T-cell/histiocyte-rich large B-cell lymphoma: a distinct clinicopathologic entity.

PURPOSE: Although it has proven difficult to delineate diagnostically reproducible and clinically relevant subgroups, the heterogeneity of diffuse large B-cell lymphomas (DLBCL) is widely acknowledged. In 1992, we reported on six cases that suggested that large B-cell lymphoma rich in stromal histiocytes and T cells may be identified as a distinct clinicopathologic entity within DLBCL. PATIENTS AND METHODS: An integrated clinicopathologic study of 40 cases of this DLBCL subtype is presented. RESULTS: Distinguishing a DLBCL rich in histiocytes and reactive T cells, designated T-cell/histiocyte--rich large B-cell lymphoma (THR-BCL), may be justified from a clinical point of view. The disease typically affects middle-aged male patients who usually present with advanced-stage disease that is not adequately managed with current therapeutic strategies. Whereas proliferation fraction and p53 overexpression, in addition to the clinical variables incorporated in the International Prognostic Index (IPI), significantly correlate with response to treatment and survival in a univariate analysis, only the IPI score identifies relevant prognostic THR-BCL subpopulations in a multivariate model. The morphologic and immunophenotypic profile of the neoplastic B cells in THR-BCL suggests that they may originate from a germinal center ancestor. CONCLUSION: THR-BCL constitutes a distinct clinicopathologic entity that is characterized by an aggressive behavior. Experimental therapeutic strategies may be indicated to obtain a more favorable response to treatment in this disease.

Histiocyte-rich, T-cell-rich B-cell lymphoma: a distinct diffuse large B-cell lymphoma subtype showing characteristic morphologic and immunophenotypic features.

AIMS: The clinicopathological features of histiocyte-rich, T-cell-rich B-cell lymphoma (HRTR-BCL) were first recognized in 1992. In this study, 60 cases of HRTR-BCL were analysed in order to provide a detailed morphological and immunophenotypical profile of the disorder. METHODS AND RESULTS: HRTR-BCL is easily distinguished from other B-cell lymphomas rich in stromal T-cells by (i) a diffuse or vaguely nodular growth pattern, (ii) the presence of a minority population of CD15-, CD20+ large neoplastic B-cells, (iii) a prominent stromal component composed of both T-cells and non-epithelioid histiocytes, and (iv) the scarcity of small reactive B-cells. These criteria also enable a reliable distinction from lymphocyte-rich classical Hodgkin's lymphoma (CHL), from lymphocyte-predominant Hodgkin's lymphoma (LPHL), paragranuloma type and from peripheral T-cell lymphoma. Based on the morphology of the neoplastic cells and on their frequent bcl-6 immunoreactivity, we speculate that HRTR-BCL may be derived from a progenitor cell of germinal centre origin. CONCLUSIONS: HRTR-BCL presents characteristic clinical features, affecting predominantly middle-aged men who present with advanced stage disease and are at high risk of treatment failure. Considering these distinctive clinicopathological features, recognizing HRTR-BCL as a lymphoma entity may be justified.

[The role of radical prostatectomy in cT3 prostate carcinoma]. / Die Rolle der radikalen Prostatektomie beim cT3-Prostatakarzinom.

A clinical cT3 prostate cancer can mean so many different tumors, that no single approach can actually be proposed. Radical prostatectomy has become standard treatment for T1/T2 tumors, but the surgical treatment for the clinical T3 prostate cancer has always been and remains controversial, although some urologists felt that radical prostatectomy remained a treatment option for T3 prostatic cancer when poor prognosis patients were excluded. The clinical staging of locally confined or locally advanced prostate cancer is not reliable. More than 70% of the clinically T2-tumors are pT3. On the others hand clinically T3-tumors are sometimes overestimated and about 20% of the clinical T3 cancers were shown to be pT2.--At the Department of Urology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Belgium--158 patients had radical prostatectomy for clinical stage T3N0M0 prostate cancer. 110 patients were surgically treated only. 30 patients had adjuvant hormone-therapy and were considered to be progressive at 1 month because PSA follow-up is unreliable. 18 other patients were irradiated postoperatively. PSA-free survival rate exceeds 70% at 24 months and the 5 years estimated PSA-free survival is more than 60%. Summarizing radical prostatectomy appears to be a justified treatment modality in pT3-prostate cancer, if PSA is < 10 ng/ml.

