<5%. Hepatosplenomegaly. \200 No identifi able cause for physiological neutrophilia, or demons tration of clonality. No Philadelphia chromosome or BCR-ABL1 fusion gene. \200 No rearrangement of PDGFRA, PDGF RB, or FGFR1. \200 No evidence for PB, ET or PMF. \200 No evidence of MDS or MDS/MPN. Prognosis Variable prognosis described for patients with CNL with survival up to 20 years.1 \200\230True \200\231 CNL may have median OS of 30 months with only 28% 5-year OS.2,3 \200 Disease acceleration: progressive treatment-refractory neutrophilia, marked splenomegaly, anemia, thrombocytopenia, and the appearance of immature myeloid proge nitors including blasts in the peripheral blood.3 A signifi cant proportion of patients with CNL will progress to AML. \200 Death due to bl ast transformation, progression without transformation, bleeding complications and infectio n. No standard treatment recommendation; optimum therapy undefi ned; Treatment may be unnecess ary if asymptomatic. Treatment \200 Hydroxycarbamide (HC) may control progressive neutrophilia and splenomegaly and maintain a prolonged stable phase; recommended 1st-line therapy with media n response of 12 months.3 Busulfan can achieve the same eff ect. \200 Interferon alfa is option as 2nd-line therapy 3 though responses to 2nd-line therapy often short-lived and poorly tolerated.4 AML-type induction therapy is ineff ective.4 \200 Splenic irradiation and splenectomy can reduce tumor bulk and relieve abdominal discomfort; splenectomy may aggravate leucocytosis.5 \200 Allogeneic SCT is pot entially curative5,6 and in view of the poor prognosis of patients with true CNL, should be considered in eligible patients. 305 CHRONIC NEUTROPHILIC leukemia References 1. Imbert, M. et al. (2001). Chronic neutrophilic leukemia. In Jaff e, E.S. et al. (eds.) Worl d Health Organization Classifi cation of Tumors. Pathology and Genetics. Tumors of Haematop oietic and Lymphoid Tissues, vol 1, pp. 27 \200\2238. Lyon: IARC Press. 2. Reilly, J.T. (2002). Chronic neutrophilic leukemia: a distinct clinical entity? Br J Hae matol, 116, 10 \200\22318. 3. Teff eri, A. et al. (2006). Atypical myeloproliferative disorders: diagnosis and treatme nt. Mayo Clin Proc, 81, 553 \200\22363. 4. Elliot, M.A. et al. (2001). Chronic neutrophilic leukemia (CNL): a clinical, pathologic and cytogenetic study. Leukemia, 15, 35 \200\22340. 5. Hasle, H. et al. (1996). Chronic neutrophilic leukemia in adolesence and young adulthood . Br J Haematol, 9, 628 \200\22330. 6. Pilotis, E. et al. (2002). Allogeneic bone marrow transplantation in the management of chronic neutrophilic leukemia. Leuk Lymphoma, 43, 2051 \200\2234. Further reading Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoie tic and Lymphoid Tissues, 4th ed. Lyon: IARC. 306 CHAPTER 7 Myeloproliferative neoplasms Eosinophilic syndromes and neoplasms Persistent eosinophilia in the peripheral blood and ti ssues may occur in a heterogeneous group of conditions and requires investigation. First st ep is to exclude a 2 eosinophilia. If reactive causes have been excluded a clonal diagnos tic entity can be expected, or if none found, idiopathic hypere- osinophilic syndrome. The diagnostic entities historically were classifi ed as myeloproliferative disorders, though d istinct categories now exist.1 Diagnostic groups/entities (discussed here)1,2 \200 Reactive or 2 eosinophilia. \200 Myeloid and lymphoid neoplasms with abnormalities of PDGFRA, PDGFRB, or FGFR1. Chronic eosinophilic leukemia, not otherwise specifi ed (CEL, NOS). \200 Lymphocyte-varia nt hypereosinophilia. \200 Idiopathic hypereosinophilic syndrome (HES), which is a diagno sis of exclusion. Investigation of a patient with eosinophilia All patients with eosinophilia should be asses sed with a detailed history including drugs and travel, a full physical examination, blood count and fi lm, routine chemistry, serum IgE, serum B12, ECG, echocardiogram, CXR, pul- mo nary function tests, and CT chest and abdomen. Further investigations may be indicated by t he fi ndings, e.g. parasite screen, HIV serology. If eosinophilia remains unexplained, the diagnostic algorithm recom- mended by Teff eri and Vardiman1 and based on the 2008 WHO criteria should be used: \200 Perform BM biopsy, try ptase stain, T-cell clonality studies (immunophenotyping and TCR gene rearrangement studies), cytogenetic studies, and FISH or RT -PCR for FIP1L1-PDGFRA: \200 FIP1L1-PDGFRA +ve l PDGFRA rearranged myeloid neoplasm with eosinophilia. 5q33 translocations l PDGFRB rearranged myeloid neoplasm with eosinophilia. 8p11 translocations l FGFR1 rearranged myeloid neoplasm with eosinophilia. BM histology shows abnormalities other than eosinophilia l use histology to make specifi c diagnosis BM unremarkable other than eosinophilia and no clonal T cells \200\223 l PB blasts >2% or BM blasts >5% or abnormal cytogenetics: CEL-NOC/HES. \200\223 l PB blasts <2% and BM blasts <5% and no abnormal cytogenetics: idiopathic HES . 