Copyright© AE&M all rights reserved. Buenos Aires,Argentina Churruca, Visca, Hospital 98 T INTRODUCTION DOI: 10.1590/2359-3997000000212 Accepted onJun/7/2016 Received onFeb/17/2016 [email protected] C1437CJPBuenos Aires,Argentina – 3400 Uspallata, Jimena Soutelo Correspondence to: 1 diagnosis oftheoncological pathologyeveninearlier thediagnosisofcancer –enablesthe and maypreceed manifestations –whichdepends onthetypeoftumor and theoriginaltumor. Thesuspicion ofthese substance totheproduced according symptoms vary endocrine, immuneandmetabolicaspects,whose whichinvolve hematologic, rheumatologicalorrenal) endocrine, manifestations (cutaneous,neurological, (1). precursors andtheir factors,cytokines,hormones growth autoantibodies, polypeptidehormones, substances are toactontarget organs.by circulation Mostofthese bytumoranddistributed by substancesproduced caused (PNS) and are called paraneoplasticsyndromes the so- theirlocalization.These are a distancefrom signsat metastases. Inaddition,tumorscanproduce ordistant localization ofneoplasmandtheirregional case report Servicio deEndocrinología, Servicio PNS presents as an heterogeneous group of group asanheterogeneous PNS presents obstruction and bulk mass on the primary andbulkmassonthe primary obstruction symptomsby invasion, umors usuallyproduce a renal tumorandBcelllymphoma and hypoglycemiainapatientwith The coexistenceofhypercalcemia Jimena Soutelo carcinomas, and it has not yet been described in renal tumors. carcinomas, andithasnotyetbeendescribedinrenaltumors. thecoexistenceoftwoormorethemisrare,exceptinhepatocellular expected inmosttumors, initial improvement after medicaltreatment. While asingleparaneoplasticmanifestationmaybe denosumabandcorticoidproduction. Hereceived therapy. The patientdiedonemonthlaterdespite PTH andhypoglycemia withinhibitedinsulinsecretion,arriving totheconclusionoftumoral peptide hypercalcemia andhypoglycemia. The laboratoryexaminationreported hypercalcemia withinhibited man witharenaltumorand T-cell rich largeBcelllymphomawhowas hospitalized duetosevere hypoglycemia determinedbyaninsulin-independentpathway. We report acaseof59-year-old- tumor consistsofararesyndromecharacterized bythepresenceofasolidtumorandseverefasting to bethemostcommoncauseofmalignancyassociatedhypercalcemia. Non-islethypoglycemic cell hormone relatedpeptide,whoseactionsaresimilartothoseoftheparathyroid hormone,isthought patients. Prognosis ofcancerpatientswithhypercalcemia isusuallypoor. A factorcalledparathyroid the substance produced and the primary tumor. Hypercalcemia is a frequent complication in cancer which involve endocrine,immuneandmetabolicaspectswhosesymptomsvaryaccordingto Paraneoplastic syndromesareaheterogeneousgroupofmalignantdiseasescausedbyevents SUMMARY Laura Salvá 1 ,Cecilia Agostinis 1 , SofíaMoldes a non-suppressible production of IGF-1, IGF-2, production a non-suppressible Tumor associatedhypoglycemia may becausedby carcinomas. lymphomasandadrenal gastrointestinal, mesenchymal, hepatocellular,hypoglycemia are handling ofcalciumandphosphate(3). andrenal boneresorption to PTHandregulates isthePTHrP,hypercalcemia similar whoseactionsare factor.prognosis inanoncologicalpatientisapoor of hypercalcemia ofpatients withmultiplemyeloma.Detection percent of patientswithcancerandinalmost100 30 percent tooccurinup20 patients andhasbeenreported (2). hyperuricemia and hypocalcemia, osteomalacia,hypercholesterolemia andhypoglycemiaaswell hypercalcemia syndrome, Cushing’s secretion, hormone antidiuretic inappropriate ofthePNS(2). disease leadstotheimprovement ofthe underlying stages. Thesuccessfultreatment 1 1 , Faraj Gabriel , CieloFrisone The tumors that more frequently cause frequently The tumorsthatmore formalignant The mainfactorresponsible is a common complication in cancer Hypercalcemia the The mostcommonendocrinemanifestationsare 1 1 ,

