Trends in the incidence of chronic Philadelphia chromosome negative (Ph-) myeloproliferative disorders in the city of Göteborg, Sweden, during 1983-99.

OBJECTIVE: In the literature the incidence rates for the chronic Philadelphia chromosome negative (Ph-) myeloproliferative disorders (MPD) are known to vary extensively; only a few studies have, however, been concerned with incidence trends over time. Therefore, the aim of the present work was to investigate possible trends as regards incidence rates over time for Ph-MPD. DESIGN: Herein, we carried out a retrospective population-based survey on the incidence of polycythaemia vera (PV), essential thrombocythaemia (ET) and chronic idiopathic myelofibrosis (IMF), in the city of Göteborg (Sweden), covering the years 1983-99. RESULTS: The study comprised 416 patients with Ph-MPD. There were 205 patients with PV, 153 patients with ET, 34 with IMF and 24 with unclassified MPD. The annual incidence for PV was 1.97 per 10(5) inhabitants; the corresponding figures for ET and IMF were 1.55 per 10(5) and 0.30 per 10(5) inhabitants, respectively. There was a significant increase in the annual incidence rate for ET (P = 0.008); this increase was significant for male subjects (P = 0.015) but did not reach significance for females (P = 0.118). No such increase over time was recorded as regards PV and IMF. CONCLUSIONS: The increasing annual incidence rate for ET is most possibly explained by the more frequent use of automated platelet counts whenever a patient consults a doctor. Thereby, an increasing number of patients with overt thrombocytosis of unknown origin are discovered and will be referred to specialists within the field of haematology for a correct diagnosis.

Hodgkin's lymphoma, Epstein-Barr virus reactivation and fatal haemophagocytic syndrome.

Haemophagocytic syndrome is a serious disorder, often related to Epstein-Barr virus (EBV) or other infectious agents. Frequently an underlying immune abnormality or a T-cell lymphoma is present. The combination of haemophagocytosis and Hodgkin's lymphoma seems to be rare. A 70-year-old female with rheumatoid arthritis was admitted with constitutional symptoms, persistent fever, pancytopenia, deranged liver enzymes, lymphadenopathy and splenomegaly. A fatal coagulopathy supervened. The clinical picture and the bone marrow findings indicated a haemophagocytic syndrome and a lymph node biopsy disclosed an EBV-positive Hodgkin's lymphoma. EBV serology pointed at viral reactivation and a high EBV DNA content was detected in serum by real-time quantitative PCR analysis (5.5 x 10(6) copies per mL). The case history is presented and the literature is reviewed.

Intratumoral microvascular density in malignant lymphomas of B-cell origin.

Sections of surgical lymph-node biopsies of four types of malignant non-Hodgkin's lymphoma of B-cell origin (B-NHL) classified according to the R.E.A.L. terminology or lymphadenitis were immunostained in order to demonstrate endothelial CD34 (QBEnd 10) and to determine the microvascular density and vessel-size distribution using an interactive image-analysis technique. Only microvessels displaying a cross-sectional area corresponding to a diameter of between 3.2 and 34.6 microm were included. The intratumoral microvascular density (iMVD) was found to be significantly higher in chronic lymphatic leukaemia (CLL, n = 13) compared with the clinically more aggressive mantle cell lymphoma (MCL, n = 9) and diffuse large B-cell lymphoma (DLBCL, n = 14). iMVD in CLL was also higher than in the follicular neoplastic parts (FL FOLL) of follicular lymphoma (FL, n = 16). In FL FOLL the microvessel density was, moreover, significantly lower than in the surrounding non-neoplastic FL tissue. In lymphadenitis (LA, n = 10) the iMVD was higher than in DLBCL, FL FOLL and MCL. The data suggest that future studies focusing on the relationship between iMVD and the clinical outcome within each particular NHL group should be carried out in order to verify whether iMVD is a prognostic factor in NHL, as it is in carcinomas.

