Diagnosis, management, and complications of glomus tumours of the digits in neurofibromatosis type 1

transcript

doi: 10.1136/jmg.2009.073965 published online June 7, 2010J Med Genet

Douglas R Stewart, Jennifer L Sloan, Lawrence Yao, et al. neurofibromatosis type 1glomus tumours of the digits in Diagnosis, management, and complications of

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Diagnosis, management, and complications of glomustumours of the digits in neurofibromatosis type 1

Douglas R Stewart,1 Jennifer L Sloan,2 Lawrence Yao,3 Andrew J Mannes,4

Armin Moshyedi,5 Chyi-Chia Richard Lee,6 Raf Sciot,7 Luc De Smet,8

Victor-Felix Mautner,9 Eric Legius10

ABSTRACTBackground Glomus tumours are benign painful tumoursof the glomus body, a thermoregulatory shunt in thedigits. Glomus tumours of the fingers and toes areassociated with the monogenic disorderneurofibromatosis type 1 (NF1) and are recentlyrecognised as part of the NF1 phenotype.Methods and Results A multi-institutional experiencewith 15 individuals with NF1 and glomus tumours of thefingers or toes is reported. The majority of individualspresented with at least two of the symptoms in theclassic triad of localised tenderness, severe paroxysmalpain, and sensitivity to cold. Appearance of the nail andfinger or toe is often normal. Women are affected moreoften than men. Multifocal tumours are common. Thereis often a delay in diagnosis of many years and clinicalsuspicion is key to diagnosis, although magneticresonance imaging may be useful in some scenarios.Surgical extirpation can be curative; however, localtumour recurrence and metachronous tumours arecommon. Three of our patients developed signs andsymptoms of the complex regional pain syndrome.Conclusions Glomus tumours in NF1 are more commonthan previously recognised and NF1 patients should bespecifically queried about fingertip or toe pain.

INTRODUCTIONNeurofibromatosis type 1 (NF1) is a common (w1/3000 birth incidence) disorder of increased tumourpredisposition that arises secondary to mutationsin the RAS regulatory gene NF1.1 Glomus tumoursare rare, benign tumours of the glomus body thatcause severe paroxysmal pain secondary to changesin temperature or pressure. Glomus tumours of thefingers and toes associated with NF12 arise due tobi-allelic inactivation of the NF1 gene3 and are onlyrecently recognised as part of the NF1 phenotype.4 5

They frequently appear as bluish subcutaneousnodules on the trunk and limbs and can be multi-focal.6 7 The first association of NF1 and glomustumourswas published in 1938. The report describeda single 13-year-old girlwith features consistentwithNF1 andmultiple soft, dark blue nodules on her rightneck, bilateral lower extremities and left heel. Alesion from the right lower leg hadhistologic featuresconsistent with a glomus tumour.8 9

Glomus bodies are thermoregulatory shuntsconcentrated in the dermis of the fingertips andother peripheral sites subject to excessive cold, andshould be distinguished from unrelated adrenal andextra-adrenal paragangliomas, also commonlycalled ‘glomus tumours’.10 Glomus tumours of the

fingers consist of a convoluted arteriovenous anas-tomosis surrounded by a thick layer of modifiedsmooth muscle cells and nerve elements (figure 1).Glomus tumours are thought to arise from themodified smooth muscle cells of glomus bodies,although they can occur in regions where glomusbodies do not normally occur.7 Typically, a glomustumour of the finger presents with a triad oflocalised tenderness, severe paroxysmal pain (out ofproportion to size), and sensitivity to cold. Theyhave a benign clinical course.7 However, glomustumours of the fingers are under-recognised. Onelarge series of sporadic glomus tumours of thefingers found that an average of 2.5 physicians(range 0e7), including psychiatrists, wereconsulted before the correct diagnosis was made.The duration of symptoms averaged 10 years (range1e40 years).11

Until recently, there were only eight cases ofglomus tumours of the fingers and toes in individ-uals with NF1 in the English language literature(table 1).2 12e15 There were no examples of multi-focal tumours in the largest retrospective review of51 sporadic cases of glomus tumours of thefingers.11

In this report, we review the published literatureand describe our multi-institutional experience (15patients) with the presentation, diagnosis, imaging,management and complications of glomus tumoursin the digits of individuals with NF1.

