REVIEWARTICLE

Advanced imaging of skeletal manifestationsof systemic mastocytosis

J. Fritz & E. K. Fishman & J. A. Carrino & M. S. Horger

Received: 5 October 2011 /Revised: 26 January 2012 /Accepted: 27 January 2012 /Published online: 26 February 2012# ISS 2012

Abstract Systemic mastocytosis comprises a group ofclonal disorders of the mast cell that most commonlyinvolves the skeletal system. Imaging can be helpful in thedetection and characterization of the osseous manifestationsof this disease. While radiography and bone scans are fre-quently used for this assessment, low-dose multidetectorcomputed tomography and magnetic resonance imagingcan be more sensitive for the detection of marrow involve-ment and for the demonstration of the various disease pat-terns. In this article, we review the pathophysiologicaland clinical features of systemic mastocytosis, discussthe role of imaging for staging and management, andillustrate the various cross-sectional imaging appearan-ces. Awareness and knowledge of the imaging featuresof this disorder will increase the accuracy of image

interpretation and can contribute important information formanagement decisions.

Keywords Mastocytosis . Computed tomography .

Magnetic resonance imaging . Diffusion-weighted imaging .

Staging

Introduction

Mast cells are derived from hematopoietic cell progenitorsand play a variety of physiological roles [1, 2]. Mast cellsassume sentinel functions at sites at which pathogens mightinvade the body. As such, mast cells are important effectorcells of the innate and acquired immune system that help inthe induction and amplification of defense responses againstbacteria, viruses, and parasites, in the recruitment of otherleukocytes, the containment of bacterial infections, and tis-sue repair.

Systemic mastocytosis comprises a group of clonal dis-orders of the mast cells and its progenitors (Table 1) [3]. Inthe majority of cases, there is a pathologically increasednumber of mast cells in both skin and extracutaneous tissuessuch as bone marrow (Fig. 1) [3–5]. In aggressive systemicmastocytosis, mast cell leukemia, and bone marrow masto-cytosis, bone marrow infiltration may be the only tissueinvolved, while no skin lesions may be present [6].

Several theories about the pathogenesis of mastocytosishave been postulated [7]. One proposed mechanism is thatautocrine or paracrine secretion of stem cell factor promoteschemotaxis and proliferation of mast cells. A second pro-posed mechanism relates to abnormal tyrosine kinase

J. Fritz : E. K. Fishman : J. A. CarrinoRussell H. Morgan Department of Radiology and RadiologicalScience, Johns Hopkins University School of Medicine,600 N Wolfe Street,Baltimore, MD 21287, USA

M. S. HorgerDepartment of Diagnostic and Interventional Radiology,Eberhard-Karls-University,Hoppe-Seyler-Strasse 3,72076 Tübingen, Germany

J. Fritz (*)Russell H. Morgan Department of Radiologyand Radiological Science,Johns Hopkins University School of Medicine,600 N Wolfe Street,Baltimore, MD 21287, USAe-mail: jfritz9@jhmi.edu

Skeletal Radiol (2012) 41:887–897DOI 10.1007/s00256-012-1374-9

receptors found on the surface of mast cells, which result inligand-independent activation of mast cells.

Systemic mastocytosis typically manifests in the 5th to8th decades of life. Women and men are affected equally.Bone marrow involvement and osseous lesions are presentin up to 90% of cases, followed by spleen, lymph nodes, andthe gastrointestinal tract [8, 9]. Clinically, bone marrow

proliferation and osseous lesions are frequently asymptom-atic [8, 9]. When symptoms are present, they are oftenreferred to as lumbar or thoracic pain and diffuse arthralgia[10].

