Hereditary Leiomyomatosis and Renal Cell Cancer Is a (4)

Home , Leiomyoma

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV This isan open access article under the CC BY-NC license.www.medicaljournals.se/acta and genodermatosis with an autosomal dominant inheri Hereditary leiomyomatosis and renal cell cancer is a (4). The syndrome was subsequently renamed HLRCC in families withanautosomal dominant inheritancepattern colleagues noticedanaccumulation oftheconditionin2 and Reed when 1973, to back dates syndrome Reed’s sis cutisetuteri,amongstother names(3). The eponym and uterineleiomyomatosis(MCUL),leiomyomato is referred to as Reed’s syndrome, multiple cutaneous syndrome the literature, the In 1954. in time first the for linked leiomyomas of the skin with uterine leiomyomas (ULM), andrenalcellcarcinomas(RCC).Blum&Jean(2) tiple cutaneous leiomyomas (CLM), uterine leiomyomas H C, Denmark.E-mail:[email protected] University of Southern Denmark, Kloevervaenget 24A 2, DK-5000 Odence Corr: Anders Würgler Hansen, Medical Student, Faculty of Health Sciences, Acta DermVenereol 2020;100:adv00012. Accepted Oct28,2019;Epubaheadofprint30,2019 uterine leiomyomas; renalcellcarcinoma;cancersurveillance. Key words: hereditary leiomyomatosis; cutaneous leiomyomas; renal tumours inalifelong surveillance programme. mutation. bemonitored patientsshould Diagnosed for inpatientswithoutproach adetectablepathogenic diagnosticmunohistochemistry ap maybeauseful Im strated hydratase. inthegeneencodingfumarate by genetic testing if a pathogenic mutation is demon high potential to metastasize.Patients are diag havea nal cellcancer-associatedrenalcarcinomas is often Hereditary leiomyomatosisnecessary. and re frequently cause symptoms, and surgical intervention hereditary leiomyomatosis andrenalcellcancer.They ne leiomyomas haveahighpenetranceinwomenwith cancausepainor Uteri itching. in particular, lesions, muscle tumours that tend to grow overtime.Larger Cutaneousleiomyomasdiagnosed. aresmall smooth worldwide, but the syndrome is believed to be under leiomyomatosis andrenal cell reported carcinoma Thereare200–300families cinoma. with hereditary and increasedsusceptibilityto develop renal cell car anduterineleiomyomas, bycutaneous characterized tance pattern. It isatumour predisposition syndrome 1 Anders WürglerHANSEN Hereditary LeiomyomatosisandRenal CellCancer characterized by thepropensity to develop single or mul (FH) (1).HLRCCisatumourpredispositionsyndrome novo mutationsinthegeneencodingfumaratehydratase dominant inheritancepattern,causedbyinheritedorde Journal Compilation ©2020ActaDermato-Venereologica. Faculty of Health Sciences, University of Southern Denmark, 3 Department of Pathology, Odense University Hospital, Odense, Denmark RCC) is a rare genodermatosiswith an autosomal ereditary leiomyomatosisandrenalcellcancer(HL 1 , Zahraa CHAYED 1 , Kristine PALLESEN REVIEW ARTICLE nosed nosed 2 Department of Dermatology and Allergy Centre, Odense University Hospital, ------

(19). The gene product is the enzyme fumarate hydratase potential pathogenicFHvariants havebeenreported unique 200 of excess An 18). (17, mutation germline mutation canbedemonstrated inadditiontotheinherited biallellic Knudson’s 2-hit hypothesis (5, 16). Tumour tissue displays sporadic casesreported(8,15). with disease dominant autosomal an is HLRCC (5). 1q caused bymutationsintheFH-geneonchromosome The geneticpredispositiontoCLM,ULMandRCCis PATHOPHYSIOLOGY number ofHLRCCfamiliesislikelytobehigher(8). believed to be an underdiagnosed syndrome, and the actual that the syndrome occurs worldwide (10–14). HLRCC is Chinese and African-American HLRCCfamiliessuggest Indian, Japanese, Colombian, of Reports HLRCC. with families Finnish 7 reported (6) al. et Lehtonen families. 21 additional an where Weireported (7), later (10) al. et Toro et al. reported 35 HLRCC families in North America reported 44 families with confirmed HLRCC in France (9). American families have beenreported(6–8).Gardieet al. (1, 3).Mostly Western-European, Finnish andNorth- 200–300 familieshavebeenreportedintheliterature The exactprevalenceof HLRCC isunknown;however, EPIDEMIOLOGY susceptibility tocertainsubtypesofRCC(5). 2001, whentheconditionwaslinkedwithanincreased so renal neoplasms are detected and treated intime. pathogenic mutation shouldbe offered lifelong surveillance should undergo genetic testing. Individuals harbouring a tures suggestive of HLRCC and at-risk family members with a high potential to metastasize. Individuals with fea associated renal cellcarcinomas are aggressive tumours surgery. Around 20%develop renal cellcarcinoma. HLRCC- often cause gynecological symptoms and typically require Most women with HLRCC develop uterine leiomyomas that which are skintumoursthatcan cause painand itching. of individuals with HLRCC develop cutaneous leiomyomas, an inherited tumour predisposition syndrome. Around 75% Hereditary leiomyomatosis and renal cell cancer (HLRCC) is SIGNIFICANCE 2 , acts as a tumour suppressor gene in accordance with FH actsasatumoursuppressorgeneinaccordancewith Ileana CODRUTA VASILESCU inactivation where an acquired somatic acquired an where inactivation FH Acta DermVenereol 2020;100: adv00012 doi: 10.2340/00015555-3366 