307 EOSINOPHILIC SYNDROMES AND NEOPLASMS Conditions associated with 2 or reactive eosinophilia \200 Allergic: asthma, allergic b ronchopulmomary aspergillosis, drug reactions. \200 Infectious and parasitic: helminths, ectoparasites (scabies), protozoa, fungi (coccidiomycosis), mycobacteria, and viruses (HIV, HSV). \200 Infl ammatory: Loeffl er syndrome, collagen vascular disorders (Wegener granulomatosis, PAN, SLE), sarcoid. Neoplastic: CML, AML with inv(16), ALL, angioimmunoblastic lymphoma, chronic MPNs, Hodgkin and non-Hodgkin lymphoma, adenocarcinoma. Immune dysregulation: Wiskott \200\223Aldrich syndrome, phenotypically aberrant T lymphocytes with abnormal release of cytokines. Metabolic: hypoadrenalism. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FG FR1 The 2008 WHO classifi cation1 has redefi ned myeloid and lymphoid neoplasms with molecu larly characterized clonal eosinophilia, previously classifi ed under CEL/HES, as a new cat egory of their own and removed them from the MPN category. Myeloid and lymphoid neoplasms associated with PDGFRA rearrangement (platelet derived growt h factor) \200 Rare disorder. Karyotype usually normal. \200 Activating mutation of the gene for PDGFRA due to interstitial deletion at 4q12 producing a FIP1L1-PDGFRA fusion gene.3 Associated with HES, CEL, and syst emic mastocytosis (SM).3 \200\2235 t(4;22)(q12;q11) producing BCR-PDGFRA fusion gene also described associated with atypical CML.6 FIP1L1-PDGFRA detected by FISH in 14% of patients with \200\230primary eosinophilia \200\231; also detectable by RT-PCR; almost all classifi ed h istologically as SM due to mast cell infi ltrates in the BM.5 SM-CEL has been suggested as nomenclature.7 Occurs almost exclusively in \231\202; associated with eosinophil- related tissue damage, elevated serum tryptase, splenomegaly, BM hypercellularity with reti culin fi brosis, and atypical mast cells. Extremely sensitive to imatinib therapy: 100mg/d achieved 100% durable clinical and hematol ogical CR in 8 patients;8 if clinical or molecular relapse occurs, the dose should be i to 400mg/d;9 concomitant prednisolone therapy (1mg/kg/d) is recommended for initial 1 \200\223 2 weeks to reduce risk of drug-induced cardiogenic shock.7 Acute phase disease may be myeloid or T-lymphoblastic. Myeloid neoplasms associated with PDGFRB rearrangement (platelet derived growth factor) \200 Rare disorder. \200 Activating mutation of PDGFRB gene at 5q33 associated with eosinophilia sometimes accompanied by monocytosis.10 Usually involves translocation e.g. t(5;12)(q33;p13) and karyotype usually abnormal. Detected in patients previously diagnosed with CEL or CMML.11 \200 Rarely aff ects \231 \200; also responds to imatinib. 308 CHAPTER 7 Myeloproliferative neoplasms Myeloid and lymphoid neoplasms associated with FGFR1 rearrangement \200 Rare aggressive d isorder also known as 8p11 myeloproliferative syndrome. Stem cell leukemia-lymphoma syndrom e causing eosinophilia associated with myeloproliferative and myelodysplastic features. Acu te phase of disease can be T-cell ALL or progression to AML.12 Translocations involving 8p11 and multiple partners result in constitutive activation of a fusion tyrosine kinase involving FGFR1.12 Unresponsive to imatinib. \200 Only allogeneic SCT is eff ective at suppressing the malig nant clone.12 CEL, not otherwise categorized (CEL-NOC) Rare condition. Clonal proliferative disorder of e osinophil precursors causing persistent i in mature and immature eosinophils in PB ( \211 1 .5 \227 109/L) and in BM. Hyper-eosinophilic syndrome (HES) is a synonym though its termin ology not recommended due to the confusion with idiopathic HES which is a diff erent diagno stic entity. WHO de \201 ned diagnostic criteria (2008 classi \201 cation) \200 Persistent periphera l blood eosinophilia \211 1.5 \227 109/L. \200 No Ph chromosome or BCR-ABL1 fusion gene or other MPN (PV, ET, PMF) or MDS/MPn (CMML or aCML). No t(5,12) or other rearrangement of PDGFRB. \200 No FIP1L1-PDGFRA fusion gene or other r earrangement of PDGFRA. \200 No rearrangement of FGFR1. \200 Blasts PB and BM <20% and no inv(16), t(16,16) or other feature diagnostic of AML. No clonal cytogenetic or molecular genetic abnormality; blast cells >2% in PB or >5% in BM. Marked \231\202 predominance; usually age 20 \200\22350 years; incidental fi nding or shor t history of fever, malaise, fatigue, sweats, weight loss, skin rash, angioedema, muscle pa ins, pruritus, diarrhea, and i susceptibility to infection; splenomegaly in 30 \200\22350%. PB eosinophils mainly mature with few eosinophilic myelocytes or pro- myelocytes; some show abnormalities: sparse granulation, vacuolation, hypersegmentation, hyposegmentation, or la rge forms; neutrophilia with left shift frequent; platelet count variable. BM hypercellular; usually 10 \200\22330% eosinophils; often >5% blasts; no spe- cifi c cyto genetic or molecular abnormality; no dysplastic features, Ph chromosome or BCR-ABL fusion g ene. Associated with tissue infi ltration by immature eosinophils, anemia, and thrombocytopenia; end-organ damage may occur due to leukaemic infi ltration or release of eosinophil cytokin es or enzymes: scarring of mitral/tricuspid valves, peripheral neuropathy, CNS dysfunction, pulmo- nary symptoms, and arthritis. 