View source for Papillary renal cell carcinoma

{{Infobox medical condition
| name          = Papillary renal cell carcinoma
| alt           = Gross appearance of Papillary renal cell carcinoma
| caption       = Papillary renal cell carcinoma, type 1, characterised by tubulopapillary architecture with admixed foamy histiocytes in the papillary cores.
| treatment     = Nephrectomy, partial nephretocmy, targeted molecular therapy
| symptoms      = Hematuria, flank pain, palpable abdominal mass
| specialty     = Oncology
| image         = Histopathology of papillary renal cell carcinoma type 1.jpg
| diagnosis     = Medical Image Test (ultrasound, computed tomography, magnetic resonance imaging)
| prognosis     = 82-90% for five-year survival rate
}}

'''Papillary renal cell carcinoma''' (PRCC) is a malignant, heterogeneous tumor originating from renal tubular epithelial cells of the kidney, which comprises approximately 10-15% of all [[kidney neoplasm]]s.<ref>{{cite journal | vauthors = Cairns P | title = Renal cell carcinoma | journal = Cancer Biomarkers | volume = 9 | issue = 1–6 | pages = 461–73 | date = 2011 | pmid = 22112490 | pmc = 3308682 | doi = 10.3233/CBM-2011-0176 }}</ref> Based on its morphological features, PRCC can be classified into two main subtypes, which are type 1 ([[basophilic]]) and type 2 ([[eosinophilic]]).<ref>{{Cite journal| vauthors = Lee J, Chae HK, Lee W, Nam W, Lim B, Choi SY, Kyung YS, You D, Jeong IG, Song C, Hong B | display-authors = 6 |date=2018-12-28|title=Comparison of Prognosis in Types 1 and 2 Papillary Renal Cell Carcinoma and Clear Cell Renal Cell Carcinoma in T1 Stage |journal=The Korean Journal of Urological Oncology |volume=16|issue=3|pages=119–125|doi=10.22465/kjuo.2018.16.3.119 |doi-access=free }}</ref>

As with other types of renal cell cancer, most cases of PRCC are discovered incidentally without showing specific signs or symptoms of cancer.<ref name=":13">{{Cite book|url=https://books.google.com/books?id=2oeADwAAQBAJ&pg=RA1-PA325|title=Encyclopedia of Cancer|date=2018-10-12|publisher=Academic Press|isbn=978-0-12-812485-7|language=en}}</ref> In advanced stages, [[hematuria]], [[flank pain]], and [[abdominal mass]] are the three classic manifestation.<ref name=":11">{{cite journal | vauthors = Courthod G, Tucci M, Di Maio M, Scagliotti GV | title = Papillary renal cell carcinoma: A review of the current therapeutic landscape | journal = Critical Reviews in Oncology/Hematology | volume = 96 | issue = 1 | pages = 100–12 | date = October 2015 | pmid = 26052049 | doi = 10.1016/j.critrevonc.2015.05.008 | hdl = 2318/1564896 | hdl-access = free }}</ref> While a complete list of the causes of PRCC remains unclear, several risk factors were identified to affect PRCC development, such as genetic mutations, kidney-related disease, environmental and lifestyle risk factors.<ref name=":10" /> For pathogenesis, type 1 PRCC is mainly caused by MET gene mutation while type 2 PRCC is associated with several different genetic pathways.<ref name=":12" /> For diagnosis, PRCC is detectable through [[CT scan|computed tomography (CT)]] scans or [[magnetic resonance imaging|magnetic resonance imaging (MRI)]], which commonly present a small homogeneous hyposvascular tumor.<ref name=":20">{{cite journal | vauthors = Couvidat C, Eiss D, Verkarre V, Merran S, Corréas JM, Méjean A, Hélénon O | title = Renal papillary carcinoma: CT and MRI features | journal = Diagnostic and Interventional Imaging | volume = 95 | issue = 11 | pages = 1055–63 | date = November 2014 | pmid = 25443332 | doi = 10.1016/j.diii.2014.03.013 | doi-access = free }}</ref> [[Nephrectomy]] or [[Nephrectomy|partial nephrectomy]] is usually recommended for PRCC treatment, often accompanied with several targeted molecular therapies to inhibit metastatic spread.<ref name=":6">{{cite journal | vauthors = Vikram R, Ng CS, Tamboli P, Tannir NM, Jonasch E, Matin SF, Wood CG, Sandler CM | display-authors = 6 | title = Papillary renal cell carcinoma: radiologic-pathologic correlation and spectrum of disease | journal = Radiographics | volume = 29 | issue = 3 | pages = 741–54; discussion 755–7 | date = 2009-05-01 | pmid = 19448113 | doi = 10.1148/rg.293085190 }}</ref><ref name="Bourlon_2015" /> PRCC patients are predominantly male with a mean age of 52–66 years.<ref name=":15">{{Cite book | author = International Agency for Research on Cancer |url=https://books.google.com/books?id=Ln1EyB2u2hYC|title=Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs|date=2004|publisher=IARC|isbn=978-92-832-2415-0|language=en}}</ref> When compared to conventional [[Clear cell papillary renal cell carcinoma|clear cell renal cell carcinoma]] (RCC), the prognosis of non-metastatic PRCC is more favorable, whereas a relatively worse outcome was reported in patients with [[Metastasis|metastatic disease]].<ref>{{cite journal | vauthors = Klatte T, Gallagher KM, Afferi L, Volpe A, Kroeger N, Ribback S, McNeill A, Riddick AC, Armitage JN, 'Aho TF, Eisen T, Fife K, Bex A, Pantuck AJ, Stewart GD | display-authors = 6 | title = The VENUSS prognostic model to predict disease recurrence following surgery for non-metastatic papillary renal cell carcinoma: development and evaluation using the ASSURE prospective clinical trial cohort | journal = BMC Medicine | volume = 17 | issue = 1 | pages = 182 | date = October 2019 | pmid = 31578141 | pmc = 6775651 | doi = 10.1186/s12916-019-1419-1 | doi-access = free }}</ref> Globally, the incidence of PRCC ranges between 3,500 and 5,000 cases, while it greatly varies depending on gender, age, and race/ethnicity.<ref name=":22">{{cite journal | vauthors = Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ | display-authors = 6 | title = Cancer statistics, 2005 | journal = CA: A Cancer Journal for Clinicians | volume = 55 | issue = 1 | pages = 10–30 | date = 2005 | pmid = 15661684 | doi = 10.3322/canjclin.55.1.10
 | s2cid = 22356919 | doi-access = free }}</ref>