3 andAnette BYGUM 2 FH 1/7 -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV www.medicaljournals.se/acta ) (3). Angio arrector pili muscles of hair follicles (Fig. 3) the mostfrequentinrelation toHLRCC,emerge fromthe being Piloleiomyomas, angioleiomyomas. and myomas CLMs are subdivided into piloleiomyomas, genital leio between 2and20mmindiameter (3,8).Histologically, lonodules (3,8,30)(Figs1and2 skin-coloured to erythematous or hyperpigmented papu smooth, firm, benign, are (8). They diagnosis a to leading disease of manifestation frequent most the are CLMs Cutaneous leiomyomas festations mightbeoverestimated(7,8,10). publications ofHLRCC,theprevalenceclinicalmani and studies in findings positive on based individuals of gene variant is not possible (1, 9, 23). inherited Due to recruitment specific a on based phenotype the Predicting 35 years, while being present in only 55% of women (6). study reportedthatCLMswerepresentinallmenbyage in menwithFHmutationscomparedwomen,asa The penetranceofCLMshasbeenreportedtobehigher severe cutaneous, uterine or renal manifestations (9, 21). with HLRCC displaysabroadclinicalspectrum,assomecases CLINICAL MANIFESTATIONS (3, 9,20,21,29). in HLRCCindividualswithoutdetectableFHmutations and large rearrangementshaverarely been demonstrated deletions exon deletions, Whole-gene 28). 27, (22, assay activity maybedetectedintumourtissuebyabiochemical table pathogenicFHmutations,areducedorabsent detec without cases In 18). 9, 8, (3, HLRCC suggestive germline mutation in 71–100% of families with clinically pathogenetic a reveals sequencing Direct (26). vival involved in angiogenesis, cell proliferation and cell sur genes target of transcription the promotes HIF-1β and elevated intracellular levels of HIF (25). HIF-1α, HIF-2α HIF, to of leading degradation the catalyses that enzyme role. Fumarate inhibits HIF prolyl hydroxylase (HPH), an way arehypothesizedtoplaya path hypoxia the in (HIF) factors stood, althoughhypoxiainducible to tumourigenesis is poorly under of FH (24). The mechanism leading accumulates incellstheabsence Fumarate 21–23). 10, (7, activity markedly reduced or absent enzyme gene product,resultinginaneither of themRNA ortruncationofthe the wildtypeallele,leadstodecay commonly amissensemutationof (20). An inactivatingmutation,most the tricarboxylicacidcycle(TCA) conversion offumaratetomalatein or fumarase,whichcatalysesthe 2/7 FH mutationsare asymptomatic while othershave A. WürglerHansenetal. - ). CLMs range in size ). CLMsrangeinsize single CLMontheupperarmofawomanwithHLRCC.(C)ClustersCLMsinwoman’s mother. A (B) (HLRCC). cancer cell renal and leiomyomatosis hereditary verified genetically with woman old (CLM) with1 prominent lesion and 2 surrounding smaller lesions located on the upper trunk of a 35-year- Fig. 1.Presentationsleiomyomas. ofcutaneous FH - - - - -

single lesion to more than 100 (7, 8). Lesions generally generally Lesions 8). (7, 100 than more to lesion single varies widelyamongaffected individuals,rangingfroma temperature or pressure (3, 7, 8, 30). The number of CLMs be provoked by direct contact, emotions, or fluctuations in variable itchingorpainfromtheirskinlesions,whichmay Approximately 75–90% of HLRCC individuals experience 23). 8, (7, age of years 9 as young as patient a in reported mean age at onset of 24–30 years, although they have been the faceandneck(3,8,30).Multiplelesionscanbedescri upper/lower extremities, shoulders and, less frequently, on They areusuallylocatedonextensorsurfacesofthetrunk, (3, 31). Piloleiomyomas can be multiple or solitary (3, 8). both rare,theformerisoftenpainfulandlatterpainless 32). While angioleiomyomasandgenitalleiomyomasare sue ofthevulva,scrotumandnipple-areolacomplex(31, prior tosurgicalexcision. (B)Keloid formationsurgical excision. following leiomyomatosis renal cellcancer. and investigation for hereditary current a 20-year-oldpatientunder leiomyomas excision ofcutaneous on thechest of Fig. 2.Surgical 23). They initiallyappearinthe2 15, 8, (7, condition the of manifestation clinical only the are they individuals of 9–15% In 21). 15, 10, (9, families HLRCC of 100% to up and patients, HLRCC of 68–84% can beunilateralorsymmetrical(3,8).CLMsappearin been reported(3,8,30). Tumors areusuallybilateral,but linear, anddisseminated distributionalpatternshavealso bed as clustered orscattered, while segmental, zosteriform, leiomyomas originatefromthedartoicsmoothmuscletis tissue inthetunicamediaofbloodvessels(31).Genital leiomyomas arederived from the vascularsmoothmuscle (A) Smallclusterof reddish cutaneous leiomyomas nd (A) Cutaneous leiomyomas to 4 to th decade, with a decade,witha - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV HLRCC families and in 76–100% of women of with 73–100% HLRCC in occur ULMs 10). (6–8, years 30 of age degrees ofnegativeimpact on qualityoflife(8). 