Radiotherapy for PSA recurrence after radical prostatectomy.

OBJECTIVES: The treatment of patients presenting with an isolated PSA recurrence after radical prostatectomy (RP) remains controversial. The present study aims at assessing the results of salvage radiotherapy (RT), to define prognostic factors and to identify subgroups of patients most suitable for RT with curative intent. MATERIALS AND METHODS: A retrospective study was performed of 53 patients, diagnosed with a rising PSA after RP, and treated with RT to the prostate bed, between July 1992 and July 1998. RESULTS: On univariate analysis, significant determinants to obtain and maintain a nondetectable PSA (< 0.02 ng/ml) were Gleason grade (< or = III vs. < or = IV), pre-RT PSA, considered as categorical or continuous variable, and pathological stage, pT (2 vs. 3). Pre-RP PSA (< or = 10 vs. >10), time interval between surgery and moment of rising PSA and pathological section margin status were not significant. On multivariate analysis, only Gleason grade and pre-RT PSA remained significant. For the patient group with a Gleason grade < or = III the PSA-free survival at 3 years was 75% (+/- 11%) compared to 27% (+/- 9%) for the patients with a Gleason grade > or = IV (p = 0.002). Pre-RT PSA significantly influenced PSA-free survival in the first group, but not in the latter. CONCLUSION: From the group of RP patients with rising PSA following a postsurgery PSA-free period, subgroups can be defined with a distinctly different probability of obtaining and maintaining nondetectable PSA levels after salvage RT.

Prognostic value of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose ([18F]FDG) after first-line chemotherapy in non-Hodgkin's lymphoma: is [18F]FDG-PET a valid alternative to conventional diagnostic methods?

PURPOSE: A complete remission (CR) after first-line therapy is associated with longer progression-free survival (PFS). However, defining CR is not always easy because of the presence of residual masses. Metabolic imaging with fluorine-18 fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) offers the ability to differentiate between viable and fibrotic inactive tissue. In this study, we evaluated the value of PET in detecting residual disease and, hence, predicting relapse after first-line treatment in patients with non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Ninety-three patients with histologically proven NHL, who underwent a whole-body [18F]FDG-PET study after completion of first-line chemotherapy and who had follow-up of at least 1 year, were included. Persistence or absence of residual disease on PET was related to PFS using Kaplan-Meier survival analysis. RESULTS: Sixty-seven patients showed a normal PET scan after first-line chemotherapy; 56 of 67 remained in CR, with a median follow-up of 653 days. Nine of these patients with a residual mass considered as unconfirmed CR received additional radiotherapy. Only 11 of 67 patients relapsed (median PFS, 404 days). Persistent abnormal [18F]FDG uptake was seen in 26 patients, and all of them relapsed (median PFS, 73 days). Because standard restaging also suggested residual disease, 12 patients received immediate secondary treatment. In 14 of 26 patients, only PET predicted persistent disease. From these patients, relapse was proven either by biopsy (n = 8) or by progressive disease on computed tomography or magnetic resonance imaging (n = 6). CONCLUSION: Persistent abnormal [18F]FDG uptake after first-line chemotherapy in NHL is highly predictive for residual or recurrent disease. In relapsing patients, PFS was significantly shorter after a positive scan than after a negative scan.

Radical prostatectomy can provide a cure for well-selected clinical stage T3 prostate cancer.

