The histopathology of chronic myeloproliferative diseases

This chapter discusses the histopathology of five groups of chronic myeloproliferative diseases: chronic myeloid leukaemia, polycythaemia vera, essential thrombocythaemia, chronic idiopathic myelofibrosis and unclassifiable myeloproliferation. Histological staging of the four haematologically defined diseases is performed by grading the three most prominent variables: megakaryocytes, fibres and blasts. Histological outcome is correlated to the staging of diagnostic bone marrow biopsies; megakaryocytic involvement is correlated with the risk of myelofibrosis. An excess of blasts is related to the risk of leukaemic transformation. The progression of myelofibrosis depends on the grade of fibre increase at diagnosis. These three statements are highly significant and valid for all types of chronic myeloproliferative disorders. The results of cytogenetics are discussed in relation to the histological classification for these patient groups. Changes in bone marrow histology following myelosuppressive therapy is presented. Prospective studies under standardized protocol therapy are recommended, so that the long-term effects of therapy can be assessed.     

Running interferon interference in treating PV/ET: meeting unmet needs

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Adriamycin cardiotoxicity: Possible pathogenic mechanisms

The antitumor agent, adriamycin, causes in humans a cardiomyopathy associated with elevated tissue Ca²⁺. Hence, adriamycin was tested for an ability to affect the Ca²⁺ influx mediated by the slow channels in ventricular cells of isolated perfused chick hearts. The fast Na⁺ channels were blocked by tetrodotoxin or voltage inactivated by elevated (25 mm) K⁺, thus rendering the hearts inexcitable. Low concentrations of adriamycin (0.01 to 0.05 mg/ml) restored excitability in the form of slow action potentials (APs), and enhanced the maximum upstroke velocity ($\text{+}\text{V}\text{?}{}_{\mathrm{<mtext>max</mtext>}}$) of slow APs induced by isoproterenol (10^?6m). Higher concentrations (0.1 to 0.5 mg/ml) did not induce slow APs, and actually depressed or blocked the isoproterenol-induced slow APs. On the contractions recorded from hearts perfused with normal Tyrode solution, adriamycin also had a dual effect: at low concentrations, it had a positive inotropic action, whereas at higher concentrations, it had a negative inotropic action. Adriamycin (0.05 mg/ml) caused the cyclic AMP level to increase by about 50% over the control within 15 min, thus suggesting that this might be responsible for its positive inotropism. Higher concentrations (0.3 mg/ml) also raised the cyclic AMP, but the ATP level was depressed. In isolated mitochondria, adriamycin (0.5 mg/ml) depressed ADP-stimulated respiration, suggesting that impaired mitochondrial function could cause the depressed ATP levels. The results indicate that low concentrations of adriamycin augment the slow current, possibly by an increase in cyclic AMP level, whereas high concentration (0.5 mg/ml) depresses the slow current, perhaps due to lowered ATP levels. The enhanced Ca²⁺ influx (via stimulation of the slow channels) could be a factor in the Ca²⁺ overload associated with the adriamycin-induced cardiomyopathy.     

Chronic myeloproliferative diseases. Diagnosis and therapy

Chronic myeloproliferative disorders (CMPD) are neoplastic disorders of the hematopoietic stem cell. Four different entities are defined: chronic myeloid leukemia (CML), polycythemia vers, essential thrombocythaemia, and idiopathic myelofibrosis. In addition, overlapping entities within the CMPDs and between CMPDs and myelodysplastic syndrome have been described. Diagnostic measures are performed to classify the subtype exactly and to assess risk factors and prognosis. Cytogenetic and molecular analyses are mandatory for the characterization of the malignant clone. Hydroxyurea and interferon-alpha have proven effective in all CMPE. In CML, specific inhibition of the elevated ABL tyrosine kinase activity with imatinib is associated with high response rates. Allogeneic stem cell transplantation is the only curative treatment option for all entities. In CML, the decision-making analysis should be based on established scores. In BCR-ABL negative CMPDs an allogeneic stem cell transplantation should only be performed in patients with unfavorable prognosis.     

Clinical aspects of chronic myeloproliferative diseases.

The nonleukemic chronic myeloproliferative disorders, polycythemia vera, essential thrombocytosis, and myeloid metaplasia with myelofibrosis, are clonal disorders with similar but distinct clinical and laboratory findings. This review will discuss the diagnostic criteria for each disease, the variable clinical picture, and the therapeutic modalities, actual and theoretical.     

Pregnancy and its management in the Philadelphia negative myeloproliferative diseases

The myeloproliferative diseases (MPDs) present several therapeutic challenges in patients of childbearing potential. The most extensive literature exists for patients with essential thrombocythaemia, with over 200 pregnancies reported in retrospective case series. Yet there is conflicting data in relation to predicting pregnancy outcome and optimal management strategy. Pregnancy is less frequently reported for polycythaemia vera and myelofibrosis. There is a need for collaboration to further our knowledge in this field. Here, the literature is reviewed in detail and experience of different therapeutic strategies in pregnancy discussed. There is increasing understanding about the pathogenesis of placental dysfunction in inherited thrombophilia and antiphospholipid antibody syndrome pregnancy outcomes in these conditions parallel those reported for MPDs. Furthermore several large studies have influenced pregnancy management in these conditions and, whilst not directly applicable to MPDs, this data have potential to inform treatment protocols. This data are reviewed and a personal management strategy for pregnancy in MPD proposed.     