309 EOSINOPHILIC SYNDROMES AND NEOPLASMS Treatment Eosinophilia may be controlled initially by steroids followed by hydroxy- carbami de (up to 2g/d); does not generally respond to imatinib. Other antimetabolites or cytostati c drugs have been used. Alemtuzumab has been used with variable results. Some patients resp ond to Imatinib (even though FIP1L1-PDGFRA \210\222ve). In younger patients consider sibli ng alloge- neic SCT. Prognosis of CEL-NOC/HES Variable survival; up to 80% at 5 years decreasing to 42% at 15 ye ars. Poor prognostic factors include presence of a concurrent myelopro- liferative disorder , lack of response to steroids, cardiac disease, \231\202 gender, and degree of eosinophil ia.13 The WHO identifi ed marked splenomegaly, PB blasts, BM blasts, cytogenetic abnormalit ies and myeloid lineage dysplasia as unfavorable features.14 Idiopathic HES Diagnosis Diagnosis of exclusion. Characterized by PB eosinophilia \211 1.5 \227 109/L for >6 months for which no underlying cause is found and by symptoms relating to end-organ damage. It requires the same fi rst 5 criteria listed for CEL-NOC in the WHO c lassifi cation,1,14 but in addition: \200 No evidence of a clonal cytogenetic abnormality , and \200 \211 2% PB blasts, and \200 \211 5% BM blasts. Often incidental fi nding o r symptoms as per CEL-NOC; \231\202: \231\200 ratio 79:1. Peak incidence in 4th decade. Note: 20 \200\22350% of patients previously diagnosed with HES had FIP1L1- PDGFR abnormalit y which occurs almost exclusively in \231\202.15 PB eosinophils indistinguishable from CEL -NOC; neutrophilia with left shift frequent; platelets variable; polyclonal increase in imm unoglobulins including IgE common; splenomegaly 40%, anemia 50%; BM hypercel- lular with 25 \200\22375% eosinophils with left shift. An episodic form associated with angioedema, urticaria, weight gain, fever, and a polyclona l gammopathy including elevated levels of IgE that follows a relatively benign course and i s steroid responsive has been described (Gleich syndrome).16 Endomyocardial fi brosis progr essing to restrictive cardiomyopathy, skin lesions (angioedema, urticaria), thromboembolic disease, pulmonary lesions, arthritis, and CNS dysfunction occur commonly due to infi ltra- tion and release of enzymes. Treatment \200 Eosinophilia may be rapidly controlled by prednisolone (1mg/kg/d) tailing slowly to a maintenance dose (70% respond). HC (starting dose 500mg bd, titrating up to 2g/d as necessary) may be added in patients with tissue damage.7 Interferon alfa (starting dose 1 million units tiw) remains an option for treatment7,17 and may maintain prolonged remissions associated with improved clinical symptoms and organ dis ease.17,18 310 CHAPTER 7 Myeloproliferative neoplasms Interferon alfa + HC allows dose reduction and better control than with either agent alone.13 Vincristine, cyclophosphamide, 6-thioguanine, and cytarabine have been used with variable results. Alemtuzumab (anti-CD52) has been used with variable results. \200 A trial of imatinib may be eff ective in some FIP1L1-PDGFRA \210\222ve patients.17 Eosinophilia associated with aberrant T lymphocytes \200 Eosinophilia may result from the presence of immunophenotypically aberrant, often demonstratively clonal, IL-5-secreting T lymphocytes.19 A study of 60 patients, recruited mainly from dermatology clinics reported 16 patients with circulating T-cells with aberrant phenotype of whom 8 had clonal T-cell receptor (TCR) rearrangement; 4 patients subsequently developed T-cell lymphoma.15 Aberrant phenotype includes absent, reduced, or i expression of several antigens (e.g. CD2, CD3, CD4, CD5, CD6, CD7, or CD95), usually CD3 \210\222, CD4+, CD8 \210\222, or expression of activation markers (CD25 or HLA-DR). Elevated serum IgE may be further evidence of Th2 activation. \200 Equal frequency in \231\202 and \231\200; dermatological involvement in majority; GI symptoms and obstructive lung disease also common but endomyocardial fi brosis and myelofi brosis rare; CD3 \210\222, CD4+, CD8 \210\222 and del(6q) associated with i ri sk of progression to T-cell lymphoma.18 In a patient with skin abnormalities, lymphocytosis, or abnormal lymphocytes, immunophenoty pe and TCR gene analysis are recommended.19 Prednisolone as a single agent or in combination with interferon alfa is usually eff ective; HC has been used with variable to good results. References 1. Teff eri, A. and Vardiman, J.W. (2008). Classifi cation and diagnosis of myel oproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care dia gnostic algorithms. Leukemia, 22, 14 \200\22322. 