Epidemiology of the myeloproliferative disorders: essential thrombocythaemia, polycythaemia vera and idiopathic myelofibrosis.

As to the epidemiology of myeloproliferative disorders (MPD) very little solid information is available in the literature. The present work attempted to study the incidence of MPD in the city of Göteborg, Sweden during a period of ten years. Therefore, retrospectively we assessed the number of subjects afflicted with polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IM) over the study period of 1983-1992. The yearly calculated incidence for PV was 2.8 per 100,000 population. For ET and IM the corresponding figures were 1.5 and 0.4, respectively. The results for PV demonstrated the highest incidence rate reported in literature so far. As to ET and IM our results largely agree with what has been reported previously in the literature.

Incidence of chronic myeloproliferative disorders in the city of Göteborg, Sweden 1983-1992.

An estimation of the incidence of polycythaemia vera (PV), essential thrombocythaemia (ET) and chronic idiopathic myelofibrosis (CIM) in the city of Göteborg, Sweden during the period 1983-1992 was made from a retrospective case analysis of patients registered as chronic myeloproliferative disorders (CMPD) at the Departments of Medicine and the Department of Pathology of the two major hospitals in the city. A total of 125 cases of PV, 56 males and 69 females were identified. The number of cases as well as the age-specific incidence increased with age. The over all annual gender-specific incidence was 2.69 cases per 10(5) male inhabitants and 3.12 cases per 10(5) female inhabitants. The incidence of PV in relation to the European Standard Population was 2.02 cases per 10(5) inhabitants and year. There were 72 cases, 20 males and 52 females, with ET. The age-specific incidence was in all ages higher for females than for males and increased with age. The annual gender-specific incidence was 0.96 per 10(5) male inhabitants and 2.35 per 10(5) female inhabitants. The incidence of ET in relation to the European Standard Population was 1.28 per 10(5) persons and year. There were 20 cases of CIM, 11 males and 9 females. The annual gender-specific incidence of CIM was 0.53/10(5) male inhabitants and 0.41/10(5) female inhabitants. The incidence of CIM in relation to the European Standard Population was 0.31 per 10(5) persons and year. Seven persons, 2 males and 5 females, had a CMPD that could not be included in any of the above-mentioned groups, but were registered as CMPD, unclassified.

Leukemic transformation of essential thrombocythemia without previous cytoreductive treatment.

Blastic transformation of essential thrombocythemia (ET) preceded by chemotherapy is occasionally described in the literature. In ET as well as in other myeloproliferative disorders the leukemogenic effect of alkylating agents and (32)P is well established, and recent reports also indicate a certain leukemogenic effect of hydroxyurea in these disorders. However, leukemic transformation in untreated ET seems to be a rare event. This is probably due to the fact that, at some time during their clinical course, most ET patients receive chemotherapy and are thereby exposed to leukemogenic challenge. We report on a woman with ET who had not received cytoreductive treatment prior to the development of acute myeloid leukemia, indicating that this transformation was a natural progression of her disorder.

Non-Hodgkin lymphoma in children: a 20-year population-based epidemiologic study in western Sweden.

