Acta Haematol 2005;114:41–51 DOI: 10.1159/000085561

Systemic Mastocytosis: Pathology, Classifi cation, and Current Therapies

A. Pardanani

Divisions of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minn., USA

Key Words sinophilic leukemia, may not be easy to categorize on the Systemic mastocytosis Histopathology basis of this classifi cation. There is no standard therapy Classifi cation Therapies for MCD and treatment has to be tailored to the needs of the individual patient. MC-cytoreductive therapies, such as interferon- and chemotherapy, are generally re- Abstract served for patients with progressive disease and or- disease (MCD) is characterized by the abnormal ganopathy. A subset of MCD patients with associated growth and accumulation of neoplastic mast cells (MC) eosinophilia who carry the FIP1L1-PDGFRA oncogene in one or more organs. The diagnosis of systemic MCD will achieve complete clinical, histological, and molecu- is most commonly established by a thorough histologi- lar remissions with imatinib mesylate therapy, in con- cal and immunohistochemical examination of a bone trast to those with c-kit D816V mutations. The BM pathol- marrow (BM) trephine specimen. In cases with patho- ogy, consensus classifi cation, and current therapies for gnomonic perivascular and -trabecular aggregates of MCD are further discussed in this article. morphologically atypical MC and signifi cant BM involve- Copyright © 2005 S. Karger AG, Basel ment, the diagnosis may be relatively straightforward. In contrast, when a sparse, loose pattern of MC infi ltra- tion predominates, or when MCs are obscured by an as- Bone Marrow Pathology sociated non-MC hematological neoplasm, a high index of suspicion and use of adjunctive tests, including spe- Upon reviewing the World Health Organization cial stains, such as tryptase and CD25, may be necessary (WHO) criteria for diagnosing mast cell disease (MCD), to reach a diagnosis. The updated classifi cation for MCD it immediately becomes obvious why the hematopatholo- clarifi es the clinical and pathological criteria for catego- gist plays a critical role in the diagnostic process. rizing patients into relatively discrete subgroups. Some The diagnosis of systemic, extracutaneous MCD is cases, however, such those with Fip1-like-1-platelet-de- most commonly established through a thorough histo- rived growth factor receptor (FIP1L1-PDGFRA) + clonal logical and immunohistochemical examination of a bone eosinophilia associated with elevated serum tryptase marrow (BM) trephine specimen, which remains the levels, with features that overlap MCD and chronic eo- most important diagnostic approach [1–7] . This is be-