Arch EndocrinolMetab. 2017;61(1):98-102 Arch Metab. Endocrinol 2017;61/1 Arch Metab. Endocrinol 2017;61/1 growth factor binding protein 3 (IGFBP3) were found. 3(IGFBP3)were factor bindingprotein growth (GH),IGF-1andinsulin hormone growth decreased Fasting hypoglycemiawith hypoinsulinemiaand itsetiology (Table todetermine 1). was performed workup filtration rate. Laboratory in the glomerular hypoglycemia persisted in despite of the improvement out.Episodesof ruled of hypoglycemiawere ical causes andpharmacolog insufficiency Adrenal showedasymptomaticfastinghypoglycemia. controls (Graphic1).Dailyglucose calcium levelsdecreased used toavoidunwantedhypocalcaemia(5).Serum function, oral vitamin D supplementation was renal subcutaneous injection. Given thepatient’s impaired with isotonicsalinehydrationand120mgdenosumab wasdiagnosed, andtreated Malignant hypercalcemia function(Table evaluatedaswellhisthyroid were 1). andcalcium tests,hislevelofphosphorus laboratory and hypercalcemia. function worsenedrenal revealed results Laboratory with ipsilateral lower limb lymphedema. left groin oneinthe lymph nodeswithapainlesshard-stone palpable condition. His physical examination revealed with asthenia,dehydrationandageneralbadclinical nephrectomy. toundergo surgery. Thepatientrefused a prescribed ofurology thedepartment therefore neoplasiawassuspectedand renal primary treatment, after chemotherapy studies. Asitdidnotimprove uptakevalue(SUV)5.2,whichwasinstaging Standard 56 X 58 mm in the anterior valve of the right kidney mass of an hypermetabolic which revealed performed response. withpartial vincristine andprednisolone hydrochloride, cyclophosphamide, doxorubicin courses ofchemotherapy consisting of rituximab, six diagnosed inMay2014.Thepatientunderwent and T-cell histiocyte-richlarge B-celllymphoma stage IV (Kidney DiseaseOutcomeQualityInitiative) Kidney Disease (CKD) tobacco smoking, Chronic of A 59-year-old male patient with a medical history CASE REPORT cell lymphoma. tumorandB –inapatientwithrenal hypercalcemia two paraneoplastic manifestations – hypoglycemia and tion (4). prolifera insulin receptors or of insulin,insulinbindingtoamonoclonalprotein ofglucose,tumor cellproduction hypermetabolism During hospitalization, he was performed routine routine During hospitalization,hewasperformed In June2015,hewasadmittedtoourhospital aPET scanwas During hematologycontrols, wedescribethecoexistence of In thiscasereport and mesentericterritory, lymphadenopathyof asmalignanttumor.interpreted Attheretroperitoneal masswere activityoftherenal to thehypermetabolic 1). These characteristics added up dilatation (Figure of thekidney’ssizeanda 20 mm ureteropelvic kidney, atrophy, cortical whichproduced reduction in theright mm solid mass withmicrocalcifications anda53x56 showed moderateleftpleuraleffusion Table 1. tests Laboratory also developed malignant hypercalcemia, whichcould also developedmalignanthypercalcemia, oursuspicion.He confirmed with glucocorticoids after being treated and the patient’s improvement tumor (NICHT), biochemical data mentioned above thediagnosisofnon-islet hypoglycemiccell confirm tromboembolism. duetopulmonary probably the patientpassedawayafterahemodynamicshock InJuly2015, with sodiumheparinwasadministered. andanticoagulationtreatment venous thrombosis the patientdevelopedaleftlowerlimbsubacutedeep (Graphic1).Duringhospitalization, improvement 12 hours was initiated with significant glycemia mg every with dexamethasone 8 treatment disease progression, Duetohematological conglomerate wasobserved. significant size,compatiblewithadenopathic growth factor. GH: growthhormone;IGF-1: insulin-likegrowthfactor1;IGFBP3: bindingproteininsulin-like PTH: parathormone; TSH: thyrotropin; T4: thyroxine;FT4: freethyroxine; T3: triiodothyronine; IGFBP3 IGF-1 GH C Peptide Insulin/glycemia Insulin Glycemia T3 FT4 T4 TSH PTH 25-hydroxyvitamin D Cortisol Albumin Phosphorus Calcium Test A chest,abdomenandpelvistomography(TC) Although we were unable to measure IGF-2to unabletomeasure Although wewere Hypercalcemia andhypoglycemiabyrenal tumor Values 0.031 18.67 14.12 < 25 1.36 2.03 1.21 0.9 2.1 1.8 3.6 3.9 67 53 8 3 8 Reference values 0.9-3.7 mg/mL 70-100 mg/dL 75-240 ng/mL h/18.7 uUI/mL 8.5-10.5 mEq 60-220 ng/dL 0.5-4 uUI/mL 11-67 pg/mL 4.5-12 ug/dL 2.5-4.5 mEq 0.8-4 ng/mL > 30ng/mL 0.6-2 ng/dL 5-25 ug/dL 3.5-5 g/dL h/3 ng/mL < 0.3 99