2. Gotlib, J. (2012). World Health Organization-defi ned eosinophilic disorders: 2012 updat e on diagnosis, risk stratifi cation, and management. Am J Hematol, 87(9), 903 \200\22314. 3. Cools, J. et al. (2003). A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 ge nes as a therapeutic target of imatinib in idiopathic eosinophilic syndrome. N Engl J Med, 348, 1201 \200\22314. 4. Vandenberghe P et al. (2004). Clinical and molecular features of FIP1L1-PDGFRA (+) chronic eosinophilic leukemias. Leukemia, 18, 734 \200\22342. 5. Pardanani, A. et al. (2004). FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlatesin 89 consecutive patients with moderate to severe eosinophilia. Blood, 104, 3038 \200\22345. 6. Trempat, P. et al. (2003). Chronic myeloproliferative disorders with rearrangement of th e platelet-derived growth factor alpha receptor: a new clinical target for STI571/Glivec. O ncogene, 22, 5702 \200\2236. 7. Teff eri, A. et al. (2006). Atypical myeloproliferative disorders: diagnosis and treatme nt. Mayo Clin Proc, 81, 553 \200\22363. 8. Elliot, M.A. et al. (2004). Immmunophenotypic normalization of aberrant mast cells accompanies histological remission in imatinib-treated patients with eosinophilia-associate d mastocytosis. Leukemia, 18, 1027 \200\2239. 311 EOSINOPHILIC SYNDROMES AND NEOPLASMS 9. Klion, A.D. et al. (2003). Molecular remission and reversal of myelofi brosis in respons e to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosi nophilic syndrome. Blood, 103, 473 \200\2238. 10. Steer, E.J. and Cross, N.C. (2002). Myeloproliferative disorders with translocations of chromosome 5q31 \200\22335: role of the platelet-derived growth factor beta. Acta Haematol, 107, 113 \200\22322. 11. Apperley, J.F. et al. (2002). Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor recep tor beta. N Engl J Med, 347, 481 \200\2237. 12. Macdonald, D. et al. (2002). The 8p11 myeloproliferative syndrome: a distinct clinical entity caused by constitutive activation of FGFR1. Acta Haematol, 107, 101 \200\2237. 13. Butterfi eld, J.H. (2005). Interferon treatment for hypereosinophilic syndromes and sys temic mastocytosis. Acta Haematol, 114, 26 \200\22340. 14. Bain, B. et al. (2001). Chronic eosinophilic leukemia and the hypereosinophilic syndrom e In Jaff e, E.S. et al. (eds.) World Health Organization Classifi cation of Tumors. Patholog y and Genetics. Tumors of Haematopoietic and Lymphoid Tissues, vol 1, pp.29 \200\22331. Lyo n: IARC Press. 15. Simon, H.U. et al. (1999). Abnormal clones of interleukin-5-producing T cells in idiopa thic eosinophilia. N Engl J Med, 341, 1112 \200\22320. 16. Gleich, G.J. et al. (1984). Episodic angioedema associated with eosinbophilia. N Engl J Med, 310: 1621 \200\2236. 17. Gotlib, J. et al. (2004). The FIP1L1-PDGFRA fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classifi cation and management. Blood, 103, 2879 \200\22391. 18. Klion, A.D. (2005). Recent advances in the diagnosis and treatment of hypereosinophilic syndromes. Hematology, 2005, 209 \200\22314. 19. Bain, B. (2004). The idiopathic hypereosinophilic syndrome and eosinophilic leukemias. Haematologica, 89, 133 \200\2237. Further reading Helbig, G. et al. (2013). Diversity of clinical manifestations and response to corticosteroids for idiopathic hypereosinophilic syndrome: retrospective study in 33 pa tients. Leuk Lymphoma, 54(4), 807 \200\22311. Klion, AD. (2011). Eosinophilic myeloprolifer ative disorders. Hematology Am Soc Hematol Educ Program, 2011, 257 \200\22363. Noel, P. et al. (2013). Eosinophilic myeloid neoplasms.Curr Opin Hematol, 20(2), 157 \200\22362. 312 CHAPTER 7 Myeloproliferative neoplasms Mastocytosis (mast cell disease) Mastocytosis is a heterogeneous group of diseases characte rized by abnormal proliferation of mast cells in 1 or more organ systems including skin, BM , liver, spleen, and lymph nodes. They range from skin lesions that may spontaneously regre ss to aggressive multisystem disease with a poor prognosis (Table 7.12). Table 7.12 WHO classifi cation of mastocytosis1 Variant Subvariants Maculopapular CM (MPCM)/urticaria Cutaneous mastocytosis (CM) pigmentosa (UP) \200 Diff use CM (DCM) \200 Mastocytoma of skin \200 Smoldering SM (S SM) \200 Isolated bone marrow mastocytosis Indolent systemic mastocytosis (ISM) (BMM) \200 SM-AML \200 SM-MDS \200 SM-MPN \200 SM-CMML \200 SM-NHL \200 SM-CEL \200 SM-HES \200 Lymphadenopathic SM with Systemic mastocytosis with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD)a Aggressive systemic mastocytosis (ASM) eosinophiliab \200 Typical MCL \200 Aleukaemic MCLc Mast cell leukemia (MCL) (Extracutaneous) mast cell sarcoma (MCS) Extracutaneous mastocytoma a The non-mast cell lineage disease must also be defi ned by WHO criteria. b In a subgroup of these patients the FIP1L1/PDGFRA-fusion gene is detectable. c Circulating mast cells <10 %. Epidemiology Occurs at any age; median age of SM 50 \200\22360 years; range 5 \200\22388; C M most common in children: median age 2.5 months, may be present at birth, usually evident by 6 months;2 after age 10 years median age of CM 26 years. Pathogenesis Mast cells are derived from pluripotential haemopoietic cells and are the eff ector cells of the immediate allergic reaction via high affi nity recep- tors for IgE. Most variants of SM are clonal and a somatic mutation of c-KIT (usually D816V on exon 17), the proto-oncogene, located at 4q12, that encodes the transmembrane tyrosine kinase receptor fo r stem cell factor (SCF), is present in >80%.3 \200\2235 Other mutations described in 725% of cases lacking the D816V mutation but each individually rare.5 \200\2237 These 313 MASTOCYTOSIS (MAST CELL DISEASE) mutations lead to constitutive activation of KIT protein independent of SCF binding, causin g mast cell proliferation and suppressing apoptosis. In pediatric mastocytosis and CM KIT-a ctivating mutations are rare. Clinical symptoms in mastocytosis are due: (i) to the release of mast cell granules contain ing pro-infl ammatory and vasoactive mediators (including histamine, tryptase, heparin, TNF - , PGD2, cytokines, and chemokines) that have both local and systemic eff ects, and (ii) to organ infi ltration. In cutaneous mastocytosis (CM) mast cell proliferation is confi ned to skin; involvement of at least one extracutaneous organ defi nes systemic mastocytosis (SM), whether there is ev idence of skin involvement or not.2 Both are discussed here. Cutaneous mastocytosis Clinical features and presentation \200 Most cases of CM are seen in infants and children; involvement is generally limited to the skin; most common form is maculopapular CM/urticaria pigmentosa (MPCM/UP) with widespread cutaneous involvement with a few or many small lightly pigmented red-brown macules and papules. Intensifi es on rubbin g (Darier \200\231s sign). Usually transient; begins in 1st year and disappears at or short ly after puberty; progression to SM is unusual.6,8 Diff use CM is less frequent, almost exclusive to children and may cause smooth, red, or greatly thickened skin. Solitary mastocytoma of the skin occurs as a tumor; rare; generally occurs in infants; benign course. Adult MCPM/UP is associated with small heavily pigmented macular lesions; onset in young ad ults; lesions remain stable or increase with time though rarely decrease spontaneously;6,8 often progressive with systemic organ involvement usually BM (46%), lymph nodes (725% at di agnosis), spleen (750% at diagnosis), liver, and GIT. Familial mastocytosis causes cutaneous disease in infancy, persists into adult life, and may progress to systemic involvement; rare. Investigation and diagnosis \200 Diagnosis of CM (usually in children) requires demonstra tion of typical clinical fi ndings with histological evidence of skin infi ltration by mast cells a nd no evidence of systemic involvement. Adults with rash frequently misdiagnosed as CM, but SM criteria present in most cases. Unde rtake SM investigations in all adult patients. \200 Assessment: Inspection of lesional skin (plus photography). \200 Skin biopsy with tryptase immunohist ochemistry (IHC). Monomorphic MC infi ltrate, either large aggregates of tryptase +ve cells (>15 per cluster) or scattered MC. KIT mutation analysis. Most patients with CM have a normal serum tryptase (median 5ng/ mL); almost all patients with SM have a level >20 ng/mL.6,9 314 CHAPTER 7 Myeloproliferative neoplasms In children with serum tryptase >100ng/mL or symptoms/signs of SM and in all adults undertake BM examination to exclude SM. In children with serum tryptase <20ng/mL diagnosis of CM may be made without marrow examina tion unless other signs of SM present. In children with serum tryptase 20 \200\223100ng/mL, without other signs of SM, provisional diagnosis CM; monitor until puberty, if persist examine BM. Grading A clinical grading system has been proposed6 based on the severity of symptoms: pru ritus, fl ushing, blistering and bullae formation (Table 7.13). Table 7.13 Grading of skin-specifi c symptomsa in patients with mastocytosis6 Grade De \201 nition Prophylaxisb, but requires no other therapyc 0 = no symptoms 1 = mild, infrequent Prophylaxis therapy as required 2 = mild/moderate, frequent Requires and can be controlled by daily therapyd 3 = severe, frequent Suboptimal or unsatisfactory control with daily and combination therapyd 4 = severe adverse evente Requires immediate