OBJECTIVE: Radical prostatectomy is commonly believed not to achieve the eradication of locally advanced disease. This retrospective study aimed to elucidate the role of radical prostatectomy in this condition. METHODS: A retrospective study of 158 patients surgically treated for clinical stage T3N0M0 prostate cancer was undertaken. Thirty patients had postoperative hormonal treatment, rendering prostate-specific antigen (PSA) follow-up unreliable, and were considered to be progressive at 1 month. Eighteen other patients received postoperative radiotherapy. One hundred and ten patients had radical prostatectomy only. PSA-relapse-free survival was analyzed. The mean follow-up time was 30 months. RESULTS: Seventy-nine percent of the resected specimens were pathologically T3 (pT3), and about 25% were pT3c. Thirteen percent were pT2 and 8% were pT4. Ninety-five specimens (60%) had positive surgical margins. There was poor accordance between the biopsy Gleason score and that of the specimen. A multivariate analysis showed that seminal vesicle and nodal invasion, margin status and a PSA level above 10 ng/ml were independent prognostic factors. In 47 cT3a patients with PSA <10 ng/ml, the PSA-free survival rate exceeded 70% at 24 months and the 5-year estimated PSA-free survival rate was more than 60%. CONCLUSIONS: Radical prostatectomy has a place in the treatment of clinical stage T3 prostate cancer patients with a PSA value lower than 10 ng/ml. There is a need to definitively rule out nodal or seminal vesicle invasion in order to select those patients that can benefit from surgery.

The impact of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) lymph node staging on the radiation treatment volumes in patients with non-small cell lung cancer.

PURPOSE: (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) combined with computer tomography (PET-CT) is superior to CT alone in mediastinal lymph node (LN) staging in non-small cell lung cancer (NSCLC). We studied the potential impact of this non-invasive LN staging procedure on the radiation treatment plan of patients with NSCLC. PATIENTS AND METHODS: The imaging and surgical pathology data from 105 patients included in two previously published prospective LN staging protocols form the basis for the present analysis. For 73 of these patients, with positive LN's on CT and/or on PET, a theoretical study was performed in which for each patient the gross tumour volume (GTV) was defined based on CT and on PET-CT data. For each GTV, the completeness of tumour coverage was assessed, using the available surgical pathology data as gold standard. A more detailed analysis was done for the first ten consecutive patients in whom the PET-CT-GTV was smaller than the CT-GTV. Theoretical radiation treatment plans were constructed based on both CT-GTV and PET-CT-GTV. Dose-volume histograms for the planning target volume (PTV), for the total lung volume and the lung volume receiving more than 20 Gy (V(lung(20))), were calculated. RESULTS: Data from 988 assessed LN stations were available. In the subgroup of 73 patients with CT or PET positive LN's, tumour coverage improved from 75% when the CT-GTV was used to 89% with the PET-CT-GTV (P=0.005). In 45 patients (62%) the information obtained from PET would have led to a change of the treatment volumes. For the ten patients in the dosimetry study, the use of PET-CT to define the GTV, resulted in an average reduction of the PTV by 29+/-18% (+/-1 SD) (P=0.002) and of the V(lung(20)) of 27+/-18% (+/-1 SD) (P=0.001). CONCLUSION: In patients with NSCLC considered for curative radiation treatment, assessment of locoregional LN tumour extension by PET will improve tumour coverage, and in selected patients, will reduce the volume of normal tissues irradiated, and thus toxicity. This subgroup of patients could then become candidates for treatment intensification.

The contribution of magnetic resonance imaging to the three-dimensional treatment planning of localized prostate cancer.

PURPOSE: To investigate whether the use of transaxial and coronal MR imaging improves the ability to localize the apex of the prostate and the anterior part of the rectum compared to the use of transaxial CT alone, and whether the incorporation of MR could improve the coverage of the prostate by the radiotherapy field and change the volume of rectum irradiated. METHODS AND MATERIALS: Ten consecutive patients with localized prostate carcinoma underwent a CT and an axial and coronal MR scan in treatment position. The CT and MR images were mathematically aligned, and three observers were asked to contour independently the prostate and the rectum on CT and on MR. The interobserver variability of the prostatic apex location and of the delineation of the anterior rectal wall were assessed for each image modality. A dosimetry study was performed to evaluate the dose to the rectum when MR was used in addition to CT to localize the pelvic organs. RESULTS: The interobserver variation of the prostatic apex location was largest on CT ranging from 0.54 to 1.07 cm, and smallest on coronal MR ranging from 0.17 to 0.25 cm. The interobserver variation of the delineation of the anterior rectum on MR was small and constant along the whole length of the prostate (0.09+/-0.02 cm), while for CT it was comparable to that for the MR delineation at the base of the prostate, but it increased gradually towards the apex, where the variation reached 0.39 cm. The volume of MR rectum receiving more than 80% of the prescribed dose was on average reduced by 23.8+/-11.2% from the CT to the MR treatment plan. CONCLUSION: It can be concluded that the additional use of axial and coronal MR scans, in designing the treatment plan for localized prostate carcinoma, improves substantially the localization accuracy of the prostatic apex and the anterior aspect of the rectum, resulting in a better coverage of the prostate and a potential to reduce the volume of the rectum irradiated to a high dose.

