients with muscle-invading bladder cancer treated with selective bladder preservation. PATIENTS AND METHODS: One hundred twenty-three eligible patients with tumor, node, metastasis system clinical stage T2 to T4aNXMO bladder cancer were randomized to receive (arm 1, n=61 ) two cycles of MCV before 39.6-Gy pelvic irradiation with concurrent cisplatin 100 mg/m2 for two courses 3 weeks apart. Patients assigned to arm 2 (n=62) did not receive MCV before concurrent cisplatin and radiation therapy. Tumor response was scored as a clinical complete response (CR) when the cystoscopic tumor-site biopsy and urine cytology results were negative. The CR patients were treated with an additional 25.2 Gy to a total of 64.8 Gy and one additional dose of cisplatin. Those with less than a CR underwent cystectomy. The median follow-up of all patients who survived is 60 months. RESULTS: Seventy-four percent of the patients completed the protocol with, at most, minor deviations; 67% on arm 1 and 81% on arm 2. The actuarial 5-year overall survival rate was 49%; 48% in arm 1 and 49% in arm 2. Thirty-five percent of the patients had evidence of distant metastases at 5 years; 33% in arm 1 and 39% in arm 2. The 5-year survival rate with a functioning bladder was 38%, 36% in arm 1 and 40% in arm 2. None of these differences are statistically significant. CONCLUSION: Two cycles of MCV neoadjuvant chemotherapy were not shown to increase the rate of CR over that achieved with our standard induction therapy or to increase freedom from metastatic disease. There was no impact on 5-year overall survival.

Xanthoma disseminatum, a rare cause of diabetes insipidus.

A 33-yr-old male developed typical symptoms and findings of diabetes insipidus. A computed tomographic scan of the hypothalamus/pituitary was normal, and he was diagnosed as having idiopathic diabetes insipidus. At age 38 yr, he developed two 1- to 2-mm reddish papules on his skin. Biopsy revealed infiltrative histiocytes laden with lipid. Bone scans and bone x-rays showed widespread osteolytic and osteoblastic disease. The disease was diagnosed as a rare disseminated histiocytic disorder, xanthoma disseminatum. A classification of histiocytic disease is presented.

A phase I/II study to evaluate accelerated fractionation via concomitant boost for squamous, adeno, and large cell carcinoma of the lung: report of Radiation Therapy Oncology Group 84-07.

PURPOSE: A Phase I/II trial was conducted by the Radiation Therapy Oncology Group from 1984 to 1989 for 355 evaluable patients with non-small-cell lung cancer to assess tolerance to and efficacy of accelerated fractionation irradiation via concomitant boost. METHODS AND MATERIALS: "Large" fields (primary tumor and locoregional lymph nodes) received 1.8 Gy followed after 4 to 6 hr by 1.8 Gy two to three times weekly to reduced "boost" fields (primary and involved nodes only). The total doses escalated during the study and started with 63 Gy in 5 weeks (45 Gy "large" field and 18 Gy "boost") for 61 patients. After follow-up for ongoing toxicity assessment, the total dose was increased to 70.2 Gy in 5.5 weeks (50.4 Gy "large" field and 19.8 Gy "boost") for the next 180 patients. The last 114 patients received 70.2 Gy in 5 weeks (45 Gy "large" field and 25.2 Gy "boost"). RESULTS: Pretreatment patient characteristics were well balanced between the three treatment arms. Grade 3 acute toxicity was 7% for the 63 Gy arm; it was 14% and 17% for the two 70 Gy arms. Grade 4 or greater acute toxicities (esophagitis and pneumonitis) were 2 to 3% for all three arms. Late toxicities ranged between 5 and 9% (> or = Grade 3) and 0 to 2% (> or = Grade 4), not statistically different among the three arms. There was no difference between the three regimens in median survival (9 months) or 1-year survival (39 to 44%). However, the 2-year survivals ranged from 16% (63 Gy) to 21% ("shortened" 70.2 Gy). Among 176 patients who had the same criteria as Cancer and Leukemia Group B protocol 84-33 (American Joint Committee on Cancer Staging, 1984, Stage III; Karnofsky performance status 70 to 100; < 6% weight loss), the 2-year survival rates ranged from 18 to 22%. CONCLUSION: Concomitant boost accelerated fractionation irradiation regimens for non-small cell lung cancer may offer improved long-term survival without enhanced late toxicity. While acute toxicity is somewhat increased, further refinement of the relationship of "large" to "boost" field doses may improve the therapeutic ratio. Further Phase I/II testing seems justified and necessary, before concomitant boost accelerated fractionation irradiation is tested in Phase III trials for NSCLC.

