Editorials and Perspectives
`
`ers in myeloproliferative diseases: relationships with JAK2
`V617 F status, clonality, and antiphospholipid antibodies. J
`Thromb Haemost 2007;5:1679-85.
`17. Falanga A, Marchetti M, Vignoli A, Balducci D, Russo L,
`Guerini V, et al. V617F JAK-2 mutation in patients with
`essential thrombocythemia: relation to platelet, granulo-
`cyte, and plasma hemostatic and inflammatory molecules.
`Exp Hematol 2007;35:702-11.
`18. Arellano-Rodrigo E, Alvarez-Larran A, Reverter JC,
`Colomer D, Villamor N, Bellosillo B, et al. Platelet turnover,
`coagulation factors, and soluble markers of platelet and
`endothelial activation in essential thrombocythemia: rela-
`tionship with thrombosis occurrence and JAK2 V617F allele
`burden. Am J Hematol 2009;84:102-8.
`19. Trappenburg MC, van Schilfgaarde M, Marchetti M, Spronk
`HM, ten Cate H, Leyte A, et al. Elevated procoagulant
`microparticles expressing endothelial and platelet markers
`in essential thrombocythemia. Haematologica 2009;
`94:911-8.
`20. Marchetti M, Castoldi E, Spronk HM, van OR, Balducci D,
`Barbui T, et al. Thrombin generation and activated protein
`C resistance in patients with essential thrombocythemia
`and polycythemia vera. Blood 2008;112:4061-8.
`21. Kornberg A, Rahimi-Levene N, Yona R, Mor A,
`Rachmilewitz EA. Enhanced generation of monocyte tissue
`factor and increased plasma prothrombin fragment 1+2 lev-
`els in patients with polycythemia vera: mechanism of acti-
`vation of blood coagulation. Am J Hematol 1997;56:5-11.
`22. Passamonti F, Rumi E, Pietra D, la Porta MG, Boveri E,
`
`Pascutto C, et al. Relation between JAK2 (V617F) mutation
`status, granulocyte activation, and constitutive mobilization
`of CD34+ cells into peripheral blood in myeloproliferative
`disorders. Blood 2006;107:3676-82.
`23. Alvarez-Larrán A, Arellano-Rodrigo E, Reverter JC,
`Domingo A, Villamor N, Colomer D, et al. Increased
`platelet, leukocyte, and coagulation activation in primary
`myelofibrosis. Ann Hematol 2008;87:269-76.
`24. Leibundgut EO, Horn MP, Brunold C, Pfanner-Meyer B,
`Marti D, Hirsiger H, et al. Hematopoietic and endothelial
`progenitor cell trafficking in patients with myeloprolifera-
`tive diseases. Haematologica 2006;91:1465-72.
`25. Sozer S, Fiel MI, Schiano T, Xu M, Mascarenhas J, Hoffman
`R. The presence of JAK2V617F mutation in the liver
`endothelial cells of patients with Budd-Chiari syndrome.
`Blood 2009;113:5246-9.
`26. Pieri L, Bogani C, Guglielmelli P, Zingariello M, Rana RA,
`Bartalucci N, et al. The JAK2V617F mutation induces consti-
`tutive activation and agonist hypersensitivity in basophils of
`polycythemia vera. Haematologica 2009;94:1537-475.
`27. Wang J, Ishii T, Zhang W, Sozer S, Dai Y, Mascarenhas J, et
`al. Involvement of mast cells by the malignant process in
`patients with Philadelphia chromosome negative myelopro-
`liferative neoplasms. Leukemia 23:1577-86.
`28. Ishii T, Wang J, Zhang W, Mascarenhas J, Hoffman R, Dai Y,
`et al. Pivotal role of mast cells in pruritogenesis in patients
`with myeloproliferative disorders. Blood 2009;113:5942-50.
`29. Kovanen PT. Mast cells: multipotent local effector cells in
`atherothrombosis. Immunol Rev 2007;217:105-22.