NIH NF1 AND GLOMUS TUMOUR CLINICALEXPERIENCETable 2 and supplementary table S1 summariseclinical findings from our three groups. PatientsNIH-1, NIH-2, and Leu-1 through Leu-7 werepreviously reported in brief tabular form.3 Leu-2and Leu-3 were briefly summarised in De Smet et al2002.2

As part of a natural history study of NF1, fourindividuals were ascertained with severe fingertippain, a lesion on magnetic resonance imaging(MRI) that correlated with symptoms and at leastone histologically proven glomus tumour (table 2and supplementary table S1; figures 1 and 2 andsupplementary figures S1 to S3). One woman(NIH-5) underwent resection of a pathologicallyproven glomus tumour in a single finger at anotherinstitution but was evaluated at follow-up at theNational Institutes of Health (NIH). Repeatsurgeries were required in two patients (NIH-1 andNIH-2; three surgeries each), both of whomharboured multifocal glomus tumours in multiple

< Additional figures and tablesare published online only. Toview these files please visit thejournal online (http://jmg.bmj.com).1Genetic Disease ResearchBranch, National HumanGenome Research Institute,National Institutes of Health,Bethesda, Maryland, USA2Genetic and Molecular BiologyBranch, National HumanGenome Research Institute,National Institutes of Health,Bethesda, Maryland, USA3Department of Radiology,Clinical Center, NationalInstitutes of Health, Bethesda,Maryland, USA4Department of Anaesthesiaand Surgical Services, ClinicalCenter, National Institutes ofHealth, Bethesda, Maryland,USA5Clinical Center, NationalInstitutes of Health, Bethesda,Maryland, USA6Laboratory of Pathology,National Cancer Institute,National Institutes of Health,Bethesda, Maryland, USA7Department of Pathology,Catholic University Leuven,Leuven, Belgium8Department of OrthopaedicSurgery, University HospitalPellenberg, Lubbeek, Belgium9Laboratory for Tumour Biologyand Developmental Disorders,Department of MaxillofacialSurgery, University HospitalEppendorf, Hamburg, Germany10Department of HumanGenetics, Catholic UniversityLeuven, Leuven, Belgium

Correspondence toDr Douglas Stewart, GeneticDisease Research Branch,National Human GenomeResearch Institute, NationalInstitutes of Health, 49 ConventDrive, Building 49, Room 4A62,Bethesda, MD 20892, USA;drstewart@mail.nih.gov

Received 9 October 2009Revised 30 November 2009Accepted 5 December 2009

Stewart DR, Sloan JL, Yao L, et al. J Med Genet (2010). doi:10.1136/jmg.2009.073965 1 of 8

Original article JMG Online First, published on June 7, 2010 as 10.1136/jmg.2009.073965

Copyright Article author (or their employer) 2010. Produced by BMJ Publishing Group Ltd under licence.

digits (supplementary table S1). Two individuals (NIH-1 andNIH-2) had local recurrence of tumour after resection or thedevelopment of new glomus tumours in other fingers andsymptoms consistent with the complex regional pain syndrome(CRPS). At 2-year follow-up, one woman (NIH-3) hadimprovement in her glomus tumour pain after resection but hadpersistent neuropathic pain in her affected hand consistent withCRPS. Two women, both with single glomus tumours, werepain-free at 18 month (NIH-4) and 4 year (NIH-5) follow-up.There was no correlation between café-au-lait macule burdenand number of neurofibromas with the development of glomustumours.

BELGIAN NF1 AND GLOMUS TUMOUR CLINICAL EXPERIENCEIn the last 10 years, eight patients with NF1 and a glomustumour of the fingertip were treated. All patients were seen byEL as part of an outpatient clinic for neurofibromatosis, andwere subsequently seen by EL and LDS in a multidisciplinaryclinic for congenital and genetic hand abnormalities at thehuman genetics outpatient clinic in Leuven, Belgium. Allsurgeries were performed by LDS and indication for surgery wasbased on the typical history and clinical examination compatiblewith glomus tumour of the fingertip. We did not performsystematic ultrasonography or MRI scanning before surgery.Fourteen pathologically proven glomus tumours were removedfrom 12 different fingers in eight patients (supplementary tableS1). Only one finger needed a surgical re-intervention 13 monthsafter the first surgery because of recurrence of a glomus tumourat exactly the same position as the first tumour (Leu-5). In thispatient, the relapsed tumour was diagnosed clinically and wasalso visible by ultrasonography, but not by MRI scan of thefinger. None of our eight patients with NF1 were diagnosed withthe complex regional pain syndrome after surgical treatment.