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 100 protein dataincludingserum Additional laboratory mustbeconsidered. forthehypercalcemia source alsolow,vitamin D intoxication. If theseare another and toassessformalignanthypercalcemia be measured pg/mL), PTH-rPandvitamin Dmetabolitesshould PTH measurement. thenextstep is serum isconfirmed, Once hypercalcemia than90%ofcases. etiologies (6)accountingformore ofthese of malignancygiventhehighestprevalence andhypercalcemia hyperparathyroidism on primary multiple pathologicentitiesbutisfocusedprimarily (6). valueused inalaboratory given reference fora calcium levelabovetheupperlimitofnormal intheserum isdefinedasanincrease Hypercalcemia DISCUSSION size, withureteropelvicdilatationof20mm. right kidneywithmicrocalcifications. Corticalatrophyandadecreaseinits Figure 1. CT, inthe whereasolidformationof53x56mmisobserved dexamethasone administration. Hypoglycemia staysbelowvaluesof60mg/dL, andincreasesafter decreases afterdenosumabwasadministered, withanexcellentresponse. (black stripes). Hypercalcemiabeginswithavalueof14.12mg/dL, and Graph 1. Clinicalcourseofhypercalcemia(blackdots)andhypoglycemia same tumor. the from manifestations of paraneoplastic secretion were mean thatboth,hypoglycemiaandhypercalcemia, Hypercalcemia andhypoglycemiabyrenal tumor 100 120 140 160 180 20 40 60 80 0

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24-Jun 0 2 10 12 14 16 4 6 8 measures canbeimplemented(3). measures taken, andevensimultaneously, pharmacological are ofhypercalcemia of thetreatment measures insipidus (6).Oncethe non-pharmacological diabetes nephrogenic and hypercalcemia-induced mentalstatus, tonausea,vomiting,altered secondary dehydrated by default duetopoor oral intakeare (3),patientswithhypercalcemiareplenishment exclusion ofallcalciumintakeandhydrosaline severity andetiology. include General measures (9). calciumreabsorption (RANKL), andrenal kligand activator of nuclear factor-of the receptor β oftheexpression up-regulation through turnover mimicking the action of PTH by stimulating bone inboneandkidney, expressed PTH/PTHrP receptor with PTHandit can stimulate the same Typeregion common causeassociatedwithcancer(6-9,10). (6-9).HHMisthemost causeofhypercalcemia a rare ofauthentic PTH, lymphomas and4)ectopicsecretion by some D secretion 3) 1,25-dihydroxyvitamin retention andenhancescalcium renal bone resorption ofPTHrP,by systemicsecretion andcausesincreased ofmalignancy(HHM) which iscaused hypercalcemia space,2)humoral malignant cellswithinthemarrow the surrounding in areas osteoclastic bone resorption of themarkedincrease from results hypercalcemia, be classified intofour types: 1)localosteolytic ofcalcitriol(8). mediated bysecretion inlymphomaisprimarily the RCC,hypercalcemia Unlikewhathappensin of patientsmaybeaffected. upto30percent large Bcelllymphomawhere diffuse excepthigh-gradelymphomassuchas 1 to4percent, with non-Hodgkin lymphoma the incidence achieves ofpatients,whileinpatients between 13to20percent affecting the mostcommonparaneoplasticsyndrome rateof2to3months(7). survival than 50% with a mean of CIH, accounting for more cancer,breast andmyelomahavethehighestincidence Lung and most common paraneoplastic syndrome. the Depending onthetypeoftumorCIHrepresents to 30%ofpatientswithcancerduringthediseasecourse. diagnosis(7). the correct (TSH),willoftenleadto hormone thyroid-stimulating for possible