10). HLRCC-associated ULMs are associated with various and many undergo surgery before the age of 30 years (7, 23), 10, (7, years 35–36 of age mean myomectomy,a at undergo surgical intervention,suchas hysterectomyor pathogenic a with women of 91% to Up achieving conceptionandoccurrenceofmiscarriages(8). sociated with female infertility characterized by difficulty prior todiagnosis(8).HLRCC-associatedULMsareas often experiencegradualworseningofthesesymptoms and irregular menses (7, 8, 21, 37). Women with HLRCC most commonlydysmenorrhea,followedbymenorrhagia associated ULMsexperiencegynaecologicalsymptoms, with HLRCC (37). The majority of women with HLRCC- diagnosed approximately10yearslaterthaninwomen are they and (38), 9% is fibroids uterine of symptomatic prevalence the public, general the In 37). 10, 8, (7, years 53 to 18 from ranging years, 28–30 is ULMs of disease manifestation (8, 10). The mean age at diagnosis (7–10, 15, 21, 23). In 7–14% of cases, ULMs are the only ULMs arediagnosedinthe2 diameter between 1 and 10 cm (7, 10). HLRCC-associated Uterine fibroids range in number between 1 and 20, and in Uterine manifestations being mistakenforleiomyosarcomas(23). the past mayhaveledtouterineandcutaneous leiomyomas culative, looserdiagnosticcriteriaofleiomyosarcomasin (36). These tumoursrarelymetastasize(3). Although spe examination of tumour tissue is required for a firm diagnosis larly shapedandincreasinglypainful(3).Histopathological clinically fromCLMs,butmaybelarger, ulcerated,irregu distinguish to difficult are Leiomyosarcomas 35). (4–6, rine leiomyosarcomashaverarelybeenlinkedtoHLRCC with rapidgrowthofanexistingCLM(23).Similarly, ute mutation carriers(7,10,23,33,34),2ofwhichpresented of cutaneousleiomyosarcomashavebeenreportedinFH into leiomyosarcomas is not well established.Only 6 cases potential ofcutaneousanduterineleiomyomastotransform on their quality of life caused by their skin lesions (8). The CLMs havereportedamoderatetoseverenegativeimpact with Individuals 21). (15, symptomatic be to tend lesions larger overtime,andespecially innumberandsize increase nd to 5 to th decade,withamean FH mutation - - - -

of theclinician.However, theindication forcosmetic of surgical intervention depends largely on the preferences triggers, such as direct contact and changes in tempera Conservative approachesinvolveavoidingsymptomatic mainly onpainandcosmeticappearanceofthelesions. The need for treatment of CLMs is individual and depends MANAGEMENT population (48,49). sporadic RCCinthegeneralEuropeanand American of diagnosis the than earlier years 20–25 approximately 47), 46, 41, 14, (6–9, years) 10–90 (range years 39–46 with RCC(21). The meanageatdiagnosisofHLRCC is diagnosed were HLRCC with patients of 6% only that found study Dutch a However, 23). 10, 9, (7, HLRCC with individuals of 16–24% in and 10), 9, (7, families RCC is diagnosed in approximately 14–62% of HLRCC median survivalof18monthsformetastaticdisease(23). a reported al. et Muller Furthermore, (7). al. Toroet by poor prognosis, with a 5-year survival of 31%, as reported the syndrome (10, 45). HLRCC-associated RCCs have a debut withRCCastheonlyclinicalmanifestationsof can Patients (3). metastases from symptoms and mass include haematuria, flank pain, lower back pain, palpable and a high potential to metastasize (14, 23, 44). Symptoms ofnearbytissue, invasion pattern,with growth aggressive and 22 2 cm in diameter (5, 7, 8). between RCCs usually display an size in vary tumours Renal 43). (40, plasm nucleoli, surroundedbyaperinuclearclearhaloofcyto large nuclei, withprominentinclusion-likeeosinophilic multifocal and bilateral (10, 14, 40, 42). Tumour cells have are predominantlysolidandunilateral,butcanalsobe RCCs 40). 23, 22, 9, (7, reported been also have origin of collectingduct,clearcell,sarcomatoidandoncocytic of a type 2 papillary morphology (PRCCII), but tumours RCCs to predisposes mainly syndrome The 39–41). 23, tubulo-papillary, tubular, solid and cystic elements (10, of architecturalgrowthpatterns,includingpapillary, HLRCC-associated RCC display a broad spectrum Renal manifestations tion, CO readily beremovedbystandard excision,electrodessica by choiceof clothing anduse ofmake-up(3).CLMscan solved be might appearance cosmetic of Issues (3). ture 2 Hereditary leiomyomatosisandrenalcellcancer laserablationorcryotherapy (3,21). The choice of cutaneous leiomyoma. Original magnification x40 staining of cutaneous leiomyoma. (B) ASMA staining desmin and vimentin. (A) Haematoxylin and eosin muscle markers alpha-smooth muscle actin (ASMA), smooth muscle cells withpositive staining for smooth nuclei. The tumour tissue predominantly consists of Tumour cells are fusiform with small clear uniform patient. leiomyomatosis renal cellcancer and a cutaneous leiomyoma in ahereditary Fig. 3. Immunohistochemical staining of Acta DermVenereol 2020 3/7 - - . Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV www.medicaljournals.se/acta recently proposedtotrigger genetictesting,incasessug was morphology ULM of screening Pathological 59). (57, HLRCC of suggestive features without individuals ULM tissue for FH-deficiency was deemed impractical in than germline mutations (57, 58). rather Therefore, screening inactivation of biallelic somatic to due is This 58). is a commonly seen phenomenon in sporadic ULMs (57, has been suggested (55, 56). Random inactivation of FH testing (50). Routine molecular screening of ULM tissue genetic through confirmed is HLRCC of diagnosis A DIAGNOSIS such therapieshavenotyetproveneffective (54). However, 53). (47, defect cycle TCA a due production for glycolysis ATPon dependent are cells tumour the as glycolysis inthetreatmentofHLRCC-associatedRCC, is currentlyongoingresearchoftheuseinhibitors of metastasized HLRCC-associated RCC (51, 52). There with erlotinib showed promising results in the treatment ces andcomorbidities(3).Bevacizumabincombination treatment modality depends largely on patient preferen order to achieve the best response (47, 51, 52). Choice in of combination, in used be may agents These 51). (47, pazopanib, axitinib,sunitinib,sorafenibanderlotinib pathways arebevacizumab,temsirolimus,everolimus, 51). The most commonly prescribed drugs targeting these (47, (EGF) factor growth epidermal and (PDGF) factor endothelial growthfactor(VEGF),platelet-derived growth (mTOR) pathway and the HIF pathway, including vascular with componentsofthemammaliantarget ofrapamycin interact usually options treatment Medical (51). able metastatic disease,andverylimitedtreatmentdataavail for option treatment standard no is There (47). function tial nephrectomyispreferredinordertopreserverenal par with surgery nephron-sparing possible, If (47). tion tissue and possibly retroperitoneal lymph node dissec even insmalltumours,withextirpationofallneoplastic associated RCCs,surgical interventionisrecommended planning priortochoiceoftreatment(21). electrosurgery (3, 8, 10). Patients are counselled on family surgical interventionsincludeuterinearteryembolismand Other (50). uterus the from fibroids the of removal with Myomectomy isauterus-preservingsurgical intervention, are most commonly myomectomy andhysterectomy. medical treatmentforULMs(3).Surgical interventions gesterone-releasing intrauterine devices can be used as sometimes attemptedtorelievepain(3,21,50). pine, gabapentin,phenoxybenzamine,anddoxazocinis pharmacological treatment with nitroglycerine,nifedi offer painreliefinsymptomaticlesions(3).Systemic scarring andkeloids(Fig.2). removal ofCLMsshouldbeweighedagainsttherisk 4/7 Due totheoftenaggressivegrowthpatternofHLRCC- Gonadotropin-releasing hormoneagonistsandpro Topical treatmentbylidocaineorbotulinumtoxinmay A. WürglerHansenetal. ------is also suspicious of HLRCC. degree familymemberwhomeetsatleast oneoftheabove-mentioned criteria of highly suggestive are HLRCC, and Majorcriteria minor criteria should raise suspicion of the firmdiagnosis. syndrome. Having a first- a set criteria Definitive tumours canreadilybeeliminatedaslikelydifferential the clinicalspectrumofCLMsisbroad,manythese Although 69–71). 30, CLMs areshowninTable(3, II relevant differential diagnosticconsiderationstopainful most The (69). pain cause may tumours skin of number always lead to a suspicion of HLRCC (1, 43, 68). A large clinical findings. CLMs are rare and their presence should The differential diagnosticconsiderationsdependonthe DIFFERENTIAL DIAGNOSES criteria ofHLRCCisshowninTable I(1,3,9,21,50). diagnostic for proposal revised A(67). unestablished is for an underlying germline mutation while the specificity CLMs ismorecost-effective andhasahighersensitivity immunostaining techniques, the very presence of multiple However,66). & Harvey Wood argue that,comparedwith65, (62, HLRCC for tool screening routine a as suggested been has CLMs of Immunostaining 64). (62, to weakeningorstrengtheningthesuspicionofHLRCC alone cannotreplacegenetictesting,itmaycontribute examination IHC While 63). 61, 59, 41, (39, HLRCC staining intumourtissueisstronglycorrelatedwith (61). Absence ofFHstainingand/orpresence2SC modification chemical stable a form to proteins cellular of fumarate interact with cysteine sulphydryl groups of a processtermedproteinsuccination,whereinhighlevels HLRCC-associated RCC (39, 41, 59). detecting 2SC is in produced in biomarker IHC specific highly another is (2SC) cysteine S-(2-succinyl) (59). staining FH absent by identified be can tissue tumour in expression FH of staining of FH-deficient tumor tissue (62). However, loss IHC by demonstrated be cannot tumors, renal to linked succinate dehydrogenase(SDH),an acid cycle enzyme of Alterations 61). 59, 41, (39, RCCs high-grade other role indifferentiating HLRCC-associatedRCCfrom 59, 61). In addition, IHC examination plays an important where a pathogenic germline mutation is not known (47, associated withHLRCCcansupportthediagnosisincases to detectwomeneligibleforgeneticcounselling(60). help might strategy This (60). deficiency FH of gestive and renalcellcancer(HLRCC) Table I. Proposeddiagnosticcriteria for hereditaryleiomyomatosis Minor criteria Major criteria Definitive criteria Criteria Immunohistochemical (IHC) examination of neoplasms • • • • • • Type 2 papillary renal cellcarcinoma onset <40 years. <40 years. Multiple severely symptomatic uterineleiomyomas onset leiomyoma. Single solitary histologicallyconfirmedcutaneous Family disposition to HLRCC and at least 1 minorcriteria. histologically confirmed. Multiple cutaneous leiomyomas with at least 1 mutation. Detection of pathogenicgermline fumarate hydratase- Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV mutation carriers, is recommended in of 20years,inFHmutationcarriers,isrecommended in ultrasonic gynaecologicalexaminations startingattheage attention incaseofrapidgrowth inskinlesions. Annual ( tion every second year, starting from the