`
`Mantle cell lymphoma
`Stefano A. Pileri1 and Brunangelo Falini2
`
`1Department of Haematology and Oncological Sciences “L. and A. Seràgnoli”, Chair of Pathology and Haemolymphopathology
`Unit, Bologna University School of Medicine; 2Department of Haematology, Laboratory of Hematopathology, Perugia University
`School of Medicine. E-mail: stefano.pileri@unibo.it doi:10.3324/haematol.2009.013359
`
`In 1982, Weisenburger et al. first introduced the con-
`
`cept of mantle-zone lymphoma.1 According to the ter-
`minology used at that time, this was regarded as a
`variant of intermediate lymphocytic lymphoma that pro-
`liferated as wide mantles around non-neoplastic appear-
`ing germinal centers (GC). One year later, Swerdlow et al.
`found that the pattern described above was part of the
`spectrum of the centrocytic lymphoma of the Kiel
`Classification and might correspond to initial lymph
`node involvement by the tumor.2,3 In 1985, Pileri et al.
`reported on 18 cases of small B-cell lymphomas display-
`ing a mantle-fashion growth around reactive GC, which
`turned out to be quite heterogeneous on closer examina-
`tion.4 In fact, at disease presentation 13 of the 18 cases
`displayed cytological and immunological findings consis-
`tent with centrocytic lymphoma, while the remaining
`ones corresponded to neoplasms that nowadays would
`be diagnosed as marginal zone lymphoma. Interestingly,
`the centrocytic lymphomas were CD5+, FMC7+ and
`CD10– and showed progression to a diffuse growth pat-
`tern in follow-up biopsies. Two important conclusions
`were reached: (i) the mantle-fashion growth was pro-
`duced by different types of B-cell lymphoma and could
`not be used as a diagnostic criterion, and (ii) conversely
`to what is reported in the Kiel Classification,3 centrocyt-
`ic lymphomas are derived from a normal counterpart
`other than GC, possibly related to mantle cells. In 1992,
`the International Lymphoma Study Group (ILSG) made
`
`its first experiment to overcome the discrepancies in
`terms of lymphoma classification that had hampered
`communication across the Atlantic for some decades.5 In
`particular, the American and European ILSG members
`agreed on the existence of a tumor derived from mantle
`B cells that was consequently termed mantle-cell lym-
`phoma (MCL). The criteria for its recognition were draft-
`ed and included 2 years later in the Revised European-
`American Lymphoma Classification that led the way to
`the latest edition of the World Health Organization
`(WHO) Classification of Tumours of Haematopoietic
`and Lymphoid Tissues.6,7 The present article will focus on
`the diagnosis and bio-pathology of MCL in the light of
`the criteria of the WHO Classification7 and recent reports
`in the literature including those of Quintinilla-Martinez et
`al., Mozos et al. and Dictor et al. in this issue of the jour-
`nal.8-10 It will not include the still ongoing debate on the
`multiple options proposed for the treatment of MCL
`patients, which often have limited efficacy (comprehen-
`sively reviewed by Ghielmini et al.).11
`
`Definition
`MCL is a distinct entity, representing from 3-10% of
`non-Hodgkin’s lymphomas and more frequently affect-
`ing middle-aged to older males (male:female ratio = 2-
`7:1).7,12 It is listed among peripheral B-cell lymphomas, is
`usually composed of small to medium-sized elements
`with irregular nuclear contours and CCDN1 transloca-
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`Editorials and Perspectives
`
`tion, and is thought to stem from peripheral B cells of
`the inner mantle-zone of secondary follicles, mostly of
`naïve pre-GC type.7,12 MCL is generally regarded as an
`aggressive, incurable disease with the median survival
`of affected patients being 3-4 years.12
`
`Clinical features
`MCL more often presents in stage III-IV with lym-
`phadenopathy, hepatosplenomegaly, bone-marrow
`involvement, and leukemic spread.7,12 The latter two
`findings can be missed by morphological studies alone
`and are shown by, respectively, immunohistochemistry
`and FACS analysis in most if not all instances.7,12
`Waldayer’s ring and the gastro-intestinal tract are fre-
`quently affected.7,12 Most cases of multiple lymphoma-
`tous polyposis correspond to MCL.
