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.

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.

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.

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.

Tumors of the thymus and thymic region: III. Clinicopathological studies on teratomas and tumors of Germ Cell type.

In a series of 82 patients with tumors of the thymus and thymic region there were 11 with teratomas and germinal tumors. Four of these patients had benign cystic teratomas, 4 had malignant teratomas, 1 had an embryonal carcinoma, and 2 had seminomas. The benign teratomas were removed by simple extirpation without complications. The malignant teratomas were highly invasive, and despite extensive operations and postoperative radiotherapy, 3 of the 4 patients died within 9 months. One patient with predominantly seminomatous differentation of the teratoma was alive and well more than 3 years after the operation. The patient with an embryonal carcinoma died after 4 months. One of the 2 patients with seminoma remained alive 20 years after radical excision and postoperative radiotherapy. The other, who had a huge seminoma, died during operation. The prognosis in patients with seminomas or with predominantly seminomatous structures in teratomas seems to be good after combined radical excision and radiotherapy, although nonradical resection followed by raditherapy may be justified in high-risk patients.

Tumors of the thymus and thymic region: I. Clinicopathological studies on thymomas.

A series of 43 patients with thymoma was reviewed. The patients were classified with respect to some factors of prognostic significance. The tumors were reclassified histologically, and a staging system with three defined stage-groups was applied to the series on the basis of operative findings and histological examination of surgical specimens. Surgical-pathological staging is of high prognostic and therapeutic importance in thymomas. Complete removal of the tumor was possible in the 25 patients with stage I or II disease and in 14 of the 18 patients with stage III tumors. Pleural metastases were observed in half of the patients with stage III disease. Even patients with extensive local spread or pleural metastases were subject to tumor resection. The treatment of choice is radical resection along in stage I; radical extirpation and, if indicated, postoperative radiotherapy in stage II; and radical resection whenever possible, even in cases of pleural spread, in stage III, with postoperative radiotherapy and chemotherapy. Myasthenia gravis is an indication rather than a contraindication to radical treatment of thymoma, although some patients may deterioratte. The importance of total thymectomy is stressed.

Tumors of the thymus and thymic region: II. Clinicopathological studies on Hodgkin's disease of the thymus.

Among 82 patients with a tumor in the thymic region, 17 had a lesion that fulfilled the criteria for Hodgkin's disease of the thymus; the histopathological differentiation of this entity from thymomas is discussed. All patients received surgical treatment and postoperative radiotherapy. After a mean observation time of 10 years there was no local recurrence and no death due to the disease, though 3 deaths were cuased by the treatment. New clinical manifestations occurred in 3 of the 14 long-term survivors: they were treated successfully by operation or irradiation. A very aggressive surgical approach involving extirpation of all tumor tissue, extensive excision of the surrounding tissues and adjacent lymph nodes, and supplementary radiotherapy seems to be the treatment of choice.

Rearrangement of chromosome no. 3 in a case of preleukemia with thrombocytosis.

The clinical and cytogenetic findings of a patient with the preleukemic syndrome and a structural rearrangement involving both chromosomes No. 3 are described. The karyotypic abnormality consisted of an insertion of a part of the long arm of one chromosome No. 3 into the other, i.e., ins(3;3)(q27;q21q27). A prominent feature of the bone marrow was a marked megakaryocytic hyperplasia. The platelet count temporarily exceeded 1000 x 10(9)/liter. The findings of the present case, together with similar observations by others, suggest that the long arm of chromosome No. 3 may contain a region involved in the regulation of megakaryopoiesis.

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.

Incidence and histopathology of metastases of mammary carcinoma in biopsies from the posterior iliac crest.

Bone marrow biopsies were taken from the posterior iliac crest in 532 women with unilateral breast cancer. Metastatic tumors were found in 10% of the biopsies. In a group with negative radiological examinations of the skeleton, the incidence of positive bone marrow biopsies was 1.6%. In a group with radiologically detectable metastases in the skeleton 28% of the biopsies were positive. In the latter group 43 out of 45 individuals with positive biopsies had negative x-rays of the pelvis. Histopathologically, 19% of the metastatic tumors were osteolytic, 65% were osteoblastic and 16% did not influence the bone structure. The fibrous reaction in and around the bone marrow tumors was similar to that found in the primary tumor. In 74% the morphological pattern was consistent throughout the biopsy, whereas in 26% the morphology was different in different parts of the biopsy. No specific histopathology was observed in the individuals with negative radiological examinations of the skeleton. Bone marrow biopsy of the posterior iliac crest does not seem to be helpful as a routine method in the initial staging of mammary carcinoma but may contribute to establish the degree of tumor spread in individuals with positive or suspicious x-ray of the skeleton.

