Shift from polyploidizing to nonpolyploidizing growth in carcinogen-treated rat liver.

Liver growth patterns in normal and carcinogen-treated young Wistar Kyoto rats were analyzed in terms of absolute hepatocyte numbers and ploidy distributions, calculated from DNA measurements made by flow cytometry and microscope counts of binucleated cells. Polyploidizing growth was observed during normal liver development, dominated by progressive polyploidization and a decrease in the number of diploid cells. Nonpolyploidizing growth was seen during liver regeneration and after treatment with 2-acetylaminofluorene (AAF). This mode of growth was characterized by an increase in all mononucleated ploidy classes in the absence of net polyploidization (no increase in binucleated cells). Additional diploid proliferation was detected after initiation with diethylnitrosamine followed by promotion with AAF. This selectively expanding diploid hepatocyte population, which persisted after AAF withdrawal, could represent the AAF-promoted progeny of diethylnitrosamine-altered cells with constitutive nonpolyploidizing growth properties.

High cure rates and reduced long-term toxicity in pediatric Hodgkin's disease: the German-Austrian multicenter trial DAL-HD-90. The German-Austrian Pediatric Hodgkin's Disease Study Group.

PURPOSE: To further reduce therapy-related late effects in patients with pediatric Hodgkin's disease (HD) while maintaining the high cure rates achieved with vincristine, prednisone, procarbazine, and doxorubicin (OPPA) or OPPA/cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) chemotherapy and involved-field radiotherapy. The risk of testicular dysfunction was addressed by substituting etoposide for procarbazine (OEPA) in the induction therapy for boys. Radiation doses and fields were further reduced. PATIENTS AND METHODS: Three hundred nineteen boys and 259 girls younger than 18 years with previously untreated HD, enrolled onto the study between 1990 and 1995, were allocated to treatment group (TG)1 (early stages), TG2 (intermediate stages), or TG3 (advanced stages). All groups underwent two cycles of OEPA (boys) or OPPA (girls) for induction chemotherapy. TG2 and TG3 continued on additional two or four cycles, respectively, of COPP. Low-dose radiotherapy was given to the initially involved sites, ie, reduced involved fields. RESULTS: Initial response to OPPA or OEPA induction was virtually identical. Eight of 578 patients experienced early progression of HD. Thirty-seven relapses, three secondary tumors, and no secondary leukemias have been recorded, with a median follow-up duration of 5.1 years (maximum, 8.1 years). Thirteen of 578 patients died. The probability of 5-year event-free survival/overall survival is 91%/98% in the total group, 94%/97% with OPPA, and 89%/98% with OEPA induction therapy. Risk factor analysis showed two significant prognostic factors: histologic subtype NS2 and "B" symptoms. OEPA induction therapy, large mediastinal tumor, and age were not significant. Preliminary studies of testicular function indicate a lower risk of germ cell damage than previously documented with OPPA. CONCLUSION: OEPA is a satisfactory alternative to OPPA. Radiotherapy can be confined to involved sites when combined with appropriate chemotherapy. The DAL-HD-90 regimen represents a comprehensive treatment program for all stages of pediatric HD and offers a favorable benefit/risk ratio, combining excellent disease control, moderate acute toxicity, and reduced long-term toxicity.

Dose-response relationship of complementary radiotherapy following four cycles of combination chemotherapy in intermediate-stage Hodgkin's disease.

