The pathogenesis of splenic extramedullary hematopoiesis in metastatic carcinoma

Splenic extramedullary hematopoiesis (EMH) is a characteristic finding in agnogenic myeloid metaplasia (AMM) and in the spent phase of polycythemia vera (PV). Evidence from our laboratory has suggested that splenic EMH in these conditions results from the filtration of circulating hematopoietic cells from the peripheral blood and does not arise de novo from splenic stem cells. To further test this hypothesis, 31 autopsy and 26 surgical cases of carcinoma metastatic to the bone marrow were studied. The presence of leukoerythroblastosis (LEB) correlated with intravascular hematopoiesis (IVH) in the bone marrows associated with reticulin fibrosis, and with splenic EMH in the autopsy cases. These studies provide evidence that stromal changes in the bone marrow with resulting IVH, LEB, and splenic EMH are not unique to AMM and PV but also occur in such unrelated conditions as metastatic carcinoma, and suggest that these phenomena are causally related.     

Nephrotic syndrome associated with agnogenic myeloid metaplasia

Extramedullary hematopoiesis being an important feature of agnogenic myeloid metaplasia (AMM), a chronic myeloproliferative disease of clonal origin, may affect the kidneys, but this condition is usually asymptomatic. Until now, there is only one reported case of nephrotic syndrome associated with AMM. We present a patient with AMM who had nephrotic syndrome and whose renal biopsy revealed membranous glomerulonephritis together with renal extramedullary hematopoiesis.     

The forgotten myeloproliferative disorder: myeloid metaplasia

Myelofibrosis with myeloid metaplasia is a hematologic disorder currently classified with polycythemia vera and essential thrombocythemia as a chronic myeloproliferative disease. The median age at diagnosis is 60 years, and more than 90% of patients are diagnosed after age 40 years. Clinical manifestations include massive splenomegaly, progressive anemia, profound constitutional symptoms, and extramedullary hematopoiesis. The diagnosis is confirmed by bone marrow examination after other causes of myelofibrosis are ruled out. Median survival is 5 years and causes of death include leukemic transformation. Prognosis is adversely affected by the presence of anemia (hemoglobin <10 g/dl), leukopenia or leukocytosis (white blood cells >30,000/ micro l), circulating blasts, and hypercatabolic symptoms. Conventional treatment is palliative and does not improve survival. In this regard, androgen preparations, corticosteroids, and erythropoietin are useful for the treatment of disease-associated anemia. Symptomatic splenomegaly is best managed by cytoreductive therapy or surgical removal. Radiation therapy is most useful in the treatment of nonhepatosplenic extramedullary hematopoiesis. New treatment approaches include the use of thalidomide alone or in combination with prednisone and hematopoietic stem cell transplantation.     

Dramatic Resolution of Pleural Effusion in Children with Chronic Myelomonocytic Leukemia Following Short-course High-dose Methylprednisolone

High-dose methylprednisolone (HDMP) which can induce—differentiation and -apoptosis of myeloid leukemic cells has been shown to be very effective in the treatment of extramedullary infiltration (EMI) of children with acute myeloblasts leukemia (AML). In the present study 2 children with chronic myelomonocytic leukemia (CMML) who had pleural effusions were given a single daily dose of oral methylprednisolone (20 mg/kg or 30 mg/kg). In addition to dramatic improvement of respiratory symptoms, pleural effusions disappeared in four days in both patients possibly due to apoptotic cell death induced by HDMP treatment. Further studies are needed to determine whether high-dose corticosteroids are also effective on the resolution of pleural effusions associated with other malignant disease.     

Pleurésie myélomateuse: à propos d’une observation

Pleural effusions are relatively rare during the course of multiple myeloma and most often occur with non-specific disorders of the disease. We report an observation of myelomatous pleural effusion; the diagnostic was ascertained by the pleural biopsy. The patient did not respond to the therapy and died after few days. Occurrence in the course of multiple myeloma of pleural effusions due to infiltration of the pleura by plasma cells reflects aggressive disease and indicates a poor prognosis.     