== Classification ==
In 2014, PRCC was first acknowledged as a renal tumor subtype by the World Health Organization (WHO) considering its distinct genetic, molecular and histologic characteristics.<ref name=":15" /> It is further divided into type 1 and type 2 based on morphological features.<ref>{{Cite book|last1=Weidner|first1=Noel |last2=Cote|first2=Richard J.|last3=Suster|first3=Saul|last4=Weiss|first4=Lawrence M. | name-list-style = vanc |url=https://books.google.com/books?id=s857Bj3NKEkC&pg=PA1056 |title=Modern Surgical Pathology E-Book|date=2009-07-08|publisher=Elsevier Health Sciences|isbn=978-1-4377-1958-1|language=en}}</ref>

=== Type 1 Papillary Renal Cell Carcinoma ===
Type 1 PRCC, also known as a renal tumor caused by a genetic predisposition of hereditary papillary renal cancer syndrome, compromises approximately 25% of all PRCCs.<ref name=":1">{{cite journal | vauthors = Haas NB, Nathanson KL | title = Hereditary kidney cancer syndromes | journal = Advances in Chronic Kidney Disease | volume = 21 | issue = 1 | pages = 81–90 | date = January 2014 | pmid = 24359990 | pmc = 3872053 | doi = 10.1053/j.ackd.2013.10.001 }}</ref><ref name=":2">{{Cite web|url=http://www.pathologyoutlines.com/topic/kidneytumormalignantrccpap.html|title=Papillary renal cell carcinoma (PRCC)|website=www.pathologyoutlines.com|access-date=2020-04-08}}</ref> In the perspective of immunochemistry, it has a profile of strong [[CK7]] and [[Alpha-methylacyl-CoA racemase|alpha-methyl acyl-CoA racemase]] (AMACR) expression at most focal CA-IX expression.<ref name=":3">{{cite journal | vauthors = Warren AY, Harrison D | title = WHO/ISUP classification, grading and pathological staging of renal cell carcinoma: standards and controversies | journal = World Journal of Urology | volume = 36 | issue = 12 | pages = 1913–1926 | date = December 2018 | pmid = 30123932 | pmc = 6280811 | doi = 10.1007/s00345-018-2447-8 }}</ref> Histologically, its [[epithelium]] is composed of relatively small-sized simple cuboidal cells lined in a single layer.<ref>{{cite journal | vauthors = Chevarie-Davis M, Riazalhosseini Y, Arseneault M, Aprikian A, Kassouf W, Tanguay S, Latour M, Brimo F | display-authors = 6 | title = The morphologic and immunohistochemical spectrum of papillary renal cell carcinoma: study including 132 cases with pure type 1 and type 2 morphology as well as tumors with overlapping features | journal = The American Journal of Surgical Pathology | volume = 38 | issue = 7 | pages = 887–94 | date = July 2014 | pmid = 24919183 | doi = 10.1097/PAS.0000000000000247 | s2cid = 1998988 | url = https://www.researchgate.net/publication/263014310 }}</ref> These cells are well-characterized by basophilic cytoplasm.<ref name=":4">{{Cite book|last1=Bukowski|first1=Ronald M. |last2=Novick|first2=Andrew | name-list-style = vanc |url=https://books.google.com/books?id=zU8R2zpNGfcC&pg=PA131 |title=Clinical Management of Renal Tumors|date=2009-12-03|publisher=Springer Science & Business Media|isbn=978-1-60327-149-3|language=en}}</ref> Due to its solid growth, an extremely compact papillary architecture is often observed.<ref name=":3" /> Other morphological characteristics include [[Hemosiderin|intracellular hemosiderin]] and foamy macrophages placed inside of papillary fibrovascular cores or [[Psammoma body|psammoma bodies.]]<ref>{{Cite web|url=https://www.cap.org/member-resources/case-of-the-month/right-kidney|title=Right Kidney|website=College of American Pathologists|language=en-us|access-date=2020-04-19}}</ref> In general, the nuclei of type 1 PRCC belong to grade 1-2 of the Fuhrman system.<ref name=":3" />
<gallery mode=packed heights=190>
File:Histopathology of papillary renal cell carcinoma type 1, high magnification.jpg|A micrograph of type 1 PRCC, illustrating features of small basophilic cells with scarce cytoplasm. A single layer of cells are surrounding the basal membrane.<ref name=":16">{{cite journal | vauthors = Muglia VF, Prando A | title = Renal cell carcinoma: histological classification and correlation with imaging findings | journal = Radiologia Brasileira | volume = 48 | issue = 3 | pages = 166–74 | date = 2014-04-10 | pmid = 26185343 | doi = 10.1590/0100-3984.2013.1927 | pmc = 4492569 | doi-access = free }}</ref> Foamy macrophages are inside of papillary fibrovascular cores.
File:Histopathology of papillary renal cell carcinoma type 1, grade 2, with variable density.jpg|Type 1 PRCC, this case being more compact at right.
</gallery>