With the exception of Leu-5, all patients were cured aftersurgery. In the case of Leu-5, all symptoms were cured afterresection of the relapsed tumour. Five of the 12 affected fingersdid not show any visible abnormalities at diagnosis. Two fingersshowed only a slight hyperaemic reddish discoloration of theskin, one finger showed a small localised swelling, one a smalllocalised swelling with a hyperaemic reddish discoloration, andone a localised swelling of the base of the nailbed with naildystrophy distal from the position of the localised tenderness(figure 3). One finger showed a split nail. The only child in theseries (Leu-7; 11 years) had a notably swollen distal phalanx ofthe right fifth finger with a hyperaemic appearance. Radiographsof the fingers showed an impression of the tumour on the distalphalanx with erosion of the distal tuft of the phalanx (figure4A). The phalanges of the right fifth finger and metacarpalappeared osteoporotic (figure 4B and 4C) and the affected fifthfinger showed a mild shortening (4.5 mm) suggesting a long-standing severe problem. She was symptomatic for more than 2years and protected the finger to prevent touch induced severeparoxysmal pain.

PRESENTATION AND DIAGNOSISTable 3 summarises and compares the demographic and physicalcharacteristics of pathologically proven glomus tumours in NF1in the published literature and in our combined experience.Recurrent tumours were excluded from the summary. We alsosummarise data from two large recent surveys of sporadicglomus tumours.11 16 In both sporadic and NF1 associatedglomus tumours, the average age of diagnosis and years ofsymptoms before diagnosis are comparable. The tumour affectsmore women than men (table 3, ‘Combined NIH/Belgian/Hamburg experience’ and ‘Previously reported NF1-associatedglomus tumors’: 4 males versus 16 females; p¼0.006, binomial

Figure 1 (A) Normal glomus body inthe left F5 of patient NIH-1. Glomusbodies are thermoregulatory shuntsthat arise from arteriovenousanastomoses and are enveloped bycondensed collagenous tissue. Thevascular lumens are surrounded byseveral layers of modified smoothmuscle cells (glomus cells; arrows).Heat-induced contraction of the glomusbody shunts blood flow through thecapillary network, resulting in heat loss.Upon exposure to cold temperatures,relaxation of the glomus body opensthe anastomosis, reducing shuntedblood flow and conserving body heat(haematoxylin and eosin (H&E) stain,403). (B) and (C): Glomus tumours arehighly cellular benign neoplasmsthought to arise from glomus cells.Grossly, they form pseudocapsules(see also supplementary figure S1,panel B). Histologically, the tumours arerelatively well-circumscribed noduleswith small dilated vascular spacessurrounded by sheets and clusters ofglomus cells; the lesional cells haverounded nuclei, moderate amounts ofeosinophilic cytoplasm and lack cytologic atypia, necrosis or increased mitotic activity (panel B, left F5 of patient NIH-1, H&E stain, 403; panel C, leftF4 of patient NIH-2, H&E stain, 203). (D) Smooth muscle actin staining of glomus tumour from left F4 of patient NIH-2. SMA positive staining supportsa smooth muscle origin of glomus cells; see also Brems et al3 (smooth muscle actin stain, 203).

2 of 8 Stewart DR, Sloan JL, Yao L, et al. J Med Genet (2010). doi:10.1136/jmg.2009.073965

Original article

distribution). There is roughly equal distribution between theright and left hand or foot. Interestingly, the fourth (ring) andthird (middle) fingers are the two most commonly affecteddigits in both NF1-associated and sporadic glomus tumours. Inthe combined series (table 3, ‘Combined NIH/Belgian/Hamburgexperience’ and ‘Previously reported NF1-associated glomustumors’) the frequencies of affected fingers are not equal (c2,p<0.014); however only the fourth finger is significantly morefrequently affected than expected (binomial distribution,p¼0.04 after Bonferroni correction for multiple testing). Noexamples of multifocal tumours were reported in individualswithout NF1.

HistoryIn the eight published descriptions (table 1) of glomus tumoursof the fingers associated with NF1 (hereafter, unless noted,‘glomus tumours’), all reported at least one element of the classicglomus tumour triad: localised tenderness, severe paroxysmalpain, and sensitivity to cold. In our experience, patients, if asked,will have at least two or more features of the triad. Paradoxically,patients may have lived with the pain for so long (in our series,up to 40 years) that they need to be specifically asked aboutthese symptoms. The tenderness is typically continuous and isexacerbated by exposure to cold (or less commonly, warm)temperatures, which can be as minor as holding a cold drink orreaching into a refrigerator. Patients may wear multiple pairs ofgloves or mittens in the cooler months to insulate their fingers.The severe paroxysms of pain can be short lived (<1 min), butare debilitating and frightening, and patients can requireconsiderable time (hours) to recover from them. Paroxysms canbe triggered by minor everyday vibration (riding a bicycle) anduse (typing on a keyboard). Patients are protective of theirfingers and may be reluctant to shake hands. The pain is typi-cally non-radiating and localised to a particular (ulnar/radial/central) aspect of a finger. If the pain radiates, it is often limitedin extent to the elbow. The distinguishing feature of glomustumour pain is its severity and location; the quality of the pain isakin to slamming a heavy drawer on a finger. Out of frustrationfor a lack of diagnosis (and thus effective treatment), we havehad patients request amputation of the affected fingers.