The diagnosis of systemic mastocytosis requires either thepresence of the major criterion and one of the minor criteria; orthree minor criteria [11]. The major criterion is multifocal,

Table 1 Categories of systemicmastocytosis according to theWorld Health Organization [3]

Category Definition

Indolent systemic mastocytosis No mast-cell-related organ dysfunction; no associatedhematological non-mast-cell lineage disorder (seebelow); skin lesions usually present

Systemic mastocytosis with an associatedhematological non-mast-cell lineagedisorder

Evidence of one of the following: myelodysplasticmyeloproliferative neoplasm, myelodysplasticsyndrome, acute myeloid leukemia, or lymphoidneoplasm (lymphoma or plasma-cell myeloma)

Aggressive systemic mastocytosis Organ dysfunction due to mast-cell infiltration (in bonemarrow, liver, spleen, gastrointestinal tract, or bones);skin lesions usually absent

Mast-cell leukemia >10% immature mast cells in blood or >20% in bonemarrow

Fig. 1 Histopathological findings of systemicmastocytosis. Hematoxylin-and-eosin stain (left upper image, 12.5×magnification) of a bone marrowcore biopsy with hypercellularity shows normal erythropoiesis in theupper half of the image (white arrow), and dense, paratrabecularspindle- and histiocyte-like shaped cell infiltrate with fibrosis in the lowerhalf of the image (black arrow). Hematoxylin-and-eosin stain (rightupper image, 200×magnification) shows a magnified view of the para-trabecular area of the left upper image with histiocytic-appearing

neoplastic mast cells with interspersed plasma cells and eosinophilicgranulocytes. Immunohistochemistry for CD25 (left lower image, 200×magnification), an antibody against IL-2 receptor α chain, demonstratesneoplastic mast cells (arrow) in the paratrabecular fibrosis. Immunohis-tochemistry for CD117 (right lower image, 200×magnification) for c-kit,which is an unspecific marker for neoplastic as well as reactive mast cellsshows strong cytoplasmic and a membrane-bound staining pattern(arrow)

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dense aggregates of mast cells (≥15) in sections of bonemarrow, another extracutaneous organ or organs, or both.Minor criteria are >25% of mast cells morphologically atyp-ical, expression of CD2 or CD25 by mast cells, presence ofKIT codon 816 mutation, and serum total tryptase >20 ng/ml.

Systemic mastocytosis may be associated with a varietyof other disorders, including myeloproliferative neoplasms,myelodysplastic syndrome, acute myeloid leukemia, andlymphoid neoplasms [12, 13].

The prognosis of systemic mastocytosis is variable. Thecategory of systemic mastocytosis is an important prognos-tic factor [14]. Indolent systemic mastocytosis carries asignificantly better survival than other types of systemicmastocytosis [14]. Advanced age at onset of systemicsymptoms, weight loss, laboratory parameters (lowplatelet count, low serum albumin, low hemoglobinlevels, high lactate dehydrogenase, and high alkalinephosphatase), hepatosplenomegaly, and ascites predict aless favorable prognosis [14–16]. The presence of osteo-sclerosis has been associated with more aggressive dis-ease [17].

Complications include organ dysfunction due to mast-cell infiltration, and fractures, especially of the vertebralbodies with nerve damage secondary to compression [18,19].

Pathophysiology and patterns of skeletal abnormalities

Systemic mastocytosis manifests with a variety of skeletalpatterns. These are thought to be the cause of the direct andindirect effects of mast cells and have been associated withthe release of mast cell mediators such as histamine, hepa-rin, prostaglandins, proteases, tumor necrosis factor, tissueinfiltration by mast cells, and the effects of localized abnor-mal cell accumulations [17].

The secreted histamine can stimulate fibroblastic activityand promote osteoid formation, and is thought to play a rolein the occurrence of osteosclerosis [18]. The secreted hepa-rin can lead to glycosaminoglycan-mediated calcium bind-ing and precipitation, and enhances factors stimulating boneresorption [20]. Diffuse osteopenia may occur in long-termheparin therapy [21]. Heparin may also play a role inpotentiating the action of basic fibroblast growth factor[22]. The secreted prostaglandins have the potential tostimulate bone resorption and have been implicated incausing the osteopenia and osteoporosis of mastocytosis[23]. Proteases can degrade bone matrix and tumornecrosis alpha may influence the function of osteoblastsand osteoclasts [10].