PURPOSE: The aim of this study was to investigate incidence, clinicopathologic features, prognostic risk factors, and long-term survival in non-Hodgkin lymphoma (NHL) in a 20-year population-based study of children using Swedish health care organizations and their central registry for childhood malignancies. PATIENTS AND METHODS: The hospital registry, the Cause of Death Registry, and the two established Swedish registries for malignancy (the Swedish Cancer Registry and the National Registry for Solid Tumours in Childhood) were searched for children in western Sweden with NHL diagnosed from 1975 to 1994. The clinical files of all children with NHL were collected and abstracted for information regarding age at diagnosis, gender, disease characteristics, treatment, and outcome of treatment. All sections from paraffin-embedded blocks of tumors with a diagnosis of malignant lymphoma were collected and reexamined histopathologically and immunohistochemically. To guarantee that no patients with NHL were misdiagnosed, a reexamination of other childhood malignancies collected from these registries was also performed. Median follow-up duration of surviving patients is 10 years. RESULTS: The annual incidence of NHL in children younger than 15 years of age was 9/million children, representing 6% of all childhood malignancies during the investigation time. The male-female ratio was 4.1:1.0. Immunologic marker studies were available for 64 of the 77 NHLs: 41 patients had B-cell, 17 had T-cell, and 6 had Ki-1-positive anaplastic large cell lymphoma (ALCL). Two patients with Ki-1-positive ALCL were originally thought to have malignant histiocytosis and Langerhans cell histiocytosis (LCH), respectively. Treatment was the most significant prognostic factor; event-free survival (EFS) was 19% in the preprotocol era (1975 to 1979) and 74% from 1980 to 1994. Other than treatment, stage was the most significant prognostic factor; EFS was 86% for patients (1980 to 1994) with stage I or II disease and 64% for patients with stage III or IV disease, with a dismal prognosis for children with initial involvement of the bone marrow or central nervous system (EFS was 38% and 20%, respectively). Bulky disease and performance state at diagnosis were independent prognostic factors. The patterns of relapse, including early recurrence of the B-cell lymphomas, are in accordance with previous experience. CONCLUSION: The incidence of NHL was found to be somewhat higher than reported in our previous Nordic study. The higher incidence found in this study might be the result of the thorough data collection (based on hospital registry and cross-checked with all registries for malignant diseases in Sweden) or because reexamination of the tissue material was performed. A more pronounced male predominance than found in previous investigations was observed. The immunophenotypic distribution and the stage distribution is in accordance with earlier investigations. Treatment was the most important factor affecting outcome. A dramatic improvement of survival was seen with the introduction of intensive therapy; treatment success can be expected in 86% of children with localized disease and 64% of children with extensive disease. The absence of improvement in survival despite further treatment stratification with the introduction of the BFM protocol for B-cell-NHL is surprising. LSA2L2-like protocols seem to be as effective. Future studies on treatment of NHL must also concentrate on reducing the intensity of therapy in patients with lower risk disease to minimize late toxic effects.

Plasma thrombopoietin levels in thrombocytopenic states: implication for a regulatory role of bone marrow megakaryocytes.

To evaluate the diagnostic value of thrombopoietin (TPO, c-mpl ligand) measurements, and clarify the regulatory mechanisms of TPO in normal and in thrombocytopenic conditions, the plasma TPO concentration was determined in normal individuals (n = 20), umbilical cord blood (n = 40), chronic idiopathic thrombocytopenic purpura (ITP; n = 16), in severe aplastic anaemia (SAA; n = 3), chemotherapy-induced bone marrow hypoplasia (n = 10), myelodysplastic syndrome (MDS; n = 11), and sequentially during peripheral blood progenitor cell transplantation (n = 7). A commercially available ELISA and EDTA-plasma samples were used for the analysis. The plasma TPO concentration in the normals and umbilical cord blood were 52 +/- 12 pg/ml and 66 +/- 12 pg/ml, respectively. The corresponding values in patients with SAA and chemotherapy-induced bone marrow hypoplasia were 1514 +/- 336 pg/ml and 1950 +/- 1684 pg/ml, respectively, and the TPO concentration, measured sequentially after myeloablative chemotherapy and peripheral blood progenitor cell transplantation, was inversely related to the platelet count. In contrast, the plasma TPO recorded in patients with ITP (64 +/- 20 pg/ml) and MDS (68 +/- 23 pg/ml) were only slightly higher than normal levels. In conclusion, TPO levels were significantly elevated in patients in which bone marrow megakaryocytes and platelets in circulation were markedly reduced, whereas TPO levels were normal in ITP patients, and only slightly increased in the MDS patients. These latter patients displayed a preserved number of megakaryocytes in bone marrow biopsies. Our data support the suggestion that megakaryocyte mass affects the plasma TPO concentration. In thrombocytopenic patients a substantially increased plasma TPO implies deficient megakaryocyte numbers. However, TPO measurements do not distinguish between ITP and thrombocytopenia due to dysmegakaryopoiesis, as seen in MDS patients.