onset of CLMs (23). We recommend a thorough dermatological examina leiomyosarcomas withHLRCChasnotbeenestablished Al programme ofpathogenicFH-mutationcarriers(30). There is a lack of consensus regarding a surveillance SURVEILLANCE sociated withanincreasedfrequencyofULMs(1). as not is BHDS (75). BHDS with associated frequently phobe RCCs,clearcellRCCsorrenaloncocytomasare chromophobe RCCandrenaloncytoma,butalsochromo most oftenpresentwithhybridtumours,acombinationof BHDS constitute in a wide histological spectrum. Patients face, neck and upper torso (75). The renal tumours seen in millimetre smalllesions,andaremainlylocatedonthe pale, painless, are trichodiscomas and fibrofolliculomas and acrochordons (skin tags) (75). Distinctive from CLMs, trichodiscomas fibrofolliculomas, including lesions, skin that may erupt and cause pneumothorax, and a triage of uterine lesions(1).BHDSisassociatedwithlungcysts, ferentiated from HLRCC by the lack of cutaneous and dif be VHLcan (74). others among pheochromocytoma haemangioblastoma, pancreatictumoursandcysts, system nervous central include findings common Other (74). cysts renal and RCC cell clear by characterized is VHL (1). HPRC of manifestation only the is RCC 1 type papillary to Predisposition (73). (BHDS) syndrome andBirt-Hogg-Dube (VHL) syndrome Hippel-Lindau Von(HPRC), cancer renal papillary hereditary dromes: tumours are the autosomal dominant renal cancer syn stitute themostcommonpelvictumourinwomen(72). quired forafirmdiagnosis(30). re findings. is clinical biopsy the A on based diagnoses leiomyomas Table II.Clinicaldifferential diagnosesof painfulcutaneous In casesof atypical presentation other diagnoses may be considered (3, 30). Adipose Tissue Eccrine Fibrous Infiltrative Muscle Neural Vascular Table III). Patients should be instructed to seek medical The maindifferential diagnosesinrelationtorenal ULMs are frequent in the general population and con though suspected,afirm association ofcutaneous Neoplasia • • • • • • • • • • • • • • • Angiolipoma Hidradenoma Eccrine spiradenoma Keloid Dermatofibroma Endometriosis Cutaneous metastasis Leiomyosarcoma Leiomyoma Glomus tumour Neuroma Neurilemmoma Granular cell tumour Reactive angioendotheliomatosis Blue rubber blebnaevus ------

gene varianttooffspring (1). risk-assessments with regards to passing onthe pathogenic pregnancy; fertilityissues,prenataltestingoptions,and starting afamily, inordertodiscussthefollowingprior carriers shouldideallyreceivegeneticcounsellingbefore with information regarding thesyndrome(1).FHmutation should beoffered geneticcounsellingandbeprovided programme. HLRCCpatientsandat-riskfamilymembers to identifythenecessityforinclusioninsurveillance mutation carriersshouldundergo genetictestinginorder At-risk family members and offspring of confirmed GENETIC COUNSELLING renal tumoursarediagnosedandtreatedintime. patients in an aggressive surveillance programme,so that imperative todiagnosethesyndromeearly, andinclude is It cancers. renal HLRCC-associated of detection the on foremost and first depends HLRCC of prognosis The PROGNOSIS surveillance programmeatanearlyage(1,78). undergo earlygenetic testing in orderto be includedinthe family membersofpatientswithprovenHLRCCshould ening ofHLRCC-associatedrenaltumours.Furthermore, scre routine for modality this recommend not does (78) in thesurveillanceprogramme(21),Schmidt&Linehan MRI assisting in role a play to suggested been has sound scans starting at age 10 years (Table III). While renal ultra youngest reported at age 10 (30), we propose annual MRI duals younger than 20 years of age (8, 40, 46, 76, 77), the REFERENCES The authorshavenoconflictsofinterest todeclare. to numerous reports of HLRCC-associated RCC in indivi and at the age of 8 years by Schmidt & Linehan (50). Due proposed tostartattheageof10yearsbyPateletal.(3), is (MRI) imaging resonance magnetic contrast-enhanced byannual programme(21).Renalsurveillance surveillance III) (3, 21, 50). Prevention of RCCs is a major focus of the order todiagnoseandmonitor asymptomatic ULMs (Table hydratase mutationcarriers Table III.Proposed surveillanceprogramme of pathogenic fumarate Renal Uterine Cutaneous Location 3. 2. 1. Patel VM, Handler MZ,Schwartz RA, Lambert WC.Hereditary Blum P, JeanL.Leiomyome eruptifdeBesnier. Bull SocFr Pithukpakorn M,Toro JR.Hereditaryleiomyomatosis andre Dermatol Syphiligr 1954; 61: 349–350. Seattle (WA) 2015. Stephens K, et al., SE, Bean LJH, editors. GeneReviews((R)). nal cell cancer. In: Adam MP, Ardinger HH, Pagon RA, Wallace Hereditary leiomyomatosisandrenalcellcancer • • • Surveillance at age10years. Annual contrast-enhanced magnetic resonance imaging starting at age20years. Annual ultrasonic gynaecological examination of womenstarting A thorough dermatological examination once every secondyear. Acta DermVenereol 2020 FH- 5/7 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV www.medicaljournals.se/acta 10. 22. 15. 21. 18. 14. 20. 19. 17. 16. 13. 12. 11. 6/7 9. 8. 7. 6. 5. 