Interfollicular Hodgkin's disease.

An unusual pattern of focal involvement of lymph nodes by Hodgkin's disease is described which we have named "interfollicular Hodgkin's disease." It is characterized by florid reactive follicular hyperplasia which overshadows involvement of the interfollicular zones by Hodgkin's disease. The pattern can be mistakenly diagnosed as one of the many causes of reactive follicular hyperplasia. The seven cases studied did not appear to differ clinically from other more recognizable forms of Hodgkin's disease. The importance of this pattern of lymph node involvement by Hodgkin's disease rests on its misdiagnosis as a benign lesion and not on any unusual clinical features.

Retroperitoneal bronchogenic cyst masquerading clinically and radiologically as a phaeochromocytoma.

Bronchogenic cysts are relatively rare congenital anomalies that represent malformations of the embryonic foregut and are morphologically expressed as maldevelopments of the respiratory system. Anatomically, they can be positioned at any location along the central axis of the respiratory system, but are more commonly discovered in the thorax. Infradiaphragmatic bronchogenic cysts are rare and retroperitoneal ones distinctly unusual. We report a retroperitoneal bronchogenic cyst clinically masquerading as a phaeochromocytoma.

Chronic diffuse interstitial fibrosis of the lung in uranium miners.

Many uranium miners have been disabled by and died of pulmonary fibrosis that was not recognized as an occupational disease. A review of animal studies, complications from whole body irradiation, pulmonary function, and mortality studies of uranium miners led us to suspect radiation-induced chronic diffuse interstitial fibrosis in miners who had inhaled excessive radon progeny. A selected group of uranium miners (22) with severe respiratory disease (but no rounded nodules in chest films) were studied. Lung tissue from five disclosed severe diffuse interstitial fibrosis, with "honeycomb lung" in all. Some also had small anthrasilicotic nodules and birefringent crystals. Although quartz crystals probably contributed, we concluded that the predominant injurious agent in these cases was alpha particles from radon progeny. This disease, after a long latent period, usually results in pulmonary hypertension, shortness of breath, and death by cardiopulmonary failure.

Well-differentiated lymphocytic lymphoma. A study of 47 patients with primary manifestation in the lung.

Forty-seven cases of primary well-differentiated lymphocytic lymphoma (WDL) of the lung were studied. Diagnosis was based on histologic identification of a lymphangitic pattern of infiltration and monomorphous (homogenous) cytologic composition. Nineteen cases (40%) had ancillary evidence supportive of a diagnosis of lymphoma including simultaneous or subsequent involvement of other organs, monoclonal immunologic markers, or a monoclonal serum gammopathy. The prognosis for the group as a whole was excellent; follow-up (median, 4 years) was available for 33 cases. Only one patient has died of lymphoma. The authors discuss the histologic differential diagnosis of lymphocytic infiltrates in the lung, propose criteria to distinguish reactive from neoplastic lymphocytic lesions, and discuss the significance of monoclonality in the management of these patients.

Expression of a T-cell antigen (Leu-1) by B-cell lymphomas.