肺癌胸膜种植转移的CT表现及其解剖分布

目的 总结胸膜种植转移的CT征象及其解剖分布。方法 回顾分析32例临床、病理确诊为原发性肺癌伴胸膜种植转移患者的CT表现。结果 本组患者的胸部CT征象主要表现为胸腔积液(24例)、脏层胸膜转移结节(10例)、壁层胸膜转移结节(16例)及胸膜增厚(3l例)。脏层胸膜转移结节中，分布于肺表面脏层胸膜9处，叶间胸膜l0处。壁层胸膜转移结节分布在膈胸膜、肋胸膜、纵隔胸膜、肺韧带，共45处。结节小至2—5mm的粟粒，大至5～10mm。胸膜增厚中因直接侵犯造成者10例，间接转移者2l例，后者中9例表现为增厚≤10mm，4例一侧胸膜环状增厚，5例纵隔胸膜增厚，3例肺韧带增厚。结论 肺癌胸膜转移最常见的CT征象为胸腔积液，其次为胸膜转移结节及胸膜增厚。转移结节最常分布在隔胸膜、肋胸膜，并可转移至肺韧带；早期表现为粟粒状，在肺窗容易发现。     

Extramedullary peritoneal hematopoiesis combined with tuberculosis in a patient with primary myelofibrosis

Primary myelofibrosis (PMF) is a myeloproliferative disorder characterized by bone marrow fibrosis or dysmegakaryocytes, extramedullary hematopoiesis, and the presence of JAK2 mutations. We present a 73-year-old man with PMF that had a fulminant clinical course. Peritoneal extramedullary hematopoiesis combined with tuberculosis was found 4 months after the diagnosis. This combination of complications has not been previously reported. These events were followed by rapid leukemic transformation and the patient’s death.     

Conventional and experimental drug therapy in myelofibrosis with myeloid metaplasia

Myelofibrosis with myeloid metaplasia (MMM) is currently classified as a classic (ie, BCR-ABL-negative) myeloproliferative disorder characterized by anemia, multiorgan extramedullary hematopoiesis, constitutional symptoms, and premature death from either leukemic transformation or other disease complications. Stem cell transplantation can be curative, but many patients either are not appropriate candidates or do not choose to accept the significant risks associated with transplantation. Current pharmacologic therapy has been beneficial mainly in terms of palliating disease-associated cytopenias, constitutional symptoms, splenomegaly, and other organ damage from excess myeloproliferation. Novel treatment strategies are under investigation, including targeted inhibition of JAK2^V617F, the activating tyrosine kinase point mutation present in about half of patients with MMM. In this article, we review both the old and new pharmacologic options for MMM.     

Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): Consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT)

The International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) is comprised of hematologists, hematopathologists, and laboratory scientists and its main goal is to provide a forum for scientific exchange and collaboration. During its first general meeting in April 2006, the IWG-MRT established uniform treatment response criteria for chronic idiopathic myelofibrosis (CIMF); also known as agnogenic myeloid metaplasia (AMM), myelofibrosis with myeloid metaplasia (MMM), and many other names in the hematologic literature. This document summarizes the proceedings from the second meeting of the IWG-MRT, in November 2006, where the group discussed and agreed to standardize the nomenclature referring to CIMF: (i) the term primary myelofibrosis (PMF) was chosen over several other designations including CIMF, AMM, and MMM, (ii) myelofibrosis that develops in the setting of either polycythemia vera (PV) or essential thrombocythemia (ET) will be referred to as post-PV MF and post-ET MF, respectively, and (iii) "leukemic" transformation will be recognized as blast phase disease (PMF-BP, post-PV/ET MF in blast phase).     