`
`Morphology
`MCL usually consists of small to medium-sized lym-
`phoid elements with irregular nuclear contours, some-
`what dispersed chromatin, inconspicuous nucleoli, and
`scant cytoplasm.7,12,13 Within this context, centroblasts,
`immunoblasts, prolymphocytes and para-immuno-
`blasts are not encountered. This is relevant for the dif-
`ferential diagnosis from follicular lymphoma, lympho-
`plasmacytic
`lymphoma and chronic
`lymphocytic
`leukemia/small lymphocytic lymphoma, which by def-
`inition, contain centroblasts, immunoblasts and prolym-
`phocytes/para-immunoblasts, respectively. Comprised
`within the neoplastic population, hyaline small vessels
`and/or epithelioid histiocytes are frequently found.
`Clusters of plasma cells can be seen: they are usually
`reactive (polytypic at immunohistochemistry), only
`exceptionally representing a feature of tumor differenti-
`ation with obvious monoclonality and tendency to
`accumulate in the center of lymphomatous nodules.14
`The number of mitotic figures varies, although it is usu-
`ally low to moderate (see below).
`In the lymph node, spleen and Waldayer’s ring, neo-
`plastic cells give rise to a mantle-fashion, nodular or –
`more frequently – diffuse growth pattern.7,12,13 Notably,
`repeated biopsies demonstrate that such patterns corre-
`spond to disease progression. In fact, in the early phas-
`es the tumor substitutes the mantle-zone; then, it
`invades reactive GC producing a nodular pattern; final-
`ly, the nodules merge together causing diffuse efface-
`ment of the organ’s structure. The bone marrow can be
`variably involved: paratrabecular infiltrates are the com-
`monest finding.
`Besides the classical type described above, there are
`some cytological and/or morphological variants of MCL
`that can cause diagnostic problems. These are termed
`blastoid, pleomorphic, small cell, and marginal zone-
`like.7,12,13 The first consists of slightly larger cells resem-
`bling lymphoblasts with dispersed chromatin and a
`high mitotic rate. Blastoid MCL is clinically aggressive,
`as is the pleomorphic form, which is characterized by a
`cell population that is highly variable in size and shape,
`with frequent mitotic figures and a proportion of rather
`large elements showing oval to irregular nuclear con-
`tours, pale cytoplasm and at times prominent nucleoli.
`Both the blastoid and pleomorphic forms occur de novo,
`
`rarely representing morphological progression of the
`disease. The small cell variant is composed of small,
`round lymphocytes with more clumped chromatin,
`mimicking chronic lymphocytic leukemia/small lym-
`phocytic lymphoma. Occasionally, the small lym-
`phomatous elements can be almost exclusively restrict-
`ed to the inner mantle zones or to narrow mantles, a
`pattern termed in situ MCL and thought to have a more
`indolent behavior.15 Finally, the marginal zone-like sub-
`type displays prominent foci of cells with abundant pale
`cytoplasm resembling marginal zone or monocytoid B-
`elements.7,12 Notably, these cases are at times character-
`ized by splenomegaly, intrasinusoidal bone-marrow
`infiltration and a leukemic picture in the absence of
`lymph node involvement. They can be easily confused
`with splenic marginal zone lymphoma and seem to
`have a very indolent course. As for in situ MCL, the diag-
`nosis of this rare form of the tumor is feasible only upon
`immunohistochemical detection of cyclin D1 (see
`below).