Skeletal abnormalities of systemic mastocytosis includelytic changes (Fig. 2), representing decreased bone mass(osteopenia/osteoporosis) and bone destruction, and sclerotic

changes, representing increased bone mass (osteosclerosis).Osteopenia and osteoporosis were found to be the most com-mon presentations, followed by osteosclerosis and mixedpatterns [15]. The morphology of either form can be diffuse,which predominates in the axial skeleton (Fig. 3), or focal,which occurs in both the axial and the appendicularskeleton (Figs. 4, 5) [24]. Diffuse osteopenia and oste-oporosis occur with increased frequency in young patientsand older patients, and may be the initial findings [10]. Frac-tures associated with decreased bonemass were found in up to16% of cases [15].

Lytic lesions may be up to 4 or 5 cm in diameter, poorlyor well defined, and sometimes surrounded by a "halo" ofsclerosis [18, 25]. Circumscribed lytic lesions occur mostcommonly in the spine, ribs, pelvis, skull, and tubular bones(Fig. 2) [19]. These findings can simulate cystic osteoporo-sis [26–28], sickle cell anemia [29], Gaucher’s disease [30],hyperparathyroidism [27], plasma cell myeloma [31, 32] orthalassemia [33].

Diffuse and focal osseous sclerosis result in an increasedvolume of trabeculations, increased thickness of the cortex,

Fig. 2 A 47-year-old man with biopsy-proven systemic mastocytosis.Coronal, non-enhanced, low-dose CT image of the thoracolumbarspine shows decreased bone density of the vertebral bodies (whitearrow), secondary to mast cell infiltration of bone marrow. Smallsclerotic areas are also present (black arrow)

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and narrowing of the marrow spaces (Figs. 6, 7) [18]. Focalsclerosis may be multiple and may resemble findings ofskeletal metastasis [34, 35], Erdheim–Chester disease [36],and tuberous sclerosis [37]. Osteosclerosis has been associ-ated with a more aggressive disease course [15]. Findingscan be similar to those of idiopathic myelofibrosis [38],fluorosis [39], sickle cell anemia [29], Paget’s disease[40–43], and renal osteodystrophy [44].

Dynamic changes of osseous abnormalities may occur[45]. Initial focal lesions may become diffuse and changesin bone density may be reversed under therapy. Increasingly,diffuse skeletal involvement has been linked to secondarybone marrow expansion as a result of increasing bone mar-row infiltration, which was associated with a poor prognosis[46].

Role of imaging

Imaging can contribute helpful information for the diagnosisand staging of systemic mastocytosis, including the demon-stration of the presence, location, extent, and type of osseousinvolvement [3, 6, 15, 18, 45]. The demonstration of osse-ous involvement in a patient converts a diagnosis of cuta-neous mastocytosis to systemic mastocytosis and guidesmanagement [3]. In addition, osseous involvement helps toguide the work-up in patients with subtypes of systemicmastocytosis such as aggressive systemic mastocytosis,mast cell leukemia, and bone marrow mastocytosis [6].These subtypes frequently represent a clinical challengebecause of the absence of cutaneous manifestations. Theimaging demonstration of the location of the mast cell

Fig. 3 A 42-year-old man withbiopsy-proven mastocytosis. aSagittal, non-enhanced, low-dose CT image of the lumbarspine shows diffuse marrowsclerosis (arrow) secondary tomast cell infiltration. b Sagittal,non-enhanced, low-dose CTimage of the right humerusshows diffuse sclerosis of themarrow space (arrow) second-ary to mast cell infiltration. cAxial, non-enhanced, low-doseCT image of the pelvis showsdiffuse sclerosis of the marrowspace (arrow) secondary tomast cell infiltration

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infiltrates of bone marrow aid in the identification of asuitable site for bone marrow biopsy. The demonstrationof the type and degree of lytic changes and description oftheir location allow for timely medical therapy in order tomodify bone mineral density. In addition, the type ofinvolvement is important information for rendering aprognosis. While lytic lesions are more prone to frac-tures [18], osteosclerosis has been associated with a moreaggressive disease course [15]. Lastly, imagingmay be used toassess the effectiveness of therapy by the demonstration of the

normalization of bone mineral density and to assess forcomplications such as fractures and neural compression[18, 45]

