Myeloid metaplasia of the central nervous system in patients with myelofibrosis and agnogenic myeloid metaplasia. Report of 3 cases and review of the literature

Foci of meningeal myeloid metaplasia were found in 3 of 11 consecutive autopsied patients with myelofibrosis and agnogenic myeloid metaplasia. The clinical and pathological findings in an additional seven published patients with agnogenic myeloid metaplasia who developed neurological manifestations due to pressue of hemopoietic tumors in the central nervous system are reviewed.     

Plasma cell dyscrasia with marrow fibrosis. Clinicopathologic syndrome

Five new cases of plasma cell dyscrasia with coexistent myelofibrosis are described and six previously reported cases are reviewed. Four of the new patients and two from the literature had features of a previously unrecognized syndrome. This syndrome was characterized by significant paraprotein levels, marked marrow fibrosis, and plasmacytosis, without features of extramedullary hematopoiesis (agnogenic myeloid metaplasia) and leukoerythroblastosis. These patients were generally severely anemic and commonly leukopenic and thrombocytopenic. In contrast, one of the new patients and four in the literature showed classic features of the myeloproliferative disease, myelofibrosis with agnogenic myeloid metaplasia, along with features of typical multiple myeloma.     

Excess of Blood Group B in Primary Myelofibrosis

The distribution of ABO and Rhesus (D) blood groups was studied retrospectively in 40 patients with primary myelofibrosis (PMF). Only patients with a leukoerythroblastic peripheral blood, splenomegaly and marrow fibrosis in whom chronic myeloid leukemia and secondary myelofibrosis was absent were included in the study. In 14 patients (35%), PMF was preceded by another myeloproliferative disorder (polycythemia rubra vera, essential thrombocythemia or unclassified myeloproliferative disorder), while 26 patients (65%) represented agnogenic myeloid metaplasia (AMM). Comparison with Hospital and Irish blood group distribution showed a significant increase in blood group B (p less than 0.01) in PMF. This increase remained statistically significant for both the AMM and the non-AMM subgroup of PMF when each subgroup was considered separately. This finding supports previous suggestions that the various myeloproliferative disorders which proceed to myelofibrosis are a closely related group rather than a heterogeneous collection of diseases.     

Elevated levels of basic fibroblast growth factor in megakaryocytes and platelets from patients with idiopathic myelofibrosis

Idiopathic myelofibrosis, or agnogenic myeloid metaplasia, is a chronic myeloproliferative disorder characterized by clonal expansion and marrow fibrosis. Although marrow fibrosis appears to be a reactive process, it substantially contributes to impaired haemopoiesis. During the last few years the implication of megakaryocyte-derived growth factors in its pathogenesis has been documented.
We previously reported increased expression of TGF-β in patients with idiopathic myelofibrosis. In the present study we show that circulating megakaryocytic cells from such patients expressed high levels of basic fibroblast growth factor (bFGF). An increased expression of bFGF was also detected in patients' platelets. Under culture conditions, bFGF present in megakaryocytic cells was not exported into the medium, consistent with the fact that bFGF is devoid of a secretion peptide signal. Interestingly, this lack of bFGF secretion was observed in all patients but one, who was in an accelerated phase of the disease and presented an important percentage of circulating megakaryoblasts.     

Increased circulating CSF-1 (M-CSF) in myeloproliferative disease: association with myeloid metaplasia and peripheral bone marrow extension

Myeloproliferative disease (MPD) is heterogeneous in phenotypic expression and may display features consistent with expansion and activation of the monocyte/macrophage population during its course. The role of colony-stimulating factor-1 (CSF-1) in the pathophysiology of MPD was investigated by measuring circulating CSF-1 levels and examining their relationship to disease phenotype. Serum CSF-1 concentrations, measured by radioimmunoassay, were elevated in all MPD phenotypes. CSF-1 levels differed significantly between groups of patients with essential thrombocythemia, polycythemia vera, and postpolycythemic or agnogenic myeloid metaplasia (in ascending order). CSF-1 serum levels were positively correlated with spleen size and the degree of peripheral bone marrow extension, determined by scintigraphy using a macrophage-seeking isotope. There was no correlation between CSF-1 concentration and circulating levels of erythrocytes, neutrophils or platelets, or the presence of bone marrow fibrosis. Elevated serum CSF-1 levels appear to be associated with an expanded monocyte/macrophage population in MPD. In view of the known cooperativity between CSF-1 and other growth factors in regulating hematopoiesis, the finding of increased serum CSF-1 concentrations and its association with myeloid metaplasia and bone marrow extension may indicate a pathophysiologic role for CSF-1 in determining the phenotypic expression of MPD.     