multiplemyeloma,and electrophoresis, The optimal treatment for CIH depends on itsThe optimal treatment anhomologyof60%in its terminal PTHrP shares associatedwith cancer can Hypercalcemia CIHis cellcarcinoma, Among patientswithrenal Cancer-induced (CIH)occurs in 5% hypercalcemia Arch Metab. Endocrinol 2017;61/1 which corresponds to70-80%(4-13). which corresponds molecular weightcalled“big IGF2”orprohormone ofhigher form life of 30minutes;c)acomplex binary minutes; b)20-30%isbound toanIGFBPwithahalf- 10 less than1%andhasahalf-lifeofapproximately IGF-2represents it isdistributedasfollows:a)free InNICTH, forms. different andexistsinthree proinsulin (4). inhibiting IGF-1andIGFBP3hepaticproduction (GH), hormone ofgrowth and inhibitsthesecretion which competesforinsulinandIGF-1receptors, insulin-like activitycausedbytheactionofIGF-2, consumption. Thesephenomenapointtoanenhanced peripheral glucose diminished lipolysis, 3) increased inhibition of glycogenolysis and gluconeogenesis2) dueto by: 1)diminishedhepaticglucoseproduction is thought to be a fasting hypoglycemia characterized 1%ofNICHT(4).NICTH tumorrepresents The renal NICTH isfourtimeslesscommonthaninsulinoma. notavailable.Ithasbeen estimated that NICTH are tumor(12). hypoglycemia-producing ofIGF-2ina the firsttodemonstratepresence for thefirsttime(11),andDaughadaycols.were a caseofhypoglycemiaassociatedwithlivercarcinoma pathway (11).In1929,NadlerandWolfer described byaninsulin-independent hypoglycemia determined fasting ofasolidtumorand severe by thepresence NICHT (4). endocrinedeficienciesand, lessfrequently,treatments, todiabetic related The mostcommoncausesare with oralintakeofglucoseorfood(Whipple’sTriad). signs andsymptomsofhypoglycemia,relief mg/dL, inpatientswithoutdiabetes,associatedwith thepatient. from response withafull subcutaneous denosumabwasprescribed contraindicated the useof intravenous bisphosphonates, which functionwasimpaired, hydration andhisrenal to intravenous oncological disease.Ashewasrefractory withlowPTHlevelsconsidering hypercalcemia toPTHrPbyconfirming secondary hypercalcemia our country, thediagnosisofmalignant wereached Din of measuringPTHrPand1,25-dihydroxyvitamin monoclonal antibodies(6-8-10). cinacalcet and calcitonin,glucocorticoids, diuretics, Arch Metab. Endocrinol 2017;61/1 IGF- 2 presents great structural similaritywith structural great IGF- 2presents of Data ontheexactincidenceandprevalence characterized syndrome NICHT consistsofarare Hypoglycemia isdefinedasbloodglucosebelow55 case, due to the impossibility the presented Regarding therapiesinclude:bisphosphonates,loop Drug provide a better treatment strategy. abettertreatment provide studyto further ofclinicalsignificanceanddeserve are they Therefore, cancerandpoorprognosis. aggressive thesignofamore ingeneralrepresent syndromes for.as hypoglycemia,shouldbesearched Paraneoplastic such otherexpressions, manifestation ashypercalcemia, tumors. describedinrenal have notbeenpreviously of patientswithHCC(16,17).However, theseassociations thesurvival reduces remarkably paraneoplastic syndromes of thepresence where in hepatocellularcarcinoma ofthem.Thatsituationisfairlyfrequent or more manifestation, beingunusualthecoexistenceoftwo (15). after thetumorwasremoved levels totheirnormal IGFBP3 andGH,whichreturned lowlevelsofinsulin,IGF1, and cols.showedvery our case,78patientsoftheseriespublishedbyFukuda NICHT, BigIGF-2negative(11),andasin 13were we emphasizethatoutofaseries44patientswith IGF 2. However, serum to determine the resources (14,15). considered isanotherparametertobe toglucocorticoids response than3.Therapid a rationofIGF-2:IGF-1greater IGFBP-3, andhighlevelsofIGF-2orbigIGF-2, triad, lowlevelsofinsulin,C-peptide,GH,IGF-1and 8. 7. 6. 5. 4. 3. 2. 1. REFERENCES was reported. relevant tothisarticle nopotentialconflictofinterest Disclosure:

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