Advanced Systemic Amyloidosis Secondary to Metastatic Renal Cell Carcinoma

Advanced systemic amyloidosis secondary to metastatic renal cell carcinoma

Maria Asunción Algarra1a , Maria José Juan Fita1, Sergio Sandiego1, Héctor Augusto Aguilar1, Pablo Álvarez1, Mateo Quispe1, Antonio Salvador2, Adoración Egido3, Javier Lavernia1, Isidro Machado4, José Rubio-Briones5 and Miguel Ángel Climent1

1Servicio de Oncología Médica, Fundación Instituto Valenciano de Oncología (IVO), Calle Profesor Beltrán Báguena, 8, 46009, Valencia, Spain 2Servicio de Cardiología, Fundación Instituto Valenciano de Oncología (IVO), Calle Profesor Beltrán Báguena, 8, 46009, Valencia, Spain 3Servicio de Medicina Interna, Fundación Instituto Valenciano de Oncología (IVO), Calle Profesor Beltrán Báguena, 8, 46009, Valencia, Spain 4Servicio de Anatomía Patológica, Fundación Instituto Valenciano de Oncología (IVO), Calle Profesor Beltrán Báguena, 8, 46009, Valencia, Spain 5Servicio de Urología, Fundación Instituto Valenciano de Oncología (IVO), Calle Profesor Beltrán Báguena, 8, 46009, Valencia, Spain ahttps://orcid.org/0000-0003-2105-8597

Abstract

Secondary amyloidosis is a rare complex complication related to chronic inflammatory disease. This complication is sparsely associated to malignant neoplasms. Renal cell carcinoma (RCC) is the most common solid organ malignancy related with this paraneoplastic syndrome. Some case reports have described stabilisation or even remission of amyloidosis with cytoreductive nephrectomy. Majority of those reports were based on locally advanced RCC. We report the first case of early aggressive systemic secondary Case Report amyloidosis in high-volume metastatic RCC. The subject was diagnosed with metastatic RCC within 6 months of secondary amyloidosis; on month 5 of initiation of targeted therapy (pazopanib) developed nephrotic syndrome with a heavy proteinuria (>18 g/day), severe hypoalbuminaemia (1.53 g/dL), intense and progressive oedema, severe pancolitis and mild dyspnoea with hypotension. A colon biopsy and the immunohistochemistry confirmed the histological diagnosis of a secondary amyloidosis. The multidisciplinary tumour board decided to perform cytoreductive nephrectomy in order to reduce the pro- inflammatory status. Pathology report showed a complete resection of clear cell RCC plus renal amyloid deposits. The patient died within 4 days of surgery due to multiorgan failure.

Keywords: nephrotic syndrome, renal cell carcinoma, AA amyloidosis, secondary amyloidosis, nephrectomy Correspondence to: M A Climent Email: [email protected] ecancer 2020, 14:1156 https://doi.org/10.3332/ecancer.2020.1156 Introduction Published: 15/12/2020 Received: 11/06/2020

Secondary amyloidosis, also called AA amyloidosis, is a rare complex complication related Publication costs for this article were supported by ecancer (UK Charity number 1176307). to chronic inflammatory disease. This complication is sparsely associated to malignant neoplasms. Renal cell carcinoma (RCC) is the most common solid organ malignancy Copyright: © the authors; licensee related with this paraneoplastic syndrome. ecancermedicalscience. This is an Open Access article distributed under the terms of the Untreated AA amyloidosis has a significant morbidity and mortality specifically due to Creative Commons Attribution License (http:// creativecommons.org/licenses/by/3.0), which end-stage renal disease. A successful treatment of the underlying inflammatory disease, permits unrestricted use, distribution, and including complete removal of the primary tumour has demonstrated stabilisation or reproduction in any medium, provided the original even remission of amyloidosis. work is properly cited.