`
`Immunophenotype
`MCL is characterized by expression of the B-cell
`markers CD19, CD20, CD22, CD79a
`and
`BSAP/PAX5.7,12,13 Notably, CD20 is strongly expressed
`on the surface of neoplastic cells, a feature that can be
`useful for the differential diagnosis from chronic lym-
`phocytic
`leukemia/small
`lymphocytic
`lymphoma,
`which shows weak CD20 positivity in the small cell
`component.13 The search for immunoglobulin (Ig) heavy
`and light chains usually reveals IgM/D positivity with
`more frequent lambda restriction.7,12 Neoplastic cells are
`usually CD5+, FMC-7+, BCL-2+, CD10–, BCL-6–, and
`IFR4–, with occasional weak expression of CD23.7,12,13 In
`the cases with nodular growth, residual GC cells
`(CD10+, BCL-6+) can be detected admixed with the neo-
`plastic population. Furthermore, aberrant phenotypes
`have been reported in MCL (such as negativity for CD5
`and positivity for CD10 and/or BCL-6), sometimes
`associated with the blastoid/pleomorphic variants or
`occurring in conjunction with BCL6/3q27 transloca-
`tions.7 Stains for CD21 and CD35 usually show loose
`follicular dendritic cell meshworks. In the light of this,
`although the phenotypic profile of MCL is distinctive, it
`is not entirely pathognomonic and as such cannot
`always assist in the differentiation of MCL from follicu-
`lar lymphoma, lymphoplasmacytic lymphoma, margin-
`al zone lymphoma and chronic lymphocytic leu-
`kemia/small lymphocytic lymphoma. For this purpose,
`the most useful examination is the strong expression of
`cyclin D1, which is never found in the above mentioned
`categories of B-type non-Hodgkin’s lymphomas.7,12,13
`This attribute is sustained by the t(11;14)(q13;q32)
`translocation (see below).7,12,13 Notably, cyclin D1
`expression is lacking in a small percentage of cases of
`MCL: because of practical and conceptual implications,
`these cases will be treated separately (see below). Last
`but not least, cyclin D1 expression is found in hairy cell
`leukemia (although weak) and in about 16% of plasma
`cell myelomas, also carrying t(11;14)(q13;q32).13 When
`commercially available, the antibody produced by one
`of the authors (Falini)16 and raised against the IRTA-1
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`Editorials and Perspectives
`
`receptor physiologically expressed by marginal zone B-
`cells, could represent a further tool to aid the differential
`diagnosis between MCL (IRTA-1–) and nodal marginal
`zone lymphoma (IRTA-1+ in about 80% of cases).17
`
`The t(11;14)(q13;q32) translocation
`The t(11;14)(q13;q32) translocation is regarded as the
`primary genetic event in MCL.7,12 It can easily be demon-
`strated by fluorescent in situ hybridization (FISH) and
`involves the Ig heavy chain gene (IGH@) at the 14q32
`locus and a region at 11q13 designated BCL1.12 The
`expression of CCND1, located in the latter and encoding
`for cyclin D1, is deregulated by the translocation.7,12 This
`causes over-expression of cyclin D1 both at the mRNA
`and protein levels in MCL. Cyclin D1 plays an important
`role in the cell cycle regulation of G1-S transition follow-
`ing mitotic growth factor signaling.7 Unlike in MCL, in
`normal cells cyclin D1 is transiently expressed and binds
`to CDK4 and CDK6 to form a CDK/cyclin complex able
`to phosphorylate the tumor suppressor gene retinoblas-
`toma (RB1) facilitating cell cycle progression.12 De-
`regulated expression of cyclin D1 is thought to over-
`come the effect of RB1 and p27/kip, leading to the devel-
`opment of MCL.7,12 Some tumors over-express shorter
`cyclin D1 transcripts, usually generated by secondary 3’
`
`rearrangements in the CCD1 locus.7,12 These truncated
`transcripts cause very strong protein expression, high
`proliferative activity and a more aggressive clinical
`course.7,12
`Notably, it has been reported that inactivating muta-
`tions of the ATM and/or CHK2 genes (recorded in 40-
`75% of MCL) are at times found in the germline of
`some patients.7,12 This might be relevant to the develop-
`ment of the tumor: in fact, such mutations cause dereg-
`ulation of the DNA damage response pathway and
`increased genomic instability.7,12 In particular, t(11;14) –
`which should affect immature/naïve B cells as suggest-
`ed by its detection in the peripheral blood of 1-2% of
`healthy individuals – would occur in the setting of a
`population carrying these mutations and lead to consti-
`tutive deregulation of cyclin D1 and early expansions of
`tumor B cells in the mantle zone of lymphoid follicles.
`This might also explain why MCL is one of the malig-
`nant neoplasms with the highest level of genomic insta-
`bility, which might cause additional oncogenic events
`needed for the expansion of MCL cells with classical
`morphology, as well as alterations of genes involved in
`cell cycle regulation and senescence regulatory path-
`ways that would lead to more aggressive variants of
`MCL.7,12,18 In particular, there is a high number of non-
`
`Figure 1. Schematic representation of the postulated steps of the pathogenesis of MCL, shown in conjunction with the main immuno-
`morphological findings. The red immunostain, corresponds to cyclin D1 determined by the alkaline phosphatase anti-alkaline phos-
`phatase complexes technique. The naïve B-lymphocyte is stained for CD20 by immunoperoxidase. The examples of “classic” MCL and
`“blastoid” MCL are stained with Giemsa, while the “pleomorphic” one is stained with hematoxylin and eosin.