Mitomycin C for metastatic prostate cancer: final analysis of a randomized trial.

BACKGROUND: Almost all patients that undergo hormonal manipulation for metastatic prostate cancer will ultimately progress because of hormone resistance. Therefore we assessed the effect of early addition of intravenous Mitomycin C to orchiectomy in patients with newly diagnosed metastatic prostate cancer. PATIENTS AND METHODS: 178 patients with histologically proven and previously untreated metastatic prostate cancer were included in a prospective, randomized multicenter trial. Randomization was done centrally between orchiectomy alone and orchiectomy with Mitomycin C. 148 patients were evaluable. RESULTS: At the final analysis 139 patients have deceased. The remaining 9 patients are still alive, but all present progression. There was no statistically significant difference in the real time to progression, or in the estimated cancer related and overall survival between both groups. Mean time to progression was 29 months in group 1 (orchiectomy alone), and 26 months in group 2 (orchiectomy and Mitomycin C) (p = 0.64). Mean time to cancer related death was 32 months and mean overall survival was 31 months in both groups. CONCLUSIONS: Mitomycin C has no beneficial effect when used in conjunction to orchiectomy in patients with newly diagnosed metastatic prostate cancer.

Sarcomatoid renal cell carcinoma: case report and review of the literature.

Sarcomatoid renal cell carcinoma (SRCC) is an uncommon tumor of the renal parenchyma, representing one to five percent of all primary kidney tumors. The major symptoms are the same as in the classic renal cell carcinoma: haematuria and flank pain. The tumor consists of a bimorph feature of clear cells with areas of spindle cells and giant cells, resembling a sarcoma. Immunohistochemistry and electronmicroscopy are often necessary to prove the epithelial origin of these spindle cells. Therapy is essentially surgical but in some cases there can be a benefit of chemotherapy.

The time course of development of late side effects after irradiation of the prostate with multiple fractions per day.

BACKGROUND AND PURPOSE: A group of patients with prostate cancer was irradiated in the early 1980s with a TID schedule, resulting in a very high frequency of side effects. The time course of development of severe late complications was evaluated. MATERIALS AND METHODS: We retrospectively reviewed the records of 91 patients with prostate cancer, irradiated on a linear accelerator or a cobalt unit between 1980 and 1983. They received a split-course irradiation with multiple fractions per day (MFD) up to a nominal dose of 60 Gy. The rate of development of severe late urological and gastrointestinal complications, grade 3 or more according to the RTOG scoring system, was analysed. RESULTS: The 5-year actuarial incidence of urological complications was 51%. After a lag time of a few months, patients develop "first events' at a nearly constant rate of 10% for 5 years after treatment. Subsequent events ("all events') seem to continue to appear even after 5 years. The actuarial incidence at 5 years of gastrointestinal complications was 14%, with no new events developing later than 3 years after treatment. CONCLUSIONS: The irradiation schedule used resulted in an unacceptable high incidence of late side effects, probably due to incomplete repair between fractions. MFD fractions to the pelvis should be avoided, unless sufficient time in between fractions can be allowed. Moreover, the fact that after this treatment schedule with very pronounced biological effects, new severe complications continued to develop up to 5 years after therapy, indicates that sufficiently long follow-up time has to be respected when investigating new radiation techniques for pelvic tumours.

Interim results on a randomized trial of mitomycin C in combination with orchidectomy for newly diagnosed metastatic prostate cancer.