Radiography of bones, bone scintigraphy, and bone den-sitometry are helpful in characterizing the skeletal involve-ment of systemic mastocytosis and may be sufficient foraccurate assessment [47]. Scintigraphy with 99mTechnetiumlabeled diphosphonates can identify skeletal involvementand assess the extent of disease and disease progression(Fig. 8) [35]. Bone scan and radiographic findings may be

Fig. 5 A 35-year-old man with biopsy-proven systemic mastocytosis.a Sagittal, non-enhanced, low-dose CT image of the sternum showssmall foci of marrow space sclerosis (arrows). b Sagittal, non-enhanced, low-dose CT image of the thoracic spine shows small foci

of marrow space sclerosis (arrows). c Sagittal, non-enhanced, low-doseCT image of the left femur shows a small focus of marrow spacesclerosis (arrow)

Fig. 4 A 19-year-old man with biopsy-proven systemic mastocytosis.a Axial, non-enhanced, low-dose CT image of the pelvis shows focalareas of marrow space sclerosis distributed in the sacrum and ileum(arrows), partially against a background of diffuse marrow sclerosis. bSagittal, non-enhanced, low-dose CT image of the thoracic spine

shows a focal area of marrow space sclerosis (arrow), against a back-ground of diffuse marrow sclerosis. c Sagittal, non-enhanced, low-doseCT image of the lumbosacral junction shows a focal area of marrowspace sclerosis (arrow), against a background of diffuse marrowsclerosis

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grossly discordant [34]. Bone scans were found to be moresensitive for the demonstration of diffuse skeletal involve-ment and detected a greater number of focal lesions thanradiography [34]. Bone densitometry is frequently utilizedto track changes in bone density and guide therapy [15].Correlation with imaging morphology is necessary sincecombinations of different patterns can give contradictoryresults.

Role of advanced imaging

Skeletal manifestations of systemic mastocytosis may alsobe imaged by multidetector computed tomography (MDCT)and magnetic resonance (MR) imaging. MDCT and MRimaging are generally more sensitive than conventionalradiography in detecting bone and bone marrow disease[48–51]. Avila et al. found that radiographs are insensitive

for the detection of marrow abnormalities in mastocytosis,while MR imaging was very sensitive [51]. Radiographyand bone scintigraphy have both low sensitivity and speci-ficity for the detection of systemic mastocytosis [19, 46].MR imaging and MDCT may be most beneficial if radiog-raphy, bone scintigraphy and bone densitometry are incon-clusive. The decision on whether to use MDCT or MRIshould be based on the individual case scenario.

Familiarity with the various MDCT and MR imagingappearances will be helpful in the following scenarios:patients with systemic mastocytosis, but non-specific con-ventional imaging findings; patients with undiagnosed mas-tocytosis undergoing imaging work-up for another reason;patients with known mastocytosis undergoing cross-sectional imaging during the course of their disease; clini-cally suspected diagnosis of systemic mastocytosis in theabsence of typical skin involvement; and cases of suspectedaggressive disease to allow for a more sensitive assessment[6, 51, 52]. The presence of mast-cell infiltration of organsother than bone marrow, such as liver, spleen or gastroin-testinal tract may indicate aggressive systemic mastocytosis(Table 1). Additionally, the diagnosis of hepatosplenome-galy and ascites are important prognostic factors [14–16].

Multidetector computed tomography

Multidetector CT techniques (120 kVp and effective mAsranging between 70 and 200) and ultra-low dose MDCTtechniques (140 kVp and 14 to 25 mAs) have been shown tobe more sensitive for the detection of bone marrow abnor-malities than radiography [48–50]. In systemic mastocyto-sis, this technique can be used for a more accurateassessment of the presence, type, and extent of skeletalabnormalities. Similar to marrow involvement in multiplemyeloma [48–50, 53], the measurement of MDCT attenua-tion of marrow space can detect, localize, and characterize