PURPOSE: To determine the appropriate irradiation dose after four cycles of modern combination chemotherapy in nonbulky involved field (IF/BF) and noninvolved extended-field (EF/IF) sites in patients with intermediate-stage Hodgkin's disease (HD). MATERIALS AND METHODS: HD patients in stage I to IIIA with a large mediastinal mass, E stage, or massive spleen involvement were treated with two double cycles of alternating cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) plus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by EF irradiation in two successive trials (HD1 and HD5). In the HD1 trial (1983 to 1988), 146 patients who responded to chemotherapy were randomized to receive 20 Gy (70 patients) or 40 Gy (76 patients) of EF irradiation in all fields outside bulky disease sites. A cohort of 111 patients who fulfilled the same inclusion criteria in the subsequent trial HD5 (1988 to 1993) were treated with 30 Gy. Bulky disease always received 40 Gy. RESULTS: Freedom-from-treatment-failure (FFTF) and survival (SV) curves showed no differences between the 20-, 30-, and 40-Gy groups. However, acute toxicities were more frequent in the 40-Gy arm. Analysis of relapse patterns showed that 18 of 26 relapsing patients either failed to respond in initial bulky sites (n = 5) or had an extranodal relapse (n = 9) or both (n = 4). After 5 years, the cumulative risk for relapse in bulky sites is 10%, despite 40 Gy of radiation. CONCLUSION: Our results strongly suggest that there is no relevant radiotherapy dose effect in the range between 20 Gy and 40 Gy in IF/BF and EF/IF after 4 months of modern polychemotherapy in patients with intermediate-stage HD. Relapse patterns indicate that patients destined to relapse need more systemic, rather than local, treatment. Based on our data, we conclude that 20 Gy is sufficient in EF/IF of intermediate-stage HD following four cycles of modern polychemotherapy.

Cytogenetic findings in T-zone lymphoma.

Five cases of T-zone lymphoma were investigated with histologic, immunologic, and cytogenetic methods. The chromosome analyses were performed on lymphoma cells prepared immediately after removal of the lymph nodes. The chromosomes involved in structural rearrangements were nos. 1, 2, 3, 4, 14, and Y. Numbers 3, 5, 6, and 13 were lost by some tumors, and nos. 3 and 9 were gained. Chromosome 3 was involved most often in structural and numerical aberrations, whereas 14q + markers occurred in only one case. The importance of multidisciplinary studies is pointed out.

Biclonal trisomy 3 in a case of epithelioid cellular lymphogranulomatosis (Lennert's lymphoma).

Biclonal trisomy 3 in a case of epithelioid cellular lymphogranulomatosis (Lennert's lymphoma) was demonstrated by Q-banding polymorphisms of chromosome #3. Seventeen of 19 mitoses with trisomy 3 showed duplication of 1 of the homologous chromosomes and the remaining 2 showed duplication of the other chromosome. It is assumed that both chromosomes #3 independently underwent nondisjunction and that this led to the development of the two abnormal clones. Moreover, there appeared to be a qualitative difference between the two clones, because one of them made up a major proportion and the other a minor proportion of the cells in both of the two samples studied at different times.

Classification of Hodgkin's disease biopsies by a panel of four histopathologists. Report of 1,140 patients from the German National Trial.

First results from reviewing the diagnostic biopsies of Hodgkin's lymphomas (HL) are reported. Biopsies from 1,140 patients were evaluated by consensus diagnoses according to an extended classification of the British National Lymphoma Investigation. 95 of the recruited cases (8.3%) were omitted and not approved as Hodgkin's lymphoma. The remaining 1,045 biopsies were classified as follows: Lymphocytic predominance 31 (2.7%); Nodular sclerosis (NS) 660 (57.9%), Mixed cellularity (MC) 159 (13.9%); Lymphocytic depletion 8 (0.7%); unclassifiable Hodgkin's 148 (13.0%). The unproved Hodgkin's cases [95 (8.3%)] were divided into non-Hodgkin's lymphomas 32 (1.9%), uncertain due to inadequate techniques 32 (2.8%), borderline between Hodgkin's- and Non-Hodgkin's lymphoma 23 (2.0%). Major dissent on this question involved 17 cases (1.5%) and 1 case which was non-malignant. All unclassifiable, borderline or dissent cases were reassessed after the histologic techniques were improved, and immunophenotyping and clinical data reevaluated. The rate of agreement among the observers was about 81.6%, varying between 23.8% in grade 2 NS to 85.0% in both NS groups. Only 62.8% of all primary diagnoses were approved by the final diagnoses of the panel. Important differences in the classification of the British National Lymphoma Investigation concerns the NS-group and mainly its grade 2 subtype. MC was identical in both classifications. Clinico-pathologic correlation of actuarial survival times revealed a significantly worse outcome of MC vs NS, < 20% after 80 months observation. Only slightly significant better survivals were found in grade 1 vs grade 2 NS. Significant differences in unclear compared to all Hodgkin's, were found and the worst survival was in the NHL group.