ecancer 2020, 14:1156; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2020.1156 1 deposits (inalmostalltheglomerulus,around blood vessels andtheperinephriticfat) (Figures 1e,3candd). RCC sarcomatoidwith features was confirmed. The immunohistochemistry study for amyloid AA showed strong anddiffuseamyloid AA additional treatment. The patient was deceased within 4days of surgery dueto multiorgan failure (Figure 2a dynamic shock,oligoanuria andacute kidney injury that didnot respond to pharmacological treatment intheintensive care unit,precluding any right nephrectomy was performed without major intraoperative complications. During postoperative recovery, thepatient developed haemo- Our multidisciplinary tumour board decided to perform cytoreductive nephrectomy inorder to reduce thepro-inflammatory status. A palliative ventricles andright atrium andlow cardiac output:left ventricular ejection fraction (LVEF) <50%(range 50%–70%)(Figure 1d ). Echocardiogram revealed advanced cardiac amyloidosis pattern, anincreasewith inthethicknessof theinterventricular septum, walls of the stain (Figure 3a The colon biopsy and the immunohistochemistry confirmedthe histological diagnosisof a secondary amyloidosis (AA subtype): Congo red ened (Figure 2b and furosemide was started while awaiting biopsy results. An improvement in diarrhoea (Grade 1) was observed, the but proteinuria wors- At worsening of hiscondition(proteinuria (18,174 mg/day) anddiarrhoea(Grade 3))treatment with corticosteroids (1mg/kg/day), albumin rocyte sedimentation rate (ESR)90). detected asevere pancolitis. Autoimmunetests were negative (ANA, ANCA, IgA andIgGnegative antiendomisio andproteinogram; eryth- pericardial effusion andincrease intargetmetastasislung size (6cm). Also, lower gastrointestinal endoscopy was performed (Figure 1c Further work-upcontrast-enhancedperformedwas with whole-bodyCTscan paraneoplastic amyloidosis isprovided. We report thefirst patient earlywith aggressive systemicsecondary amyloidosis inhigh-volume metastatic RCC. A literature review on ecancer 2020, 14:1156; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1156 such asCrohn’s diseaseandulcerative colitis. However, malignant neoplasmsare rarely reported to beassociated with AA amyloidosis [1–4]. inflammatory diseasessuch as inflammatory arthritis,sarcoidosis, familial Mediterranean fever, chronic infections, inflammatory bowel disease AA amyloidosis isthe worst potential complication of any chronic inflammatory condition. The mostcommon underlyingcausesare chronic Discussion m teinuria:7,610 mg/day (range 0–80mg/day), preservedwith renal function:estimated glomerular filtration rate (eGFR) >90ml/minute/1.73 nephroticsyndrome non-infectiouswith diarrhoea was obtained(hypoalbuminaemia: 1.53g/dL (range 3.4–5.4g/dL),a severe 24-hour pro- he developed a decay on his performance status, grade 2 diarrhoea(up to seven stools per day) and whole-body oedema. A diagnosis of lung metastasis. A second-line therapy was ordered checkpointwith immune inhibitor (nivolumab). Before thepatient could start nivolumab, ation Criteria In Solid Tumors (RECIST)1.1 criteria of thetarget lungmetastasis). Further follow-up showed adiseaseprogression of several Atfirst assessment, disease a stable was observed (stabilisationof theright renal anincrease massbut of lessthan20%by Response Evalu- started inanoutsidehospital. 8.8 mg/dLCalcium: mal (range 8.5–10.2mg/dL)and Karnofsky Index: 80%(range 80%–100%). Treatment with Pazopanib 800mg/day was g/dL), thrombocytosis: 641,000/µL (range normal 150,000–400,000/µL), lactate dehydrogenase 244 U/L(LDH): (range 140–280 U/L), nor At systemictreatment, initiation parameters show apoor riskprognosis metastatic RCC asper Heng criteria grade 3anaemia:6.4g/dL (>12 cm onright inferior lobe). A lungbiopsy confirmed clear RCC metastasis. vic CT scan was performed with diagnosis of right renal mass (14 cm), renal vein thrombosis and synchronic pulmonary metastasis (largest 2 cal History was relevant for lactose intolerance. Family History showed asecond degree relative gastriccancer.with A thoraco-abdominopel- A healthy 48-year-oldman presented Caucasian to Emergency Room with asthenia,anorexia and weight lossover last6months. Past Medi- Case report 2 (range 90–130ml/minute/1.73 m ) andapplegreen birefringence under polarisedlight were positive (Figure 3b ). 2 ), analteration of Quick haemostasis: index 75%(range 80%–120%)andanegative stool culture). (Figure 1a–b) which revealed bilateral pleural effusion and ). ). ). It 2 -