© 2005 S. Karger AG, Basel A. Pardanani, MD 0001–5792/05/1141–0041$22.00/0 Divisions of Hematology and Internal Medicine, Mayo Clinic Fax +41 61 306 12 34 200 First Street SW E-Mail [email protected] Accessible online at: Rochester, MN 55905 (USA) www.karger.com www.karger.com/aha Tel. +1 507 284 3417, Fax +1 507 266 4972, E-Mail [email protected] cause the BM is almost always involved in systemic MCD, While MC atypia has been proposed as a criterion for and standards regarding diagnostic aspects of normal and aggressive MCD [3, 15], other studies have questioned neoplastic mast cells (MCs) in other extracutaneous tis- the precise prognostic value of such morphological abnor- sues have not been clearly defi ned yet [8] . malities [4, 10]. Lennert and Parwaresch [3] proposed Normal MC are round or oval, with a round, centrally cytological and cytochemical characteristics of MC as one located, nonlobated nucleus, and densely packed, uni- feature that distinguishes ‘benign’ from ‘malignant’ formly distributed cytoplasmic granules. BM aspirate MCD. The latter exhibits MC with large, irregularly smears in MCD (except MC leukemia; MCL) generally shaped nuclei, increased mitotic activity, and decreased show slightly increased numbers of MC, which may ac- metachromatic granules, sometimes resembling mono- count for 2–5% of nucleated marrow cells [2] . Neoplastic cytes [1, 3]. MC vary in their morphological appearance, from the Three major histological patterns of BM MC infi ltra- typical round MC to the larger fusiform shapes with uni- tion have been described [2]. The commonest, Type I, formly distributed fi ne granules and long, polar cytoplas- exhibits focal MC infi ltration, with a normal distribution mic processes. The fusiform MC may also demonstrate of fat cells and hematopoietic elements in the uninvolved hypogranulation and uneven granule distribution, as well marrow space. Patchy MC infi ltration with osteosclerosis as nuclear lobation [2, 3, 9–11]. BM aspirate smears from and fi brosis also characterizes the Type II pattern, but, in some patients show an abundant number of atypical MC contrast to Type I, marked hypercellularity is noted in the (50–95% of nucleated cells), frequently with lobulated nu- non-MC involved marrow space. The increased cellular- clei [2] . These patients with MCL have diffuse marrow ity results from a variable increase in the number of im- infi ltration with circulating MC. mature , , immature monocytes, The characteristic BM MC lesion, variously referred small , or blast cells. A subset of these to as MC granuloma [12, 13], eosinophilic fi brohistio- cases will meet WHO criteria for diagnosis of a clonal, cytic lesion [14], or MEL (MC, , lymphocyte) non-MC lineage hematological disorder associated with lesion [5] , is usually comprised of perivascular and/or - MCD (MCD-AHNMD). Type III pattern represents trabecular aggregates of MC. These aggregates may be MCL, and is characterized by a diffuse marrow infi ltra- relatively monomorphic, comprised mainly of fusiform tion with neoplastic, morphologically atypical MC, com- MC with pale cytoplasm and inconspicuous nuclei resem- monly with circulating MC. Not all cases can be neatly bling histiocytes, or more polymorphic, with MC found categorized on the basis of this histological classifi cation, to be admixed with lymphocytes, eosinophils, neutro- such as those with borderline fi ndings between Types I phils, histiocytes, endothelial cells, and fi broblasts [1] . and II, and those with diffuse BM MC infi ltration, but Some lesions may reveal a central focus of lymphocytes, without other features of MCL [16] . surrounded by MC, or vice versa. Eosinophils are fre- In general terms, MC are not readily recognized by quently found in MC lesions, with the highest concentra- hematoxylin-and-eosin staining, and may be confused tion being described at the periphery of the lesions. BM with a variety of other cells that include fi broblasts, his- specimens may reveal a preponderance of fusiform or tiocytes, hairy cells, and monocytes [1, 17]. In addition, round-shaped MCs, or a mixture of round and fusiform BM MC lesions may be signifi cantly polymorphic, with shapes [2, 10]. While irregular trabecular thickening is MC being admixed with lymphocytes, eosinophils, neu- commonly noted, particularly when MC aggregates abut trophils, histiocytes, endothelial cells, and fi broblasts [1] . the trabeculae, other cases may be characterized by a Metachromatic stains, such as Giemsa or toluidine blue, marked thinning of BM trabeculae and osteopenia. The are useful for demonstrating the basophilic MC granules perivascular lesions exhibit hypertrophy of the medial [18], but such staining is diminished or often lost with the and adventitial layers of the vessel wall, with a surround- decalcifi cation process with acidic solutions that is neces- ing cuff of infi ltrating MC [1]. BM MC infi ltrates com- sary for sectioning of paraffi n-embedded BM tissue [17]. monly exhibit a dense network of reticulin fi bers. In cas- The cytoplasmic granules of MC, including those of im- es with diffuse BM infi ltration by monomorphous, spin- mature MC, are also intensely stained with naphthol-AS- dled MC resembling fi broblasts, a diagnosis of idiopathic D-chloroacetate esterase [19], which has been historically myelofi brosis may be erroneously made, especially given useful. Among the immunohistochemical markers, stain- the accompanying decrease in normal hematopoietic ele- ing for tryptase is considered the most sensitive, being ments. able to detect even small-sized MC infi ltrates [6, 20]. Giv- en that virtually all MC, irrespective of their stage of mat-