`
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`
`random secondary chromosomal aberrations in MCL,
`including gains of 3q26, 7p21 and 8p24 (MYC), and
`losses of 1p13-p31, 6q23q27, 9p21, 11q22-q23, 13q11-
`q13, 13q14-q34, and 17p13-ter.7,18 Trisomy 12 is detect-
`ed in about 25% of cases. Tetraploid clones are more
`common in the pleomorphic and blastoid variants than
`in the classical type (80%, 36% and 8%, respective-
`ly).7,12 t(8;14)(q24;q32) involving MYC is rare, but asso-
`ciated with a more aggressive clinical course. Finally,
`MCL carries frequent mutations of TP53, homozygous
`deletions of the INK4a/ARF, amplifications of the BMI1
`polycomb and CDK4 genes, and occasional micro-dele-
`tions of the RB1 gene, all producing high proliferative
`activity.7,12
`The possible steps of the molecular pathogenesis of
`MCL are outlined in Figure 1 in relation to immuno-
`morphological findings.
`
`Antigen receptor genes
`Ig genes are rearranged. IGH@ genes are unmutated
`in most cases, although mutations are found in a minor-
`ity of MCL.7,12 The load of the latter is lower than in
`mutated chronic lymphocytic leukemia.7,12 In addition,
`in MCL IGH@ somatic mutations do not correlate with
`ZAP70 expression and survival.7,12 A biased usage of
`IGH@ genes has been reported in some cases, suggest-
`ing that MCL may originate from specific B-cell subsets.
`Unlike in chronic lymphocytic leukemia, in MCL VH3-
`21 usage occurs in unmutated cases and bears a lower
`amount of genomic imbalances and a better prognosis.7
`
`Gene expression profile
`In 2003,
`the Lymphoma/Leukemia Molecular
`Profiling Project group showed that MCL has a specific
`gene signature that differs from the signatures of small
`lymphocytic lymphoma and diffuse large B-cell lym-
`phoma of both the GC B cell-like and activated B cell-
`like types.19 Interestingly, this signature encompassed
`the usual cyclin D1-positive cases and a small subgroup
`of cyclin D1-negative MCL. Besides elucidating the
`pathogenesis of the tumor, the gene expression profile
`(GEP) revealed 20 proliferation-associated genes whose
`expression measurement identified subsets of patients
`whose median survival differed by more than 5 years.
`Differences in cyclin D1 mRNA abundance synergized
`with INK4a/ARF locus deletions to dictate tumor prolif-
`eration rate and survival. Two years later, the same
`group reported on six cases of MCL lacking cyclin D1
`that exhibited the same clinical, morphological and GEP
`features as classical MCL but did not carry the
`t(11;18)(q12;q32), as determined by FISH.20 These cases
`did, however, express either cyclin D2 or cyclin D3 at
`both the mRNA and protein levels, suggesting that up-
`regulation of these cyclins may substitute for cyclin D1
`in the pathogenesis of MCL.