=== Type 2 Papillary renal cell carcinoma ===
[[File:Type 2 Papillary Renal Cell Carcinoma.jpg|thumb|A micrograph of Type 2 PRCC, showing cells containing abundant eosinophilic granular cytoplasm with prominent nucleoli.<ref name=":16" />]]
Accounting for 25% of PRCCs, type 2 PRCC is the pathological subtype that is most commonly associated with [[hereditary leiomyomatosis and renal cell carcinoma]] (HLRCC) syndrome.<ref name=":1" /><ref name=":2" /> When compared to type 1, it shows more variation in protein expression mostly by loss of CK7.<ref name=":3" /> In a gross examination, it shows papillae covered by large cells abundant in eosinophilic cytoplasm.<ref name=":4" /> Its large spherical nuclei on papillary cores are arranged in a pseudo-stratified manner.<ref name=":3" /> Unlike type 1 PRCC, foamy macrophages and psammoma bodies are less common in case of type 2.<ref name=":2" /> The majority of type 2 PRCC has high Fuhrman grade nuclei with prominent nucleoli.<ref name=":3" />

== Signs and Symptoms ==

Due to its asymptomatic nature, PRCC is often undetectable, and the majority of cases are incidentally diagnosed during the radiological workup of unrelated diseases.<ref name=":13" /><ref name=":6" /> Its clinical manifestations are similar to those of [[Clear cell papillary renal cell carcinoma|clear cell RCC]], which are the classical triad of renal cell carcinoma ([[hematuria]], [[flank pain]] and palpable [[abdominal mass]]; only 6-10% of patients) or even nonspecific symptoms including [[fatigue]], [[weight loss]], [[fever]], and [[Anorexia (symptom)|anorexia]].<ref name=":11" /><ref name=":15" /><ref name=":0">{{Cite web|url=https://www.ebi.ac.uk/ols/ontologies/efo/terms?short_form=EFO_0000640|title=papillary renal cell carcinoma|website=www.ebi.ac.uk|access-date=2020-04-08}}</ref> Since early diagnosis is relatively uncommon, PRCC patients may experience symptoms caused by the metastatic spread to secondary sites. Specifically, [[metastasis]] occurs most frequently in the lungs followed by bone and the brain, exhibiting a wide range of symptoms including [[bone pain]] to a [[Cough|persistent cough]].<ref name=":6" /><ref name=":0" />