42 Acta Haematol 2005;114:41–51 Pardanani

uration, activation status, or tissue of localization, ex- Table 1. Classifi cation of mast cell neoplasms [3] press tryptase, staining for this marker detects even those infi ltrates that are primarily comprised of immature, non- Benign 1 Mastocytoma (mast cell nevus) granulated MC [21]. Tryptase immunostaining is partic- 2 Cutaneous mastocytosis ularly useful for the diffuse pattern of MC infi ltration, a) diffuse (mostly urticaria pigmentosa) where a loose MC distribution, in lieu of the discrete MC b) localized aggregates, is seen [20]. It must be emphasized t hat nei- 3 Systemic mastocytosis with skin involvement (mostly urticaria ther tryptase, nor other immunohistochemical markers, pigmentosa) such as chymase, KIT/CD117, and CD68, can distin- Malignant guish between normal and neoplastic MC [22] . Also, ab- 1 Malignant mastocytosis (mast cell reticulosis) normal seen in some cases of acute and chron- a) primary b) secondary to cutaneous or systemic mastocytosis ic basophilic leukemia, as well as in chronic myeloid leu- 2 Mast cell sarcoma kemia, and blasts in some acute myelogenous leukemia 3 Mast cell leukemia, occurring with 1 or 2 cases may be tryptase + , and may prove diffi cult to distin- guish from MC [23]. Recently, CD25, a low-affi nity re- ceptor for interleukin-2, has been proposed as an immu- nohistochemical marker that reliably distinguishes be- tween normal and neoplastic MC, for all major subgroups Classifi cation of MCD [21]. In 72 of the 73 MCD cases analyzed, a strong, annular, membrane-staining pattern for CD25 MCD is characterized by the abnormal growth and ac- was detected across all subgroups, and in these, the num- cumulation of neoplastic MC in one or more organs of ber of CD25 + cells was closely correlated with the number the body. In general terms, MCD exhibits immense di- of tryptase + cells. Cells coexpressing tryptase and CD25 versity in its clinical presentation and disease course, its in the setting of hematological disease are highly likely to pattern of organ involvement, histological features, its be neoplastic MC. In contrast, none of the 75 control potential overlap with other hematological neoplasia, and cases showed CD25 + expression on BM MC by immuno- increasingly, in the molecular lesions that are associated histochemistry. Signifi cantly, 2 urticaria pigmentosa with this disease. Historically, these factors have made (UP) cases, who did not exhibit the pathognomonic com- the task of classifying MCD into discrete clinicopatho- pact BM MC infi ltrates on initial review, were re-exam- logical entities a challenging endeavor. ined by CD25 immunostaining. Both patients were found The classifi cation of MCD has evolved over the years; to have CD25 + MC, of which 125% had a spindled mor- the fi rst recognition of cutaneous MCD came from Un- phology, in a loosely scattered, interstitial pattern. These na’s [25] recognition in 1887 that UP lesions were histo- 2 patients were reclassifi ed as having indolent MCD giv- logically comprised of MC infi ltrates. Subsequently, al- en that 3 minor criteria of the WHO system were satisfi ed. though the systemic nature of MCD was alluded to in case CD25 expression was correlated with presence of the c-kit descriptions in the early 1900s by Sézary et al. [26] and D816V mutation in 72 of 73 systemic MCD and 2 of 3 Jeanselme and Touraine [27], systemic MC infi ltrates UP cases. Consistent with our previously published fl ow were histologically demonstrated by Ellis [28] only in cytometry data [24], screening for CD2 expression on BM 1949, thus differentiating skin delimited MCD from the MC by immunohistochemistry has low diagnostic value more extensive systemic MCD. Subsequently, a dichoto- because a signifi cant proportion of cases stain negative, mous view prevailed, wherein ‘benign’ MCD was sepa- and CD2 expression on BM MC is generally weak in the rated from ‘malignant’ MCD, based upon the presence or cases that are positive [6, 21, 22]. In one study, CD2- absence of associated UP, organomegaly, cytological and positivity by immunohistochemistry was 81% (35/43) in cytochemical features of BM MC, as well as the clinical indolent MCD, 55% (11/20) in MCD-AHNMD, 29% course (table 1) [3, 29–31]. Following this, based on the (2/7) in aggressive MCD, and 67% (2/3) in MCL [21] . recognition that not all patients classifi ed as having ‘be- CD2-positivity, as determined by fl ow cytometry, was: nign’ MCD have a favorable outcome, and that ‘malig- 46% (6/13) in indolent MCD, 29% (2/7) in MCD-AHN- nant’ MCD was comprised of relatively distinct clinico- MD, 13% (1/8) in aggressive MCD, and 0% (0/2) in MCL pathological entities, revised classifi cations that proposed [24]. four or fi ve broad MCD subgroups were proposed [1, 32]. More recently, updated diagnostic criteria (table 2) and