Physical examinationOn physical examination, the nail and pulp of the affectedfingertip is often entirely normal. Patients may guard theaffected finger since even a gentle examination is likely to elicitparoxysms of pain. The location of glomus tumours may eitherbe subungual or in the pulp of the fingertip. In a large series ofsporadic glomus tumours, a blue discoloration of the nail wasobserved in 43% of subungual tumours and 10% of tumours ofthe pulp.11 In the same series, a nail deformation was noted in47% of subungual tumours. We observed no examples of bluishdiscoloration of the nails and three examples (NIH: 1; Belgium:2) of nail abnormalities in our patients. Tumour nodules areinfrequently palpable on examination. However, the location ofthe tumour can be mapped with some precision by applyinggentle pressure from the head of a sterile straight pin (Love’stest).17 Love’s test has a sensitivity of 100% and 78% accuracy.18

Other useful physical examination techniques include Hildreth’stest (application of a tourniquet to the base of an affected fingerand repeating Love’s test; pain should be abolished) and the coldsensitivity test (placing affected hand in cold water). Hildreth’stest has a sensitivity of 71.4%, a specificity of 100%, and anaccuracy of 78%, and the cold sensitivity test has a sensitivity,specificity and accuracy each of 100%.18Ta

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Original article

ImagingThere is an extensive literature on the imaging of glomustumours.19e21 In one large series, plain radiography revealeda bony defect in the distal phalanx in 36% of patients,11 and maybe a useful adjunct given sufficient clinical suspicion. Four of ourpatients (NIH-1, NIH-2, NIH-3, Leu-7) had plain radiographs ofthe hands. Of the eight fingers in these four patients harbouringglomus tumours at the time of radiography, only two (NIH-2,right F1; Leu-7, left F5) had lytic lesions consistent with glomustumours. We have had little experience with fingertip ultra-sound; it has some theoretical advantages and is reported to beuseful in locating glomus tumours as small as 3 mm in size,especially if located in the pulp of the fingertip, but is operatordependent.20 Other modalities (thermography, scintigraphy,arteriography) are no longer indicated.

High resolution MRI is capable of detecting normal glomusbodies with a T2 weighted sequence after gadoliniuminjection.19 Glomus tumours are proliferations of glomus cellswith a relative paucity of vascular lumen. Their signal is thussimilar to the surrounding tissue (especially those in the highlyvascular nailbed) and can be difficult to detect on T1sequences.20 Post-contrast imaging with gadolinium may behelpful. Normal glomus bodies and glomus tumours exhibithyperintensity on T2 sequences relative to surrounding reticulardermis. Glomus tumours are delimited by a pseudocapsule thatforms as a reaction to the surrounding connective tissue. Thecapsule is best seen on T2 weighted images or on three dimen-sional gradient echo images.20 The NIH imaging protocolincludes coronal STIR (short TI inversion recovery), axial T1spin echo, axial fast spin echo, T2 weighted and three dimen-sional gradient echo post-contrast imaging in axial and coronalplanes with a dedicated receive-only wrist coil.

The usefulness of MRI in the diagnosis of glomus tumours iscontroversial.21 In one study of 42 individuals with glomustumours symptomsundergoinghand surgery, 40hadhistologicallyproven glomus tumours.All hadMRI imaging preoperatively.MRIhad 90% sensitivity, 50% specificity, a positive predictive value of

