- Email: [email protected]
Pseudo-myelofibrosis: A new clinical entity
European Journal of Internal Medicine 23 (2012) e78–e80
Contents lists available at SciVerse ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Letter to the Editor Pseudo-myelofibrosis: A new clinical entity
Keywords: Pseudo-myelofibrosis Myelofibrosis Lazy leukocyte syndrome Phagocytosis
To the Editor: Primary myelofibrosis (MF) is an established clinical entity due to a clonal disorder of myeloid stem cells. The major diagnostic demonstration rests on the presence of fibrosis of the bone marrow, megakaryocyte and platelet alterations, and of extramedullary erythromyelopoiesis, mainly in the liver and spleen. Reactive MF has been described in a number of conditions, like the human immunodeficiency syndrome [1], tuberculosis [2], toxic exposure to x-rays and chemicals, repeated bacterial infections [3], and treatment with thrombopoietic agents [4]. We herein report two patients exhibiting features of a new entity that we call pseudo-myelofibrosis (PMLF), to be distinguished from both true and reactive MF. A 55 year old Caucasian male (patient 1) had suffered from repeated respiratory and sinus infections since childhood. Anaemia and thrombocytopenia occurred at the age 27, when a bone biopsy prompted the diagnosis of MF, confirmed 5 times in the ensuing 28 years by repeated biopsies. He was admitted because of disseminated bronchopneumonia, and cutaneous necrotic ulcers in the malar and periorbital regions. WBC were 23.740/μL, neutrophils 21.900/μL, Hb 13.8 gr%, platelets Plts 82.000/μL. The peripheral blood smear did not disclose erythroblasts or giant platelets, while myelocytes and promyelocytes were seen. The cutaneous biopsy was compatible with an acute bacterial infection. A CAT of the abdomen showed a spleen of 14 cm. In the bone marrow aspirate BCRABL translocation and JAK2 mutation were negative. The bone biopsy, even when repeated after the acute infection had healed, was considered diagnostic of MF. An 83 year old Caucasian female (patient 2) was examined for severe anaemia and interstitial pneumonia. Anaemia disappeared after discontinuing oncocarbide, which she had taken during the previous 10 years following the diagnosis of chronic myelogenous leukaemia (CML). There was a history of recurrent sinusitis and mastoiditis since childhood, requiring mastoidectomy at age 8, pneumonia in her twenties, bullous eruption due to neutrophilic cutaneous abscesses at age 73. Subsequently, she developed cellulites, pneumonia, acute diverticulitis with perforation and abdominal abscess, rectovaginal fistula, abdominal wall abscess (Staphilococcus Guarnieri), hemicolectomy with surgical repair in 2005. In 2010 we repeated the bone marrow biopsy that was considered suggestive of MF. The Philadelphia chromosome, BCR-ABL rearrangement and JAK2 mutation were negative. Moderate spleen (20 cm) and slight liver
enlargement had remained stable over the last 10 years. Her WBC count never exceeded 20.000/μL, Hb remaining normal, platelet count 300.000 to 500.000/μL. A thorough review of all her bone marrow biopsies was considered consistent with MF instead of CML. A few months later the patient developed skin lesions with evidence of infiltration by blastic elements with high mitotic index and a phenotype (CD10+, CD79a+/−, CD34−, CD117−, CD99−, CD2−, CD20−, PAX5−, myeloperoxidase −) compatible with acute B-lymphocytic leukaemia. She died from myocardial infarction shortly thereafter. In both patients, WBC migration was investigated by the Department of Internal Medicine of the Genova University (Professor Franco Dallegri). Cells were allowed to migrate through an 8-mm pore-size ester filter, during challenge either with a chemoattractant tested at different concentrations or with the medium alone, acting as control. After incubation for 2 h at 37 °C, the filters were removed, fixed in ethanol, and stained with haematoxylin: the distance reached by the leading front of cells was measured in millimetres on a microscope [5]. In patient 1 chemotaxis was absent for all stimuli, while patient 2 exhibited neutrophil motility to IL-8 of 98 μm and to N-formylmethionyl-leucyl-phenylalanine (FMLP) of 107 μm, values at the lower limits of normal. All biopsies of these two patients were then reviewed by the same pathologist. Essentially, the distinguishing features were: scanty or no progression of the changes during the time course of the disease; myeloid