Clinical, pathological and molecular features of the chronic myeloproliferative disorders: MPD 2005 and beyond

The combined use of bone marrow histopathology, biomarkers and clinical features has the potential to diagnose, stage and distinguish early and overt stages of ET, PV and idiopathic myelofibrosis, that has an important impact on prognosis and treatment of MPD patients. As the extension of the PVSG and WHO for ET, PV and agnogenic myeloid metaplasia (AMM), a new set of European clinical and pathological (ECP) criteria clearly distinct true ET from early or latent PV mimicking true ET, overt and advanced polycythemia vera (PV), and from thrombocythemia associated with prefibotic, early fibrotic stages of chronic megakaryocytic granulocytic metaplasia (CMGM) or chronic idiopathic myelofibrosis (CIMF). Cases of atypical MPD and masked PV are usually overlooked by clinicians and pathologists. Bone marrow biopsy will not differentiate between post-PV myelofibrosis versus so-called classical agnogenic myeloid metaplasia. The recent discovery of the JAK2 V617F mutation can readily explain the trilinear megakaryocytic, erythroid and granulocytic proliferation in the bone marrow, but also the etiology of the platelet-mediated microvascular thrombotic complications at increased platelet counts and red cell mass in essential thrombocythemia and polycythemia vera.     

Paroxysmal nocturnal hemoglobinuria as a marker for clonal myelopathy.

Paroxysmal nocturnal hemoglobinuria (PNH) is recognized as a clonal disorder manifested as increased sensitivity of marrow cells to complement. Case reports have associated this condition with leukemia, myelodysplasia, and myeloproliferative disorders. We identified 47 patients with PNH from 1976 to 1990. In 9 of the 47 patients, PNH was associated with another clonal myelopathy. Five patients had PNH and a myelodysplastic syndrome, and four had PNH and agnogenic myeloid metaplasia. PNH preceded the development of myelodysplastic syndrome but occurred after the development of agnogenic myeloid metaplasia. This is the largest series of PNH and other clonal myelopathies. We suggest that the PNH defect may represent a second manifestation of a single stem cell disorder.     

Increased serum procollagen III aminoterminal peptide in myelofibrosis

Myelofibrosis has been shown to involve an increase in type III collagen in the marrow. The aminoterminal procollagen III (PC III) peptide fragment is released during the production of PC III by fibroblasts and its serum level is therefore a marker for type III collagen synthesis. Using a recently developed sensitive radioimmunoassay, serum levels of PC III peptide were measured in 30 patients with myeloproliferative disease and 23 normal volunteers. Levels were found to be elevated above normal values in patients with polycythemia vera, even more elevated in patients with polycythemia and evidence of secondary myelofibrosis with myeloid metaplasia, and most strikingly elevated in patients with agnogenic myeloid metaplasia and severe marrow fibrosis. There was a significant association between serum levels of PC III peptide and the extent of reticulin fibrosis in bone marrow biopsies. Serum PC III level appears to be a quantitative marker for myelofibrosis.     

High levels of circulating CD34 cells, dacrocytes, clonal hematopoiesis, and JAK2 mutation differentiate myelofibrosis with myeloid metaplasia from secondary myelofibrosis associated with pulmonary hypertension

We studied 25 patients with myelofibrosis with myeloid metaplasia and 19 patients with secondary myelofibrosis associated with pulmonary hypertension (PH). In these 2 groups, we compared the peripheral-blood CD34 count, the clonality of granulocytes and platelets in peripheral blood, the mutational status of the JAK2 kinase gene, and the morphology of the peripheral blood and bone marrow. We found that the following were distinctive features of myelofibrosis with myeloid metaplasia but not of secondary myelofibrosis due to PH: high circulating CD34 cell count, the presence of clonal platelets and granulocytes and of peripheral-blood dacrocytes, and a JAK2 1849G>T (V617F) mutation. We conclude that these are intrinsic features of clonal progenitors present in patients with myelofibrosis due to myeloproliferative disorders and that these features are not due to the abnormal marrow architecture seen in secondary myelofibrosis.     

