Chronic myeloproliferative disorders: prognostic importance of new working classification.

Variants of chronic myeloproliferative disorders (CMPD) were compared according to their clinical features and classified by bone marrow biopsy appearances. Subsequently, this classification was further evaluated using survival data and histological variables from iliac crest biopsy specimens of an additional 1391 patients, making a total of 2241 patients available for analysis of outcome. The patients were grouped again into three main classes: "typical"; "variant"; and "transformed". "Typical" comprised the "classic" groups. "Variant" included the less uniform myeloproliferative syndromes, distinguished also by more variable clinical features, a different prognosis, and a greater tendency to fibrotic and blastic transformation. "Transformed" defined the end stages of both "typical" and "variant" types. Ten subgroups were distinguished by different histology and prognosis. Particular prognostic importance was assigned to atypia and immaturity of haemopoiesis, predominance of individual haemopoietic cell line, number and anomalies of megakaryocytes and progressive fibrosis. It is suggested that the proposed subclassification would be helpful for studies of epidemiology and therapeutic trials by allowing more homogeneous groups to be recognised.

Comparison of bone marrow histology in early chronic granulocytic leukemia and in leukemoid reaction.

A retrospective study was performed on bone marrow biopsies of 50 untreated patients with leukemoid reactions (LR) and 50 untreated patients with early chronic granulocytic leukemia (CGL). A comparison was made between hematopoietic and adipose tissues, bone and its cells, as well as other stromal components in these two disorders. Histologic and histomorphometric analyses revealed significant differences in trabecular structure, in localization of fat cells, in numbers of sinusoids, capillaries and various stromal elements. No significant differences between LR and CGL were detected in the quantity of erythro- and granulocytopoiesis and of megakaryocytes, but these were smaller in CGL than in LR. This histologic and histomorphometric evaluation demonstrates that certain histologic features may serve as valuable aids in distinguishing LR from CGL.

[Diagnosis and prognosis of hairy cell leukemia]. / Die Diagnose und Prognose der Haarzell-Leukämie.

During 1966 and 1986 202 patients with hairy cell leukemia in the bone marrow biopsy were observed. All hairy cells were categorized according to their nuclear morphology into ovoid subtype, convoluted subtype and indented subtype. The overall survival of 113 non-splenectomised patients was 11 months. However, the median survival time of each subtype differed considerably with 55 months for the ovoid subtype, 8 months for the convoluted and 6 months for the indented type. The prognosis of splenectomy patients were significantly better at a p-value of less than 0.0001 than the survival of the non-splenectomised patients. The median survival time was 59 months. Also in this group of patients the prognosis was different for the ovoid, convoluted and indented subtype. The median survival time of the ovoid subtype is not yet reached, despite a observation time of more than 180 months. In contrast, the survival time for the convoluted and indented subtypes was 26 months. These data elucidate that at least part of the heterogeneity in the clinical course of this disease can be explained by the morphologically distinct subtypes and that splenectomy prolongs profoundly but to a different degree the survival of patients with all three histological subtypes. The response rate to r.-IFN alpha-2b is higher in patients with the ovoid than with the convoluted and indented subtypes.

Histologic classification and staging of multiple myeloma. A retrospective and prospective study of 674 cases.

Bone marrow biopsies of 674 patients with multiple myeloma (MM) were processed for diagnostic evaluation. Histologic variables were correlated with the clinical features to determine factors of value in predicting prognosis. Four of these were used to classify MM into six histologic types: Marschalko type; small cell type; cleaved type; polymorphous type; asynchronous type; and blastic type. These six types were subsequently combined into three prognostic grades: low, intermediate, and high, analogous to the malignant lymphomas. The quantity of plasma cell burden in the biopsy proved to be a useful criterion for histologic staging of MM, supplementing any clinical staging system in use. Both these parameters, grade and stage, provide information required for decisions on treatment modalities, while the effects of therapy can be monitored by sequential biopsies.

Changes in trabecular bone, hematopoiesis and bone marrow vessels in aplastic anemia, primary osteoporosis, and old age: a comparative histomorphometric study.

Retrospective histologic analyses of bone biopsies and of post mortem samples from normal persons of different age groups, and of bone biopsies of age- and sex-matched groups of patients with primary osteoporosis and aplastic anemia show characteristic age dependent as well as pathologic changes including atrophy of osseous trabeculae and of hematopoiesis, and changes in the sinusoidal and arterial capillary compartments. These results indicate the possible role of a microvascular defect in the pathogenesis of osteoporosis and aplastic anemia.