Systemic Mastocytosis Acta Haematol 2005;114:41–51 43 Table 2. WHO criteria for diagnosis of systemic MCD [35] an updated consensus classifi cation (table 3), based on refi nements of prior systems, was proposed for MCD in Major 2001 [33] , and was subsequently adopted by the WHO Multifocal dense infi ltrates of mast cells in bone marrow or other extracutaneous organs (>15 mast cells aggregating) [34]. This version incorporates recent advances in our understanding of MCD, including the role of activating Minor c-kit receptor mutations, presence of cell surface markers 1 Mast cells in bone marrow or other extracutaneous organs show an abnormal (spindling) morphology (>25%) that reliably distinguish neoplastic from normal MC, and 2 Codon 816 c-kit mutation D816V in extracutaneous organs detection of elevated levels of circulating MC mediators 3 Mast cells in the bone marrow express CD2, CD25, or both as a surrogate measure of systemic MC burden. The WHO 4 Serum tryptase >20 ng/ml (does not count in patients who classifi cation takes into account the gamut of clinical have an associated clonal hematological non-mast cell disease; manifestations of MCD, from the relatively benign pedi- AHNMD) atric-onset MCD with skin-limited disease, to the persis- tent, clonal, myeloproliferative variants seen in adults that may exhibit an inexorably progressive disease course, and that are often associated with a non-MC hematolog- Table 3. WHO variants of mastocytosis [35] ical malignancy. The diagnosis of systemic MCD is established when 1 Cutaneous mastocytosis (CM): either 1 major and 1 minor criterion, or 3 of the minor a) Maculopapular CM b) Diffuse CM criteria, are satisfi ed (table 2). Described below are the c) Mastocytoma of skin major clinicopathological categories (except cutaneous 2 Indolent systemic mastocytosis MCD) included in the WHO classifi cation: a) Smoldering SM Indolent Systemic MCD. The majority of adult sys- b) Isolated BM mastocytosis temic MCD patients have indolent disease, with a low 3 Systemic mastocytosis with an associated clonal hematological non-MC lineage disease (MCD-AHNMD) systemic MC burden, associated UP, and, generally, a 4 Aggressive systemic mastocytosis good prognosis. A subgroup of these patients, however, With eosinophilia may have severe symptoms from MC-mediator release, 5 Mast cell leukemia (MCL) and may die from anaphylactic shock [2, 15, 32]. Trans- Aleukemic MCL 6 Mast cell sarcoma formation of disease into an aggressive variant or devel- 7 Extracutaneous mastocytoma opment of an associated malignancy, while possible, is infrequent in this group of patients [2, 4, 9, 32] . The fol- lowing have to be ruled out before a patient is classifi ed as having indolent disease: (1) manifestations of end-or- gan dysfunction (‘C’ fi ndings – table 4) such as cytope- Table 4. ‘C’-fi ndings = indication of impaired organ function due nias, weight loss secondary to malabsorption, ascites, hy- to MC infi ltration (has to be confi rmed by biopsy in most cases) persplenism, and pathological fractures, all of which [35] have to be proven to result from MC infi ltration of un- 1 Cytopenia(s): Absolute count <1,000/l, or derlying organs, (2) clear evidence of an AHNMD, and hemoglobin <10 g/dl, or platelets <100,000/l (3) MCL [34] . Previous studies, both prospective and 2 Hepatomegaly with ascites and impaired liver function retrospective, have identifi ed other prognostic variables 3 Palpable splenomegaly with hypersplenism in multivariate analyses that may be partially correlated 4 Malabsorption with hypoalbuminemia and weight loss 5 Skeletal lesions: large-sized osteolysis or severe osteoporosis with ‘C’ fi ndings (i.e. MC-related organopathy), includ- causing pathological fractures ing older age [9, 32], absence of UP [9] , type of BM MC 6 Life-threatening organopathy in other organ systems infi ltration pattern [2, 9], BM eosinophilia [35], atypical that defi nitively is caused by an infi ltration of the tissue BM MC morphology [3, 7, 15, 29, 32], high BM MC by neoplastic mast cells burden [15, 35] , and presence of c-kit D816V mutation [36] . Identifi cation of favorable prognostic features at the time of MCD diagnosis may help identify those pa- tients more likely to experience an indolent clinical course.