== Causes ==
Currently, the exact cause of PRCC remains unclear. Possible risk factors have been identified that contribute to PRCC development, which include genetic mutations, hereditary syndrome, renal injuries, and lifestyle factors. [[Germline mutation]] of [[C-Met|c-MET]] oncogene and fumarate hydratase gene elevates the risk of type 1 and type 2 PRCC respectively through distinct signaling pathways.<ref>{{Cite web|url=https://www.cancer.org/cancer/kidney-cancer/causes-risks-prevention/what-causes.html|title=What Causes Kidney Cancer?|website=www.cancer.org|language=en|access-date=2020-04-08}}</ref><ref name="Comprehensive Molecular Characteriz">{{cite journal | vauthors = Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, Davis C, Wheeler DA, Murray BA, Schmidt L, Vocke CD, Peto M, Al Mamun AA, Shinbrot E, Sethi A, Brooks S, Rathmell WK, Brooks AN, Hoadley KA, Robertson AG, Brooks D, Bowlby R, Sadeghi S, Shen H, Weisenberger DJ, Bootwalla M, Baylin SB, Laird PW, Cherniack AD, Saksena G, Haake S, Li J, Liang H, Lu Y, Mills GB, Akbani R, Leiserson MD, Raphael BJ, Anur P, Bottaro D, Albiges L, Barnabas N, Choueiri TK, Czerniak B, Godwin AK, Hakimi AA, Ho TH, Hsieh J, Ittmann M, Kim WY, Krishnan B, Merino MJ, Mills Shaw KR, Reuter VE, Reznik E, Shelley CS, Shuch B, Signoretti S, Srinivasan R, Tamboli P, Thomas G, Tickoo S, Burnett K, Crain D, Gardner J, Lau K, Mallery D, Morris S, Paulauskis JD, Penny RJ, Shelton C, Shelton WT, Sherman M, Thompson E, Yena P, Avedon MT, Bowen J, Gastier-Foster JM, Gerken M, Leraas KM, Lichtenberg TM, Ramirez NC, Santos T, Wise L, Zmuda E, Demchok JA, Felau I, Hutter CM, Sheth M, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Zhang J, Ayala B, Baboud J, Chudamani S, Liu J, Lolla L, Naresh R, Pihl T, Sun Q, Wan Y, Wu Y, Ally A, Balasundaram M, Balu S, Beroukhim R, Bodenheimer T, Buhay C, Butterfield YS, Carlsen R, Carter SL, Chao H, Chuah E, Clarke A, Covington KR, Dahdouli M, Dewal N, Dhalla N, Doddapaneni HV, Drummond JA, Gabriel SB, Gibbs RA, Guin R, Hale W, Hawes A, Hayes DN, Holt RA, Hoyle AP, Jefferys SR, Jones SJ, Jones CD, Kalra D, Kovar C, Lewis L, Li J, Ma Y, Marra MA, Mayo M, Meng S, Meyerson M, Mieczkowski PA, Moore RA, Morton D, Mose LE, Mungall AJ, Muzny D, Parker JS, Perou CM, Roach J, Schein JE, Schumacher SE, Shi Y, Simons JV, Sipahimalani P, Skelly T, Soloway MG, Sougnez C, Tam A, Tan D, Thiessen N, Veluvolu U, Wang M, Wilkerson MD, Wong T, Wu J, Xi L, Zhou J, Bedford J, Chen F, Fu Y, Gerstein M, Haussler D, Kasaian K, Lai P, Ling S, Radenbaugh A, Van Den Berg D, Weinstein JN, Zhu J, Albert M, Alexopoulou I, Andersen JJ, Auman JT, Bartlett J, Bastacky S, Bergsten J, Blute ML, Boice L, Bollag RJ, Boyd J, Castle E, Chen YB, Cheville JC, Curley E, Davies B, DeVolk A, Dhir R, Dike L, Eckman J, Engel J, Harr J, Hrebinko R, Huang M, Huelsenbeck-Dill L, Iacocca M, Jacobs B, Lobis M, Maranchie JK, McMeekin S, Myers J, Nelson J, Parfitt J, Parwani A, Petrelli N, Rabeno B, Roy S, Salner AL, Slaton J, Stanton M, Thompson RH, Thorne L, Tucker K, Weinberger PM, Winemiller C, Zach LA, Zuna R | display-authors = 6 | title = Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma | journal = The New England Journal of Medicine | volume = 374 | issue = 2 | pages = 135–45 | date = January 2016 | pmid = 26536169 | pmc = 4775252 | doi = 10.1056/NEJMoa1505917 }}</ref> Regarding hereditary conditions, patients with hereditary papillary renal cancer syndrome showed a greater risk of type 1 PRCC, whereas those with [[Hereditary leiomyomatosis and renal cell cancer syndrome|hereditary leiomyomatosis and renal cell cancer]] (HLRCC) syndrome have an increased risk of type 2 PRCC.<ref>{{Cite web|url=https://www.cancer.net/cancer-types/hereditary-papillary-renal-carcinoma|title=Hereditary Papillary Renal Carcinoma|date=2012-06-25|website=Cancer.Net|language=en|access-date=2020-04-08}}</ref><ref name=":10">{{Cite web|url=https://www.cancer.org/cancer/kidney-cancer/causes-risks-prevention/risk-factors.html|title=Risk Factors for Kidney Cancer|website=www.cancer.org|language=en|access-date=2020-04-08}}</ref> Moreover, patients who experienced chronic kidney diseases or acute kidney injury exhibited a higher incidence of PRCC.<ref>{{cite journal | vauthors = van de Pol JA, van den Brandt PA, Schouten LJ | title = Kidney stones and the risk of renal cell carcinoma and upper tract urothelial carcinoma: the Netherlands Cohort Study | journal = British Journal of Cancer | volume = 120 | issue = 3 | pages = 368–374 | date = February 2019 | pmid = 30563989 | pmc = 6353869 | doi = 10.1038/s41416-018-0356-7 }}</ref><ref>{{cite journal | vauthors = Peired AJ, Antonelli G, Angelotti ML, Allinovi M, Guzzi F, Sisti A, Semeraro R, Conte C, Mazzinghi B, Nardi S, Melica ME, De Chiara L, Lazzeri E, Lasagni L, Lottini T, Landini S, Giglio S, Mari A, Di Maida F, Antonelli A, Porpiglia F, Schiavina R, Ficarra V, Facchiano D, Gacci M, Serni S, Carini M, Netto GJ, Roperto RM, Magi A, Christiansen CF, Rotondi M, Liapis H, Anders HJ, Minervini A, Raspollini MR, Romagnani P | display-authors = 6 | title = Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells | journal = Science Translational Medicine | volume = 12 | issue = 536 | date = March 2020 | pages = eaaw6003 | pmid = 32213630 | doi = 10.1126/scitranslmed.aaw6003 | s2cid = 214671587 | url = https://www.science.org/doi/10.1126/scitranslmed.aaw6003 }}</ref> Additionally, other risk factors such as smoking, obesity, and high blood pressure can influence the pathogenesis of PRCC.<ref name=":10" />

== Pathogenesis ==
[[File:MET-pathway.jpg|thumb|An overview of the MET molecular pathway in PRCC<ref name=":12" />|301x301px]]
Different molecular mechanisms are involved in PRCC development, which further result in distinct histologic features and clinical outcomes.{{citation needed|date=April 2021}}