Working classification of chronic myeloproliferative disorders based on histological, haematological, and clinical findings.

Bone marrow biopsies of 850 patients with chronic myeloproliferative disorders were taken at initial diagnosis; and 169 sequential biopsies over periods of one to 188 months. Three micron sections of all biopsies were evaluated semiquantitatively with reference to the proliferating cell lines, anomalies of megakaryocytes, and fibrosis or osteosclerosis. Correlations between initial histological findings, clinical, haematological, and survival data were analysed statistically. The predominant cell lines distinguished the classical entities of polycythaemia vera, primary thrombocythaemia, and chronic myeloid leukaemia and correlated with their different prognoses, while megakaryocytes characterised subgroups that were prone to fibrotic or blastic transformation. Based on the initial histological, clinical, and haematological data analysed a working classification of chronic myeloproliferative disorders was proposed that permits recognition of both typical and atypical cases of chronic myeloproliferative disorders.

Chronic myeloproliferative disorders (CMPD).

The wide clinical range of CMPD can be understood as leukaemia of pluripotent stem cells according to the pathogenic concepts reviewed above. Blastic metamorphoses of CMPD are regressions to a more primitive level of cellular differentiation. The predominant proliferative cell line characterizes the classical entities of PV, PT and CML, and their different prognoses. Pure erythrocytic and megakaryocytic proliferations are more compatible with sustained physiologic bone marrow functions than granulocytic proliferations. The combinations of granulocytic and megakaryocytic growth are especially prone to develop MF/OMS, in which participation of immune reactions, of granulocytic and of platelet factors is probable. An etiologic role for ineffective thrombocytopoiesis is supported by experimental as well as by histologic evidence. Myelofibrosis and osteomyelosclerosis may have similar causes, but develop independently. The prevalence of the female sex among thrombocythaemic patients was proven statistically also for the increase of giant type megakaryocytes in the form of clusters in the bone marrow, and for longer median survival of females in CMPD, especially when there is megakaryocytosis in the bone marrow. It is assumed that females may be better protected against the detrimentous effects of abnormal platelet production. An arbitrary classification according to haematologic and histologic criteria was applied to PV, PT and CML, and groups with typical and atypical haematologic and histologic signs were distinguished. The latter cannot be separated from each other by their various haematologic manifestations, but by histology and their different propensity to progress into more immature and/or fibrotic stages. Three major groups are characterized by histology: mixed granulocytic-megakaryocytic myelosis with giant megakaryocytic clusters, a similar variant with diffuse distribution of giant megakaryocytes, and immature and/or pleomorphic megakaryocytic myelosis. Transitions from each of these groups have been observed as well as transitions from each of the typical CMPD-entities into these less typical forms. CML, frequently accompanied by dwarf-megakaryocytes, often develops into pleomorphic megakaryocytic or blastic myelosis. Blastic dedifferentiation and myelofibrosis manifest themselves as closely related end stages, to which principally all groups proceed after a longer or shorter period of time, modified by the proliferating cell lines in each group. Clinical, experimental and histologic evidence of this natural history has been reviewed, with special emphasis on the re-evaluation of technically optimal bone marrow biopsies of untreated patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Assessment of bone marrow histology in the malignant lymphomas (non-Hodgkin's): correlation with clinical factors for diagnosis, prognosis, classification and staging.

Bone marrow biopsies of 678 untreated patients with established malignant non-Hodgkin's lymphomas (ML) were investigated. The bone marrow was involved in 468 cases, an overall frequency of 69%. The Kiel classification of the ML (based on lymph node histology) was applied and the biopsies were classified: ML lymphocytic 36%, ML 'hairy cell' 24%, ML lymphoplasmacytic/cytoid 24%, ML centrocytic 6%, ML centroblastic/centrocytic 4%, ML lymphoblastic (without ALL) 3%, ML centroblastic 2% and ML immunoblastic 1%. The life tables of the patients were similar whether classified according to the histology of the lymph node or the bone marrow. A multivariate computer based analysis of both clinical and histological data was performed to test their prognostic relevance. The cell type, the proliferation pattern and the extent of infiltration in the bone marrow all proved to be factors of prognostic significance. The results indicate that classification of the ML based on lymph node histology is applicable to the bone marrow, is reproducible and has prognostic significance. Consequently, a bone marrow biopsy is a useful clinical tool for staging and for histological classification of patients with ML.

Bone marrow histology in myeloma: its importance in diagnosis, prognosis, classification and staging.