97% and a negative predictive value of 20%. The low negativepredictive value arose from patients with smaller (2e3 mm)tumours with a lack of clear delineation.21 The authors note thata glomus tumour of the hand is a clinical diagnosis and thatcompelling evidence to use preoperative MRI imaging is lacking.The NIH experience with the use of MRI to diagnose glomus

tumours in NF1 is summarised in supplementary table S1. Inclassic, uncomplicated presentations of glomus tumour symp-toms (eg, NIH-4 and the initial surgery for NIH-1 and NIH-2),we observed a perfect correlation among clinical impression,MRI imaging, and pathology. In these cases, the clinical exam-ination was likely sufficient to diagnose and even plan surgicalresection. However, in more complicated scenarios like patientswith CRPS (eg, NIH-3 and second and third surgeries of NIH-1and NIH-2), the predictive power of the clinical examinationdeclines, and the usefulness of MRI increases. In these cases, wefound that MRI correctly predicted the pathological diagnosis ofglomus tumour with greater sensitivity than the clinical exam-ination. In patients with CRPS many fingers (indeed the entirehand or limb) hurt, making it difficult for the patient andexaminer to distinguish ‘glomus tumour ’ pain from ‘CRPS’ pain.In CRPS, where avoidance of additional ‘pain generators’ (likesurgical exploration) is paramount, MRI can be useful to avoidunnecessary procedures.In our experience, glomus tumours on MRI tend to be nodular

and exhibit hyperintensity on T2 weighted imaging. A capsuleor pseudocapsule was not typically appreciated on T2 imaging.Lesions tend to be isointense and poorly visualised on non-enhanced T1 imaging. Glomus tumours exhibited a variabledegree of enhancement on T1 post-contrast imaging, with mostlesions showing mild to moderate enhancement, but somelesions remaining isointense to the surrounding, enhancingnailbed. Potential lesions that exhibit focal hyperintensity onlyon a STIR or T2 sequence (eg, NIH-1, left F3, surgery number 2)but without correlative findings on other sequences are morelikely to be false positives. In addition, it is important toremember that multiple glomus tumours may be present in one

Figure 2 MRI images from NIH-1. 35year-old Hispanic woman with NF1 andsevere pain in the third, fourth and fifthdigits of both hands, exacerbated bycold temperatures, on disability. Shealso presented with signs andsymptoms of the complex regional painsyndrome: allodynia, swelling andvasomotor changes. Over 3 years, sherequired multiple surgeries to treatrecurrent and metachronous glomustumours (supplementary table S1).Before her first surgery, coronal T2weighted MRI revealed a w5 mm lesionin left F4 (A) and w6 mm lesion in rightF3 (B). Coronal T1 weighted pre- (C) andpost- (D) gadolinium imaging revealeda w1.8 mm lesion in left F5. All threelesions were glomus tumours onpathologic examination. No enhancinglesions were visible in othersymptomatic fingers.

Original article

finger (supplementary table S1: NIH-1, left F4, surgery 1,procedure 1; Leu-3, left F4, surgery 2, procedure 1). Evaluation ofthe postoperative nailbed may be hampered by artefact, andrequires careful comparison to prior imaging exams.

MANAGEMENTFor symptomatic glomus tumours, surgical extirpation is theonly effective treatment and can be curative. Two surgical

approaches are used, depending on the location of the tumour:direct transungual excision (for sub-ungual tumours) or a lateralsub-periosteal approach (for both subungual tumours andtumours of the pulp).16 The lateral approach may reduce the riskof nail deformity but may afford a more narrow view of thetumour bed, and thus a higher risk of incomplete excision andthus recurrence.22 Either can be performed under local anaes-thesia with or without sedation. Although typically small

Figure 3 Fingernail and nailbedabnormalities in four patients with NF1and glomus tumour. Split nail of left F4in Leu-3 (A). Reddish discoloration atradial side of left F3 in Leu-5 at thelocation of the tumour (B). Swelling onradial side of right F4 of Leu-4 (C).Swelling and nail deformation in left F4in Leu-8 (D).

Figure 4 Right hand radiograph ofpatient Leu-7 (female, age 11 years)shows soft tissue swelling (solidarrows) and erosion of the distal tuft(arrowhead) of right F5 (A and B). Thedistal phalanges of F5 appearedosteoporotic (B) when compared tophalanges of F5 of unaffected left hand(C).

Original article

(<5 mm), glomus tumours of the fingers have a pseudocapsule,making excision relatively easy. The tumours are frequentlyapposed to the bone, necessitating bony curettage to reduce thechance of recurrence. Nail deformities are seen in a smallminority of patients especially after use of the transungualapproach.16 Pathologically, glomus tumours are almost alwaysbenign but can be misdiagnosed as haemangiomas or venousmalformations.7

In the Belgian and Hamburg experience, all patients brought tosurgery had pathologically proven glomus tumours of the fingersor toes. In the NIH experience, three patients (NIH-1, NIH-2, andNIH-3; supplementary table S1) had, concurrent with successfultumour resection in other digits, fingertip explorations in whichno glomus tumour was found. However, all three patients hadmultiple painful fingertips due to CRPS, lack of imaging of thepainful but non-glomus tumour finger, and/or atypical MRIabnormalities (see ‘Recurrence of pain’, below).