Type 1 PRCC is caused by a genetic mutation or a gain in chromosome 7 where the MET gene is positioned, resulting in the promotion of oncogenic pathways in renal epithelial cells.<ref name=":12">{{cite journal | vauthors = Rhoades Smith KE, Bilen MA | title = A Review of Papillary Renal Cell Carcinoma and MET Inhibitors | journal = Kidney Cancer | volume = 3 | issue = 3 | pages = 151–161 | date = November 2019 | pmid = 31867475 | pmc = 6918905 | doi = 10.3233/KCA-190058 }}</ref> Typically, the MET gene is upregulated for renal tissue repair and regeneration by encoding the receptor tyrosine kinase c-MET of [[hepatocyte growth factor]].<ref name=":12" /> However, activation of the oncogenic pathway in the MET gene will manifest invasion, anti-apoptosis, angiogenesis, and metastasis.<ref name=":12" />

Type 2 PRCC is associated with irregularity of several signaling pathways, which includes [[CDKN2A]] silencing, mutation in chromatin-modifying genes, and a GpG island methylator phenotype (CIMP).<ref name=":21">{{cite journal | vauthors = Malouf GG, Joseph RW, Shah AY, Tannir NM | title = Non-clear cell renal cell carcinomas: biological insights and therapeutic challenges and opportunities | journal = Clinical Advances in Hematology & Oncology | volume = 15 | issue = 5 | pages = 409–418 | date = May 2017 | pmid = 28591094 }}</ref> CDKN2A is a tumor suppressor gene, while loss of its expression results in enhanced [[tumorigenesis]] and metastasis.<ref name=":21" /><ref>{{cite journal | vauthors = Zhao R, Choi BY, Lee MH, Bode AM, Dong Z | title = Implications of Genetic and Epigenetic Alterations of CDKN2A (p16(INK4a)) in Cancer | journal = eBioMedicine | volume = 8 | pages = 30–39 | date = June 2016 | pmid = 27428416 | doi = 10.1016/j.ebiom.2016.04.017 | pmc = 4919535 | url = https://www.researchgate.net/publication/301832323 | doi-access = free }}</ref> Moreover, mutation of gene involved in chromatin remodeling ([[SETD2]], [[BAP1]], or [[PBRM1|PBRM]]) may lead to higher rate of [[TFE3]]/[[TFEB]] fusion.<ref name=":21" /> Additionally, CIMP papillary renal cell carcinoma tumors exhibited somatic FH gene mutation, which is closely associated with HLRCC syndrome.<ref name="Comprehensive Molecular Characteriz"/>

== Diagnosis ==
Currently, cross-sectional imaging with [[computed tomography]] (CT) and [[magnetic resonance imaging]] (MRI) is known as the best option for diagnosing papillary renal tumors.<ref>{{Cite web|url=https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq|title=Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)–Health Professional Version|date=2013-11-01|website=National Cancer Institute|language=en|access-date=2020-04-08}}</ref>
[[File:CT scan of PRCC in a 54-year-old woman.png|thumb|Unenhanced (left) and nephrographic phase (right) CT scans display a 1-cm low-attenuation PRCC tumor (arrow) in the right renal cortex<ref name=":6" />]]

=== Computed tomography (CT) ===
[[Contrast CT|Contrast-enhanced computed tomography]] (CT) is most commonly used to identify the subtypes of RCC. PRCC can be differentiated from other types of RCC due to its distinguishing features, displaying a small hypovascular renal tumor on T2 weighted images.<ref name=":20" /> Typically, PRCC tends to appear homogeneous while clear cell RCC is likely to be in a heterogeneous form when the tumor is less than 3&nbsp;cm in diameter.<ref>{{cite journal | vauthors = Herts BR, Coll DM, Novick AC, [[Nancy Obuchowski|Obuchowski N]], Linnell G, Wirth SL, Baker ME | title = Enhancement characteristics of papillary renal neoplasms revealed on triphasic helical CT of the kidneys | journal = AJR. American Journal of Roentgenology | volume = 178 | issue = 2 | pages = 367–72 | date = February 2002 | pmid = 11804895 | doi = 10.2214/ajr.178.2.1780367 }}</ref> Comparatively, in cases of tumors larger than 3&nbsp;cm in diameter, PRCC is generally heterogeneous with areas of [[necrosis]] and [[Bleeding|hemorrhage]] compared to [[Chromophobe renal carcinoma|chromophobe RCC]].<ref name=":6" /><ref>{{cite journal | vauthors = Kim JK, Kim TK, Ahn HJ, Kim CS, Kim KR, Cho KS | title = Differentiation of subtypes of renal cell carcinoma on helical CT scans | journal = AJR. American Journal of Roentgenology | volume = 178 | issue = 6 | pages = 1499–506 | date = June 2002 | pmid = 12034628 | doi = 10.2214/ajr.178.6.1781499 }}</ref> Solid, small PRCC tumors (<3&nbsp;cm in diameter) are more easily viewed on nephrographic, excretory phase images rather than on unenhanced, corticomedullary phase images.<ref name=":6" />