4. Wei MH, Toure O, Glenn GM, Pithukpakorn M, Neckers L, Gardie B, Remenieras A, Kattygnarath D, Bombled J, Lefevre Alam NA, Barclay E, Rowan AJ, Tyrer JP, Calonje E, Manek Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner Alam NA, Rowan AJ, Wortham NC, Pollard PJ, Mitchell M, Tyrer Alam NA,Bevan S, ChurchmanM,Barclay E,Barker K,Jae Lehtonen HJ, Kiuru M, Ylisaukko-Oja SK, Salovaara R, Herva Smit DL, MensenkampAR,Badeloe S, BreuningMH,Simon Lehtonen HJ. Hereditaryleiomyomatosis andrenal cellcan Wong MH, Tan CS, Lee SC, Yong Y, Ooi AS, Ngeow J, et al. Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Bayley JP, Launonen V, Tomlinson IP. The FH mutation data Knudson AG,Jr. Mutationandcancer:statisticalstudyof Kiuru M,LaunonenV, HietalaM,AittomakiK,VierimaaO, Soni SS, Gowrishankar S, Adikey GK,Raman AS. Hereditary Kamai T, AbeH,Arai K,Murakami S, SakamotoS, Kaji Y, et Arenas Valencia C,Rodriguez LopezML,CardonaBarreto Reed WB, Walker R, Horowitz R. Cutaneous leiomyomata with spectrum ofphenotypes expressed infamilieswithhere Stolle C,etal.Novel mutationsinFHandexpansionof the J MedGenet2011;48: 226–234. patients withisolatedtype 2papillaryrenal cell carcinoma. hereditary leiomyomatosis and renal cell cancer (HLRCC) and S, Perrier-Trudova V, Novel etal. with families in mutations FH Dermatol 2005;141:199–206. leiomyomatosis: anunderdiagnosedtumorsyndrome.Arch S, etal.Clinical featuresofmultiplecutaneousanduterine in NorthAmerica.AmJHumGenet 2003; 73:95–106. hereditary leiomyomatosis and renal cell cancer in families ML, etal.Mutationsinthefumarate hydratase genecause leiomyomatosis andrenalcancer, andfumarate hydratase multiple cutaneous anduterine leiomyomatosis, hereditary JP, et al. Genetic and functional analyses of FH mutations in 2006; 43: 523–526. with fumarate hydratase germlinemutation.JMedGenet R, Koivisto PA, etal.Increasedriskof cancerinpatients germline mutation analysis. ClinGenet 2011; 79:49–59. renal cellcancer infamilies referredforfumarate hydratase ME, van Spaendonck KY, et leiomyomatosisal. Hereditary and renal cell cancer (HLRCC). Fam Cancer 2014; 13: 281–289. Potential genetic anticipation in hereditary leiomyomatosis- cell cancer. Proc Natl Acad Sci U S A 2001; 98: 3387–3392. et al. Inherited susceptibility to uterine leiomyomas and renal papillary renal cell cancer. Nat Genet 2002; 30: 406–410. dominantly inherited uterine fibroids, skin leiomyomata and Kelsell D, to predispose FH in mutations Germline etal. retinoblastoma. Proc Natl Acad Sci U S A 1971; 68: 820–823. two-hit condition associated with renal cell cancer of cha Salovaara R,etal.Familial cutaneousleiomyomatosis isa Venereol Leprol2008;74: 63–64. leiomyomatosis JDermatol Indian carcinoma. cell renal with an at-risk individualfrom afamily withhereditaryleiomyo for locally advanced type 2 papillary renal cell carcinoma in al. Radical nephrectomy and regional lymph node dissection AY, Garavito Rodriguez E,ArteagaDiaz CE.Hereditaryleio uterine leiomyomata. Acta Derm Venereol 1973; 53: 409–416. genital fumarase deficiency. BMC MedGenet2008;9:20. involved in the MCUL (HLRCC) tumor syndrome and con base: anonlinedatabaseoffumarate hydratase mutations Cancer 2011;10: 397–411. cer: update on clinical and molecular characteristics. Fam racteristic histopathology. Am J Pathol 2001; 159: 825–829. 1q42.3–q43. AmJ Hum Genet2001;68: 1264–1269. cutaneous leiomyomata and uterine fibroids to chromosome ger EE, et al. Localization of a gene (MCUL1) for multiple 2016; 16: 232. matosis and renal cell cancer: a case report. BMC Cancer gene inaColombianfamily. Fam Cancer2017;16:117–122. and clinical characterization of a novel mutation in the FH identification syndrome: cancer cell renal and myomatosis 2006; 43: 18–27. ditary leiomyomatosis and renal cell cancer. J Med Genet and review. J Am Acad Dermatol 2017; 77: 149–158. leiomyomatosis andrenalcellcancersyndrome:anupdate A. WürglerHansenetal. ------28. 40. 27. 39. 23. 26. 38. 25. 37. 35. 33. 30. 29. 24. 41. 36. 34. 32. 31. Pithukpakorn M,Wei MH, Toure O, Steinbach PJ, GlennGM, Merino MJ, Torres-Cabala C, Pinto P, Linehan WM. The morp Hatch MD. Asimplespectrophotometricassay forfumarate Chen YB, Brannon AR, Toubaji A, Dudas ME, Won HH, Al- Muller M,Ferlicot S, Guillaud-Bataille M,LeTeuff G, Gene Semenza GL.Targeting HIF-1forcancertherapy. NatRev Fernandez Chabbert H, Buffet N, S.Allouche Prévalence Henegan JC,Jr.,Henegan cancersyndromes Heritable CR. Gomez Stewart L, Glenn GM, Stratton P, Goldstein AM, Merino MJ, Ylisaukko-oja SK,KiuruM,LehtonenHJ, LehtonenR,Pukkala Wang C, Tetzlaff M, Hick R, Duvic M. Reed syndrome presen Malik K,Patel P, ChenJ, Khachemoune A. Leiomyoma cutis:a Ahvenainen T, Lehtonen HJ, Lehtonen R, Vahteristo P, Ait Isaacs JS, JungYJ, MoleDR, LeeS, Torres-Cabala C,Chung Trpkov K,HesO, Agaimy A, Bonert M,MartinekP, Magi- Pijpe J, Broers GH,PlaatBE, Hundeiker M,OttoF, MastikMF, Weiler L, Poulalhon N, Slama A, Guillaud-Bataille M, Thomas Hammer P, White K, Mengden S, Korcheva V, Raess PW. Ramesh P, Annapureddy SR, Khan F, Sutaria PD. Angioleio Zbar B, et al. Fumarate hydratase enzyme activity in lymp 271–275. hydratase incrudetissueextracts. AnalBiochem 1978;85: Am J SurgPathol 2014;38:627–637. detecting aberrant succination by immunohistochemistry. of the syndrome by pathologic features and the utility of carcinoma syndrome-associated renal cancer: recognition Ahmadie HA,etal.Hereditaryleiomyomatosis and renalcell Cancer 2003;3:721–732. 721–727. 