Fig. 6 A 43-year-old womanwith biopsy-proven systemicmastocytosis. a Axial non-enhanced, low-dose CT imageshows markedly increased softtissue attenuation of the marrowspace of the left and righthumerus (arrows) as the corre-late of bone marrow infiltrationof mastocytosis. b Sagittal non-enhanced, low-dose CT imageof the left femur shows differ-ence in CT numbers of fattymarrow (white arrow) andmarrow infiltration (blackarrow) of mastocytosis

Fig. 7 A 35-year-old man with biopsy-proven systemic mastocytosis.Non-enhanced volume-rendered CT image shows nodular mast cellinfiltration (white arrow) and markedly increased cortical width (blackdouble arrow), narrowing the marrow space

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the degree of marrow infiltration when non-enhanced stan-dardized MDCT protocols are used (Fig. 6). QuantitativeMDCT attenuation shows potential as a surrogate marker forthe monitoring of therapies [32], warranting future studies totest this hypothesis.

MDCT is well suited to monitoring cortical thickness andthe associated narrowing of the marrow space, which can besevere (Fig. 7). In focal marrow lesions, modern post-processing techniques, such as volume rendering techniqueand volumetry, facilitate quantitative monitoring of size andattenuation, can help to communicate findings to clinicalcolleagues, and can be valuable in patient communicationby helping patients understand their situation (Fig. 7).

Magnetic resonance imaging

Magnetic resonance imaging is more sensitive for thedetection of marrow abnormalities of systemic mastocy-tosis because of its better tissue contrast and thus abilityto detect cellular infiltration, compared with radiography[51].

Magnetic resonance imaging findings seem to parallelhistopathological findings which may demonstrate uniformlydispersed mast cells or focal accumulation in the form oflarger aggregates, resembling a mast cell granuloma (Figs. 9,10) [51].

Bone marrow infiltration by mast cells results in hypoin-tense T1 signal that is generally lower than the T1 signal ofintervertebral discs and muscle [54, 55]. T2 and STIR signalsare frequently hyperintense compared with muscle; however,they may be hypointense, depending on the degree of marrowinfiltration and fibroblast proliferation (Figs. 9, 10). Scleroticlesions are hypointense on T1-weighted and T2-weightedMRimages. Contrast-enhanced MR imaging may not contributeadditional information, but if administered, marrow enhance-ment indicates areas of increased mast cell infiltration (Fig. 9).Decreasing T2 and increasing T1 signals usually indicateresponse to treatment.

In cases of low-degree mast cell infiltration, differentia-tion between pathological marrow infiltration and normalhematopoietic marrow may be difficult, especially in youn-ger patients. Knowledge of the normal distribution of hema-

Fig. 8 A 29-year-old woman with biopsy-proven systemic mastocy-tosis. a Anterior (left) and posterior (right) delayed Technetium-99 mmethylene diphosphonate whole body bone scan image shows markedskeletal uptake (white arrows) with no activity in the renal system(superscan; black arrows). b Delayed Technetium-99 m methylenediphosphonate spot view of the chest and abdomen shows marked

skeletal uptake (white arrow) with no activity in the renal system(superscan; black arrows). c Corresponding T1-weighted coronal MRimage shows diffusely abnormal, hypointense signal of bone marrowof the thoracic spine (arrow) compatible with diffuse marrow infiltra-tion of mastocytosis and concomitant diffuse sclerosis

Fig. 9 A 39-year-old man withbiopsy-proven systemic masto-cytosis. a Coronal STIR MRimage of the proximal left andright tibia shows diffusely ab-normal hyperintense marrowsignal (arrows) secondary tomast cell infiltration. b Axial,contrast-enhanced, T1-weighted MR image with fatsaturation shows abnormalbone marrow enhancement(arrows) secondary to mast cellinfiltration

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topoietic marrow is useful for interpretation in such cases [56].The use of diffusion-weighted imaging, which provides qual-itative and quantitative functional information concerning themicroscopic movements of water at the cellular level, may behelpful for the differentiation of normal red marrow fromabnormal marrow.