The cellular infiltrate in contact hypersensitivity to picryl chloride in the mouse.

In the present work, the contact hypersensitivity skin test reaction to picryl chloride in CBA mice was examined. The test was performed by applying the contact allergen to the ear skin and making a series of histological analyses up to 24 hours after challenge. An increment in ear thickness, measured with an engineer's micrometer 24 hours after challenge, was obvious in a group of sensitized mice when compared with a nonsensitized control group, and the difference was found to be highly significant. One hour after challenge, mononuclear cells appeared in the dermis, increasing in numbers during the following 12 hours. At this time, neutrophil granulocytes were the dominant cells in the infiltrate and remained so up to 24 hours after challenge. On the basis of the experiments performed here we conclude that measuring of the ear swelling with a micrometer 24 hours after challenge is a useful and reliable test of contact sensitivity in the mouse.

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.

The ultrastructure of the megakaryocytes in idiopathic thrombocytopenic purpura (ITP) in relation to thrombokinetics.

The ultrastructure of megakaryocytes was examined in eight patients with idiopathic thrombocytopenic purpura (ITP) and the results were compared with those obtained from controls and with data obtained from platelet kinetic studies. Platelet production was significantly increased in (ITP) and related to the megakaryocyte number and volume. In all cases of ITP megakaryocytes containing tubular demarcation membranes were found. The granular content and the distribution of the demarcation membrane system in these megakaryocytes from cases of ITP were similar to those features seen in normal cells of the same degree of maturity. In three cases of ITP an increased content of a dilated demarcation membrane system was found in promegakaryocytes and granular megakaryocytes, in one of these cases with the additional formation of large membrane complexes. The ultrastructural findings lend support to the results obtained from the thrombokinetic studies namely that the megakaryocytes in the bone marrow react to thrombocytopenia with an increased production of platelets.

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.

On the analysis of platelet survival curves and the calculation of platelet production and destruction.

Platelet survival, platelet production and megakaryocyte quantifications were studied in control subjects and in patients with idiopathic thrombocytopenic purpura (ITP) and primary thrombocythaemia (PT). A platelet death probability function (DPF), which gives the expected probability of a randomly chosen platelet to be destroyed within the nextcoming short time interval, was constructed on the basis of the present knowledge of platelet function and the factors that influence its survival. Starting from this function platelet age and life span distributions and the function for the survival curve were derived. Platelet mean life span (MLS) was in controls 6.9d, in PT 5.2Dd and in ITP 0.44d. Determinations of platelet life span and platelet age distributions revealed a considerable variation in platelet life spans about these means and a great difference in platelet age compositions between the 3 groups of subjects studied. The function for the platelet survival curve, derived from the DPF, was employed in the calculation of platelet production and there was a highly significant relationship between platelet production and megakaryocyte volume per microliter bone marrow giving mutual confirmation to the 2 determinations and to the correctness of the death probability function.

Regression of lymphomatous polyposis of the rectum after COP-treatment.

A case of localized lymphomatous polyposis of the rectum successfully treated with a combination of cyclophosphamide, vincristine and prednisone (COP regimen) is reported and the literature is briefly reviewed.

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

Megakaryocyte quantifications in relation to thrombokinetics in primary thrombocythaemia and allied diseases.

Megakaryocyte morphology was studied quantitatively in primary thrombocythaemia (PT) and in chronic myelogenous leukaemia (CML). The relation of thrombokinetics to megakaryocyte quantifications was evaluated in PT and compared to previously obtained results in polycythaemia vera (PV) and idiopathic thrombocytopenic purpura (ITP). Megakaryocyte area, number and volume per mul bone marrow were significantly higher in PT as compared to controls. The nuclear lobe number was significantly increased and the megakaryocytes were shifted towards more mature forms, suggesting a prolonged megakaryocyte generation time. In CML the megakaryocyte number and volume per mul bone marrow were also significantly above normal, but the megakaryocyte area, number of lobes and degree of megakaryocytic maturation were significantly below normal. Platelet production was in PT 6.2 times normal and proportional to the increase in megakaryocyte volume which was 6.8 times normal. In PV with major splenomegaly the mean platelet production rate was higher (9.5 times normal) although their peripheral platelet count was lower than in PT. This discrepancy is explained by the greatly enlarged splenic platelet pool in the PV patients. In ITP the mean platelet production rate was 2.2 to 3 times normal and was significantly lower than in PT and PV.