Hypermethylation of the P15INK4b and P16INK4a in agnogenic myeloid metaplasia (AMM) and AMM in leukaemic transformation

Hypermethylation of p15 and p16 genes was determined in 32 patients with agnogenic myeloid metaplasia(AMM), also known as idiopathic myelofibrosis (MF). These included 10 patients in leukaemic transformation phase. Using polymerase chain reaction-based methylation analysis assay methods, with substantiation using Southern blot analysis, the study showed no hypermethylation of p15 or p16 genes in the chronic phase of AMM, but p15 gene hypermethylation was found in four patients (40%) and p16 gene hypermethylation in two patients (20%) when they were in leukaemic transformation stage. Furthermore, two of the patients in leukaemic transformation were found to have both p15 and p16 gene hypermethylation, demonstrating possible multiple gene hypermethylation in the same patient. Thus, hypomethylation agents for treating patients with AMM in leukaemic transformation may be appropriate for future trials.     

Myelofibrosis in Chronic Granulocytic Leukaemia

Serial trephine biopsies were performed in 45 cases of chronic granulocytic leukaemia (CGL) in order to determine the frequency and significance of secondary myelofibrosis in the evolution of the disease. Histological changes were graded 1-5b, ranging from no increase in reticulin to dense osteomyelosclerosis. Many cases showed a progressive increase from Grade 1 to Grade 3, and accelerated disease, or blast crisis, often supervened when Grade 3 changes were present. However, a significant number of cases showed Grade 4 and 5 changes, which were indistinguishable histologically from those found in agnogenic myeloid metaplasia (AMM) (idiopathic myelofibrosis), at the time of diagnosis. These patients did not always show a rapidly fatal course and may be considered as an example of 'transitional myeloproliferative disorder', with features intermediate between CGL and AMM.     

Studies of the production and life span of erythrocytes in myeloid metaplasia

1. Four patients with agnogenic myeloid metaplasia and one patient withpolycythemia vera and myeloid metaplasia were studied with Fe⁵⁹, Cr⁵¹ andglycine-2-C¹⁴.

2. Three of the patients with agnogenic myeloid metaplasia had activesplenic, hepatic or renal erythropoiesis. One had deficient erythropoiesis.

3. The red cell life span was short in all of the patients with agnogenicmyeloid metaplasia, definite splenic sequestration occurring in two patients.The red cell life span was normal in the patient with polycythemia vera andmyeloid metaplasia.

4. The possible indications for splenectomy were discussed.

Submitted on July 25, 1958 Accepted on October 12, 1958     

Urinary hydroxyproline excretion in myelofibrosis

Urinary hydroxyproline measurements were performed in a group of health volunteers as well as patients with cancer and myelofibrosis. Patients in whom there was no metastatic involvement of bone marrow excreted an amount of hydroxyproline not different from that of the control group. Those who had marrow metastasis produced elevated levels of hydroxyproline; the highest excretions were observed when marrow fibrosis was associated with metastasis. These results contrasted with those observed in agnogenic myeloid metaplasia patients whose excretions were equivalent to the control group. The result suggests differences in the pathogenesis of myelofibrosis and a technique potentially useful for distinguishing between patients who may otherwise be diagnostic problems.     

Immunoreactive prolyl hydroxylase in patients with primary and secondary myelofibrosis

Prolyl hydroxylase (PH) is an important enzyme in collagen synthesis. It is required for the hydroxylation of prolyl residues in peptide chains in collagen synthesis. Serum PH activity was measured in patients with primary myelofibrosis (agnogenic myeloid metaplasia and myelofibrosis with prior history of polycythaemia vera), in patients with secondary myelofibrosis (in association with carcinoma metastasis), in patients with other myeloproliferative disorders and in controls (anaemia patients and normal volunteers). Both primary and secondary myelofibrosis had significantly elevated PH values, while other myeloproliferative disorders did not differ from normal controls. Increased PH levels in patients with primary and secondary myelofibrosis may signify increased collagen synthesis and may serve as an indicator for the development of fibrosis in the course of myeloproliferative disease.     

Pulmonary hypertension in patients with myelofibrosis secondary to myeloproliferative diseases