`
`Cyclin D1-negative mantle cell lymphoma
`Since cyclins D2 and D3 are also expressed by normal
`B cells and most, if not all, B-cell non-Hodgkin’s lym-
`phoma,8 although at lower levels,12 these markers can-
`not be confidently used for differentiating cyclin D1-
`negative MCL from other small B-cell tumors.8,12 In
`
`2008, this led Campo et al. to conclude that “the only
`reliable criteria to establish the diagnosis of cyclin D1-
`negative MCL seemed to be the microarray profile that
`is limited to research environments”.12 In this issue of
`the journal, three reports focus on tools that can allow
`the easy identification of such cases and can be applied
`in most histopathology labotatories.8-10 First of all,
`Quintinilla-Martinez et al. propose FISH analysis and/or
`quantitative reverse transcriptase polymerase chain
`reaction as a means for making the differential diagno-
`sis of cyclin D1-negative MCL.8 This approach is based
`on the one hand on previous observations of bone fide
`cyclins D1–/D2+ MCL carrying translocations involving
`the CCND2
`locus with
`either
`the
`IGK@
`[t(2;12)(p12;p13)] or IGH@ locus [t12;14](p13;q32)], not
`recorded in either chronic lymphocytic leukemia or
`CD5+ mantle zone lymphoma, and, on the other hand,
`on the at least 10-times higher mRNA levels of cyclin
`D2 in D1–/D2+ MCL in comparison with normal lym-
`phoid tissue, follicular lymphoma, mantle zone lym-
`phoma and chronic lymphoma and chronic lymphocy-
`tuc leukemia.8 Mozos et al. candidate the expression of
`the neural transcription factor SOX11 as a powerful bio-
`marker for the identification of cyclin D1-negative
`MCL.9 In fact, GEP showed significantly higher expres-
`sion of the SOX11 gene in classical MCL than in
`Burkitt’s lymphoma, diffuse large B-cell lymphoma, pri-
`mary mediastinal B-cell lymphoma and follicular lym-
`phoma.9 However, one third of cases of Burkitt’s lym-
`phoma revealed SOX11 mRNA levels similar to those in
`MCL, thus indicating that SOX11 over-expression is not
`restricted to MCL.9 These findings were corroborated
`by immunohistochemical studies that showed nuclear
`SOX11-positivity in most, if not all, MCL tested, includ-
`ing 12 cyclin D1-negative cases.9 Interestingly, 25% of
`Burkitt’s lymphomas, all examples of B- and T-lym-
`phoblastic
`leukemia/lymphoma,
`one
`classical
`Hodgkin’s
`lymphoma and 2/3 T-prolymphocytic
`leukemias also turned out to be positive.9 Equivalent
`results were reported by Dictor et al., who immunos-
`tained 172 specimens for the SOX11 N and C termini.10
`Their findings indicate that SOX11 can represent a use-
`ful tool for the differentiation of MCL from other small
`B-cell lymphomas in general but is certainly of pivotal
`importance for identifying the cyclin D1-negative cases.
`Of course, it should be integrated in a panel of markers
`in order to avoid any confusion between a potential
`cyclin D1-negative blastoid MCL and lymphoblastic
`leukemia/lymphoma, which may be confused morpho-
`logically but are easily differentiated by the global phe-
`notypic profile.
`
`Prognostic factors
`Apart from the rare forms with an indolent behavior
`reported above, MCL has a particularly poor outcome7,12
`Several attempts have been made to subdivide patients
`into different risk groups. In particular, the European
`MCL Network has shown that the number of mitotic
`figures and Ki-67 marking can allow the identification
`of three subgroups with different proliferation rates
`(mitotic indices: <25, 25-49, and >50/mm2 and Ki-67
`indices: <10%, 10-40%, and <40%, respectively) signif-
`
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`
`icantly different outcomes.21 Such differences are con-
`served in advanced-stage MCL patients treated with
`anti-CD20 immuno-chemotherapy.22 Interestingly, these
`findings are in keeping with the above reported GEP
`data19 and point to the prognostic value of proliferation
`in MCL. Additional bio-pathological adverse prognosti-
`cators – which may be independent of proliferative
`activity – have been reported, such as blastoid/pleomor-
`phic morphology, trisomy 12, karyotype complexity,
`TP53 mutation/over-expression/loss, gains of chromo-
`some 3q, deletions of 9p, and a series of clinical param-
`eters including overt peripheral blood involvement.7,12
`Recently, a clinical MCL index (MIPI), based on age,
`ECOG, performance status, lactate dehydrogenase val-
`ues and leukocyte count, and a five-gene model (RAN,
`MYC, TNFRSF10B, POLE2, and SLC29A2) applicable to
`both frozen and routine samples and based on quantita-
`tive reverse transcriptase polymerase chain reaction
`analysis, have been proposed as further prognostic indi-
`cators.23,24
`
`This manuscript was supported by grants from BolognAIL,
`Centro Interdipartimentale di Ricerche sul Cancro “Giorgio
`Prodi” and Fondazione Cassa di Risparmio in Bologna
`(Bologna, Italy).
`
`Dr. Stefano A. Pileri is Full Professor of Pathology and
`Director of the Hematopathology Unit at Bologna University.
`Dr. Brunangelo Falini is Full Professor of Hematology at
`Perugia University.
`
`References
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