肺癌术中胸腔冲洗液细胞学检查及DNA倍体分析

目的探讨术前无胸腔积液肺癌患者术中胸腔冲洗液细胞学检查及DNA倍体分析的临床价值。方法151例行肺切除手术的患者,开胸后未作任何胸内操作前冲洗胸腔,收集胸腔冲洗液行细胞学检查及DNA倍体分析。结果细胞学检查阳性率为13.9%(21/151),DNA异倍体检出率为35.1%(53/151),其中9例肺良性疾病患者细胞学检查阳性率及DNA异倍体检出率均为0(0/9)。结论对术前无恶性胸腔积液肺癌患者,术中胸腔冲洗液细胞学检查可能找到癌细胞,DNA异倍体检出率高于细胞学检查阳性率,对临床诊断及术后辅助治疗有指导意义。     

Risks and benefits of splenectomy in myelofibrosis with myeloid metaplasia: a retrospective analysis of 26 cases

BACKGROUND AND OBJECTIVES: To evaluate the outcomes of splenectomy in myelofibrosis and myeloid metaplasia (MMM). METHODS: We retrospectively reviewed our records of 26 patients with MMM who underwent an open splenectomy at Boston University Medical Center between 1979 and 1995. Fourteen patients had agnogenic myeloid metaplasia (AMM) and 12 had myelofibrosis with antecedent myeloproliferative disorders (MF). The main indications for splenectomy were progressive transfusion-dependent anemia, painful splenomegaly, and hypercatabolic symptoms associated with cytopenia. RESULTS: Median time to splenectomy after the diagnosis of MMM was 29 months ranging from 1 to 96 months. Three patients (11%) died within 1 month after the surgery because of sepsis. The most common peri- and postoperative complications were pneumonia and other bacterial infections (42%), cardiac events (19%), acute bleeding (15%), ileus (15%), and venous thrombosis (12%). Of the eight surviving patients who underwent splenectomy for transfusion dependent anemia, six (75%) had improvement in their hematocrit levels with abolishment of blood transfusions. A durable symptomatic palliation was achieved in all patients. Liver enlargement was noted in seven patients at 1-year evaluation. None of these patients developed hepatic failure. Leukemic transformation occurred in 8 of 18 patients (44%) postsplenectomy. The median overall survival for the entire group was 58.5 and 28 months from the diagnosis of MMM and the time of splenectomy, respectively. There was no difference in survival rates between patients with AMM and MF. CONCLUSIONS: Splenectomy is an effective palliative procedure with an acceptable morbidity in selected patients with MMM. Progressive transfusion-dependent anemia should also be considered an indication for splenectomy in the absence of leukemic evolution.     

Effective combination chemotherapy of carboplatin and paclitaxel in the treatment of a recurrent small-cell lung cancer patient

Although small-cell lung cancer (SCLC) is a highly chemosensitive tumor, most patients relapse and have a poor prognosis. Relapsed patients become candidates for second-line or salvage chemotherapy. We report an effective case of weekly chemotherapy with carboplatin and paclitaxel in the treatment of a recurrent SCLC patient. A 58-year-old man diagnosed as SCLC received four courses of concurrent chemoradiotherapy with etoposide and cisplatin, and achieved a complete response. Solitary pulmonary metastasis was detected 9 months after chemoradiotherapy. He received second-line chemotherapy with irinotecan and cisplatin, but the mass remained as stable disease. Thus, thoracotomy was performed for the resection of the mass, and histological examination revealed a recurrence of SCLC. Pleural dissemination and multiple pulmonary metastases were detected, and he received third-line chemotherapy with amrubicin. However, there was evidence of recurrence, and he was given fourth-line chemotherapy with topotecan. Marked growth of pleural dissemination caused severe back pain, hence fifth-line chemotherapy using paclitaxel (70 mg/m(2); days 1, 8, and 15) and carboplatin (AUC 2; days 1, 8, and 15) was initiated. After three courses of chemotherapy, a good response was confirmed. The toxicity of chemotherapy was mild, and his symptoms including back pain completely disappeared. The patient has been alive now for 42 months after the initial therapy. Our result suggests that weekly chemotherapy with carboplatin and paclitaxel could be a well-tolerated and effective regimen for salvage chemotherapy of recurrent SCLC.     