hyperplasia, even more evident during infections and leukemoid reactions; normal erythroid differentiation, with an unusual admixture between myeloid and normoblastic cells in the bone marrow; megakariocyte hyperplasia and atypical clustering with reduced ploidy; extensive fibrosis and reticulin deposition, considered typical for primary MF; the cutaneous lesions were inflammatory intraepidermic infiltrates containing neutrophils and scanty eosinophils. Restricting observation to the bone marrow biopsies, the diagnosis was MF for both patient 1 and patient 2. However, in each case the spleen was only moderately enlarged, there were no signs of peripheral red cell fragmentation, nor signs of extramedullary erythropoiesis. More important, the clinical picture had remained stable for decades. The history of relapsing pyogenic infections in both cases suggests a defect of the immuno-phagocytic system. Phagocytosis is a process that includes chemotaxis, opsonisation, migration, adhesion, ingestion of bacteria and their killing by activation of the respiratory burst and production of superoxide moieties. A defect of any component of this sequence results in delayed or ineffective killing of encapsulated bacteria, with severe and repeated upper and lower respiratory infections, muco-cutaneous phlegmons, pustules and cellulitis [6–9]. Table 1 reports the major related genetic defects so far reported, and their related diseases. The critical aspect of the history of these patients is that the diagnosis of MF was based solely on the histological report, relying heavily on increased reticulin/collagen deposition within the bone marrow. However, fibrosis can also occur after repeated stimulation of bone marrow by bacterial infections and leukemoid reactions, because
0953-6205/$ – see front matter © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2011.11.014
Letter to the Editor
e79
Table 1 Diseases with defect of the immuno-phagocytic system. Disease
Pathogenetic pathway and clinical manifestations
Chronic granulomatous disease [Heyworth PG et al. Blood Cells Mol Dis. 2001;27:16–26] Mutations on NADPH-oxidase genes often “gp9lphox” on X chromosome
Impairment (or defect) of the production of hydrogen peroxide and superoxide radicals, which leads to the inability to kill bacteria Recurrent life-threatening bacterial and fungal infections (mainly skin and lung) Defective microsomal glucose-6-phosphate or pyrophosphate/phosphate transport Tremors, convulsions, miopathy, recurrent life-threatening bacterial and fungal infections (mainly skin and lungs) Defective intracellular protein transport Hypopigmentation of skin, eyes, and hair; prolonged bleeding time; easy bruising; recurrent infections (pneumonias, pyodermitis, cellulitis) abnormal natural killer cell function; peripheral neuropathy, aphthous stomatitis Defect on the gene coding for CAAT/enhancer binding protein (C/EBP, a myeloid-specific transcription factor) Cutaneous and pulmonary recurrent pyogenic and fungal infections Defective myeloperoxidase output, essential component of the oxygen-dependent microbicidal system of neutrophils and monocytes which leads to bacterial killing Increase in frequency and duration of infectious diseases (mainly respiratory diseases). Rarely life threatening diseases, patients are often asymptomatic. Apparent combined immuno-deficiency: Defective immune response of T-lymphocytes and neutrophils. Excessive levels of gamma-interferon results in marked elevation of immunoglobulin E by B-cells activity, causing defective neutrophil chemotaxis. Recurrent staphylococcal and candidal infections, pneumonias (often dry abscesses) and eczematoid skin. Characteristic facial, dental, and skeletal abnormalities. Deficiency of the β-2 integrin subunit (CD18), of the leukocyte cell adhesion. That leads to a leukocyte adhesion and rolling defect Recurrent pulmonary and cutaneous infections; slow recovery from injuries; scanty production of pus The reason of chemotaxis defect in patients with this mutation remains unclear. Pancreatic failure, delayed puberty; Mild-to-moderate psychomotor and/or developmental delay; Recurrent pulmonary and cutaneous infections and abscesses). Abnormality of actin polymerization in the neutrophils. Neutropenia, synusitis, otitis and recurrent pneumonia. Reduced mucociliary clearance for grossly impaired ciliary transport, defective directional migration of neutrophils. Sinusitis, pneumonias and bronchiectasis, infertility.