COMPLICATIONSRecurrence of tumourIn the majority of published cases of glomus tumours in NF1(table 1), no comment is made on the recurrence of tumourfollowing surgery. In six large published series (n¼12 to 51patients) of sporadic glomus tumours of thefingers, the recurrencerate, when noted, ranged from 0e33.3%.16 18 23 Early recurrencemay occur within weeks to months of surgery, and presumablyreflects inadequate excision. Later recurrence (years) is probablythe result of the development of a new tumour.16 Three of ourpatients had repeat surgery onfivefingerswith histologic evidenceof tumour recurrence within 13 months of the initial procedure(supplementary table S1: NIH-1: left F4; NIH-2: left F2 and left F4and right F1; Leu-5: left F3). In four of the five fingers, bonyinvolvement or erosion was noted on initial preoperative MRIimaging or at time of the first surgery. Recurrence occurred despitebony curettage at the time of initial operation.

Recurrence of painIn our experience, recrudescence of glomus tumour symptomsmaybe due to recurrence of tumour (above), growth of a new tumour in

a previously unaffected finger (eg, NIH-2: right F4) or the develop-ment of CRPS,whichwe diagnosed in three patients (NIH-1, NIH-2,NIH-3). Of these three causes, CRPS is themost difficult to treat.

CRPS is a poorly understood chronic pain syndrome affectingone or more limbs. It has a variable course and a heterogeneouspathogenesis.24 CRPS is classified into type 1 (no known incitinginjury; formerly known as reflex sympathetic dystrophy, RSD)and type 2 (known or suspected inciting injury, formerly knownas causalgia). We diagnosed three patients (NIH-1, NIH-2, andNIH-3) with CRPS type 2 before excision, suggesting that thesyndrome arose secondary to the glomus tumours, and notsurgery. Patients presented with allodynia, hyperesthesia,dysesthesia, oedema, sudomotor and vasomotor changesprimarily affecting one limb, a clinical picture not consistentwith neurofibromatous neuropathy, an uncommon but wellrecognised neurologic complication in NF1.25e27 To our knowl-edge, these three patients are the first reported with CRPS inNF1 and the first with CRPS secondary to glomus tumours ofthe fingers. One case report described reflex sympatheticdystrophy in a female with a glomus tumour of the leg.28

Individuals with NF1 may be at an increased risk of developingchronic pain syndromes such as CRPS since neurofibromin (theprotein product of NF1) plays a key role in the excitabilityregulation of nociceptive sensory neurons.29

Avoidance or elimination of chronic inciting ‘pain generators’in CRPS is critical. Specifically in the case of glomus tumours,this is difficult to achieve in practice since the tumours areunder-recognised and patients may have symptoms for years ordecades before proper diagnosis. Thus, we advocate promptremoval of symptomatic glomus tumours. Similarly, in patientswith a previous resection of glomus tumours, MRI of recurrentor newly painful fingers may help to distinguish between truetumour recurrence and the development of CRPS.Lastly, prevention is the best strategy in managing CRPS.

Although the prevalence of glomus tumours in NF1 is notknown, it is likely to be higher than previously supposed. Toscreen for glomus tumours of the fingers, we suggest simplyasking all individuals with NF1 about chronic, cold sensitivefingertip pain and mechanical allodynia.

Table 3 Summary of demographic and physical features of pathologically proven sporadic and neurofibromatosis type 1 associated glomus tumoursof the fingers and toes. Data on patients Leu-2 and Leu-3 excluded from ‘Combined NIH/Belgian/Hamburg experience’ since they were previouslyreported2 and thus accounted in ‘Previously reported NF1-associated glomus tumours’. Includes data on NIH-5. Data on ‘Previously reported NF1-associated glomus tumours’ from references listed in table 1. Data on sporadic glomus tumours from van Geertruyden et al11 and Vasisht et al16

Feature

Combined NIH/Belgian/Hamburg experience inpathologically proven glomustumours

Previously reported NF1associated glomus tumours(pathologically proven)

Sporadic glomus tumours(data combined from vanGeertruyden et al11 and Vasisht et al16)

Male: female 2 M (15%); 11 F (85%) 2 M (29%); 5 F (71%) 11 M (16%); 59 F (84%)

Right: left (fingers and toes) Right: 42%; left: 58% Right: 41%; left: 59% van Geertruyden: right: 47%; left: 53%;Vasisht: right: 57%, left: 42%

Location of tumour

Thumb (F1) 1 (5%) 2 (10%) 17 (24%)