30–55 ans. JGynecolObstetBiolReprod (Paris) 2014;43: à partir d’une enquête menée auprès de 2500 femmes de vie de qualité la sur impact et France en utérin fibrome du deficiency. HumMolGenet 2003;12:1241–1252. related to thehypoxia pathway. Front Oncol 2016; 6: 68. Dermatol 2008;144:1584–1592. with hereditary leiomyomatosis and renal cell cancer. women Arch in fibroids uterine and gene hydratase fumarate Tucker MA, et al. Associationof germline mutations in the a population-based series of early onset uterine leiomyosar E, Arola J, et al. Analysis of fumarate hydratase mutations in focused reviewonpresentation,management, and associa in regulation of HIF stability. Cancer Cell 2005; 8: 143–153. fumarate hydratase in renal cancer: novel role of fumarate YL, etal.HIFoverexpression correlates withbialleliclossof mutation and hereditary leiomyomatosis and renal cell car carcinoma isstronglycorrelated withfumarate hydratase cell renal hydratase-deficient Fumarate al. et C, Galluzzi and leiomyoma. Sarcoma 2002; 6: 105–110. leiomyosarcomasuperficial and deep parametersin clinical tumor-biological et between histological, al. The relation and Dermatol 2016; 175:1104–1106. of mutation germline the fumarate hydratase gene. Br J L. Isolated cutaneous leiomyosarcoma revealing a novel histologic appearances. J Cutan Pathol 2019; 46: 343–346. Nipple leiomyoma: a rare neoplasm with a broad spectrum of 2008; 183:83–88. myomatosis andrenal cellcancer. CancerGenetCytogenet cation: detectionof exonic deletioninapatient withleio amplifi probe ligation-dependent multiplex by hydratase tomaki K, Baynam G, et al. Mutation screening of fumarate 2006; 43: 755–762. leiomyomatosishereditary and cancer.renal cell J Med Genet hoblastoid cells and fibroblasts of individuals in families with Genet 2017; 92:606–615. carcinoma syndrome in French FH mutation carriers. Clin associated with hereditary leiomyomatosis and renal cell stie C, Deveaux S, et al. Reassessing the clinical spectrum Surg Pathol 2007;31: 1578–1585. matosis and renal cell carcinoma (HLRCC) syndrome. Am J hologic spectrum of kidney tumors in hereditary leiomyo coma patients.Int J Cancer2006; 119: 283–287. ting withleiomyosarcoma. JAAD Case Rep 2015; 1: 150–152. J Clin Pract 2004; 58: 587–591. myoma: aclinical,pathological and radiological review. Int tion with malignancy. Am J Clin Dermatol 2015; 16: 35–46. ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 55. 51. 48. 59. 57. 54. 50. 47. 45. 43. 60. 58. 56. 53. 52. 49. 46. 44. 42. Martinek P, GrossmannP, HesO, BoudaJ, EretV, Frizzell N, Park I, Shim YS, Go H, Hong BS, Lee JL. Long-term re Doehn C,Grunwald V, SteinerT, Follmann M,Rexer H,Krege Andrici J, Gill AJ, Hornick JL. Next generation immunohisto Harrison WJ, AndriciJ, MacleanF, Madadi-Ghahan R,Farzin Yamasaki T, Tran TA, OzOK, Raj GV, Schwarz RE,Deberardinis Schmidt LS, Linehan WM. Hereditary leiomyomatosis and renal Menko FH, Maher ER, Schmidt LS, Middelton LA, Aittomaki Noguchi G,Furuya M,OkuboY, Nagashima Y, Kato I,Mat Skala SL, Dhanasekaran SM, Mehra R. Hereditary leiomyo Rabban JT, ChanE,MakJ, Zaloudek C,GargK.Prospective Lehtonen R, Kiuru M, Vanharanta S, Sjoberg J, Aaltonen LM, Tolvanen J, Uimari O, Ryynanen M, Aaltonen LA, Vahteristo Linehan WM, Rouault TA. pathways: Molecular Fumarate Choi Y, Keam B, Kim M, Yoon S, Kim D, Choi JG, et al. Beva Karakiewicz PI, Jeldres C, Suardi N, Hutterer GC, Perrotte P, Alrashdi I,LevineS, Paterson J, Saxena R,Patel SR, Depani Grubb RL, 3rd, Franks ME, Toro J, Middelton L, Choyke L, Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. than 30years oldmightprovide aneffective screeningap et al. Genetic testing of leiomyoma tissue in women younger S. Thediagnosis,treatment,andfollow-up of renalcellcar leiomyomas occurinboththesyndromicandsporadic set uterine hydratase-deficient Fumarate al. et L, Sioson M, 8: 165–171. of an FH-deficient type-2 papillary RCC. Nat Rev Urol 2011; RJ, et al. Exploring a glycolytic inhibitor for the treatment cell carcinoma. Int J Nephrol Renovasc Dis 2014; 7: 253–260. treatment. Fam Cancer 2014; 13:637–644. cell cancer (HLRCC): renal cancer risk, surveillance and K, Tomlinson I,etal.Hereditaryleiomyomatosis andrenal detection of germline mutation offumarate mutation ofgermline detection hydratase in in othertumors.Am J Pathol 2004;164: 17–22. (FH) occursinnonsyndromicuterine leiomyomas butisrare inactivation Biallelic K,etal. Aittomaki offumarate hydratase 27: 1865–1869. fumarate hydratase mutationscreening.HumReprod 2012; P. Strong family history of uterine leiomyomatosis warrants effect incancer. ClinCancerRes 2013; 19:3345–3352. the Warburg targeting – cancer kidney hydratase-deficient with nephrectomy. Can UrolAssocJ 2008; 2: 610–617. treated patients in survival carcinoma-specific cell renal of Capitanio U, etal. Ageatdiagnosisisadeterminant factor Fam Cancer 2010;9:239–243. very early diagnosis of renalcancerinapaediatricpatient. S, etal. Hereditaryleiomyomatosis and renal cellcarcinoma: discussion 9–80. of inherited renal cancer. J Urol 2007; 177: 2074–2079; cancer: a syndrome associated with an aggressive form Fowler S, et al. Hereditary leiomyomatosis and renal cell tumours. EurUrol2016; 70: 93–105. organs–parta:renal,penile,andtesticular and malegenital