Glycogen storage disease type Ib [Shin YS. Semin Pediatr Neurol. 2006;13:115–20] Mutation in the gene GSD-Ib on chromosome11q23
Chediak-Higashi [Barbosa MD et al. Nature. 1996;382:262–5] Mutation in CHS1 gene on chromosome1q4243
Specific granule deficit [Gallin JI. Annu Rev Med. 1985;36:263–74] Mutation of the C/EBPe gene, on chromosome3q21–q23 Deficit of myeloperoxidase [Hampton MB, et al. Blood. 1998;92:3007–17] Defect of 17q23.1 gene
Hyper-IgE syndrome (Job's Syndrome) [DeWitt CA, et al. J Am Acad Dermatol. 2006;54:855–65] Mutation of the 4q21 gene.
Leukocyte adhesion defects [Etzioni A, et al. N Engl J Med. 1992;327:1789–92] Mutation of the 21q22.3 gene
Shwachman-Diamond [Ginzberg H, et al. J Pediatr. 1999;135:81–8] Mutation of the 7q11 gene
Lazy leukocyte syndrome [Patrone F, et al. Blut. 1979; 39:265–9] Defect of microfilaments Primary ciliary dyskinesia [Santamaria F, et al. Chest. 2008; 134:351–7] Mutation of the gene DNAH5 on Chromosome 5p
The table shows in the left column diseases of phagocytosis and their causative genetic mutations, while reporting on the right the mechanistic pathways. The clinical manifestations of each disease are written in italics. For each disease an appropriate reference is reported.
bone marrow cells release cytokines and these, in turn, stimulate fibroblast proliferation and collagen deposition. Bone marrow fibrosis (reactive MF) can thus occur as a consequence of different injuries [1–3], and of thrombopoietic stimuli releasing cytokines [4,10]. We believe that these two patients were affected by the new clinical entity of pseudo-myelofibrosis (PMLF). At variance with primary MF and chronic granulomatous disease and its related conditions (Table 1), we observed a conflict between the data of our patients and three basic diagnostic aspects of primary MF: 1) the bone marrow, considered diagnostic of primary MF; 2) the peripheral blood smear, typical of CML, even though the total white cell count never exceeded 20.000/μL; and 3) the clinical picture of a palpable, enlarged spleen, of non progressively increasing size, never reaching the umbilical line; slight liver enlargement; history of bacterial infections since childhood; and a non progressive clinical course, never displaying bone marrow failure, with a survival exceeding that expected for MF. The recognition of this clinical picture should prompt the differential diagnosis between MF and PMLF, while all the specific defects in phagocytic function, except the lazy leukocyte syndrome, can be ruled out by their distinctive clinical-laboratory features reported in Table 1. The hyper-IgE and Job-syndromes, the deficit of IgA and cystic fibrosis could be excluded on the ground of the clinical presentation and lab results. When all these conditions can be confidently excluded, PMLF should be suspected.
The lazy leukocyte syndrome, exhibited by patient 1, is defined by recurrent infections due to a defect in neutrophil chemotaxis and deficient random motility of neutrophils, associated with neutropenia [5]. The less severe abnormality exhibited by patient 2 can be diagnosed in the context of PMLF, even though the test of leukocyte migration was borderline normal. After these data are gathered, the bone marrow biopsy should establish the presence of myelofibrosis to confirm the diagnosis of PMLF. Alternatively, the clinical picture could prompt the execution of the bone marrow biopsy first, and the description of MF by the pathologist should trigger the differential diagnosis between MF and PMLF. Reactive MF is easily ruled out as it lacks liver–spleen enlargement and the alterations of the peripheral blood smear. In conclusion, we described two patients formerly labelled as affected by MF and/or CML, who were instead examples of a new entity, which we call PMLF. Knowledge of this non-progressive disease will help the physician to avoid misdiagnosing it as MF or Ph-negative CML, by executing tests to identify defects of phagocyte function. The demonstration of lazy leukocytes or even of a minor deficit establishes the diagnosis of PMF. Conflict of interest No author had any actual or potential conflict of interest.