therapy and hospitalization a Pruritus, fl ushing, blistering, bullae formation. b All patients with mastocytosis are a dvised to avoid precipitating factors and events \200\224for most, prophylactic antihistami nes (H1 and H2 receptor antagonists) are recommended. c Unless patient is focused on cosmet ic consequences of the disease or suff ers from systemic mediator-related symptoms. d Despi te avoidance of precipitating factors. e The frequency of severe adverse events should be r eported: 4A: <1/year; 4B: >1/year and <1/month; 4C: >1/month. Management \200 Patients should avoid agents and situations that provoke a reaction. \200 Grade 0 patients are usually not treated unless they suff er from signifi cant non-or ganic symptoms or systemic mediator-related symptoms; grade 4 patients may be hospitalized and require antimediator drugs, stabilizing agents and topical therapy. Therapeutic approac h is shown in Table 7.14. Response to therapy is scored as complete regression, major regression (>50% reduction in aff ected skin), partial regression (10 \200\22350%), and no regression (<10%).6 Serum tryptase can be used for monitoring patients with CM if elevated at baseline; a signifi cant increase can be regarded as evidence of an increase in MC burden and an indication for histological re-assessment of the BM to exclude indolent S M.9 315 MASTOCYTOSIS (MAST CELL DISEASE) Table 7.14 Therapeutic options for cutaneous symptoms in patients with mastocytosis6 Symptom (variant) 1st-line, grade 1 \200\2232 1st-line, grade 3 and 2nd-line grade 2 Pruritus (all) H1 antihistamines Topical sodium cromoglicate UV irradiation, PUVA, H1 and H2 antihistamines, leukotriene antagonists, glucocorticoids Flushing (all) H1 antihistamines Leukotriene antagonists H1 and H2 antihistamines UV irradiation, PUVA H1 and H2 antihistamines Systemic glucocorticoids Topical sodium cromoglicate Blistering (all) Local therapy H1 antihistamines Local care, dressing H1 and H2 antihistamines Systemic glucocorticoids Topical sodium cromoglicate Bullae (usually diff use CM and mastocytomas) Excision Local immunosuppressants, local UV irradiation and psoralen bath or cream Mastocytoma lesion with symptoms or increasing size References 1. Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoieti c and Lymphoid Tissues, 4th ed. Lyon: IARC. 2. Valent, P. et al. (2001). Mastocytosis (mast cell disease) In Jaff e, E.S. et al. (eds.) World Health Organization Classifi cation of Tumors. Pathology and Genetics. Tumors of Hae matopoietic and Lymphoid Tissues, vol 1, pp. 291 \200\223302. Lyon: IARC Press. 3. Buttner C et al. (1998) Identifi cation of activating c-kit mutations in adult-, but not in childhood-onset indolent mastocytosis: a possible explanation for divergent clinical behavi or. J Invest Dermatol, 111, 1227 \200\22331. 4. Fritsche-Polanz, R. et al. (2001). Mutation analysis of C-KIT in patients with myelodysp lastic syndromes without mastocytosis and cases of systemic mastocytosis. Br J Haematol, 11 3, 357 \200\22364. 5. Orfao, A. et al. (2007). Recent advances in the understanding of mastocytosis: the role of KIT mutations. Br J Haematol, 138, 12 \200\22330. 6. Valent, P. et al. (2007). Standards and standardization in mastocytosis: Consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Inve st, 37, 435 \200\22353. 7. Valent, P. and Metcalfe, D.D. (2004). Mast cell proliferative disorders: diagnosis, clas sifi cation and therapy. Hematology, 2004, 153 \200\22362. 8. Wolff , K. et al. (2001). Clinical and histopathological aspects of cutaneous mastocytos is. Leuk Res, 25, 519 \200\22328. 9. Horny, H.P. et al. (2007). Mastocytosis: state of the art. Pathobiology, 74, 121 \200 \22332. 316 CHAPTER 7 Myeloproliferative neoplasms Systemic mastocytosis Clinical features and presentation \200 Patients typically present with symptoms of media tor release which vary in severity (mild to life-threatening) and may be chronic and recurr ent, or acute, lasting minutes or hours: \200 Urticaria, fl ushing, dermatographism, prur itus, angioedema, anaphylaxis. Paroxysmal hyper- or hypotension. \200 GI symptoms (80%): abdominal cramps, dyspepsia, na usea, diarrhea, malabsorption, multiple peptic ulcers, hemorrhage; consider aggressive SM if mala bsorption or weight loss. Wheezing, dyspnoea, rhinorrhoea. \200 Neuropsychiatric symptoms (headache, fatigue, irrit ability, cognitive disorganization, nightmares). Musculoskeletal pain (25%). Less often, patients present with an abnormal blood count (720%), organomegaly, lymphadenopathy, or pathological fracture. \200 May present without skin in volvement; frequent in aggressive SM (ASM) and mast cell leukemia though may have isolated BM involvement in subvariant of in dolent SM (ISM). SM may follow either an indolent or an aggressive course; organomegaly due to mast cell infi ltration may occur