The 2016 WHO classification of tumours of the urinary system Diagn Pathol 2018;35:161–169. chemistry: emergingsubstitutes togenetictesting?Semin tings. AmJSurgPathol 2016; 40: 599–607. Arch2015;467:185–191. Virchows cer syndrome(HLRCC). leiomyomatosisproach forthehereditary can cell andrenal Korean patients.Cancer Res Treat 2019;51: 1549–1556. renal cell carcinoma: a multicenter retrospective analysis in reditary leiomyomatosis and renal cell carcinoma-associated cizumab plus erlotinib combination therapy for advanced he treatment failures. BMC Urol 2019; 19: 51. bevacizumab pluserlotinibaftertemsirolimusandaxitinib cell carcinomasyndromeassociatedrenalto sponse of metastatic hereditary leiomyomatosis and renal cinoma. Dtsch ArzteblInt2016;113:590–596. siblings. IntJ Urol 2018; 25:832–835. cancer without cutaneous manifestations in two Japanese sumoto K,etal.Hereditaryleiomyomatosis andrenalcell Pathol LabMed2018; 142: 1202–1215. diagnosis for HLRCC-associated renalcellcarcinoma.Arch temporary review and practical discussion of the differential matosis and renal cell carcinoma syndrome (hlrcc): a con cinoma syndrome.AmJSurgPathol 2016; 40: 865–875. ------74. 73. 72. 71. 70. 77. 69. 65. 63. 76. 68. 61. 64. 62. 78. 75. 67. 66. Haas NB, Nathanson KL. Hereditary kidney cancer syndro Moch H, Ohashi R, Gandhi JS, Amin MB. Morphological clues Drayer SM,CatherinoWH.Prevalence, morbidity, andcurrent Lima LAF, Lisboa GM, Silva Filho EAD, Rabelo G. Multiple Bin Saif GA, Buraik MA, Pokharel A, Sangueza OP. Recurrent van Spaendonck-Zwarts KY, Badeloe S, Oosting SF, Hovenga Cohen PR, Erickson CP, Calame A. Painful tumors of the Buelow B, CohenJ, Nagymanyoki Z,Frizzell N,JosephNM, Llamas-Velasco M,Requena L,AdamJ, Frizzell N,Hartmann Refae MA, Wong N, Patenaude F, Begin LR, Foulkes WD. Stewart L,Glenn G, Toro JR. Cutaneous leiomyomas: a clinical Bardella C,El-Bahrawy M,Frizzell N,AdamJ, Ternette N, Chan E, Rabban JT, Mak J, Zaloudek C, Garg K. detailed Carter CS, SkalaSL,Chinnaiyan AM,McHughJB, Siddiqui Schmidt LS, Linehan WM. clinical features, genetics and po Jensen DK, Villumsen A, Skytte AB, Madsen MG, Sommerlund Harvey NT, Wood BA. Is immunohistochemical screening of Llamas-Velasco M,Requena L,Kutzner H,ScharerL,Rutten Semin Diagn Pathol 2018; 35:184–192. neoplasms. renal ofhereditary recognition to theappropriate Obstet 2015; 131:117–122. medical management of uterine leiomyomas. Int J Gynaecol dermatomyofibromas. An Bras Dermatol 2018; 93: 268–270. Int J Dermatol 2015;54: e480–e482. reactive angioendotheliomatosis in pregnancy: a case report. S, SemmelinkHJ, van Moorselaar RJ, etal.Hereditary leio Investig Dermatol 2019; 12: 123–132. skin: “CALM HOG FLED PEN AND GETS BACK”. Clin Cosmet McCalmont T, etal.Immunohistochemistryfor2-succino identify patientswithmultiplecutaneousanduterineleio S-(2-Succino)-cysteine detectedwith succination to staining A, Mentzel T. Loss of fumarate hydratase and aberrant protein Pract Oncol 2007; 4: 256–261. and aggressive form of hereditary renal carcinoma. Nat Clin Hereditary leiomyomatosis andrenalcellcancer:an unusual cancer. Dermatol Nurs 2006; 18:335–341;quiz42. marker of risk for hereditary leiomyomatosis and renal cell Hatipoglu E, et al. Aberrant succination of proteins in fuma syndrome (HLRCC).AmJSurgPathol 2019;43:1170–1179. with hereditary leiomyomatosis and renal cell carcinoma myomectomy and hysterectomy specimens from women morphologic andimmunohistochemicalcharacterization of syndromes. AmJSurgPathol 2017; 41: 801–809. in cutaneous leiomyomas for detection of familial cancer fumarate hydratase (fh) and succinate dehydrogenase (sdh) J, Cao X, et al. Immunohistochemical characterization of a review of the literature. Eur Clin Respir J 2017; 4: 1292378. M, Bendstrup E. Birt-Hogg-Dube syndrome: a case report and Am J Dermatopathol 2018; 40:939–940. leiomyomatosis and renal cell carcinoma syndrome justified? cutaneous leiomyomas fortheearlydetection of hereditary A, Hantschke M, et al. Fumarate hydratase immunohistoche 639–655. single institutional experience. Am J Surg Pathol 2019; 43: leiomyomatosis renal cell carcinoma syndrome: a 5-year based screeningtotriggergeneticcounselingfor hereditary women withuterine smooth muscle tumors using pathology- (hereditary leiomyomatosis andrenalcellcarcinoma syn leiomyomas may aid in identification of patients with HLRCC cysteine (2SC)andfumarate hydratase (FH)incutaneous cancer syndrome. Am J Dermatopathol 2016; 38: 887–891. myomatosis andhereditaryleiomyomatosis and renalcell biomarker ofmutationstatus. J Pathol 2011; 225: 4–11. rate hydratase-deficient mice andHLRCC patientsis a robust Expert Opin Orphan Drugs 2015; 3: 15–29. tential therapeutic approachesfor Birt-Hogg-Dube syndrome. lance. Fam Cancer2012; 11: 123–129. kidney cancerat18years ofage:implications forsurveil myomatosis and renal cell cancer presenting as metastatic mes. Adv Chronic Kidney Dis 2014; 21:81–90. Cutan Pathol 2014; 41: 859-865. leiomyomatosis and renal cellcancer(HLRCC)syndrome.J taneous anduterineleiomyomatosis (MCUL)andhereditary may staining mical toidentify cu help multiple with patients drome). AmJSurgPathol 2016;40:982–988. Hereditary leiomyomatosisandrenalcellcancer Acta DermVenereol 2020 7/7 ------