e80
Letter to the Editor
References [1] O'Malley DP, Sen J, Juliar BE, Orazi A. Evaluation of stroma in human immunodeficiency virus/acquired immunodeficiency syndrome-affected bone marrows and correlation with CD4 counts. Arch Pathol Lab Med 2005;129:1137–40. [2] Viallard JF, Parrens M, Boiron JM, Texier J, Mercie P, Pellegrin JL. Reversible myelofibrosis induced by tuberculosis. Clin Infect Dis 2002;34:1641–3. [3] Kuter DJ, Bain B, Mufti G, Bagg A, Hasserjian RP. Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres. Br J Haematol 2007;139:351–62. [4] Ghanima W, Junker P, Hasselbalch CH, Baiocchi L, Geyer JT, Feng X, Gudbrandsdottir S, Orazi A, Bussel JB. Fibroproliferative activity in patients with immune thrombocytopenia (ITP) treated with thrombopoietic agents. Br J Hematol 2011;166:248–55. [5] Patrone F, Dallegri F, Rebora A, Sacchetti C. Lazy leukocyte syndrome. Blut 1979;39:265–9. [6] Winkelstein JA, Drachman RH. Phagocytosis: the normal process and its clinically significant abnormalities. Pediatr Clin North Am 1974;21:551–69. [7] Holland SM, Gallin JI. Evaluation of the patient with recurrent bacterial infections. Annu Rev Med 1998;49:185–99. [8] Yang KD, Hill HR. Neutrophil function disorders: pathophysiology, prevention, and therapy. J Pediatr 1991;119:343–54. [9] Klein JO, Mattia AR. Case 35–1993 — a two-year-old boy with recurrent infections, cervical lymphadenopathy, and fever. N Engl J Med 1993;329:714–21. [10] Kuter DJ, Bain B, Mufti G, Bagg A, Hasserjian RP. Bone marrow fibrosis: pathophysiologic and clinical significance of increased bone marrow fibres. Br J Hematol 2007;139:351–62.
Ettore Bartoli Università del Piemonte Orientale (Amedeo Avogadro), Dipartimento di Medicina Clinica e Sperimentale, Azienda Ospedaliera Maggiore dalla Carità, Novara, Italy
Daniele Sola⁎ Pier Paolo Sainaghi Luca Rossi Università del Piemonte Orientale (Amedeo Avogadro), Dipartimento di Medicina Clinica e Sperimentale, Azienda Ospedaliera Universitaria Maggiore dalla Carità, Novara, Italy ⁎Corresponding author at: Dipartimento di Medicina Clinica e Sperimentale, Azienda Ospedaliera Universitaria Maggiore della Carità, 28100, Novara, Italy. Tel.: + 39 03213733810; fax: + 39 03213733600. E-mail address: [email protected](D. Sola). Renzo Boldorini Università del Piemonte Orientale (Amedeo Avogadro), Dipartimento di Scienze Mediche, Azienda Ospedaliera Universitaria Maggiore dalla Carità, Novara, Italy
Contents lists available at SciVerse ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Letter to the Editor Pseudo-myelofibrosis: A new clinical entity
Keywords: Pseudo-myelofibrosis Myelofibrosis Lazy leukocyte syndrome Phagocytosis
To the Editor: Primary myelofibrosis (MF) is an established clinical entity due to a clonal disorder of myeloid stem cells. The major diagnostic demonstration rests on the presence of fibrosis of the bone marrow, megakaryocyte and platelet alterations, and of extramedullary erythromyelopoiesis, mainly in the liver and spleen. Reactive MF has been described in a number of conditions, like the human immunodeficiency syndrome [1], tuberculosis [2], toxic exposure to x-rays and chemicals, repeated bacterial infections [3], and treatment with thrombopoietic agents [4]. We herein report two patients exhibiting features of a new entity that we call pseudo-myelofibrosis (PMLF), to be distinguished from both true and reactive MF. A 55 year old Caucasian male (patient 1) had suffered from repeated respiratory and sinus infections since childhood. Anaemia and thrombocytopenia occurred at the age 27, when a bone biopsy prompted the diagnosis of MF, confirmed 5 times in the ensuing 28 years by repeated biopsies. He was admitted because of disseminated bronchopneumonia, and cutaneous necrotic ulcers in the malar and periorbital regions. WBC were 23.740/μL, neutrophils 21.900/μL, Hb 13.8 gr%, platelets Plts 82.000/μL. The peripheral blood smear did not disclose erythroblasts or giant platelets, while myelocytes and promyelocytes were seen. The cutaneous biopsy was compatible with an acute bacterial infection. A CAT of the abdomen showed a spleen of 14 cm. In the bone marrow aspirate BCRABL translocation and JAK2 mutation were negative. The bone biopsy, even when repeated after the acute infection had healed, was considered diagnostic of MF. An 83 year old Caucasian female (patient 2) was examined for severe anaemia and interstitial pneumonia. Anaemia disappeared after discontinuing oncocarbide, which she had taken during the previous 10 years following the diagnosis of chronic myelogenous leukaemia (CML). There was a history of recurrent sinusitis and mastoiditis since childhood, requiring mastoidectomy at age 8, pneumonia in her twenties, bullous eruption due to neutrophilic cutaneous abscesses at age 73. Subsequently, she developed cellulites, pneumonia, acute diverticulitis with perforation and abdominal abscess, rectovaginal fistula, abdominal wall abscess (Staphilococcus Guarnieri), hemicolectomy with surgical repair in 2005. In 2010 we repeated the bone marrow biopsy that was considered suggestive of MF. The Philadelphia chromosome, BCR-ABL rearrangement and JAK2 mutation were negative. Moderate spleen (20 cm) and slight liver