A non-chemotherapy treatment of a primary effusion lymphoma: durable remission after intracavitary cidofovir in HIV negative PEL refractory to chemotherapy.

A 78-year-old male of Italian heritage was evaluated for progressiveshortness of breath over two months and recurrent pleural effusions.He had a 5-year history of fluctuating anemia and mild lymphadenopathyand had previously undergone a bone marrow examination thatwas normal. An excisional lymph node biopsy revealed only reactivechanges. Upon evaluation, he had bilateral pleural effusions, a smallpericardial effusion, pericardial     

Orbital apex syndrome: a rare presentation of extramedullary hematopoiesis: case report and review of literature

We describe a case of compressive neuropathy in the orbital apex due to extramedullary hematopoiesis (EMH). A 64-year-old man with Polycythemia Rubra Vera developed unilateral visual loss, proptosis, complete ophthal-moplegia, and facial paresis. Bone marrow biopsy showed myelofibrosis. Magnetic resonance imaging demonstrated enhancement at the orbital apex and subtle optic canal narrowing. Decompression of the optic nerve with biopsy of surrounding bone showed EMH. The patient received a course of radiation without benefit. We suggest including the diagnosis of EMH of the orbital apex bones in the differential diagnosis of patients with myeloproliferative disorders who develop an orbital apex syndrome.     

Efficacy of combination chemotherapy for stage IV colon cancer with extensive peritoneal dissemination and multiple liver metastases: a case report

A patient was diagnosed as having subacute ileus due to advanced cancer of the descending colon with multiple liver metastases and was treated by palliative left hemicolectomy. He was considered to have Stage IV cancer based on the finding of extensive peritoneal dissemination. Histopathological examination showed that the tumor was moderately differentiated adenocarcinoma. Postoperative palliative chemotherapy was given with 5-FU and LV twice a month as 1 course, and he received a total of 3 courses. As a result, the multiple liver metastases were completely eliminated. However, his liver metastases recurred, so CPT-11 was added to 5-FU and LV for another 3 courses. When bilateral pleural effusions developed about 1 year postoperatively, CPT-11 was changed to CDGP. Jaundice and massive ascites eventually developed, and he died about 1 year and 5 months postoperatively.     

High level of vascular endothelial growth factor in hemorrhagic pleural effusion of cancer

Angiogenic cytokines, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenin, are candidates for the induction of pleural effusions because they have been implicated in the induction of neovascularization, vascular permeability, and hemorrhage both in the inflammatory process and in tumor progression. Thus, we hypothesized that these angiogenic factors in effusion might be involved in the clinical manifestation of malignant pleural disease. We measured the levels of VEGF, bFGF, and angiogenin in pleural effusions and sera from 40 patients. Pleural effusions due to malignancy (1,350 pg/ml) contained significantly higher levels of VEGF than effusions due to inflammatory diseases (102 pg/ml; p = 0.034). Furthermore, hemorrhagic effusions showed significantly higher VEGF levels (1,942 pg/ml) than non-hemorrhagic effusions (202 pg/ml; p = 0.016) in malignant patients. In contrast, neither bFGF nor angiogenin were correlated with any clinical manifestation of pleural effusion. Immunohistochemical study revealed that malignant cells in the pleura were stained with anti-VEGF antibody. Our data suggest that VEGF secreted from tumor cells may be involved in the accumulation of pleural effusion in malignancy, and that increased levels of VEGF may induce hemorrhagic effusion.     