Diffusion-weighted imaging is furthermore a promisingtool for the assessment and monitoring of bone marrowabnormalities [57]. Diffusion-weighted images of infiltratedbone marrow frequently show restricted diffusion, althoughthe benefit of diffusion-weighted imaging in comparison to

conventional MR imaging is currently not known (Figs. 11,12). Since the induction of chemotherapy leads to disinte-gration of cell membranes, the use of diffusion-weightedimaging is a promising tool for the non-invasive monitoringof the degree of marrow cellularity during therapy.

The differential diagnosis of MR imaging findings insystemic mastocytosis includes processes like Gaucher’sdisease, metastatic disease (especially of breast and prostatecancer), leukemia, and myeloma.

In focal marrow involvement of systemic mastocytosis,the differential diagnosis includes enostoses, sarcoidosis, hypo-

Fig. 11 A 48-year-old man with biopsy-proven systemic mastocytosis.a Axial, diffusion-weighted MR image at level of the sternum showsabnormal, hyperintense signal of the marrow spaces of the sternum and

posterior elements of the spine (arrows), secondary to diffuse marrowinfiltration of mastocytosis. b Corresponding axial apparent diffusioncoefficient (ADC) map confirms restricted diffusion (arrows)

Fig. 10 A 48-year-old man with biopsy-proven systemic mastocyto-sis. a Coronal, whole-body T1-weighted MR image shows diffuse fociof decreased T1 signal of bone marrow (arrows). b Coronal, whole-

body STIR MR image shows these foci to be hyperintense.Corresponding CT images showed faint foci of bone marrow sclerosis(not shown)

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parathyroidism, and osteopoikilosis. In diffuse marrow involve-ment of systemic mastocytosis, the differential diagnosisincludes osteopetrosis, myelofibrosis, and fluorosis. In pediatricpatients, sclerosing bone dysplasias (e.g., Ribbing disease,Camurati–Engelmann, etc.) should be primarily excluded [58].

Whole-body MR imaging facilitates assessment of theentire skeleton with highest sensitivity for bone marrowabnormalities by the acquisition of MR images from head

to toe in a single session [59]. This technique is helpful inyounger patients because it does not involve exposure toradiation [60]. Whole-body MR imaging is generally lessprone to missing subclinical, focal bone marrow infiltrationcompared with a focused approach, which is limited to apredefined area of the body (Fig. 13) [61]. Whole-body MRimaging is an accurate technique to differentiate diffusemarrow infiltration from osteoporosis in patients with dif-fuse loss of bone density, which is frequently not possiblewith radiography. Similar to CT, important prognostic fac-tors such as hepatosplenomegaly, ascites, and mast-cellinfiltration of the liver, spleen or gastrointestinal tractcan be readily diagnosed with whole-bodyMRI [14–16].Withwhole-bodyMR imaging, the entire marrow space burden canbe assessed, which is potentially helpful in staging mastocy-tosis, analogous to the work-up of multiple myeloma [61].However, future studies are required to determine the benefitof this technique.

Positron emission tomography

Little is known about fluorodeoxyglucose (FDG) positronemission tomography (PET) in systemic mastocytosis. Acase series of five patients found normal FDG distributionfindings in areas of radiologically diagnosed osteolyticlesions [62], whereas one case report demonstrated increasedactivity in cortical bone and marrow space [63]. While theauthors of the above case series felt that FDG PET is notuseful for the staging and follow-up of aggressive systemicmastocytosis, more data are probably needed to determine therole of FDG-PET in systemic mastocytosis [62].

Conflict of interest The authors declare that they have no conflict ofinterest.

Grants None.

Fig. 12 A 53-year-old man with biopsy-proven systemic mastocyto-sis. a Axial, diffusion-weighted MR image at the level of the sacroiliacjoints shows abnormal, patchy hyperintense signal of the marrowspaces (arrows), secondary to mast cell infiltration of bone marrow.

b Corresponding ADC map confirms restricted diffusion (arrows). cCorresponding, axial, unenhanced CT image shows diffuse marrowsclerosis with foci of sclerosis (arrows)

Fig. 13 A 62-year-old man with biopsy-proven systemic mastocyto-sis. Coronal, T1-weighted whole-body MR image demonstrating focalbone marrow infiltration (arrow) of the T9 vertebral body

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