enlargement had remained stable over the last 10 years. Her WBC count never exceeded 20.000/μL, Hb remaining normal, platelet count 300.000 to 500.000/μL. A thorough review of all her bone marrow biopsies was considered consistent with MF instead of CML. A few months later the patient developed skin lesions with evidence of infiltration by blastic elements with high mitotic index and a phenotype (CD10+, CD79a+/−, CD34−, CD117−, CD99−, CD2−, CD20−, PAX5−, myeloperoxidase −) compatible with acute B-lymphocytic leukaemia. She died from myocardial infarction shortly thereafter. In both patients, WBC migration was investigated by the Department of Internal Medicine of the Genova University (Professor Franco Dallegri). Cells were allowed to migrate through an 8-mm pore-size ester filter, during challenge either with a chemoattractant tested at different concentrations or with the medium alone, acting as control. After incubation for 2 h at 37 °C, the filters were removed, fixed in ethanol, and stained with haematoxylin: the distance reached by the leading front of cells was measured in millimetres on a microscope [5]. In patient 1 chemotaxis was absent for all stimuli, while patient 2 exhibited neutrophil motility to IL-8 of 98 μm and to N-formylmethionyl-leucyl-phenylalanine (FMLP) of 107 μm, values at the lower limits of normal. All biopsies of these two patients were then reviewed by the same pathologist. Essentially, the distinguishing features were: scanty or no progression of the changes during the time course of the disease; myeloid hyperplasia, even more evident during infections and leukemoid reactions; normal erythroid differentiation, with an unusual admixture between myeloid and normoblastic cells in the bone marrow; megakariocyte hyperplasia and atypical clustering with reduced ploidy; extensive fibrosis and reticulin deposition, considered typical for primary MF; the cutaneous lesions were inflammatory intraepidermic infiltrates containing neutrophils and scanty eosinophils. Restricting observation to the bone marrow biopsies, the diagnosis was MF for both patient 1 and patient 2. However, in each case the spleen was only moderately enlarged, there were no signs of peripheral red cell fragmentation, nor signs of extramedullary erythropoiesis. More important, the clinical picture had remained stable for decades. The history of relapsing pyogenic infections in both cases suggests a defect of the immuno-phagocytic system. Phagocytosis is a process that includes chemotaxis, opsonisation, migration, adhesion, ingestion of bacteria and their killing by activation of the respiratory burst and production of superoxide moieties. A defect of any component of this sequence results in delayed or ineffective killing of encapsulated bacteria, with severe and repeated upper and lower respiratory infections, muco-cutaneous phlegmons, pustules and cellulitis [6–9]. Table 1 reports the major related genetic defects so far reported, and their related diseases. The critical aspect of the history of these patients is that the diagnosis of MF was based solely on the histological report, relying heavily on increased reticulin/collagen deposition within the bone marrow. However, fibrosis can also occur after repeated stimulation of bone marrow by bacterial infections and leukemoid reactions, because
0953-6205/$ – see front matter © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2011.11.014
Letter to the Editor
e79
Table 1 Diseases with defect of the immuno-phagocytic system. Disease
Pathogenetic pathway and clinical manifestations
Chronic granulomatous disease [Heyworth PG et al. Blood Cells Mol Dis. 2001;27:16–26] Mutations on NADPH-oxidase genes often “gp9lphox” on X chromosome