The Leu-1 antigen has been defined by monoclonal antibodies (L17F12, T101, and OKT-1) as a pan-T-cell antigen present on all human peripheral blood T cells and thymocytes. Although originally thought to be confined to T-cell lineage, some cases of B-cell chronic lymphocytic leukemia have been found to react with these antibodies. Using a frozen section immunoperoxidase staining technique, 125 lymphomas with B-cell differentiation were examined for the presence of Leu-1 antigen. Leu-1 antigen was detected in 4 of 11 cases of diffuse small lymphocytic lymphoma (Rappaport's DWDL) and 3 of 4 cases of diffuse intermediate lymphocytic lymphoma. Follicular lymphomas less often expressed this antigen--2 of 29 cases of the small cleaved cell type (Rappaport's NPDL), none of 13 cases of mixed small cleaved and large cell type (Rappaport's NM), and 1 of 6 cases of large cell type (Rappaport's NH). Diffuse lymphomas of presumed follicular center cell origin expressed this antigen infrequently as well--1 of 3 cases of the small cleaved cell type (Rappaport's DPDL), neither of 2 cases of mixed small cleaved and large cell type (Rappaport's DM), and 3 of 43 of large cell type (cleaved/noncleaved) (Rappaport's DH). Diffuse large cell, immunoblastic lymphoma of B-cell type expressed Leu-1 in 1 of 6 cases. None of the 3 cases of Burkitt's lymphoma or of the three small noncleaved non-Burkitt's lymphoma (Rappaport's undifferentiated) expressed detectable Leu-1. B-lymphoblastic lymphoma (1 case) and B-cell unclassified lymphoma (1 case) both failed to express detectable Leu-1. It appears that this pan-T-cell antigen is mainly found on those B-cell lymphomas composed predominantly of small lymphocytes. This finding may be of use in distinguishing extranodal neoplastic collections of small lymphocytes from lymphocytic hyperplasias.

The immunologic and clinicopathologic heterogeneity of cutaneous lymphomas other than mycosis fungoides.

Twenty-one cases of non-Hodgkin's lymphoma with cutaneous involvement, other than mycosis fungoides, were evaluated immunologically, histologically, and clinically. Ten patients presented with skin disease alone, seven with concurrent cutaneous and extracutaneous disease, and four with extracutaneous disease only. Twenty of the 21 cases were nonepidermotropic tumors and were equally likely to express B or T phenotypes. None of the cases expressed a true histiocytic phenotype. Almost all cases expressed la and class 1 HLA determinants. Immunophenotypes were stable regardless of time interval, therapy, or body site sampled in seven of eight patients studied serially. In contrast to mycosis fungoides, the T lymphomas exhibited noncerebriform cytology, tumor la expression, lack of mature helper T-cell phenotype, nonepidermotropic histology, a tendency for marrow involvement, and presented as nodules rather than patches or plaques. Since each T lymphoma expressed an abnormal but uniform T-cell phenotype other than mature cytotoxic/suppressor or helper, the neoplastic population could be distinguished from reactive T cells. Reactive elements averaged one-third of the cellular infiltrates and were mainly T cells and macrophages. Langerhans cells were generally normal in number and distribution. Several histopathologic subtypes were identified with diffuse large cell lymphomas, including immunoblastic lymphomas, comprising 71% of cases (15/21). Prediction of the immunophenotype based on cytologic criteria was correct in 67% of cases (14/21). All errors occurred among the 13 high-grade lymphomas. Survival data were consistent with those of prior studies that have indicated that clinical course is dependent on stage and histologic subtype. Non-Hodgkin's cutaneous lymphomas constitute an immunologically, histologically, and clinically heterogeneous group of neoplasms.

The immunologic characterization of 95 nodal and extranodal diffuse large cell lymphomas in 89 patients.