44 Acta Haematol 2005;114:41–51 Pardanani

In general, the BM MC burden in indolent MCD is signifi cance and systemic MCD, cannot be discounted in less than 5–10%, depending upon the methodology used some cases [23, 40]. The diagnosis of MCD-AHNMD for MC quantifi cation [15, 35]. Typically, a patchy infi l- should be made cautiously, and according to well-estab- tration pattern with a perivascular and/or -trabecular MC lished WHO criteria, for both the MCD, as well as the aggregates is noted, with noninfi ltrated regions exhibiting associated hematological neoplasm [41] . a normal distribution of fat cells and other hematopoi- MCD-AHNMD is the second most common MCD etic elements [2, 35]. Less commonly, a diffuse interstitial category; more frequent than aggressive systemic MCD pattern of MC with little tendency to form compact MC and the rare true MCL [23] . Sagher and Even-Paz [30] aggregates may be seen [8] . A spectrum of atypical mor- described malignant transformation in 7% of patients phological features including cell ‘spindling’, cytoplasmic with childhood-onset MCD, and in 33% of patients with hypogranulation, uneven granule distribution, cytoplas- adult-onset systemic MCD. Lennert and Parwaresch [3] mic processes, and nuclear abnormalities characterize described MCL or AML developing in 16 of 43 systemic BM MC from these patients. Less commonly, MC mor- MCD cases (37%), and Horny et al. [2] have reported a phology may be relatively normal [3, 8, 10, 15, 32]. When coexistent leukemia in 14 of 45 (29%) and in 25 of 61 such MC predominate, a diagnostic challenge may result, (40%) [31] MCD patients. In a study by Travis et al. [16] , and may require the use of adjunctive tests, such as screen- 22 of 66 (33%) systemic MCD patients had an associated ing for MC CD25 expression and for the c-kit D816V hematological disorder. mutation. Whether a unilateral BM biopsy is suffi cient to Most hematological disorders associated with system- rule out BM MC infi ltration in indolent MCD has re- ic MCD involve dysmyelopoiesis or neoplasia of the my- cently been questioned. In 23 patients who underwent eloid elements, and are associated with characteristic cy- bilateral BM biopsies as part of the diagnostic workup, 4 togenetic abnormalities that are known to occur in acute cases (17%) had only a unilateral positive BM result [37]. leukemias, MPD, and myelodysplastic syndromes (MDS) Three of the four patients had a serum tryptase value of [16, 23]. While most case series describe chronic MPD less than 25 ng/ml, and hence would not have been clas- (except Philadelphia + chronic myeloid leukemia) and sifi ed as systemic MCD, as per the WHO consensus clas- acute leukemias as the most frequent hematological neo- sifi cation, without the second BM biopsy. It is recom- plasia associated with systemic MCD [31] , myelodyspla- mended that BM trephines from adult patients with clin- sia may have been relatively under-appreciated [10, 16] . ically proven cutaneous MCD (usually UP) be screened The recognition in several case series that the commonest for MC infi ltrates by tryptase immunostaining, which can myeloid neoplasm associated with systemic MCD is detect even very small infi ltrates comprised of 10–15 chronic myelomonocytic leukemia, an MPD/MDS hy- cells. brid, supports the contention that dysmyelopoiesis is a In one study, MCD patients with a Type I pattern of prominent feature of systemic MCD [23, 40, 42, 43]. BM MC infi ltration (largely found in indolent disease) In general, the BM examination reveals a hypercellular had an actuarial 5-year survival rate of 0.75, as compared marrow (Type II or III pattern of MC infi ltration [2]) with to patients with Type II (aggressive MCD or MCD-AHN- effacement of the underlying architecture, although some MD) or III (MCL) patterns, who had 5-year survival rates patients cannot be neatly categorized on this basis, and of 0.17 and 0.0, respectively [2] . MDS, which may represent the largest group of associ- The relatively infrequent smoldering MCD and iso- ated hematological disorders, may present with either a lated BM MCD subcategories of indolent systemic MCD normo- or hypocellular marrow [16, 32]. In many cases, are not discussed here. the BM MC infi ltrates may be obscured by the associated Systemic MCD-AHNMD. The association of MCD hematological neoplasm if only hematoxylin-and-eosin with a broad spectrum of hematological disorders has pre- or Giemsa stains are employed [23]. In such cases, the viously been well described [1–3, 16, 31, 32, 38–40]. The MC infi ltrates are relatively easy to identify within sheets frequent coexistence of systemic MCD with dysmyelo- of monotonous blast cells than within more polymor- poiesis and myeloid neoplasms is consistent with the view phous infi ltrates seen in MPD and MDS. A thorough ex- that systemic MCD is a clonal myeloproliferative disor- amination of the BM specimen after tryptase immuno- der (MPD) that involves a hematopoietic progenitor, staining, however, will often reveal foci of spindled MC, commonly a myeloid progenitor. However, the indepen- thus allowing the diagnosis of MCD to be established. dent codevelopment of two discrete hematological neo- Infrequently, compact MC infi ltrates, the major diagnos- plasms, such as a monoclonal gammopathy of uncertain tic criterion as per the WHO classifi cation, are not de-