F2 1 (5%) 3 (14%) 8 (11%)

F3 6 (32%) 5 (24%) 18 (26%)

F4 8 (42%) 7 (33%) 18 (26%)

F5 3 (16%) 4 (19%) 9 (13%)

Finger totals 19 (100%) 21 (100%) 70 (1005)

Toes 1 1 0

Patients with multifocal tumours 3/15 (20%) 5/6 (83%) None

Years of symptoms before diagnosis 1 to 40+ years Up to 20 years 1 to 40 years

Average age of diagnosis (years) 40 (combined, range 11e57); 54 (M,range: 50e57); 38 (F, range 11e57)

33 (combined, range 17e53); 40 years(M, range: 35e45); 31 years (F, range:17e53)

van Geertruyden: 44 (combined, range26e83); Vasisht: 43 (combined, range:14e95); 40 (M, range: 28e72); 43 (F,range: 14e95)

Original article

SUMMARY AND RECOMMENDATIONSFrom our experience, we advocate the following:< Glomus tumours of the fingers (and, more rarely, toes) are

associated with NF1 and are part of the tumour spectrum of thedisorder. Recently published genetic, functional and clinicalevidence shows that glomus tumours in NF1 arise secondaryto bi-allelic inactivation of NF1.3

< Glomus tumours in NF1 are more common than previouslysuspected. Although some of our patients were evaluatedfollowing specific referral, many were not, and werediagnosed because we specifically asked about fingertippain. From our experience, we estimate that glomustumours of the fingers may affect up to 5% of the adultNF1 population. Their prevalence in toes is unknown butmuch lower than that of fingers.

< Glomus tumours can cause considerable morbidity and screeningefforts should be established. In our experience, glomus tumoursprofoundly affect quality of life (disability, CRPS) and, in thepublished literature, can result in unnecessary surgery (seepatient 1 from Sawada et al 199513). A simple question (‘Dothe tips of your fingers ever hurt, especially when cold orbumped?’) should be asked as part of the routine care ofadults with NF1.

< The natural history of sporadic and NF1-associated glomustumours is similar (presentation, recurrence of tumour), with someimportant differences. Specifically, individuals with NF1 canpresent with multiple tumours in single or multiple fingers.There may be theoretical reasons why individuals with NF1are at an increased risk to develop CRPS.

< Glomus tumours are a clinical diagnosis. In our experience, inuncomplicated cases, MRI correlated highly with physicalexam findings. In certain scenarios (recurrence of tumour,CRPS, surgical planning), MRI may be useful.The establishment of glomus tumours of the fingers and toes

as part of the tumour spectrum of NF1 over 100 years after vonRecklinghausen’s description exemplifies the need for openmindedness and creativity, even when evaluating familiarphenotypes. It is our hope that greater awareness of glomustumours in NF1 leads to improved care.

Funding The work was supported in part by the Division of Intramural Research of theNational Human Genome Research Institute (DRS), research grants from the Fondsvoor Wetenschappelijk Onderzoek Vlaanderen (G.0096.02, EL), the InteruniversityAttraction Poles granted by the Federal Office for Scientific, Technical and CulturalAffairs, Belgium (2007-2011; P5/25, EL), and by a Concerted Action Grant from theK.U. Leuven (EL, RS).The content of this publication does not necessarily reflect theviews or policies of the Department of Health and Human Services, nor does mentionof trade names, commercial products or organisations imply endorsement by the USGovernment.

Competing interests None.

Patient consent Obtained.

Ethics approval This study was conducted with the approval of the InstitutionalReview Board of the National Human Genome Research Institute.

Provenance and peer review Not commissioned; externally peer reviewed.

REFERENCES1. Huson SM. The neurofibromatoses: classification, clinical features and genetic

counseling. In: Kaufmann D, ed. Neurofibromatoses. Basel: Karger 2008:1e21.2. De Smet L, Sciot R, Legius E. Multifocal glomus tumours of the fingers in two

patients with neurofibromatosis type 1. J Med Genet 2002;39:e45.3. Brems H, Park C, Maertens O, Pemov A, Messiaen L, Upadhyaya M, Claes K,

Beert E, Peeters K, Mautner V, Sloan JL, Yao L, Lee CC, Sciot R, De Smet L, Legius E,Stewart DR. Glomus tumors in neurofibromatosis type 1: genetic, functional, andclinical evidence of a novel association. Cancer Res 2009;69:7393e401.

4. Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M,Towers R, Gleeson M, Steiger C, Kirby A. Guidelines for the diagnosis andmanagement of individuals with neurofibromatosis 1. J Med Genet 2007;44:81e8.