=== Magnetic resonance imaging (MRI) ===
[[Magnetic resonance imaging]] (MRI) is recommended instead of CT for patients with an allergy to iodinated contrast materials.<ref name=":6" /> As some renal tumors do not enhance significantly on CT, MRI examination is required to be performed with more sensitive contrast enhancement.<ref name=":20" /> On MRI, the distinct features of PRCC are fibrous capsules and homogeneously low single intensity on both [[T1-weighted|T1-]] and [[T2-weighted|T2-weighted images]].<ref name=":6" /><ref name=":7">{{cite journal | vauthors = Gurel S, Narra V, Elsayes KM, Siegel CL, Chen ZE, Brown JJ | title = Subtypes of renal cell carcinoma: MRI and pathological features | journal = Diagnostic and Interventional Radiology | volume = 19 | issue = 4 | pages = 304–11 | date = 2013-03-11 | pmid = 23439256 | doi = 10.5152/dir.2013.147 }}</ref> Specifically, PRCC exhibits hypointensity due to its dense collagenous matrix or deposition of calcium and hemosiderin within the tumor.<ref>{{cite journal | vauthors = Hiraki Y, Okamoto D, Nishie A, Asayama Y, Ishigami K, Ushijima Y, Takayama Y, Fujita N, Eto M, Kinoshita F, Honda H | display-authors = 6 | title = Papillary renal cell carcinoma with massive hematoma mimicking hemangioma | journal = Radiology Case Reports | volume = 14 | issue = 8 | pages = 1003–1006 | date = August 2019 | pmid = 31198484 | pmc = 6556879 | doi = 10.1016/j.radcr.2019.05.025 }}</ref> Such visual features help PRCC to be differentiated from clear cell RCC, which has heterogeneously higher single intensity shown on T2-weighted images.<ref name=":6" /><ref name=":7" /> PRCC displays the smallest tumor-to-cortex enhancement at corticomedullary and nephrographic phases when juxtaposed with clear cell and chromophobe RCCs.<ref name=":7" />

=== Grading System ===
[[File:Histopathology of papillary renal cell carcinoma type 1 grade 2, very high magnification, annotated.jpg|thumb|Papillary renal cell carcinoma type 1, grade 2: Nucleoli (one annotated by arrows) are conspicuous and eosinophilic at <math>\times</math>400 magnification and visible but not prominent at <math>\times</math>100 magnification.]]
The WHO/ISUP system is histological tumor grading system for renal cell carcinoma, suggested by the International Society of Urologic Pathologists (ISUP) in 2012 to diagnose tumor grades based on nucleolar prominence.<ref name=":14">{{cite journal | vauthors = Moch H | title = [The WHO/ISUP grading system for renal carcinoma] | journal = Der Pathologe | volume = 37 | issue = 4 | pages = 355–60 | date = July 2016 | pmid = 27271258 | doi = 10.1007/s00292-016-0171-y | s2cid = 8644427 }}</ref> Currently recommended by the WHO, this four-tiered WHO/ISUP grading system has also been validated for PRCC.<ref name=":14" />
{| class="wikitable"
|+WHO/ISUP system for Papillary Renal Cell Carcinoma (PRCC) Grading<ref>{{cite journal | vauthors = Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM | title = The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours | journal = European Urology | volume = 70 | issue = 1 | pages = 93–105 | date = July 2016 | pmid = 26935559 | doi = 10.1016/j.eururo.2016.02.029 }}</ref>
!Grade
!Definition
|-
|1
|Nucleoli are absent or inconspicuous and basophilic at <math>\times</math>400 magnification.
|-
|2
|Nucloeli are conspicuous and eosinophilic at <math>\times</math>400 magnification and visible but not prominent at <math>\times</math>100 magnification.
|-
|3
|Nucleoli are conspicuous and eosinophilic at <math>\times</math>100 magnification
|-
|4
|There is extreme nuclear pleomorphism, multinucleate giants cells, and/or rhabdoid an/or sarcomatoid differentiation
|}

Earlier, the Fuhrman system was largely used, and was similarly based on nuclear features.<ref name="WeissGelb1995">[https://www.researchgate.net/figure/FUHRMAN-SYSTEM-FOR-ASSESSING-NUCLEAR-GRADE-IN-RENAL-ADENOCARCINOMA_tbl3_298727034 Table 3] from: {{cite journal|last1=Weiss|first1=Lawrence M.|last2=Gelb|first2=Arnold B.|last3=Jeffrey Medeiros|first3=L.|title=Adult Renal Epithelial Neoplasms|journal=American Journal of Clinical Pathology|volume=103|issue=5|year=1995|pages=624–635|issn=0002-9173|doi=10.1093/ajcp/103.5.624|pmid=7741111 }}</ref>

== Treatment ==
First-line treatment for metastatic PRCC has not been standardized. Thus, similar treatment approaches for clear cell RCC have been used for PRCC, even though it has a distinct tumor histology.<ref name="Bourlon_2015">{{cite journal | vauthors = Bourlon MT, Meneses-Medina M, Vázquez-Manjarrez S, Bustamante-Romero FM, Gallegos-Garza AC, Lam ET | title = A Patient With Newly Diagnosed Metastatic Type 2 Papillary Renal Cell Carcinoma | journal = Oncology (Williston Park, N.Y.) | volume = 29 | issue = 11 | pages = 880–6 | date = November 2015 | pmid = 26573066 }}</ref><ref>{{cite journal | vauthors = Liu K, Ren Y, Pang L, Qi Y, Jia W, Tao L, Hu Z, Zhao J, Zhang H, Li L, Yue H, Han J, Liang W, Hu J, Zou H, Yuan X, Li F | display-authors = 6 | title = Papillary renal cell carcinoma: a clinicopathological and whole-genome exon sequencing study | journal = International Journal of Clinical and Experimental Pathology | volume = 8 | issue = 7 | pages = 8311–35 | date = 2015-07-01 | pmid = 26339402 | pmc = 4555730 }}</ref>