Extramedullary non-gastrointestinal plasmocytoma. An immunohistochemical study of sixteen cases.

Sixteen cases of extramedullary non-gastrointestinal plasmocytoma were studied for intracytoplasmic immunoglobulins by means of the immunoperoxidase-complex technique. Of the sixteen cases IgG class were observed in 4, IgM in one and IgA in 9 cases. Kappa light chains were found in 9 cases and lambda light chains in 6 cases. In one case a bitypic pattern of k- and lambda-positivity was encountered. In 2 cases only kappa light and no heavy chains were detected. The predominance of the IgA class in extramedullary, non-gastrointestinal plasmocytomas is in contrast to the prevalence of IgG type in multiple myeloma. The better possible behaviour of IgA-plasmocytomas is discussed further.

An approach to reduce treatment and invasive staging in childhood Hodgkin's disease: the sequence of the German DAL multicenter studies.

UNLABELLED: From June 1978 through March 1987, 506 children under the age of 16, representing approximatively 70% of the children with Hodgkin's disease in West-Germany entered 3 consecutive multicenter studies at 68 centers. The general objective of these study sequence is to maximize the chance of cure while minimizing radiotherapy and chemotherapy as much as possible in a combined modality treatment concept. The purpose was also to reappraise the need for splenectomy and laparotomy and to define a staging policy which provides adequate evaluation of intraabdominal disease. Study II (HD-82) is described in detail. 203 protocol patients were enrolled between Dec. 1981 and Dec. 1984. Laparotomy was performed in 202 patients, but splenectomy only in 78 (38.4%) using an intraoperative decisional strategy, developed in Study I (HD-78). Patients were stratified according to stage into 3 groups (PS I/IIA, IIB/IIIA and IIIB/IV) receiving 2, 4 or 6 cycles of OPPA/COPP-chemotherapy. Radiotherapy was given only to the involved fields, the dose depending on the extent of chemotherapy (35, 30 or 25 Gy). RESULTS AND CONCLUSIONS: The event-free survival rates after 5 years are 96% (entire group), 99% (stage I/IIA), 96% (stage IIB/IIIA) and 90% (stage IIIB/IV). Thus, only involved field radiotherapy with reduced doses is needed, if a stage-dependent chemotherapy with 2, 4 or 6 cycles of OPPA/COPP is given. The strategy of selective splenectomy has proven very useful. Based on statistical analyses concerning abdominal involvement a clinical decisional strategy for selective laparotomy was developed. Further efforts are needed to reach a stepwise cautious and controlled narrowing-in on the therapy combining the lowest long-term toxicity with the highest chance of cure.

[Non-Hodgkin's lymphoma. Cytology and cytochemistry]. / Non-Hodgkin-Lymphome. Cytologie und Cytochemie.