The interim results of a randomized trial comparing orchidectomy alone versus orchidectomy and mitomycin C in 178 newly diagnosed metastatic prostate cancer patients are presented. Of 148 evaluable patients 75 were treated with orchidectomy alone and 73 received adjuvant intravenous mitomycin C. Mean time to progression was 15 months in the orchidectomy group versus 14 months in the mitomycin C group. Interim analysis did not demonstrate a favorable effect of the combination with this chemotherapeutic agent compared to orchidectomy alone (P = .45).

In vivo cell kinetic measurements in human oesophageal cancer: what can be learned from multiple biopsies?

The importance of intratumour variability of cell kinetics was studied in 60 patients with cancer of the oesophagus. Five biopsies per tumour were taken. The labelling index, S-phase duration and potential doubling time (Tpot) were measured using flow cytometry. The mean Tpot value was 5.56 +/- 4.43 days (+/- 1S.D.) for adenocarcinomas and 4.40 +/- 2.45 days (+/- 1S.D.) for squamous cell carcinomas. These values were statistically significantly different. Although intratumour variation in Tpot measurements occurred, the intertumour variability was more important (P < 0.00001). This feature permits classification of tumours into slow and fast proliferating groups, leaving an intermediate group of tumours that could not be unequivocally categorised. The relative distribution of tumours into these three categories depends on the intratumour and intertumour variability of Tpot, and on the cut-off values used. Increasing the number of biopsies from one to five reduces the number of non-classifiable tumours.

Radiation response of mouse lip mucosal epithelium: a cell kinetic study.

Changes in the cell proliferation kinetics of the epithelium of mouse lip mucosa have been assessed after local irradiation with a single dose of 18 Gy of 60Co gamma-rays. By the fifth day after irradiation, two distinct sub-populations of epithelial cells could be discerned. The larger of the two populations consisted of cells exhibiting varying degrees of radiation-induced damage, and the smaller population was composed of cells of normal size and appearance, intermingled between the radiation-damaged cells. There was a progressive decline in the epithelial cell density with time after irradiation, and focal denudation was seen after 11 days. Cell colonies were evident in the remnants of the epithelium by day 7. Degenerate cells could be identified in the basal layer of the mucosal epithelium, both before and after irradiation. The proportion of degenerate cells was increased 5 days after irradiation with the maximum number, approximately 3.6% being counted on days 7 and 8. In the first 2 days after irradiation, there was a reduction in the labelling index (LI) of basal cells in the epithelium. This was followed by recovery to control values on day 3. The LIs of both the radiation-damaged cells and those with a normal appearance remained relatively constant between days 5 and 11, at approximately 10 and approximately 60%, respectively. The LI of basal cells in the cell colonies was very high (approximately 70%). The estimated turnover time (TT) for the basal cell population with a normal appearance and for those in cell colonies (groups of normal cells with a cord length > or = 10 cells), was extremely short < 1 day. There was some fluctuation in TT values for basal cells exhibiting radiation-induced damage, with the shortest value (approximately 3 days) at 7 and 8 days after irradiation. It was concluded from the cell kinetic data that repopulation of the lip mucosal epithelium started between 3 and 5 days after irradiation and the overall response of the mucosa to irradiation was consistent with that predicted by a hierarchical model of cell proliferative organization.

Intracranial ependymoma: long-term results of a policy of surgery and radiotherapy.

Ninety-three patients with primary intracranial ependymoma were treated at the Royal Marsden Hospital, between 1952 and 1988, with postoperative radiotherapy. The survival probability at 5, 10, and 15 years was 51%, 42% and 31%, respectively, and the corresponding progression free survival (PFS) probability, 41%, 38%, and 30%. Tumor grade was the single most important prognostic factor for survival and PFS with gender of lesser prognostic significance. Treatment parameters were stratified for grade. In patients with low grade tumors survival and PFS were better following complete macroscopic excision compared to incomplete surgery. The extent of resection had no significant influence on survival or PFS in patients with high grade tumors. Extent of irradiation did not influence PFS, irrespective of tumor grade, while patients with high grade tumors had marginally better survival following extensive irradiation compared to more limited radiotherapy. The main problem in the treatment of ependymoma remains local progression which was the cause of death in all but two patients. New treatment strategies should focus on improvement of local control, especially in incompletely resected low grade tumors and all high grade tumors. The use of spinal irradiation is unlikely to significantly improve treatment results.