=== Surgery ===
[[Nephrectomy]] or [[Nephrectomy|nephron-sharing partial nephrectomy]] is widely recommended to reduce the risk of metastasis by eliminating all or part of the kidney.<ref name=":6" /> Surgery procedures for PRCC depend on the patient's status and are very similar to procedures performed on [[Renal cell carcinoma|RCC]] patients.{{citation needed|date=April 2021}}

=== Targeted Therapy ===
Several medications that target molecular pathways in RCC have been possible options for advanced and metastatic PRCC.<ref name="Bourlon_2015" /> Among different medications, [[tyrosine kinase inhibitors]] (TKIs) and [[MTOR|mammalian target of rapamycin]] (mTOR) inhibitors are effective in inhibiting [[angiogenesis]], blocking growth and suppressing spread of the tumor.<ref name=":17">{{cite journal | vauthors = Zarrabi K, Fang C, Wu S | title = New treatment options for metastatic renal cell carcinoma with prior anti-angiogenesis therapy | journal = Journal of Hematology & Oncology | volume = 10 | issue = 1 | pages = 38 | date = February 2017 | pmid = 28153029 | pmc = 5288948 | doi = 10.1186/s13045-016-0374-y | doi-access = free }}</ref> [[Sunitinib]], [[sorafenib]], and [[axitinib]] are TKIs with anti-[[vascular endothelial growth factor]] (VEGF), which inhibit cellular signaling by targeting multiple receptor tyrosine kinase.<ref name=":17" /><ref>{{cite journal | title = First-line treatment with sunitinib for type 1 and type 2 locally advanced or metastatic papillary renal cell carcinoma: a phase II study (SUPAP) by the French Genitourinary Group (GETUG)† | language = en | journal = Annals of Oncology | volume = 26 | issue = 6 | pages = 1123–1128 | date = 2015-06-01 | pmid = 32018840 | doi = 10.1093/annonc/mdv149 | doi-access = free | last1 = Ravaud | first1 = A. | last2 = Oudard | first2 = S. | last3 = De Fromont | first3 = M. | last4 = Chevreau | first4 = C. | last5 = Gravis | first5 = G. | last6 = Zanetta | first6 = S. | last7 = Theodore | first7 = C. | last8 = Jimenez | first8 = M. | last9 = Sevin | first9 = E. | last10 = Laguerre | first10 = B. | last11 = Rolland | first11 = F. | last12 = Ouali | first12 = M. | last13 = Culine | first13 = S. | last14 = Escudier | first14 = B. }}</ref><ref>{{cite journal | vauthors = Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM | display-authors = 6 | title = Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America | journal = Cancer | volume = 116 | issue = 5 | pages = 1272–80 | date = March 2010 | pmid = 20082451 | doi = 10.1002/cncr.24864 | s2cid = 205659715 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kamai T, Abe H, Arai K, Murakami S, Sakamoto S, Kaji Y, Yoshida KI | title = Radical nephrectomy and regional lymph node dissection for locally advanced type 2 papillary renal cell carcinoma in an at-risk individual from a family with hereditary leiomyomatosis and renal cell cancer: a case report | journal = BMC Cancer | volume = 16 | pages = 232 | date = March 2016 | pmid = 26983443 | pmc = 4794818 | doi = 10.1186/s12885-016-2272-7 | doi-access = free }}</ref> [[Everolimus]] and [[temsirolimus]] are used in deregulating the mTOR pathway.<ref name=":19">{{cite journal | vauthors = Zanardi E, Verzoni E, Grassi P, Necchi A, Giannatempo P, Raggi D, De Braud F, Procopio G | display-authors = 6 | title = Clinical experience with temsirolimus in the treatment of advanced renal cell carcinoma | journal = Therapeutic Advances in Urology | volume = 7 | issue = 3 | pages = 152–61 | date = June 2015 | pmid = 26161146 | pmc = 4485412 | doi = 10.1177/1756287215574457 }}</ref><ref name=":18">{{cite journal | vauthors = Coppin C | title = Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib | journal = Biologics: Targets and Therapy | volume = 4 | pages = 91–101 | date = May 2010 | pmid = 20531964 | pmc = 2880340 | doi = 10.2147/btt.s6748 | doi-access = free }}</ref> Specifically, mTOR inhibitors have crucial roles in regulating cell growth, cell proliferation and metabolism of highly active tumor cells.<ref name=":17" /> Other targeted agents such as [[C-Met inhibitor|MET inhibitors]], [[epidermal growth factor receptor]] (EGFR) inhibitors, and [[Monoclonal antibody|monoclonal antibodies]], are also promising treatment approaches for PRCC.<ref name="Bourlon_2015" /> [[Foretinib]] is one example of a multikinase inhibitor targeting c-MET.<ref name=":9">{{cite journal | vauthors = Choueiri TK, Vaishampayan U, Rosenberg JE, Logan TF, Harzstark AL, Bukowski RM, Rini BI, Srinivas S, Stein MN, Adams LM, Ottesen LH, Laubscher KH, Sherman L, McDermott DF, Haas NB, Flaherty KT, Ross R, Eisenberg P, Meltzer PS, Merino MJ, Bottaro DP, Linehan WM, Srinivasan R | display-authors = 6 | title = Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma | journal = Journal of Clinical Oncology | volume = 31 | issue = 2 | pages = 181–6 | date = January 2013 | pmid = 23213094 | pmc = 3532390 | doi = 10.1200/JCO.2012.43.3383 }}</ref> Considering that MET gene mutation is one oncogenic pathway of PRCC, MET inhibitors like [[tivantinib]] and [[volitinib]] are currently being investigated as a new targeted therapy option.<ref name="Bourlon_2015" /><ref name=":9" />