Granulomatous diseases and pathogenic microorganism

Granuloma formation is a chronic inflammatory reaction where macrophage system and other inflammatory cells are involved. After some antigen exposure and processing, T cells, macrophages, epithelioid cells, and giant cell are activated, and granulomas are formed. Granuloma is considered as a defense mechanism against antigens, which stay in the organs without inactivation. Granulomas including fibroblasts extra-cellular matrix surround and isolate the antigens. Granulomas are classified to noninfectious granulomas and infectious granulomas. However recent studies revealed pathogenic microorganism are suspected to be a cause of granuloma in non-inflammatory diseases. Balance between pathogenic microorganisms and defense mechanisms of the host might be important in the special immunologic reaction. In some cases, it is hard to clearly classify infectious and noninfectious granulomas. Recently, Eishi et al. reported that latent infection of Propionibacterium acnes might be cause of sarcoidosis. Several hypersensitivity pneumonias are considered to be caused by exogenous microorganisms. The symposium was organized to know and clarify the new mechanisms of non-infectious granulomatous lung diseases and pathogenic microorganisms. This report is a summary of a symposium entitled "Granulomatous Diseases and Pathogenic Microorganism", organized in the 82nd Japanese Society for Tuberculosis (president Dr. Mitsunori Sakatani, M.D.). 1. Imaging of Granulomatous Lung Diseases: Masanori AKIRA (Department of Radiology, National Hospital Organization Kinki-chuo Chest Medical Center) High-resolution computed tomography (HRCT) is a useful tool in the evaluation of parenchymal changes in patients with a granulomatous lung disease. In sarcoidosis, the HRCT findings include small, well-defined nodules in relation to lymphatic roots, lymph node enlargement, and middle or upper lobe predominance. The appearances of subacute hypersensitivity pneumonitis include ill-defined centrilobular nodules, ground-glass opacity, and air trapping especially on expiratory CT scan. Those of Langerhans cell histiocytosis include bizarre thin-walled lung cysts, centrilobular nodules and upper lobe predominance. Each of granulomatous lung disease has some characteristic HRCT appearances, but they all are non-specific for diagnosis. HRCT is also useful for grading of parenchymal changes in granulomatous lung diseases. 2. Histopathology of granulomatous lung diseases with special reference to differential diagnosis of infectious disease: Tamiko TAKEMURA (Department of Pathology, Japanese Red Cross Medical Center) The lung is commonly involved by various granulomatous diseases of various etiology. It is difficult to pathologically differentiate these granuloumatous diseases to conduct appropriate therapy, because of morphological similarity of epithelioid cell granuloma, variable etiology, and difficulty of identification of causative agents. Granulomatous diseases generally are divided into infectious and non-infectious ones for treatment. Although infectious granulomas usually reveal necrosis and abscess, non-infectious ones occasionally also reveal necrosis. In cases with granulomas in the lung, it is necessary to explore the etiologic agents including environmental ones. 3. Sarcoidosis and Propionibacterium acnes: Yoshinobu EISHI (Department of Pathology, Tokyo Medical and Dental University) P. acnes can cause latent infection in peripheral lung tissue and the mediastinal lymph nodes and persist intracellularly in a cell-wall-deficient form. This dormant form of P. acnes can be activated endogenously under certain environmental conditions (hormones, stress, living habits, etc.) and proliferate in cells at the sites of latent infection. Granulomatous inflammation occurs in sarcoidosis patients with hypersensitivity to intracellular proliferation of the cell-wall-deficient bacteria, which can infect other cells or organs when spread via the lymphatic or blood streams. The timely use of antibiotics may not only kill the bacteria proliferating at the site of disease activity, but also prevent endogenous activation of P. acnes. If long term administration of antibiotics eradicates dormant forms of the bacteria persistent in organs, it may lead to complete remission of sarcoidosis. 4. Farmer's lung and thermophilic actinomycetes: Takashi MOURI (Pulmonary Division, Iwate Prefectural Kitakami Hospital), Kohei YAMAUCHI, Hiroshi INOUE (Third Department of Internal Medicine, Iwate Medical University, School of Medicine), Kazuki KONISHI (Morioka Tsunagi Onsen Hospital) Farmer's lung is caused by the allergic reaction to inhalation of thermophilic actinomycetes. Acute symptoms are chill, fever, cough and dyspnea. Fine crackles is characteristic. Pathologically, alveolitis with lymphocytes infiltration and epithelioid cell granuloma and Masson's body are characteristics. Bronchoalveolar lavage analysis shows elevated lymphocytes and diverse CD4/8 ratio (high in average). Isolation from the environment improves the symptoms. Sometimes patients need steroid therapy, 0.5 to 1.0 mg/kg of predonisolone. Pulse therapy can be applied for severe cases. SLX analogue can prevent lymphocytes infiltration and granuloma formation in mice model. Some of acute farmer's lung show poor long term prognosis, showing emphysematous, fine granular or small nodules in chest CT. These chronic farmer's lung might be diagnosed as IIPs. 5. Hot tub lung: Takashi OGURA (Kanagawa Cardiovascular and Respiratory Center) Hot Tub Lung (HTL) is a disorder caused by exposure to Mycobacterium avium complex (MAC) organisms contaminating hot tub water. Whether this disease represents true infection or hypersensitivity pneumonitis is contoroversial. Recent reports support the theory that this disease represents a hypersensitivity pneumonitis rather than infection. The physicians should suspect a hypersensitivity pneumonitis reaction to MAC in the investigation of patients with hypersensitivity pneumonitis of unknown cause.     