Flow cytometric analysis of megakaryocyte ploidy in chronic myeloproliferative disorders and reactive thrombocytosis.

Megakaryocyte (MK) ploidy patterns were analysed by flow cytometry in 29 newly diagnosed and previously untreated patients with chronic myeloproliferative disorders (MPD) and concomitant thrombocytosis, in 9 patients with reactive thrombocytosis (RT) and in 12 healthy individuals. Unfractionated bone marrow from routine aspirates was used. MKs were identified with a fluorescein labelled monoclonal antibody specific for glycoprotein IIIa (GPIIIa) and DNA was stained with propidium iodide. For the 12 healthy volunteers the mean modal ploidy number was 16 N; the 9 patients with RT displayed an identical MK ploidy pattern. The frequency of MKs with a ploidy > or = 32 N was 45% among the patients with essential thrombocythaemia (ET) compared to 32% among the healthy volunteers (p < 0.001). MKs with ploidy number > or = 64 N, comprising approximately 13% of the total number of MKs, was a characteristic finding in the patients with ET. Similar findings were present in 8 patients with polycythaemia vera (PV). In patients with PV 34% and 6% of the MKs displayed ploidies > or = 32 N and > or = 64 N, respectively. In contrast, a distinct shift towards lower ploidy number, with 63% of MKs < or = 8 N, was found among the 4 patients with chronic myeloid leukaemia (CML). The present results indicate that by using flow cytometric analysis of MK ploidy distribution in patients with thrombocytosis, those with a reactive cause are likely to be discriminated from patients with myeloproliferative thrombocytosis, i.e. PV and ET on one hand and CML on the other hand. The distinction between ET and PV, however, has to be made on other grounds.

Bulky centroblastic non-Hodgkin's lymphoma of the cranium vault mimicking brain involvement managed with chemotherapy: a case report.

BACKGROUND: Patients with central nervous system (CNS) involvement by high grade non-Hodgkin's lymphoma (NHL) have a poor prognosis. The roles of computed tomography, radiotherapy, and intrathecal and systemic chemotherapy still need to be defined. METHODS: A patient with bulky cranial lymphoma mimicking brain involvement is reported. A 62-year-old man was admitted with a huge scalp lump, headache, fatigue, and focal and generalized neurologic symptoms. Computed tomography showed an abnormal mass in the frontoparietal region involving the subcutaneous scalp, osteolytic destruction of the cranial vault, and a bulky mass that was interpreted to be intracranial. A systemic survey also revealed bulky retroperitoneal involvement and focal involvement of the spleen. Biopsy revealed a B-cell NHL of centroblastic type according to the Kiel classification. RESULTS: The patient was treated with a modified combination of cyclophosphamide plus mitoxantrone plus vincristine plus prednisone (CNOP) and intrathecal methotrexate. The patient responded with complete remission, including partial bone restoration of the cranium. At the time of this writing, his relapse free survival lasted 5 years. CONCLUSIONS: The initial interpretation of this case indicated that systemic chemotherapy with modified CNOP plus intrathecal methotrexate would be useful in the management of NHL with CNS involvement. The clinical outcome with rapid neurologic repair and also bone restoration of the cranial vault within 5 years suggests that the lymphoma probably never penetrated the dura and a successful treatment was achieved with combination chemotherapy only.

Peripheral and intrasplenic platelet kinetics and bone marrow megakaryopoiesis in alpha-2b-interferon treated hairy cell leukemia.