We examined the clinical characteristics of six patients with myelofibrosis secondary to myeloproliferative diseases whose clinical courses were complicated by pulmonary hypertension to determine possible causal links between the two disorders. Six patients (four male, two female), with diagnoses of myeloproliferative disease, myelofibrosis (one with polycythemia vera, three with agnogenic myeloid metaplasia, one with unclassified myeloproliferative syndrome, one with essential thrombocytosis), and pulmonary hypertension are presented. Measurement of the pulmonary artery pressure was performed by Doppler echocardiography in all patients and by right sided heart catheterization in four patients. The range of resting pulmonary artery systolic pressure was 35 to 47 mmHg above the mean right atrium by echocardiography. One patient had autopsy evidence of pulmonary myeloid metaplasia and interstitial fibrosis; another had acute leukemic infiltration of the lung parenchyma. All patients had thrombocytosis; symptomatology in one patient with marked thrombocytosis improved with plateletpheresis. Two patients suffered systemic thrombosis. All patients had severe hepatomegaly. Two patients had evidence of left ventricular dysfunction. The interval between the development of dyspnea and death was less than seven months in five of the patients. A causal link between pulmonary hypertension and myelofibrosis secondary to myeloproliferative diseases is suggested for each patient. Hematopoietic infiltration of the pulmonary parenchyma, portal hypertension, thrombocytosis, hypercoagulability, and left ventricular failure may account in part for the development of pulmonary hypertension in these patients. Patients with myelofibrosis and dyspnea should have Doppler echocardiography to evaluate pulmonary artery pressures. Am. J. Hematol. 60:130–135, 1999. © 1999 Wiley-Liss, Inc.     

Splenectomy in chronic myeloid leukemia and myelofibrosis with myeloid metaplasia

Myelofibrosis with myeloid metaplasia (MMM) is a collective term that describes the related disorders AMM, PPMM, and PTMM. The chronic myeloid disorders include chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and agnogenic myeloid metaplasia (myelofibrosis). These disorders display varying propensities for pathologic enlargement of the spleen which can lead to mechanical discomfort, hypercatabolic symptoms, anemia, thrombocytopenia, and portal hypertension. Splenectomy has been found to be of little benefit in the early stages of chronic myeloid leukemia. Similarly, the benefit of splenectomy in advanced cases is limited to symptomatic palliation and treatment of delayed engraftment after allogeneic bone marrow transplantation. Although polycythemia vera and essential thrombocythemia are also characterized by splenomegaly, splenectomy is not considered a therapeutic option in the absence of transformation of the disease into myelofibrosis with myeloid metaplasia. Splenectomy has been studied most in myelofibrosis with myeloid metaplasia. Although there is no clear survival advantage to splenectomy in this disorder, the surgical procedure can result in substantial palliation of mechanical discomfort, hypercatabolic symptoms, portal hypertension, and anemia. However, the procedure is associated with an approximately 9% mortality rate, and the postsplenectomy occurrence of extreme thrombocytosis, hepatomegaly, and leukemic transformation is of major concern.     

Agnogenic myeloid metaplasia with pulmonary hematopoiesis

Agnogenic myeloid metaplasia (AMM) is characterized by bone marrow fibrosis, splenomegaly and leukoerythroblastic anemia and is frequently accompanied by extramedullary hematopoiesis (EMH). Pulmonary interstitial EMH associated with myelofibrosis has rarely been described in the medical literature and is usually fatal. We report the case of a 77-year-old man with agnogenic myeloid metaplasia (AMM) treated with hydroxyurea, who seven years after diagnosis presented with dyspnea and severe hypoxemia. Radionuclide bone marrow scanning demonstrated increased tracer activity on the bases of both lungs, consistent with non-hepatosplenic EMH. Pulmonary EMH is rare in patients with AMM, but should be considered in patients with hypoxemia and respiratory distress.     

'Early' splenectomy and survival in agnogenic myeloid metaplasia. An analysis of 338 cases published since 1940

The data available for 338 cases of splenectomy in agnogenic myeloid metaplasia published since 1940 were retrieved from the literature and analyzed. The median survival of cases operated upon at an early stage of the disease (as judged by their hemoglobin level, platelet number, and splenic size) was compared with the survival reported in conservatively treated patients diagnosed at an early stage of agnogenic myeloid metaplasia. Survival time since diagnosis of patients with early splenectomy was similar to, or shorter than, that reported in conservatively treated patients with early agnogenic myeloid metaplasia.     

Agnogenic myeloid metaplasia with pulmonary hematopoiesis

Agnogenic myeloid metaplasia (AMM) is characterized by bone marrow fibrosis, splenomegaly and leukoerythroblastic anemia and is frequently accompanied by extramedullary hematopoiesis (EMH). Pulmonary interstitial EMH associated with myelofibrosis has rarely been described in the medical literature and is usually fatal. We report the case of a 77-year-old man with agnogenic myeloid metaplasia (AMM) treated with hydroxyurea, who seven years after diagnosis presented with dyspnea and severe hypoxemia. Radionuclide bone marrow scanning demonstrated increased tracer activity on the bases of both lungs, consistent with non-hepatosplenic EMH. Pulmonary EMH is rare in patients with AMM, but should be considered in patients with hypoxemia and respiratory distress.