Ninety-five diffuse large cell lymphomas in 89 patients were stained in cryostat sections with a panel of monoclonal antibodies. Lymphoma cells from 47 patients (53%) expressed either kappa or lambda light chains, usually in combination with mu heavy chains. Fifteen samples from 12 patients (14%) expressed two or more T-cell antigens and commonly expressed Ia antigens. Lymphoma cells from 10 of these patients uniformly lacked one or more pan T-cell antigens; lymphoma cells from 4 of these patients also lacked both T-subset antigens--findings which should prove useful in diagnosis. Lymphomas from 28 patients (31%) did not express immunoglobulin or T-cell antigens but commonly expressed the B-lineage antigen B1; and the remaining 9 cases generally expressed Ia antigens, common ALL antigens, or both. Our findings confirm the marked immunologic heterogeneity of diffuse large cell lymphomas; the phenotypic heterogeneity observed in T-cell cases in many instances is difficult to reconcile with current models of T-cell differentiation.

Clinical relevance of immunologic phenotype in diffuse large cell lymphoma.

The immunologic phenotypes of 78 diffuse large cell lymphomas were determined by an immunoperoxidase technique using a panel of monoclonal antibodies. The phenotypes were correlated with clinical and morphological parameters by univariate and multivariate analysis. Forty-one lymphomas (53%) expressed immunoglobulin (Ig+). Of the 37 cases that did not express immunoglobulin (Ig-), 9 expressed T cell antigens. Although the T cell phenotypes were antigenically heterogeneous, all cases represented mature T cell phenotypes. The majority of the remaining 28 cases expressed the B cell-associated antigen, B1. At 5 yr, actuarial survival for the Ig- patients was 63%, compared with 15% for the Ig+ patients. A significantly greater proportion of patients with Ig+ lymphomas were over the age of 65 at diagnosis. All of the 9 patients with marrow involvement were Ig+. Multiple factors were analyzed by the Cox regression procedure for their impact on survival, including antigenic profile, histologic grade, morphological classification, and numerous clinical parameters previously recognized to be of prognostic significance. In this analysis, stage, age greater than 65 yr, systemic symptoms, and marrow involvement had the greatest influence on survival. The survival difference between Ig- and Ig+ patients is explained by a higher proportion of Ig+ patients with these unfavorable prognostic factors. With our current immunologic methods, retrospective cell phenotyping analysis has not provided independent prognostic significance in diffuse large cell lymphoma. A prospective evaluation of similarly treated patients is needed to characterize the influence of phenotype fully and to determine its potential usefulness for therapy.

DNA cytometry and cytology by quantitative fluorescence image analysis in symptomatic bladder cancer patients.

A semi-automated quantitative fluorescence image analysis (QFIA) technique was developed with the Leitz TAS-Plus to detect bladder cancer using hyperploidy in urinary cells. Absolute nuclear fluorescence intensity (ANFI) (emission at 540 nm with excitation at 436 nm) of individual acridine-orange-stained cells was quantitated using (1) QFIA and (2) simple filter microspectrofluorophotometry (SFM). Both methods employed an internal phosphor particle standard which, when once calibrated against the DNA content of normal cells, obviates the necessity of routinely calibrating against normal cells in each sample. Results of SFM and QFIA were compared with routine Papanicolaou (Pap) cytopathology, using histopathology as the diagnostic standard in 272 samples from 67 symptomatic patients. The sensitivities for detecting low-grade transitional-cell carcinoma were 86% for SFM, 76% for QFIA, and 33% for Pap cytology. QFIA and SFM were significantly more sensitive at detecting bladder cancer than was Pap (0.01 greater than p greater than 0.001). Comparison of sensitivity obtained with bladder washings and urine samples showed that noninvasively obtained urines can be used. ANFI also detected recurrent and precancerous bladder lesions and kidney, ureter, and prostate lesions. This approach may prove generally useful in quantifying biochemical and immunological probes and should be broadly applicable as a research tool for studying the relationship of biochemical markers in the pathogenesis of disease and as a test for cancer control.