Systemic Mastocytosis Acta Haematol 2005;114:41–51 45 tected in MCD-AHNMD. In such cases, adjunctive test- the peripheral blood. The sine qua non for diagnosing ag- ing, including screening for the c-kit D816V mutation gressive MCD is demonstrating impaired organ function and for CD25 expression on BM MC, as well as demon- (i.e. ‘C’ fi ndings; table 4 ) resulting directly from neoplas- stration of MC atypia (‘spindling’), is critical towards tic MC infi ltration of the involved organ(s) [46] . In real- reaching a diagnosis of MCD [34]. A pattern of loosely ity, however, biopsy of an organ other than that of BM is scattered atypical/neoplastic MC without focal aggregates rarely undertaken, and organopathy is generally demon- has been described in MCD with associated Chronic my- strated by clinical tests alone. elomonocytic leukemia, AML, multiple myeloma [23] , Patients with aggressive systemic MCD are a subset of as well as in cases with prominent eosinophilia that car- the erstwhile ‘malignant mastocytosis’ category that also ry the Fip1-like-1platelet-derived growth factor recep- includes MCD-AHNMD and MCL (see relevant sections tor (FIP1L1-PDGFRA) oncogene [44]. Most MCD- in this review), and thus all share common features, such AHNMD cases are positive when tested for the c-kit as older age, absence of UP lesions, presence of organo- D816V mutation [23] , although other mutations have megaly, anemia, eosinophilia, a high BM MC burden, also been described [45] . MC morphological atypia (i.e. high-grade morphology), In most cases, a diagnosis of MCD is made inciden- BM features of dysmyelopoiesis/myeloproliferation, an tally, usually after an examination of BM and other tis- elevated serum tryptase level, activating c-kit receptor sues for evaluation of the associated hematological disor- mutations, and/or a rapid clinical course [1–3, 9, 15, 32, der [16, 23]. In such cases, it is diffi cult to ascertain if 35]. systemic MCD existed prior to the onset of the hemato- The BM shows a high, but variable degree of MC in- logical disorder, although some cases have UP lesions as fi ltration, with features of myelodysplasia and/or myelo- well as symptoms of MC-mediator release that clearly proliferation, except that WHO criteria for an associated predate the diagnosis of the associated hematological dis- hematological malignancy (MCD-AHNMD) and MCL order. are not satisfi ed [34] . Given the degree of BM involve- The median age of systemic MCD patients with an as- ment, testing for CD25 expression on BM MC, or for c-kit sociated hematological disorder is greater than patients D816V mutations, is often less critical in this subgroup without them, and the length of the prediagnostic inter- of systemic MCD. vals is signifi cantly shorter in the former [16, 31]. MCD- MCL. This is an aggressive hematological malignancy AHNMD patients are more likely to present with consti- characterized by progressive organopathy, including BM tutional symptoms, but less likely to experience symp- failure from MC infi ltration, and the presence of a con- toms of MC-mediator release, including skin symptoms, siderable number of atypical MC in the BM smear (gen- and also less likely to present with UP lesions. In 2 pub- erally 120% of nucleated cells), as well as in the periph- lished series, 5-year survival of MCD-AHNMD patients eral blood (generally 110% of leukocytes) [47–59] . as compared to those with systemic MCD alone was 17 MCL may arise de novo, or evolve from known pre- versus 75%, and 28 versus 61%, respectively [2, 16]. The existing systemic MCD. In a review of 17 published MCL adverse prognosis of this group of patients largely stems cases, the median age of MCL patients was noted to be from the unfavorable clinical course of the specifi c associ- 49 years (range: 18–75 years), with a mean survival time ated hematological disorder, rather than the systemic of only 6.6 months (range: 2–14 months) [60] . Anemia is MCD component. In general, patients with refractory virtually always present, as are circulating MC (range: anemia with ringed sideroblasts, polycythemia vera, or !1–96% of leukocytes); however, cutaneous UP lesions essential thrombocytosis, expectedly have a more indo- are usually absent. MCL patients may present with peptic lent course than patients with chronic myelomonocytic ulcer disease (often severe) [55], hepatosplenomegaly, leukemia or AML [16] . Thus, in most cases, the associ- high serum tryptase levels refl ecting a high systemic MC ated hematological disorder tends to overshadow MCD burden [59] , and the c-kit D816V mutation [60, 61]. in terms of both, the clinical presentation, as well as the In MCL, the BM generally reveals a dense, diffuse in- clinical course of the patient, refl ecting its more aggres- fi ltration by markedly atypical MC which may comprise sive biological nature. the majority of nucleated BM cells, with effacement of Aggressive Systemic MCD. This is the third common- the underlying architecture (Type III pattern [2] ). The est subcategory of systemic MCD [23]. As per the WHO MC are immature, sometimes blastic, and often have classifi cation [34] , this condition is characterized by sparse metachromatic granules, and hence may be missed !20% MC in BM smears, and !10% circulating MC in on routine staining unless tryptase [8, 15] and/or CD25