Case Report ecancer 2020, 14:1156; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1156 possibilities canbeinvolved [10]. produce SAA. Pro-inflammatory cytokines canalsobeproduced by anti-tumour lymphocytes or macrophages. A combination of thesethree can leadto amyloidosis. Malignant cells candirectly produce SAA [8],or secrete pro-inflammatory cytokines [9] which signaltheliver to a half-lifewith of <24hours [6,7]. There are several bymechanisms possible which highlevels of SAA inpatients with malignant neoplasms an inflammatoryhigh levels stimulus, of SAAremain can persistently elevated. But, once ends,there thestimulus isadeclineof circulating SAAreactantacute-phase is a dynamic protein andcirculatinglevels canincrease from abaselineof <3mg/L to ashigh2,000mg/L.During loid proteins are derived from fragments of theSAA. IL-6 canresultwhich in increased circulating SAA [5].Systemic AA amyloidosis involves thedepositof amyloid protein intissues. These amy- from several pro-inflammatory cytokinesas IL-6, such IL-1 and TNF-a. Renal cell tumours are known to produce highlevels of tumour-derived AA amyloidosisoccurs inpatients high levelswith ofamyloid serum A protein (SAA), which isproduced by liver cells inresponse to signals 25%–42% of reported cases.But, conversely, amyloid depositsare only seen in2.1%–3.2%of patients who died with aRCC [3,4]. Largetissues. autopsy seriessuggeststhat RCC isclearlymost common the solidorgan malignancy to cause AA amyloidosis, representing progression ofthat malignancies deaththe causes of majority the of patients before significant systemic depositionof amyloid proteins in Malignantareneoplasms inflammatoryunderlying the driver in<7%of AA amyloidosis [3,4].One reason for thelow incidence istherapid removed piece from nephrectomy showing renal tumour. Echocardiography showing cardiac amyloidosis pattern. Increase inthethickness of theinterventricular septum and walls of the ventricles. (e): Surgically pericardial effusion withanincrease inthesize of thelungmetastasis (6cm). (c): Lower gastrointestinal endoscopy demonstrating a severe pancolitis. (d): Figure 1.(a) and(b): Contrast-enhanced whole-body CT scanrevealing stabilisation of theright renal mass,new bilateral pleural effusion and new a d b e c 3

Case Report ecancer 2020, 14:1156; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1156 around blood vessels. (d): Congo red stainshowed red depositioninalmostalltheglomerulus andaround blood vessels. polarisation microscopy. (c): Immunohistochemistry study for amyloid AA showing strong anddiffuse amyloid AA depositsinalmostalltheglomerulusand Figure 3.(a): Congo red stainof colon mucosa showing periglandular amyloid deposits.(b): Green birefringence of colon mucosa was observed by Figure 2.(a) and(b): First graph shows thetimeline of thecase. The second graph shows theprogression of proteinuria over time. a c d b 4

Case Report other locations persisted. ecancer 2020, 14:1156; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1156 tumour removal onabaselineadvanced systemic amyloidosis isapoor prognosis factor. achieved. Previousreports wererenal inlocalised tumours metastaticwithout burden. Itseems to suggest that notachieving acomplete Sparse reportedtoup cases date suggestthat nephrectomy prevent can further amyloid depositsand,insomecases,regression might be problem.serious Rigoroustreatment of is necessarycause underlying the to decrease theinflammatory status, maindriver of thecondition. AA amyloidosis is a serious and rare complication describedin malignancies. RCC is the most common solid organ malignancy to cause this Conclusion rentscenario predicted afatal fate asper several organ amyloidosis. Besides Unfortunately, inour patient,surgerydebulking didnotachieve stabilisation or regression of thesystemic AA amyloidosis. Probably, our cur trials traindicated thestandard second-line treatment Nivolumabwith or Cabozantinib basedondata from Checkmate 025andMeteor clinical proteinuria,the complexity thus of diagnosisasthere was noproteinuria control while receiving it.Due to thesevere proteinuria that con- in our patient was dueto his treatment Pazopanibwith duringtheprevious 5months. A common side-effect of tyrosine-kinase inhibitors is The relevance ofcurrent the report presenceis basedonthe of high-volume metastatic RCC. The complexity indiagnosingthissyndrome primary tumour [17–21]. oftion amyloidEitherdeposits. or partial complete remissionof amyloidosis was achieved inthemajority of thecasesafter removal of the tumourincluding surgicalresection lead to can stabilisation the or improvement inrenal proteinuria function, reduction andpartialresolu- baseline end-stagealbuminaemia, renal failure andelevated SAA duringfollow-up of374 cases AA amyloidosis,survivalthe mean from time diagnosis to death was 133months. Poor prognostic factors were: elderly, hypo- Untreated, AA amyloidosis isasevere disease a highmorbiditywith andmortality dueto end-stage renal disease [1,15,16].In areview of occurred inlocalisedrenal tumours [13]. resected 8 years ahead[10].Besides thosetwo casereports, allthereported casesof theco-existence of amyloidosis andRCC to date have of apatient who developeda systemic AA amyloidosistodue asolitary lungmetastasis from RCC, theprimary but cancer was completely case reporton RCC metastasismuscle with andsecondary amyloidosis hasbeenreported in Japanese language [14]. Another casereported We report thefirst English-language caseof systemic AA amyloidosis dueto metastatic RCC with high-volume metastatic disease. A single upper respiratory tract. Four casesof retroperitoneal amyloid have deposits alsobeenreported. of type AA. Amyloid deposits were found to occur in various at tissues extracellular sites: kidney, liver, spleen,adrenals andmucosa of the was of type AL (amyloid light-chain amyloidosis),patientsthese but hadaconcomitant myeloma and,intheother patients, theamyloid was A review of 20reported casesof theco-existence of amyloidosis andlocalisedRCC [12].In hasbeenpublished two cases,theamyloidosis examination usingpolarisingmicroscopy hasanoverall sensitivity of 57%to 85%andaspecificity of 92%to 100%for secondary amyloidosis. uninvolvedfat, sites,as subcutaneous such minor salivary glandsor rectal mucosa; or from dysfunctional organs. Congo red stainingand and clinicalmanifestations, even thoughitis not always afirst option in differential diagnosis. Biopsies canbe obtained from either clinically The definitive method for diagnosisof amyloidosisbiopsy, istissue althoughthepresence of amyloidosis may besuggested by thehistory that canleadto diastolic dysfunction, peripheral and autonomic neuropathy andimpaired coagulation [11]. or clinically apparentnephrotic syndrome. Othermanifestations typical are hepatomegaly with or splenomegaly,without cardiac involvement Commonsites of involvementin secondary amyloidosisare kidneys. the Renal involvement mostoften presents asasymptomatic proteinuria of theseother factors isnot entirely clear. that there may be other factors involved such as extracellular matrix components, macrophage factors and SAA isotype. However, the role Maintained highcirculating levels of SAA are arequisite for thedevelopment of AA amyloidosisare but clearly not sufficient. It isbelieved [22, 23], a palliative cytoreductive nephrectomy was performed to rapidly decrease tumour burden andsystemic inflammatory status. , nephrectomy was ableto decrease tumour burden butseveral [1, 16].Effective treatment of theinflammatory cause, 5 -