Cardiac and vascular changes in cirrhosis： Pathogenic mechanisms

Cardiovascular abnormalities accompany both portal hy-pertension and cirrhosis.These consist of hyperdynamiccirculation,defined as reduced mean arterial pressureand systemic vascular resistance,and increased cardiacoutput.Despite the baseline increased cardiac output,ventricular inotropic and chronotropic responses tostimuli are blunted,a condition known as cirrhotic car-diomyopathy.Both conditions may play an initiating oraggravating pathogenic role in many of the complicationsof liver failure or portal hypertension including ascites,variceal bleeding,hepatorenal syndrome and increasedpostoperative mortality after major surgery or livertransplantation.This review briefly examines the majormechanisms that may underlie these cardiovascular ab-normalities,concentrating on nitric oxide,endogenouscannabinoids,central neural activation and adrenergicreceptor changes.Future work should address the com-plex interrelationships between these systems.     

Malignant lymphoma, multiple myeloma and myeloproliferative diseases in the elderly

Hematopoietic and immune function tend to deteriorate in the elderly. The incidence of hematologic diseases in the elderly is increasing as the percentage of elderly people in the whole population increases. Acute leukemia, myelodysplastic syndrome, malignant lymphoma, multiple myeloma, and myelodysplastic syndromes are commonly seen in the elderly. Malignant lymphomas are frequently seen in the elderly, and many elderly patients have poor performance status, and because they are more likely to suffer from impaired cardiac, respiratory, hepatic and renal function, as well as glucose intolerance, they are also more likely to suffer side effects due to chemotherapy. Particularly in patients aged over 80 years, to avoid side effects it is essential to adjust dosage and route of administration of chemotherapy. Although age is a significant negative prognostic factor for non-Hodgkin's lymphoma, it is possible for patients to enter complete remission with improvement of host-side factors. The clinical application of Rituximab is expected to improve chemotherapy outcomes in elderly B-cell lymphoma. The median age at the time of initial diagnosis of multiple myeloma (MM) is 60-70 years, and age is a negative prognostic factor. Clinically, higher rates of infection and heavy comorbidity are characteristic of this condition in the elderly. Although the incidence of bony lesions in elderly patients with MM is not different from the non-elderly, they do have a higher incidence of bone pain and pathologic fractures compared with the non-elderly patients. As the response to chemotherapy is good in the elderly, it is worth trying chemotherapy for MM. Polycythemia vera must be treated in the elderly, because chemotherapy decreases the incidence of thrombosis.     

The prothrombotic state in cancer: pathogenic mechanisms

Thrombosis and disseminated intravascular coagulation (DIC) are common complications in cancer. Patients with malignancy have a prothrombotic state due to the ability of almost all type of cancer cells to activate the coagulation system. However, none of the haemostatic markers of coagulation has any predictive value for the occurrence of the thrombotic events in one individual patient. The pathogenesis of the prothrombotic state in cancer is complex and, probably, multifactorial. Prothrombotic factors in malignancy include the tumour production of procoagulants (i.e., tissue factor (TF) and cancer procoagulant (CP)) and inflammatory cytokines, and the interaction between tumour cells and blood (i.e., monocytes/macrophages, platelets) and endothelial cells. Other mechanisms of thrombus promotion include some general responses of the host to the tumour (i.e., acute phase, inflammation, angiogenesis), decreased levels of inhibitors of coagulation, and impaired fibrinolysis. In addition, the prothrombotic tendency of cancer patients is enhanced by anticancer therapy, such as surgery, chemotherapy, hormone therapy and radiotherapy, by indwelling central venous catheter, and by haemodinamic compromise (i.e., stasis). However, not all of the mechanisms allowing the prothrombotic state of cancer are entirely understood. Therefore, it is presently difficult to rank the relative weight of these multiple interactions on the basis of the well-recognised clinical evidences of enhanced thrombotic episodes in patients with cancer.

In this review we attempt to describe the current proposed mechanisms for the pathogenesis of the prothrombotic state in cancer patient. A better understanding of these mechanisms could help clinicians in the developments of more targeted treatment to prevent thromboembolic complications in cancer patient.