In eight patients with previously untreated hairy cell leukemia (HCL), by using 111In-labelled platelets and megakaryocyte quantitation, the splenic platelet pooling and the platelet production rate (P) were evaluated before and during alpha-2b-interferon (IFN) treatment. Both before and after 8 months of IFN therapy the spleen was shown to pool a sizeable amount of the total body platelet mass. The average splenic platelet pools, prior to and after 8 months of IFN, were 58 +/- 17 and 47 +/- 11%, respectively. At the time when treatment was initiated, the patients were heterogeneous as regards the spleen size, platelet kinetics, and the bone marrow morphology. Three patients had values for P below the 95th percentile for a group of healthy control subjects; following IFN therapy they displayed a substantial increase in P. In three other HCL patients, with the largest spleens, the pre-treatment P was normal, or slightly above the values seen for the control subjects. In these patients, changes in splenic platelet pool size, blood volume, and platelet mean life-span accounted for the increase in platelet count observed in response to IFN. The mean megakaryocyte number and volume per microliter bone marrow increased during IFN therapy, while the mean P remained slightly reduced. It is concluded that splenic platelet pooling would explain the previously described difference in platelet counts between splenectomized and non-splenectomized patients treated with IFN.

Endometrial thickness as measured by transvaginal sonography: interobserver variation.

Transvaginal sonography of the uterus has become an important tool for diagnosing endometrial pathology in women with postmenopausal bleeding. One parameter that has been claimed to be important for curly detection of endometrial pathology in this group of women is the endometrial thickness. The purpose of this study was to evaluate the reproducibility of measurements of endometrial thickness as performed by five inexperienced doctors and one doctor experienced in the transvaginal sonography technique. The endometrial thickness as measured by the experienced doctor was regarded as the 'true measurement', and the mean discrepancy from this true measurement was 1.5 mm for the inexperienced doctors. No endometrial pathology was found at the histopathological examination after dilatation and curettage (D & C) when the endometrial thickness was measured as

Dysplastic megakaryopoiesis with thrombocytopenia and chromosomal aberration.

A case of isolated thrombocytopenia with decreased platelet production and abnormal megakaryopoiesis is described. In the bone marrow, a chromosomally aberrant clone, 45,XX,-11,-18,+der (11;18)(11q13;18p11), was found. These findings indicate a myelodysplastic nature of the abnormal thrombocytopoiesis. The described case demonstrates the value of a bone marrow examination including histopathology with immunologic techniques to evaluate the megakaryopoiesis in thrombocytopenia and the interest of cytogenetic studies not only in instances with overt hematologic malignancies or complete myelodysplastic syndromes, but also when morphologic abnormalities occur in a single cell line.

The effect of alpha-interferon on bone marrow megakaryocytes and platelet production rate in essential thrombocythemia.

In 10 patients with previously untreated essential thrombocythemia (ET), by using 111In-labeled platelets and megakaryocyte morphometry, the relation between platelet production rate and bone marrow megakaryocytes was evaluated before and during alpha-2b-interferon (IFN) therapy. A highly significant decrease in platelet count occurred during IFN therapy; the platelet counts, at baseline and after 2 and 6 months of IFN therapy, were 1,102 +/- 345 x 10(9)/L, 524 +/- 169 x 10(9)/L (P less than .0001), and 476 +/- 139 x 10(9)/L (P less than .0001), respectively. The decrement in platelet count was mainly a result of diminished platelet production rate, which at baseline and after 2 and 6 months of IFN therapy was 89 +/- 30 x 10(10) platelets/d, 53 +/- 18 x 10(10) platelets/d (P = .0033), and 45 +/- 20 x 10(10) platelets/d (P less than .0001), respectively. Also, a slight shortening of platelet mean life-span (MLS) was observed in response to IFN treatment; platelet MLS was 7.96 +/- 0.69 days at baseline and 6.68 +/- 1.30 days (P = .012) after 6 months of IFN therapy. IFN induced a significant decrease in bone marrow megakaryocyte volume; both megakaryocyte nuclear and cytoplasmatic volumes were affected. The mean megakaryocyte volume was 372 +/- 126 x 10(2) pL/microL at baseline and 278 +/- 147 x 10(2) pL/microL (P = .049) after 6 months of IFN therapy. However, the number of megakaryocytes did not show any significant change in response to IFN. It is concluded that alpha-IFN reduces platelet production rate and the peripheral platelet count in ET mainly through an anti-proliferative action on the megakaryocytes and to a considerably lesser degree by a shortening of platelet MLS.