A study has been made of 420 bone marrow biopsies from patients with multiple myeloma (220), idiopathic monoclonal gammapathy (50), reactive plasmacytosis (42) and solitary plasmacytoma (22). Histology and immunohistological parameters were more reliable than cytology in distinguishing a reactive from a neoplastic plasmacytosis. Histological variables were correlated with the clinical features of the patients to determine the factors which were of value in predicting prognosis. Plasma cell maturity and the extent of infiltration in the biopsy by myeloma cells proved to be highly significant in predicting the duration of survival. On the basis of these criteria multiple myeloma was classified into two types: plasmacytic of low-grade malignancy and plasmablastic of high-grade malignancy; and into three stages which accurately reflected the progression of the disease. We conclude that a bone biopsy provides useful information for the diagnosis, classification and staging of patients with multiple myeloma.

Detection of haematologic and nonhaematologic cancer by bone biopsy.

A retrospective study was carried out to test the efficacy of routine bone marrow biopsies for the diagnosis, classification, and prognosis of different forms of neoplastic involvement. Trephine and needle biopsies of the iliac crest of 3,626 patients with haematologic and 838 patients with nonhaematologic neoplasias were embedded without prior decalcification. 43 histologic variables were evaluated in 3-millimicrons sections of each biopsy, stained by five different techniques. The incidence of bone marrow involvement, in decreasing order of frequency, was as follows: plasmacytoma 55% and 95% of 428 cases, malignant lymphoma 37% and 79% of 1.112 cases, metastatic carcinoma 20% and 63% of 838 cases, and Hodgkin disease 3% and 28% of 772 cases each without and with manifest systemic dissemination. In the group of the metastatic carcinomas, there was a striking incidence of bone marrow involvement--82%--due to occult primary tumours. From a comparison of these figures with those reported in the literature, it is concluded that the large variations in positive and negative results are due to 1) differences in the size and the preparation of the specimens, 2) extent of the neoplastic dissemination at the time of the biopsy, and 3) the incidence of bone marrow involvement characteristic for a particular type of neoplasia. In addition, a subclassification of the chronic myeloproliferative disorders is proposed; it is based on histologic criteria whose prognostic relevance was tested and demonstrated by statistical analysis of the survival rates. The high incidence of detection reported in this study in patients without other evidence of systemic spread, or even in patients with occult neoplasias, provides a strong justification for the use of bone marrow biopsy as a primary diagnostic tool as well as a staging procedure, in both haematologic and nonhaematologic cancer.

[Twelve theses on the pathogenesis of primary and secondary osteoporosis based on histological observations]. / Zwölf histobioptische thesen zur pathogenese der primären und sekundären osteoporose.

In spite of a well defined clinical syndrome and a wealth of biochemical information, the pathogenesis of primary osteoporosis is still uncertain. Microscopic evaluation of semithin sections of 1727 bone biopsies from patients suffering from "idiopathic" osteoporosis and 288 from patients with secondary osteoporosis has lead to the recognition of a pathogenetic relationship between changes of the bone marrow capillaries and atrophy of the trabecular bone in these groups. A new hypothesis is proposed for the structural and functional role of the bone marrow capillaries in normal and abnormal osseous remodelling; this is based on comparative morphometric analysis of normal cases and of hypo- and hyperplastic changes of the myelogenous and osseous tissues in various haematological and bone disorders. The hormonal and nervous regulation of the microcirculation of bone marrow may offer a new approach to the understanding and cure of so-called idiopathic osteoporosis.

The clinical study of micro-metastatic cancer by bone biopsy.

Bone marrow biopsies were investigated for the presence of neoplastic cells in 3150 patients with known or suspected malignancies. Marrow involvement was found in 42 per cent (359 of 838) cases of carcinomas, 15 per cent of 772 cases of Hodgkin's disease, 55 per cent of 1125 cases of malignant lymphoma, 75 per cent of 428 cases of multiple myeloma. In 139 cases of occult primaries the incidence of marrow involvement was 82 per cent. Micrometastases were found in 18 per cent of 359 positive biopsies from patients with solid tum ours. In this group no correlation was established between haematological findings in the peripheral blood and the size of the metastases. There was a striking variability in the type and components of the marginal zone at the interface between metastases and hematopoietic tissue, most probably due to differences in characteristics of the neoplastic cells. The high percentage of marrow involvement by metastatic carcinoma indicates that bone marrow biopsy could profitably be included in the initial investigation of patients with solid tumours.