46 Acta Haematol 2005;114:41–51 Pardanani

immunostaining is performed [21, 60]. Rare aleukemic the vast majority, the MCD component is only coinciden- variants of MCL have also been described [60]. Rarely, tally detected [23], the treatment plan primarily takes into patients may present with large numbers of metachro- account the generally more aggressive associated hema- matically granulated, primitive, blast-like cells, with tological malignancy. Here, it is important to keep in prominent mediator-release symptoms. In such cases, mind the inherent resistance of neoplastic MC to chemo- differentiating MCL from tryptase- and/or c-kit D816V- therapy, which may lead to persistent MCD even when positive AML [62, 63], acute basophilic leukemia [64], the associated disease is in remission [73] ; (4) in cases and the myelomastocytic overlap syndrome [65] is a carrying the FIP1L1-PDGFRA oncogene, with clonal eo- diagnostic challenge, in the absence of well-defi ned cri- sinophilia, elevated serum tryptase levels and BM in- teria. volvement by neoplastic MC, imatinib mesylate ought to considered as fi rst-line therapy given the dramatic clinical and molecular responses to this drug (see below) [44, 74, Current Therapy of Systemic MCD 75]. Such patients, however, are a minority and the du- rability of the therapeutic response is unknown. Historically, therapy for systemic MCD has been Commonly employed fi rst- and second-line cytostat- largely empirically derived, given the relative rarity of ic/-reductive agents for the treatment of systemic MCD this disease, its biological heterogeneity, and the lack of at the present time include: simple, widely agreed upon criteria to assess treatment (1) Interferon alpha (IFN- ): It is often considered the response. Presently, while there is no standard therapy fi rst-line therapy for aggressive systemic MCD, both with for systemic MCD, several general statements can be and without an associated hematological malignancy. made, albeit with important caveats [41, 66–72] : (1) Cy- Since the original report of its effi cacy [76] , several groups toreductive therapy, especially chemotherapy, is gener- have studied its therapeutic effi cacy in systemic MCD ally reserved for patients with progressive disease and [77–92]. In published case reports/series, IFN- therapy documented organopathy (‘C’ fi ndings; table 4) from tis- has been described to improve mediator-related symp- sue MC infi ltration. In select patients, however, the dis- toms [88], decrease BM MC burden [76, 83, 84, 86, 89, tinction as to whether the organopathy has resulted from 93], and ameliorate MCD-related ascites [76, 89], cyto- MC infi ltration, an immunological component of the dis- penias [94], and osteoporosis [84, 86]. A recent review ease, or from an associated hematological disorder (MCD- identifi ed 14 cases of aggressive systemic MCD in the lit- AHNMD) may be diffi cult or impossible to make, which erature, who were treated with IFN- . Of these, only 3 may complicate the selection of appropriate therapy; patients (20%) achieved a ‘major’ response to therapy (2) patients with recurrent or persistent mediator-related [67]. Other studies have reported clinically signifi cant re- symptoms may require treatment with appropriate ‘anti- sponses ranging from 0% [87] to 60% [94] . mediator’ drugs, which include histamine receptor- Issues relating to the use of IFN- in MCD include: blockers, glucocorticoids, sodium cromolyn, acetylsali- (a) variability in reported response rates. This is related cylic acid, leukotriene antagonists, and in patients who not only to the underlying biological heterogeneity of have developed or are at risk of developing anaphylactic MCD, but also to the use of nonuniform treatment re- shock, on-demand epinephrine via a self-injector (Epi- sponse criteria. For instance, some studies have used the Pen). In all cases, avoidance of triggers for MC degranu- recently proposed response criteria [67], wherein resolu- lation remains the cornerstone for therapy. In the rare tion of one ‘C’-fi nding (e.g. increase in the absolute neu- case of patients with severe and/or recurrent life-threat- trophil count from !1.0 to 61.0 ! 10 9/l), without prog- ening episodes of mediator-release events that are refrac- ress in other ‘C’-fi ndings, constitutes a ‘major response’ tory to antimediator drugs, cautious consideration may [94]. In contrast, other studies have required normaliza- be given to the use of cytostatic or -reductive agents, keep- tion of histological abnormalities in addition to resolu- ing in mind the severe side effects and potential muta- tion of all symptoms and signs of disease, to defi ne the genic effects of the latter, and only after a full discussion best response [88]; (b) uncertainties regarding the optimal of potential risks and benefi ts of such treatment with the dose and duration of therapy. In a prospective, multi- patient; (3) for MCD-AHNMD patients, it is recom- center study, patients receiving the highest doses of IFN- mended that a treatment plan that takes into account (i.e. 13 MU/m 2 /day) all responded to therapy [88] . The both components of disease, as well as the individual pa- time to best response may be up to 12 months or longer tient’s performance status, be formulated. Given that in [94] and delayed responses to therapy have been de-