Imprints of lymph nodes and tumor specimens from 442 patients with non-Hodgkin's lymphoma (NHL) were evaluated cytologically and cytochemically. With the exception of hairy cell leukemia, special forms of peripheral pleomorphic T-cell lymphoma, and lymph node plasmacytoma, all types of NHL of the Kiel classification were included in this study. The investigations were performed on slides stained with Pappenheim (May-Grünwald-Giemsa) or conventional cytochemical techniques for substrate and enzyme demonstration, such as periodic acid Schiff (PAS), neutral and acid non-specific alphanaphthyl acetate esterase, and acid and alkaline phosphatase. In certain cases further techniques for substrate and enzyme demonstration, including myeloperoxidase and naphthol AS-D chloroacetate esterase, were used. We combined the cytologic and cytochemical evaluation with an attempt to diagnose the type of lymphoma on imprints without prior knowledge of the histologic findings or clinical data, in other words, blind. At the same time, we attempted to distinguish the NHL from reactive lymph node lesions, nonlymphoid malignant tumors, and systemic diseases. For this purpose, 75 cases of lymphadenitis and 33 cases of nonlymphoid neoplasia were mixed with the NHL for a blind test. In the following we will summarize the results pertaining to the NHL only. Chronic lymphocytic leukemia of B type (B-CLL; n = 75) was cytologically characterized by the presence of so-called prolymphocytes and paraimmunoblasts and a predominance of lymphocytes. In our opinion, there are four main variants of B-CLL: small-cell ("mature") CLL, a type in which prolymphocytes are plentiful ("immature" CLL), LP immunocytoma-like ("basophilic") CLL, and a type of CLL with centrocyte-like lymphocytes ("B2-CLL"). B-CLL had no cytochemical profile of its own. The reproducibility of the diagnosis on imprints was 80%. In prolymphocytic leukemia of B type (B-PLL; n = 1) prolymphocytes and blast cells were plentiful. In the case studied, acid phosphatase activity was moderately strong (evident as granules distributed in a semicircular fashion and focally accumulated). In the blind test we diagnosed it only descriptively as an "acid phosphatase-rich lymphoma of low-grade malignancy with a high prolymphocyte and blast cell content". Chronic lymphocytic leukemia of T type (T-CLL) and prolymphocytic leukemia of T type (T-PLL) could not be distinguished with certainty in sections or imprints. There was also no strict delineation between T-CLL and T-PLL in blood smears. The T-CLL and T-PLL cases we evaluated (n = 4) belonged to the so-called helper cell type.(ABSTRACT TRUNCATED AT 400 WORDS)

The origin of (Kolmer's) epiplexus cells. A combined histomorphological and histochemical study.

The morphology and the histochemically proofed enzyme pattern of the (Kolmer's) epiplexus cells found at the telencephalic chorioid plexus of humans indicate that these cells are of monocytogenetic origin, that they are monocytes and monocytogenetic macrophages respectively.

[Pathoanatomical features of isolated congenital mitral stenosis in twins (author's transl)]. / Pathologische Anatomie der isolierten kongenitalen Mitralstenose bei einem Zwillingspaar

The pathoanatomical features of isolated congenital mitral stenosis in female twins are presented. At the age of 7 months one of the infants underwent an emergency mitral valvotomy and died the next day due to mitral insufficiency. A total mitral valvectomy and an implantation of a Björk-Shiley prosthesis were performed on the second child at the age of 27 months. Death occurred 6 months later due to malfunction of the prosthesis caused by a circular fibrous endocardial bulge on both the atrial and ventricular side of the prosthesis. The bulging endocardial fibrosis may have been favored by a local thrombosis, which was found circularly around the bed of the prosthesis after it was removed. Since the child suffered from postoperative serum hepatitis, anticoagulants could not be applied on a regular basis in sufficient doses. The relation of the endocardial fibroelastosis to the congenital valve disease and the implantation of a prosthesis is discussed. The site of the postoperative valve in the first child and the state of the second child after implantation of the mitral valve prosthesis are discussed in detail.

Pathoanatomical features of the kidney in myelomonocytic and chronic lymphocytic leukemia.

The kidneys of 18 autopsy cases of myelomonocytic leukemia (MML) were examined for MML-specific features. Nine cases of chronic lymphocytic leukemia (CLL) served as controls. The kidneys of the cases of MML showed macroscopically detectable signs of hemorrhagic diathesis and secondary uric acid diathesis more often than those of CLL. In the MML group most of the kidneys weighed more than the normal average for the corresponding age group, but the average renal weights for the 2 groups were about the same. Renal weight and grade of leukemic infiltration, particularly in MML, revealed no significant positive correlation. In most of the cases of MML there were unevenly distributed poorly defined leukemic, infiltrates in the renal cortex and medulla. The histology resembled that of pyelonephritis. In CLL, on the other hand, the leukemic infiltrates were usually sharply defined and localized in foci in the outer cortex and the corticomedullary border region. Renal dysfunction in cases of MML has been attributed by others to hyperlysozymemia. It was found occasionally but there was no MML-typical morphological substrate in our material. Hyaline droplet change of the tubular epithelium was more frequent and more pronounced in MML than in CLL. However, we also determined that it was nonspecific and that it was not a parameter of cell damage. Tubular hyaline droplet change and the morphological criteria of acute renal failure were not positively correlated with the degree of leukemic infiltration of the kidneys or with the leukemic proliferation as a whole. Instead, they were considered to be signs and symptoms of accompanying or secondary diseases which complicated the leukemia.