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ecancer 2020, 14:1156; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1156 References The authors did not receive any fundingfor this work. Funding statement Verbal informed consent was obtained from thepatientin thecasereport included admission duringhospital Informed consent The authors declare that they have noconflict of interest. Conflicts of interest Compliance with ethical standards nuclear antibody; ANCA, Anti-neutrophil cytoplasmic antibody; IgA, Immunoglobulin A; IgG, Immunoglobulin G. SAA, Serumamyloid A protein;RCC, Renal cell carcinoma;IL-1, Interleukin 1;IL-6, Interleukin 6; TNF-a, Tumour necrosis factor-a; ANA, Anti- List of abbreviations 9. 8. 7. 6. 5. 4. 3. 2. 1. 197–200 https://doi.org/10.3109/13506129.2012.71292622928906 PMID: NobataSugaH, and ItohN, A (2012)Systemyc AA amyloidosis in a patient with lung metastasis from renal cell carcinoma tures Lung Cancer 63425–429https://doi.org/10.1016/j.lungcan.2008.07.018 Suzuki M,Shinagawa N, and Oizumi S(2009) 20713982 PMCID: ain o a oe n vra tumorigenesis ovarian in role a for cation impli- Urieli-Shovaltumors: S,Finci-Yeheskelepithelial ovarian human in a amyloid serum of Z,andDishon S, et (2010)Expression al cies andevidence of afourth SAA gene product Westermark GT, Sletten K,andGrubb A (1990) blood monocytesJExpMed 4181020–1031https://doi.org/10.1084/jem.148.4.1020 Lavie G,Zucker-Franklin D, andFranklin EC (1978)Degradationof serum Lett carcinomas cell renal in factorgrowth autocrine vitro in MikiIwano S, and Miki M, an as Y(IL-6) (1989)Interleukin-6functions Azzopardi andLehnerJG T (1966)Systemicamyloidosis malignantand disease Scand A89(6)411–416PMID: Dictorand Hasserius M (1981) Systemic R amyloidosisand non-hematologic malignancy in a large autopsy series jcp.19.6.539 https://doi.org/10.1016/0002-9343(82)90747-1 type AA the of carcinoma cell renal with PrasFranklin M, associated EC, andShibolet(1982) AmyloidosisS 2361–2371 https://doi.org/10.1056/NEJMoa070265 Lachmann HJ,Lachmann Goodman HJ, andGilbertson JA (2017)Natural history andoutcome insystemic AA amyloidosis 250 607–610https://doi.org/10.1016/0014-5793(89)80805-1 PMID: PMID: 2958134 5953729 PMCID: 6278822 473378

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Case Report