DNA content and nuclear size of megakaryocytes in thrombocythaemia.

Total nuclear DNA content and nuclear size of megakaryocytes were studied in biopsies of the iliac bone marrow of individuals with normal or increased platelet counts. The DNA content was determined using Feulgen cytophotometry of bone marrow smears and the nuclear area by morphometric analysis of megakaryocytes of bone marrow sections. The mean DNA content and the mean nuclear area were both significantly larger in megakaryocytes of patients with thrombocytosis as a result of myeloproliferative disease than in patients with secondary thrombocytosis as well as in two control groups of individuals with normal platelets counts, one comprising healthy volunteers, the other with various non-haematological disorders. There was a statistically significant correlation between the DNA content and nuclear area of the megakaryocytes (r = 0.92) in the entire group of bone marrows studied.

Primary gastrointestinal lymphoma incidence, clinical presentation, and surgical approach.

During a 5-year period, 15 cases of primary gastrointestinal lymphoma, corresponding to 14% of the non-Hodgkin's lymphomas, were diagnosed in a population of 200,000. Most patients had a short duration of symptoms--less than 3 months--and a clinical picture dominated by abdominal pain. All patients were laparotomized and six patients presented with an acute abdomen and were subjected to emergency operations. In seven cases, gastrointestinal malignancy was not suspected preoperatively. The patients were treated with a combination of surgery, cytostatic therapy, and/or radiotherapy. Cases with localized disease had a favorable prognosis, seven of nine patients being alive 31 to 70 months after diagnosis. A statistically significant difference in median survival was also noted between patients with lymphomas of low-grade and high-grade malignancy (70+ vs. 10.5 months).

The bone marrow in urticaria pigmentosa and systemic mastocytosis. Cell composition and mast cell density in relation to urinary excretion of tele-methylimidazoleacetic acid.

The bone marrow sections from five normal subjects and 18 patients with mastocytosis were examined to establish criteria to distinguish urticaria pigmentosa from systemic mastocytosis. Nine patients had increased numbers of mast cells in bone marrow sections stained with a long toluidine blue staining technique specific for mast cells, whereas five patients exhibited increased numbers of mast cells on May-Grünwald-Giemsa-stained smears of bone marrow. A positive correlation between the number of mast cells in sections of the bone marrow and the urinary excretion of the main histamine metabolite tele-methylimidazoleacetic acid was found. In ten of the examined bone marrow specimens, focal lesions containing mast cells, lymphocytes, and eosinophils appeared. The presence of these focal lesions together with either an increased number of mast cells in bone marrow sections and/or increased urinary excretion of telemethylimidazoleacetic acid is considered diagnostic of systemic mastocytosis. No patient exhibited myeloproliferative condition or other major hematologic abnormality.

The relation of platelet kinetics to bone marrow megakaryocytes in chronic granulocytic leukaemia.

The relation of thrombokinetics to quantitative determinations of megakaryocytes (mgkc) in bone marrow sections was studied in 11 consecutive cases of untreated Ph1-positive chronic granulocytic leukaemia (CGL). The results were compared with controls and with previously obtained data in polycythaemia vera (PV), primary thrombocythaemia (PT) and in idiopathic thrombocytopenic purpura (ITP). Platelet survival was significantly reduced in CGL. Platelet production was 5.8 x normal and the mgkc number and volume/microliter bone marrow were significantly increased as compared to controls. The increase in mgkc volume was not in proportion to that of number due to a significant decrease of mgkc size. Platelet production was strongly related to mgkc number/mm2 and to the mgkc volume/microliter bone marrow. The platelet production rate in relation to a unit of mgkc volume/microliter bone marrow was, however, greater in CGL than in controls, PV, PT and ITP. The chief reason for this is most probably the greater expansion of the total bone marrow mass in CGL.