[The significance of the autopsy--now and in the future]. / Die Bedeutung der Autopsie--heute und morgen.

The significance of the autopsy is reflected in the quality control of medical diagnosis and therapy, as well as in the social relevance of the autopsy findings for the individual, family and society in general ("individual" and social epidemiology). Contemporary statistics from research of the literature and internet will be presented and interpreted in a modern context. A pre-requisite for a quality control function is an adequately high autopsy rate, which should be a factor taken into consideration for the registration und certification of a clinic or hospital. There are some valuable studies cited which assess the significance of autopsy as a means of quality control in clinical surgery, oncology and general internal medicine. There is, on the other hand, a decline of autopsy rates worldwide, but especially in the Federal Republic of Germany since the beginning of the 90ties. In addition, the causes will be demonstrated and discussed briefly. The attitude of medical colleagues and health insurance companies, as well as public opinion and politics, all influence the significance of and attitude to the autopsy, including the readiness to create and maintain a transparent legal and cost-covering framework. A spectrum of the differing opinions, obtained from various discussions, will be given. In addition, the necessary legal and financial regulations to facilitate and sustain the autopsy service at a sufficiently high rate (at least 30%, based on statistical considerations) will be discussed in the context of desirable short- and long-term solutions.

Immunoblastic sarcoma with leukemic blood picture in the terminal stage of mycosis fungoides.

A 76 year old man with mycosis fungoides developed an immunoblastic sarcoma and a leukemic blood picture in the final tumor stage after 6 years, in which the disease had clinically progressed in a typical manner. The results of histological and cytochemical studies of autopsy material are presented. Based on these findings and evidence of the T cell nature of mycosis fungoides, the immunoblastic sarcoma observed in the terminal stage of this case of mycosis fungoides might be of the rare T cell type.

The pathological anatomy of surgically reconstructable or prosthetically correctable congenital valvular malformation of the mitral region.

The special pathology of reconstructable or only prosthetically correctable congenital malformations of the mitral valve is described on the basis of the following examples taken from our own operative and autopsy material of the last 5 years: 1. Congenital isolated mitral stenosis in female twins (7 month old infant and 33 month old child). 2. Congenital isolated mitral insufficiency in a 7 1/2 year old boy. 3. Combined mixed mitral valve malformations with a parachute valve-like mitral valve anomaly, combined with hypoplasia of the ascending and descending aortas, in a 6 1/2 year old girl. 4. Congenital mitral insufficiency with a parachute mitral valve, combined with supravalvular aortic stenosis and multiple peripheral stenoses of the pulmonary arteries in a 13 1/4 year old boy. 5. Insufficiency of the mitrally inverted tricuspid valve with so-called corrected transposition of the great vessels in a 6 year old boy and with Ebstein's anomaly in a 2 1/2 year old boy. 6. A second mitral ostium in the aortic mitral leaflet with a partial atrioventricular canal in a 6 3/4 year old girl with Ellis-van Creveld syndrome. 7. Bland-White-Garland syndrome with relative mitral insufficiency in a 5 month old and a 4 month old boy. Despite the recurrence of similar and comparable findings, each of our cases of congenital or early acquired noninfectious mitral valve malformation was formally different. n his was also true for the cases of congenital isolated mitral stenosis in twins. Therefore, surgical correction requires a unique procedure for each case. It is possible to reliably infer the degree of malfunction of the atrioventricular valve in a mitral position from the special pathology only by considering the clinical data. On the other hand, a detailed evaluation of congenital mitral valve malformations is possible only through direct inspection--either by the surgeon or through an autopsy--despite modern cardiodiagnostic methods. Typical secondary findings are also discussed--for instance, endocardial fibrosis of the left atrium and the configuration of the heart. The anatomical prerequisites for surgical reconstruction or replacement of the valve with a prosthesis are mentioned.