Impairment (or defect) of the production of hydrogen peroxide and superoxide radicals, which leads to the inability to kill bacteria Recurrent life-threatening bacterial and fungal infections (mainly skin and lung) Defective microsomal glucose-6-phosphate or pyrophosphate/phosphate transport Tremors, convulsions, miopathy, recurrent life-threatening bacterial and fungal infections (mainly skin and lungs) Defective intracellular protein transport Hypopigmentation of skin, eyes, and hair; prolonged bleeding time; easy bruising; recurrent infections (pneumonias, pyodermitis, cellulitis) abnormal natural killer cell function; peripheral neuropathy, aphthous stomatitis Defect on the gene coding for CAAT/enhancer binding protein (C/EBP, a myeloid-specific transcription factor) Cutaneous and pulmonary recurrent pyogenic and fungal infections Defective myeloperoxidase output, essential component of the oxygen-dependent microbicidal system of neutrophils and monocytes which leads to bacterial killing Increase in frequency and duration of infectious diseases (mainly respiratory diseases). Rarely life threatening diseases, patients are often asymptomatic. Apparent combined immuno-deficiency: Defective immune response of T-lymphocytes and neutrophils. Excessive levels of gamma-interferon results in marked elevation of immunoglobulin E by B-cells activity, causing defective neutrophil chemotaxis. Recurrent staphylococcal and candidal infections, pneumonias (often dry abscesses) and eczematoid skin. Characteristic facial, dental, and skeletal abnormalities. Deficiency of the β-2 integrin subunit (CD18), of the leukocyte cell adhesion. That leads to a leukocyte adhesion and rolling defect Recurrent pulmonary and cutaneous infections; slow recovery from injuries; scanty production of pus The reason of chemotaxis defect in patients with this mutation remains unclear. Pancreatic failure, delayed puberty; Mild-to-moderate psychomotor and/or developmental delay; Recurrent pulmonary and cutaneous infections and abscesses). Abnormality of actin polymerization in the neutrophils. Neutropenia, synusitis, otitis and recurrent pneumonia. Reduced mucociliary clearance for grossly impaired ciliary transport, defective directional migration of neutrophils. Sinusitis, pneumonias and bronchiectasis, infertility.
Glycogen storage disease type Ib [Shin YS. Semin Pediatr Neurol. 2006;13:115–20] Mutation in the gene GSD-Ib on chromosome11q23
Chediak-Higashi [Barbosa MD et al. Nature. 1996;382:262–5] Mutation in CHS1 gene on chromosome1q4243
Specific granule deficit [Gallin JI. Annu Rev Med. 1985;36:263–74] Mutation of the C/EBPe gene, on chromosome3q21–q23 Deficit of myeloperoxidase [Hampton MB, et al. Blood. 1998;92:3007–17] Defect of 17q23.1 gene
Hyper-IgE syndrome (Job's Syndrome) [DeWitt CA, et al. J Am Acad Dermatol. 2006;54:855–65] Mutation of the 4q21 gene.
Leukocyte adhesion defects [Etzioni A, et al. N Engl J Med. 1992;327:1789–92] Mutation of the 21q22.3 gene
Shwachman-Diamond [Ginzberg H, et al. J Pediatr. 1999;135:81–8] Mutation of the 7q11 gene
Lazy leukocyte syndrome [Patrone F, et al. Blut. 1979; 39:265–9] Defect of microfilaments Primary ciliary dyskinesia [Santamaria F, et al. Chest. 2008; 134:351–7] Mutation of the gene DNAH5 on Chromosome 5p
The table shows in the left column diseases of phagocytosis and their causative genetic mutations, while reporting on the right the mechanistic pathways. The clinical manifestations of each disease are written in italics. For each disease an appropriate reference is reported.
bone marrow cells release cytokines and these, in turn, stimulate fibroblast proliferation and collagen deposition. Bone marrow fibrosis (reactive MF) can thus occur as a consequence of different injuries [1–3], and of thrombopoietic stimuli releasing cytokines [4,10]. We believe that these two patients were affected by the new clinical entity of pseudo-myelofibrosis (PMLF). At variance with primary MF and chronic granulomatous disease and its related conditions (Table 1), we observed a conflict between the data of our patients and three basic diagnostic aspects of primary MF: 1) the bone marrow, considered diagnostic of primary MF; 2) the peripheral blood smear, typical of CML, even though the total white cell count never exceeded 20.000/μL; and 3) the clinical picture of a palpable, enlarged spleen, of non progressively increasing size, never reaching the umbilical line; slight liver enlargement; history of bacterial infections since childhood; and a non progressive clinical course, never displaying bone marrow failure, with a survival exceeding that expected for MF. The recognition of this clinical picture should prompt the differential diagnosis between MF and PMLF, while all the specific defects in phagocytic function, except the lazy leukocyte syndrome, can be ruled out by their distinctive clinical-laboratory features reported in Table 1. The hyper-IgE and Job-syndromes, the deficit of IgA and cystic fibrosis could be excluded on the ground of the clinical presentation and lab results. When all these conditions can be confidently excluded, PMLF should be suspected.