in patients with an indolent course;1 aggressive SM is characterized by progressive mast cell infi ltration of organs causing im paired function: BM failure, hepatocellular failure with ascites, severe diarrhea and malab sorption, pathological fractures, organomegaly, and pancytopenia. Clinical features of SM have been classifi ed as \200\230B-fi ndings \200\231 and \200\230C-fi ndings \200\231 and assist in staging, identifi cation of clinical variants, selection of therapy, and assessment of response:2 \200\2234 \200 B-fi ndings: defi ne sp read of disease; indication of high burden of mast cells, and expansion of the disease with out impairment of organ function; B = borderline benign:2,5 \200\223 BM biopsy showing >30 % infi ltration by mast cells (focal, dense aggregates) and/or serum tryptase level >200ng/mL. \200\223 Signs of dysplasia or myeloproliferation, in non-mast cell lineage, but insuffi c ient for a diagnosis of AM-AHNMD, with normal or slightly abnormal blood counts. \200\223 Hepatomegaly without impaired liver function, and/or palpable splenomegaly withou t hyperplenism and/or lymphadenopathy on palpation or imaging. C-fi ndings: defi ne aggressiveness of the infi ltrate; indication of impaired organ function due to mast cell infi ltration:2,6 \200\223 BM dysfunction: \211 1 cytopenia(s): ANC <1.0 \227 109/L, Hb <10g/dl, Plt <100 \227 109/L. \200\223 Palpable hepatomegaly with impairment of liver function, ascites and/or portal hypertension. \200\223 Skeletal involvement with large osteolytic lesions and/or pathological fractures. 317 SYSTEMIC MASTOCYTOSIS \200\223 Palpable splenomegaly with hypersplenism. \200\223 Malabsorption with weight los s due to GI mast cell infi ltrates. Investigations and diagnosis When SM is suspected a biopsy of the aff ected organ should be done if possible and a BM (aspirate and trephine) examined with tryptase stain, fl ow cyto metry for phenotypically abnormal mast cells (CD25+), and, if available, mutation screening for KIT-D816V.7 BM biopsy/tissue biopsy \200 Diagnostic criteria as per Table 7.15. \200 Usually sharply demarcated mast cell aggregates in perivascular or peritrabecular loc ations or randomly distributed; often comprise varying proportions of mast cells, lymphocyt es, eosinophils, and fi broblasts; frequently signifi cant fi brosis (90%) and thickening o f adjacent bone; in advanced SM diff use infi ltration with marked reticulin or collagen fi brosis.2 Exclude a coexisting haematopoietic neoplasm (SM-AHNMD), hypercellularity or dysmyelopoiesi s (prognostic value); exclude reactive non-clonal mast cell hyperplasia that may accompany several hematological disorders where mast cells lack atypia and are sprinkled throughout t he marrow rather than in aggregates.2 \200 Immunohistochemistry for tryptase, CD117 (KIT) and CD25 to demonstrate infi ltrate of tryptase +ve spindle-shaped mast cells. \200 If i solated infi ltrate only or multifocal small aggregates (<15 MCs) consider minor diagnostic criteria (Table 7.15). If subdiagnostic (n <3), repeat biopsy; if remains subdiagnostic in patient with high clini cal suspicion monitor closely. KIT-mutation analysis might help. Table 7.15 WHO diagnostic criteria for SM2 \200\2234 Major criteriona Multifocal, dense infi ltrates of mast cells ( \211 15 mast cells per aggregate) in BM and/ or other extracutaneous organ(s) confi rmed by tryptase immunohistochemistry Minor criteriaa 1. In biopsy sections of BM or other extracutaneous organs >25% of mast cells show an abnormal spindle- shaped morphology or >25% of mast cells in BM aspirate smears are immature or atypical 2. Detection of c-KIT mutation D816V or other activating mutation at codon 816 in extracuta neous organ(s); marrow is recommended for screening 3. KIT+ MCs in BM or other extracutaneous organs express CD2 or/and CD25 4. Serum tryptase >20ng/mL (does not count in patients who have AHNMD-type disease) a If at least 1 major and 1 minor criterion or at least 3 minor criteria are fulfi lled, th e diagnosis of SM can be established. 318 CHAPTER 7 Myeloproliferative neoplasms BM aspirate \200 \211 5% mast cells suggests an unfavorable prognosis; \211 20% defi ne s mast cell leukemia; mild myelodysplasia is found in most patients with SM.3 Mast cells in SM show aberrant morphological features.3 \200 Non-metachromatic myeloblast s suggest AHNMD and dysplasia; >5% SM-MDS and >20% SM-AML. Aspirate can be negative whilst trephine is diagnostic. Flow cytometry \200 Neoplastic SM mast cells usually aberrantly express CD25 CD2. \200 BM cells should be analyzed; minimum recommended panel includes CD2, CD25, CD45, and CD117; CD34 may be added when CD117 expression low (frequent in KIT mutation8) to defi ne M C as CD34-/ CD117+/CD45+.3 KIT-D816V and other KIT mutation analysis \200 Neoplastic mast cells in >80% adults with SM have