The role of prophylactic spinal irradiation in localized intracranial ependymoma.

A review of the clinical literature on ependymoma, published between 1969 and 1989, was carried out to assess the influence of tumor grade and site, tumor control at the primary site, and extent of irradiation on the incidence of spinal seeding after initial treatment. The pooled data show that the incidence of seeding was 8.4% (7/83) for high grade tumors and 4.5% (6/132) for low grade tumors. Seeding occurred more frequently in infratentorial tumors than in supratentorial tumors. For high grade tumors the incidence was 0% (0/26) for supratentorial and 15.7% (6/38) for infratentorial lesions; for low grade tumors the respective incidence was 2.7% (1/37) and 5.5% (4/73). Spinal seeding was 9.5% (15/157) in the event of failure at the primary site compared to 3.3% (4/122) when local control was achieved. The development of spinal metastases was not influenced by the extent of irradiation. For high grade tumors the incidence was 9.4% (5/53) with spinal irradiation and 6.7% (2/30) without prophylactic treatment; for low grade tumors the respective values were 9.3% (4/43) and 2.2% (2/89). These results indicate that tumor grade, tumor localization, and control of the tumor at the primary site are all factors which may influence the risk of spinal seeding. On the present evidence spinal metastases are not prevented by prophylactic spinal irradiation, regardless of tumor grade and site.

Radiotherapy by multiple fractions per day (MFD) in head and neck cancer: acute reactions of skin and mucosa.

The feasibility of several unusual fractionation schedules in the radiotherapy of head and neck tumors was assessed, especially the acute reactions of skin and mucosa. All schedules were based on the principle of multiple fractions per day (MFD) leading to highly concentrated treatment series, alternating with rest periods. The fraction sizes used were between 1.6-2 Gy, overall treatment time was about 6 weeks, and total dose ranged from 60 to 67.2 Gy. The most important parameter that was modified was the size of the dose given in one treatment series. The first schedule consisted of two unequal radiation series: 48 Gy/12 days, followed by a second series of 19.2 Gy/4 days after a 3- to 4-week interval. All subsequent treatment schedules were divided in equal series: the first in 2 times 30 Gy, the second in 3 times 22.4 Gy, and the third in 4 times 16 Gy. Comparison of acute reactions in skin and mucosa after these irradiations to different dose levels has made it possible to obtain a precise idea of the time course in the development of radiation induced damage and of the dose-effect relationship. Such dose-response curves will be extremely useful in further studies on the dose-modifying effects of sensitizers and cytostatic drugs. Conclusions of this study: 1. In human oral mucosa, the threshold dose for the development of confluent mucositis (patches of 0.5 cm) after fractionated irradiation appears to be around 20 Gy. 2. Intervals of 12 days allow full repair of mucosa damage after a dose of about 20 Gy and repeating the irradiation leads to an identical reaction after second, third or fourth treatments, demonstrating that no cumulative effect exists for acute damage. This phenomenon could be exploited to reduce the acute side effects in radiotherapy. 3. The reactions observed in skin are less pronounced than those of mucosa, possibly due to the dose distribution of high energy photons. The changes are, however, slower to develop and intervals of 2 weeks are insufficient for the skin to fully recover from the radiation damage. Subsequent treatment series led to a cumulative reaction pattern. 4. Finally, a number of treatments were associated with misonidazole, an anoxic cell sensitizer, which did not appear to modify significantly the radiation reactions in either skin or mucosa.

Breast conserving treatment of Paget's disease.

Between 1971 and 1984, 13 patients with histologically proven Paget's disease were treated conservatively with radiotherapy only. The disease was clinically confined to the nipple or surrounding skin, without signs of an underlying tumor. With a mean follow-up of 58.6 months (ranging between 15 and 118 months), and a median follow up of 52 months, no recurrences locally or at distance were seen. Therefore in these selected cases a mastectomy could be avoided. The results with this breast conserving management suggest a place for radiotherapy in the treatment of Paget's disease limited to the nipple.