The lazy leukocyte syndrome, exhibited by patient 1, is defined by recurrent infections due to a defect in neutrophil chemotaxis and deficient random motility of neutrophils, associated with neutropenia [5]. The less severe abnormality exhibited by patient 2 can be diagnosed in the context of PMLF, even though the test of leukocyte migration was borderline normal. After these data are gathered, the bone marrow biopsy should establish the presence of myelofibrosis to confirm the diagnosis of PMLF. Alternatively, the clinical picture could prompt the execution of the bone marrow biopsy first, and the description of MF by the pathologist should trigger the differential diagnosis between MF and PMLF. Reactive MF is easily ruled out as it lacks liver–spleen enlargement and the alterations of the peripheral blood smear. In conclusion, we described two patients formerly labelled as affected by MF and/or CML, who were instead examples of a new entity, which we call PMLF. Knowledge of this non-progressive disease will help the physician to avoid misdiagnosing it as MF or Ph-negative CML, by executing tests to identify defects of phagocyte function. The demonstration of lazy leukocytes or even of a minor deficit establishes the diagnosis of PMF. Conflict of interest No author had any actual or potential conflict of interest.
e80
Letter to the Editor
References [1] O'Malley DP, Sen J, Juliar BE, Orazi A. Evaluation of stroma in human immunodeficiency virus/acquired immunodeficiency syndrome-affected bone marrows and correlation with CD4 counts. Arch Pathol Lab Med 2005;129:1137–40. [2] Viallard JF, Parrens M, Boiron JM, Texier J, Mercie P, Pellegrin JL. Reversible myelofibrosis induced by tuberculosis. Clin Infect Dis 2002;34:1641–3. [3] Kuter DJ, Bain B, Mufti G, Bagg A, Hasserjian RP. Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres. Br J Haematol 2007;139:351–62. [4] Ghanima W, Junker P, Hasselbalch CH, Baiocchi L, Geyer JT, Feng X, Gudbrandsdottir S, Orazi A, Bussel JB. Fibroproliferative activity in patients with immune thrombocytopenia (ITP) treated with thrombopoietic agents. Br J Hematol 2011;166:248–55. [5] Patrone F, Dallegri F, Rebora A, Sacchetti C. Lazy leukocyte syndrome. Blut 1979;39:265–9. [6] Winkelstein JA, Drachman RH. Phagocytosis: the normal process and its clinically significant abnormalities. Pediatr Clin North Am 1974;21:551–69. [7] Holland SM, Gallin JI. Evaluation of the patient with recurrent bacterial infections. Annu Rev Med 1998;49:185–99. [8] Yang KD, Hill HR. Neutrophil function disorders: pathophysiology, prevention, and therapy. J Pediatr 1991;119:343–54. [9] Klein JO, Mattia AR. Case 35–1993 — a two-year-old boy with recurrent infections, cervical lymphadenopathy, and fever. N Engl J Med 1993;329:714–21. [10] Kuter DJ, Bain B, Mufti G, Bagg A, Hasserjian RP. Bone marrow fibrosis: pathophysiologic and clinical significance of increased bone marrow fibres. Br J Hematol 2007;139:351–62.
Ettore Bartoli Università del Piemonte Orientale (Amedeo Avogadro), Dipartimento di Medicina Clinica e Sperimentale, Azienda Ospedaliera Maggiore dalla Carità, Novara, Italy
Daniele Sola⁎ Pier Paolo Sainaghi Luca Rossi Università del Piemonte Orientale (Amedeo Avogadro), Dipartimento di Medicina Clinica e Sperimentale, Azienda Ospedaliera Universitaria Maggiore dalla Carità, Novara, Italy ⁎Corresponding author at: Dipartimento di Medicina Clinica e Sperimentale, Azienda Ospedaliera Universitaria Maggiore della Carità, 28100, Novara, Italy. Tel.: + 39 03213733810; fax: + 39 03213733600. E-mail address: [email protected](D. Sola). Renzo Boldorini Università del Piemonte Orientale (Amedeo Avogadro), Dipartimento di Scienze Mediche, Azienda Ospedaliera Universitaria Maggiore dalla Carità, Novara, Italy