activating KIT mutation at codon 816; D816V most common (SM 70 \200\22390%; CM 10 \200\22330%), all others rare.3 RT-PCR and RFLP analysis of unfractionated BM cells after RBC-lysis or marrow mononuclear c ells; PB is not an acceptable alternative as often \210\222ve in ISM.3 If \210\222ve result with small infi ltrate, interpret with caution; if large infi ltrate, confi rm \210\222ve result in reference laboratory as wt-KIT and certain othe r mutants confer imatinib-sensitivity. Serum tryptase \200 Almost all patients with SM have serum tryptase level >20ng/mL. \200 In severe allergic reactions, tryptase may be markedly elevated so wait 2d after clinical resolution before measuring; if elevated, consider SM.3 \200 Also elevated in myeloid no n-mast cell disorders, AML, CML, MPN, and MDS; therefore a minor criterion only in absence of AHNMD. \200 Tryptase level higher with high mast cell burden; in ISM level remains rea sonably constant over years; in ASM or mast cell leukemia levels often increase as disease progresses. In ASM or mast cell leukemia tryptase levels often decrease with successful cytoreduction.3 FBC and \201 lm \200 No characteristic features; circulating mast cells very rare (2%) unless very advanced disease or mast cell leukemia. Mild-to-moderate anemia 745%; eosinophilia up to 25%; thrombocytopenia 720%; monocytosis 715%; pancytopenia may develop due to BM infi ltration o r hypersplenism. Other investigations \200 Bone scan/skeletal survey shows bone lesions in 60%; generalize d osteosclerosis, focal sclerosis, osteopenia, osteoporosis, or osteolysis. Bone densitometry (DEXA scan) in all patients with SM. \200 Ultrasound abdomen. \200 Se rum biochemistry. 319 SYSTEMIC MASTOCYTOSIS Coagulation screen. \200 Endoscopy in patients with GI symptoms. \200 EEG: if clinicall y indicated. Variants of SM \200 Indolent SM (ISM): most common form of SM (766%); no \200\230B \200 \231 or \200\230C \200\231 fi ndings; mast cell burden low; usually involves skin and BM; associated with maculopapular skin lesions (90%); fl ushing and abdominal cramps frequently reported; slow involvement of organs; prolonged course and good prognosis in almost all wi th survival >20 years; poor quality of life if inadequate control of mediator symptoms; sma ll number transform into ASM or SM-AHNMD.2,5,6 Subvariants identifi ed:4 \200 BM mastocyt osis (BMM): rare subvariant of ISM with isolated marrow involvement and no skin lesions or multiorgan involvement, low MC burden and good pr ognosis.2 Smoldering SM (SSM): as ISM with 2 or more \200\230B \200\231 fi ndings but no \200\230C \200\231 fi nding; some have prolonged stable course others develop ASM or AHNMD.2,3,5,6 Aggressive SM (ASM): 75% of all SM patients; \211 1 \200\230C \200\231 fi nding; may present with hepatosplenomegaly and/or generalized lymphadenopathy without typical skin les ions; characterized by impaired organ function due to progressive infi ltration of BM, live r, spleen, GI tract, or skeletal system; predisposition to severe mediator release attacks with haemorrhagic complications; median survival 3 \200\2235 years:2,6 \200 Lymphadenopat hic mastocytosis with eosinophilia: rare subvariant of ASM; progressive lymphadenopathy wit h PB eosinophilia often with extensive bone involvement and hepatosplenomegaly but usually without skin lesions.2,6 SM with associated hematological non-mast cell disease (SM-AHNMD): 20 \200\22330% of SM pat ients; <50% have skin lesions; 80 \200\22390% myeloid, most commonly CMML; 10 \200\22320% l ymphoid, most commonly myeloma; classify using WHO criteria; prognosis poor, largely determ ined by accompanying disorder and poorer survival than patients without SM.2,6 Mast cell leukemia: rare; \211 20% MC in BM aspirate and \211 10% in PB (aleukaemic varia nt <10%); diff use infi ltration on trephine biopsy; no skin lesions, severe peptic ulcer d isease, hepatosplenomegaly, anemia, multiorgan failure; poor response to chemotherapy and s hort survival (most <1 year).2,5,6 Mast cell sarcoma (MCS): extremely rare; unifocal tumor consisting of atypical mast cells; high grade cytology; locally destructive growth; no skin or systemi c involvement at diagnosis; prognosis grave; rapid progression with terminal phase resembli ng Mast cell leukemia.2,6 \200 Extracutaneous mastocytoma: extremely rare; most reported cases involve lung; unifocal tumor; low-grade cytology; non-destructive growth pattern; no skin or systemic involvement.2,6 320 CHAPTER 7 Myeloproliferative neoplasms Diff erential diagnosis Diagnosis often delayed due to non-specifi c symptoms and presentat ion. Exclude reactive mast cell hyperplasia, mast cell activation syndromes, MPNs with i ma st cells, carcinoid syndrome, phaeochromocytoma, liver disease, CEL/HES, and lymphoma. Management \200 No curative therapy; management consists of prevention of