Incidence,risk factors and management of pleural effusions during dasatinib treatment in unselected elderly patients with chronic myelogenous leukaemia

To assess the most important features and clinical impact of pleural effusions, which are a common toxicity during dasatinib treatment and often impair its high efficacy, 172 unselected consecutive patients with chronic myelogenous leukaemia in chronic phase treated in 27 Italian centres, with dasatinib when aged >60 years for resistance/intolerance to imatinib, were examined. During treatment, 52/172 patients (30.2%) presented pleural effusion, which was grades 1–2 in 38 patients and grades 3–4 in 14 patients (8.1% of the entire cohort of patients), according to the WHO scale; in 14/52 patients (26.9%), there was a concomitant pericardial effusion. Pleural effusion was recurrent in 25/52 patients (48.0%). Median time from dasatinib to first pleural effusion was 11.0 months (interquartile range 3.6–18.6). Eleven patients (6.4%) required permanent dasatinib discontinuation. Only presence of concomitant pulmonary disease ( p = 0.035) and initial daily dose of dasatinib (140 mg vs 100 mg, p = 0.014) were significantly associated with pleural effusions. There were no differences among patients with or without pleural effusions as concerns response rates and overall survival. Pleural effusions were common in our unselected ‘real‐life’ population of elderly patients but were clinically manageable and did not seem to affect treatment results. Copyright © 2012 John Wiley & Sons, Ltd.     

手术联合胸腔内循环热化学灌注治疗恶性胸腔积液

目的总结手术联合胸腔内循环热化学灌注治疗恶性胸腔积液的经验。方法11例恶性胸腔积液患者在手术治疗后接受了胸腔内循环热化学灌注。结果所有患者胸水都得到了有效控制,生活质量明显提高,预后良好。结论手术联合胸腔内循环热化学灌注多学科治疗模式对恶性胸腔积液有较好的疗效,不良反应小,值得推广。     

Hepatocyte growth factor/scatter factor is present in most pleural effusion fluids from cancer patients.

Pleural effusion samples were obtained from 55 patients with malignant disease, including patients with primary lung cancers and those with a variety of other tumours metastatic to the pleura. The effusions were assayed for the presence of hepatocyte growth factor/scatter factor (HGF/SF), by both ELISA and bioassay. The presence of malignant cells in the effusions was also assessed. Detectable amounts of the factor, as judged by both criteria, were found in over 90% of all the effusions, including those from patients with a wide variety of carcinomas and also lymphomas. A wide range of HGF/SF levels were found for all tumour classes, some effusions containing high levels above 4 ng ml-1. It is concluded that tumours within the pleura and adjacent lung tissue are usually exposed to biologically significant levels of HGF/SF.     

Surgical and radiotherapeutic approaches for myelofibrosis with myeloid metaplasia

Sequestration of circulating immature myeloid progenitors in the chronic myeloproliferative disorder myelofibrosis with myeloid metaplasia (MMM) leads to extramedullary hematopoiesis (EMH), as well as end organ enlargement and dysfunction. When medical therapy is inadequate to control symptomatic myeloproliferation, both surgical resection and/or external beam radiotherapy may provide palliative cytoreduction in specific situations. Therapeutic splenectomy may provide relief of pain, mass effect, an improvement in cytopenias, or even palliation of portal hypertension. However, the risks of perioperative and long-term complications limit the use of splenectomy in MMM to specific candidates. In addition to splenectomy, portal hypertension has been palliated by either elective esophageal variceal ligation or porto-systemic shunting (through either open or invasive radiographic means). External beam radiotherapy can provide palliative cytoreduction in afflicted organs, with the greatest benefit seen in the lungs and spine. Splenic radiation also can provide a decrease in the size of the organ but carries the risk of myelosuppression and potentially increases the risk associated with subsequent splenectomy. Hepatic and abdominal radiation may palliate hepatomegaly and/or ascites, but cytopenias are common and responses brief. Novel therapies aimed at the pathogenesis of the disorder are needed for more efficacious and targeted therapy of MMM.