5. Huson S. Neurofibromatosis: emerging phenotypes, mechanisms and management.Clin Med 2008;8:611e17.

6. Parsons ME, Russo G, Fucich L, Millikan LE, Kim R. Multiple glomus tumors. Int JDermatol 1997;36:894e900.

7. Gombos Z, Zhang PJ. Glomus tumour. Arch Pathol Lab Med 2008;132:1448e52.8. Klaber R. Morbus Recklinghausen with glomoid tumors. Proc Roy Soc Med

1938;31:347.9. Twiston Davies JH, Hellier FF, Klaber R. The glomus tumour: doubts and difficulties

in diagnosis. Br J Dermatol 1939;51:312e18.10. Strauchen JA. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J

Med 2002;347:854e5; author reply -5.11. Van Geertruyden J, Lorea P, Goldschmidt D, de Fontaine S, Schuind F, Kinnen L,

Ledoux P, Moermans JP. Glomus tumours of the hand. A retrospective study of 51cases. J Hand Surg Br 1996;21:257e60.

12. Park YH, Choi SW, Cho BK. Solitary type of glomus tumour developed in multiplesites. Ann Dermatol 1994;6:225e9.

13. Sawada S, Honda M, Kamide R, Niimura M. Three cases of subungual glomustumors with von Recklinghausen neurofibromatosis. J Am Acad Dermatol 1995;32(2Pt 1):277e8.

14. Okada O, Demitsu T, Manabe M, Yoneda K. A case of multiple subungual glomustumors associated with neurofibromatosis type 1. J Dermatol 1999;26:535e7.

15. Kim YC. An additional case of solitary subungual glomus tumor associated withneurofibromatosis 1. J Dermatol 2000;27:418e19.

16. Vasisht B,Watson HK, Joseph E, Lionelli GT. Digital glomus tumors: a 29-yearexperiencewith a lateral subperiosteal approach.Plast Reconstr Surg 2004;114:1486e9.

17. Love JG. Glomus tumours: diagnosis and treatment. Mayo Clinic Proceedings1944;19:113e16.

18. Bhaskaranand K, Navadgi BC. Glomus tumour of the hand. J Hand Surg (Br)2002;27:229e31.

19. Drape JL, Idy-Peretti I, Goettmann S, Wolfram-Gabel R, Dion E, Grossin M,Benacerraf R, Guerin-Surville H, Bittoun J. Subungual glomus tumors: evaluation withMR imaging. Radiology 1995;195:507e15.

20. Drape JL. Imaging of the tumors of the perionychium. Hand Clin 2002;18:655e70.discussion 71.

21. Al-Qattan MM, Al-Namla A, Al-Thunayan A, Al-Subhi F, El-Shayeb AF. Magneticresonance imaging in the diagnosis of glomus tumours of the hand. J Hand Surg Br2005;30:535e40.

22. McDermott EM, Weiss AP. Glomus tumors. J Hand Surg Am 2006;31:1397e400.23. De Maerteleire W, Naetens P, De Smet L. Glomus tumors. Acta Orthop Belg

2000;66:169e73.24. de Mos M, Sturkenboom MC, Huygen FJ. Current understandings on complex

regional pain syndrome. Pain Pract 2009;9:86e99.25. Creange A, Zeller J, Rostaing-Rigattieri S, Brugieres P, Degos JD, Revuz J,

Wolkenstein P. Neurological complications of neurofibromatosis type 1 in adulthood.Brain 1999;122( Pt 3):473e81.

26. Drouet A, Wolkenstein P, Lefaucheur JP, Brugieres P, Degos JD, Revuz J,Wolkenstein P. Neurofibromatosis 1-associated neuropathies: a reappraisal. Brain2004;127(Pt 9):1993e2009.

27. Ferner RE, Hughes RA, Hall SM, Upadhyaya M, Johnson MR. Neurofibromatousneuropathy in neurofibromatosis 1 (NF1). J Med Genet 2004;41:837e41.

28. Cooke ED, Harris J, Fleming CE, Steinberg MD, Foster JM. Correlation of pain withtemperature and blood-flow changes in the lower limb following chemical lumbarsympathectomy in reflex sympathetic dystrophy. A case report. Int Angiol1995;14:226e8.

29. Hingtgen CM. Neurofibromatosis: The role of guanosine triphosphatase activatingproteins in sensory neuron function. Sheng Li Xue Bao 2008;60:581e3.

Original article

Diagnosis, management, and complications of glomus tumours of the digits in neurofibromatosis type 1

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