Systemic Mastocytosis Acta Haematol 2005;114:41–51 47 scribed [95] . Data from one study suggested that treat- for transfusions (n = 3), deep venous thrombosis (n = 1), ment duration of 6 months or less may not be suffi cient- and Sweet syndrome/toxicodermia (n = 1). One patient ly long enough to reduce the systemic MC burden [88]; with an associated myelodysplastic syndrome with tri- (c) occurrence of signifi cant toxicity. There is a variable, somy 8 experienced prolonged BM aplasia, and subse- but signifi cant incidence (up to 50%) of dose-limiting tox- quently received a stem cell allotransplant. One initial icity related to IFN- treatment, including fl u-like symp- responder experienced a primarily biochemical relapse 6 toms, bone pain, fever, cytopenias, depression, and hy- months after completion of 2-CdA therapy, and achieved pothyroidism [88, 89]. Anaphylaxis, as a response to IFN- a second response after retreatment with the same injections, has also been described [79]. (d) are IFN- agent. combinations superior to IFN- monotherapy? Several Despite 2-CdA’s considerable activity in treating investigators have used IFN- in combination with pred- MCD, its precise indication(s), as well as the dose and nisone [76, 94] to avert treatment-induced untoward re- schedule of administration in this setting remain unclear. actions. Whether this combination is superior to IFN- Given the potential for prolonged BM aplasia and lym- monotherapy in terms of effi cacy and/or tolerance is cur- phopenia, its use is probably best restricted to select cas- rently unknown in the absence of a randomized clinical es with IFN- -refractory disease, after careful consider- trial; (e) how durable are the objective responses? A sig- ation of the risk:benefi t ratio, as well as other available nifi cant proportion of patients have been reported to ex- therapies for individual patients. perience clinical and/or biochemical relapse within (3) Imatinib mesylate (Gleevec): With molecular test- months of IFN- treatment being discontinued, outlining ing, subgroups of MCD patients with specifi c mutations the largely ‘static’ effect of IFN- on neoplastic MC [88, in imatinib-responsive molecular targets can be identi- 89]. fi ed. Based on these mutation(s), it may be possible to (2) 2-chlorodeoxyadenosine (Cladribine/2-CdA): The predict a priori, whether a patient will either respond, or therapeutic activity of this investigational agent, fi rst de- be refractory to imatinib therapy. scribed in a case with aggressive systemic MCD [96] , has FIP1L1-PDGFRA fusion: Eosinophilia (BM and/or been confi rmed in other studies involving a small number peripheral blood) commonly accompanies systemic MCD of patients, mostly with either IFN- -refractory disease, (in 20–40% of cases – termed MCD-eos) [9, 32, 35, 104], or IFN- intolerance, albeit with variable treatment and is demonstrably clonal in a proportion of such cases schedules [97–100]. The rationale for its use in this set- [105]. Approximately one half of MCD-eos patients carry ting stems from its known potent activity against mono- the FIP1L1-PDGFRA fusion oncogene [44] , which re- cytes both in vitro and in vivo [101], and the concept that sults from an 800-kb interstitial deletion of chromo- MC and monocytes arise from a common progenitor some 4q12, thereby generating a constitutively active [102]. 2-CdA is a purine analog, which accumulates in PDGFRA tyrosine kinase [106]. These patients exhibit cells as 2-CdA 5 -phosphate after its phosphorylation by clinical and histological features of myeloproliferation deoxycytidine kinase [103]. In this form, it blocks DNA and generally have an elevated serum tryptase level, but synthesis in dividing cells by inhibiting the enzyme ribo- lack pathognomonic clusters of atypical MC in the BM nucleotide reductase, and DNA repair in resting cells, on routine hematoxylin-and-eosin staining [44, 74, 75, leading to DNA strand breaks and apoptosis. In a pro- 107]. Regardless of whether the FIP1L1-PDGFRA+ cas- spective, multicenter, pilot study, 2-CdA was found to be es are classifi ed as a unique subtype of systemic MCD [44, therapeutically active in patients with indolent MCD 75] or a ‘myeloproliferative variant’ of hypereosinophilic (n = 3), smoldering MCD (n = 1), aggressive MCD (n = 3), syndrome [74, 107], or as chronic eosinophilic leukemia and in MCD-AHNMD (n = 3) [98]. All patients had a [108], or a myelomastocytic overlap syndrome [65] , they favorable clinical response, with a median time to best generally exhibit a complete and durable (4–30 months) response of 6 months. Objective responses included a de- response to ‘low-dose’ (100 mg/day) imatinib [44, 108, crease in serum tryptase levels and urine methylhista- 109], which is currently considered fi rst-line therapy for mine excretion in all patients, partial remission of UP these patients [110]. It is currently recommended that all lesions in all 7 patients with such lesions, and BM MC suspected MCD-eos cases be screened for the FIP1L1- cytoreduction in 9 of 10 patients. While 2-CdA was gen- PDGFRA fusion by either fl uorescence in situ hybridiza- erally well tolerated, treatment complications seen in this tion or reverse transcriptase-polymerase chain reaction cohort included cytopenia(s), with fever of unknown ori- [70, 72]. Imatinib therapy in FIP1L1-PDGFRA+ clonal gin (n = 2, includes herpes zoster in 1 patient) and need eosinophilia has occasionally been associated with car-

48 Acta Haematol 2005;114:41–51 Pardanani

diogenic shock [111, 112]. It is currently recommended 118]. Imatinib, thus, is unlikely to be benefi cial for the that patients receive concomitant corticosteroids (1 mg/ treatment of those adult and atypical pediatric patients kg/day) for 1–2 weeks in the presence of either an abnor- who carry the D816V mutation. Preliminary studies, mal echocardiogram or elevated serum troponin levels however, reveal the enzymatic site mutations to be inhib- pretreatment. ited by newer generation small molecule inhibitors, which C-kit Mutations. The c-kit point mutation, D816V, is will likely enter clinical trials soon [119] . In contrast to found in all subsets of systemic MCD, and may occur D816V, the rare germ-line F522C mutation, which is as- with or without accompanying eosinophilia. This muta- sociated with an unusual variant of systemic MCD, is tion maps to the receptor enzymatic site and renders it inhibited by imatinib [120]. These data underscore the resistant to inhibition by imatinib, both in vitro [113, importance of performing a mutational analysis of c-kit 114] and, as shown preliminarily, in vivo as well [75, 117, prior to contemplating therapy with imatinib mesylate.

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