== Prognosis ==
The five-year survival rate of PRCC has been reported as 82-90%, which is slightly higher than that of other kidney cancers.<ref>{{Cite book|last=Nosé|first=Vania | name-list-style = vanc |url=https://books.google.com/books?id=RtjQDwAAQBAJ&pg=PR9|title=Diagnostic Pathology: Familial Cancer Syndromes E-Book|date=2020-02-14|publisher=Elsevier Health Sciences|isbn=978-0-323-71205-7|language=en}}</ref> The reduced survival rate has been positively correlated to several factors, which are high nuclear grade and stage, vascular invasion, [[Aneuploidy|DNA aneuploidy]], and more.<ref name=":5">{{Cite book|last1=Bostwick|first1=David G. |last2=Cheng|first2=Liang | name-list-style = vanc |url=https://books.google.com/books?id=QZUKH7WuISMC |title=Urologic Surgical Pathology|date=2008-01-01|publisher=Elsevier Health Sciences|isbn=978-0-323-01970-5|language=en}}</ref> Patients with type 1 PRCC have significantly improved survival rates than those with type 2, which is a reflection of its lower TNM stage with a well-encapsulated tumor.<ref>{{Cite web|url=https://profreg.medscape.com/px/sso/oauthlogin?oauth=1&client_id=29210617-47A2-49CB-A6C8-38A252ED3F14&response_type=code&redirect_uri=https://www.mdedge.com/services/medauth/authenticated&state=https%253A%252F%252Fwww.mdedge.com%252Fhematology-oncology%252Farticle%252F173337%252Frenal-cell-carcinoma%252Fstudy-sheds-new-light-prognostic-factors&status=5e8d4be8569de|title=MDEdge Oauth|website=profreg.medscape.com|access-date=2020-04-08}}</ref> Compared to other common types of RCC, PRCC exhibits a relatively lower risk of tumor recurrence and cancer-related death after nephrectomy.<ref>{{cite journal | vauthors = Zucchi A, Novara G, Costantini E, Antonelli A, Carini M, Carmignani G, Cosciani Cunico S, Fontana D, Longo N, Martignoni G, Minervini A, Mirone V, Porena M, Roscigno M, Schiavina R, Simeone C, Simonato A, Siracusano S, Terrone C, Ficarra V | display-authors = 6 | title = Prognostic factors in a large multi-institutional series of papillary renal cell carcinoma | journal = BJU International | volume = 109 | issue = 8 | pages = 1140–6 | date = April 2012 | pmid = 21871053 | doi = 10.1111/j.1464-410X.2011.10517.x | s2cid = 205545457 | doi-access = free }}</ref> Specifically, the cancer-specific survival rate at five years following surgery with PRCC has reached up to 91%, while clear cell RCC and chromophobe RCC were 72% and 88%, respectively.<ref name=":5" />

== Epidemiology ==
Among different histologic subtypes of RCC, PRCC is the second most predominant type and accounts for 10-15% of all renal tumors.<ref>{{Cite book|last1=Singh|first1=Shree Ram|url=https://books.google.com/books?id=PbW9BAAAQBAJ&pg=PA217 |title=MicroRNA in Development and in the Progression of Cancer|last2=Rameshwar|first2=Pranela | name-list-style = vanc |date=2014-04-21|publisher=Springer Science & Business|isbn=978-1-4899-8065-6|language=en}}</ref> In the case of the United States, it is estimated that the incidence of PRCC will rise to 3,500 to 5,000 cases annually.<ref name=":22" /> Generally, PRCC is more prevalent among men than women, while the reported sex ratio (M: F) varies from 1.8:1 to 3.8:1.<ref>{{cite journal | vauthors = Fernandes DS, Lopes JM | title = Pathology, therapy and prognosis of papillary renal carcinoma | journal = Future Oncology | volume = 11 | issue = 1 | pages = 121–32 | date = 2015-01-01 | pmid = 25572787 | doi = 10.2217/fon.14.133 | url = https://www.futuremedicine.com/doi/10.2217/fon.14.133 | hdl = 10216/72945 | hdl-access = free }}</ref> The mean age at presentation is identified as 52–66 years old; however, no statistically significant difference was found in the incidence of PRCC between the younger (< 40 years) and older adult groups (>40 years).<ref name=":15" /><ref>{{cite journal | vauthors = Suh JH, Oak T, Ro JY, Truong LD, Ayala AG, Shen SS | title = Clinicopathologic features of renal cell carcinoma in young adults: a comparison study with renal cell carcinoma in older patients | journal = International Journal of Clinical and Experimental Pathology | volume = 2 | issue = 5 | pages = 489–93 | date = 2009-01-30 | pmid = 19294008 | pmc = 2655150 }}</ref> In terms of racial variation, several studies have proven that people with African or Afro-Caribbean ancestry tend to have higher chances of being diagnosed with PRCC. According to the National Cancer Database, PRCC was more common in the Non-Hispanic Black population (38.9%) when compared to other races – Asian American (18.0%), Non-Hispanic White (13.2%), and Hispanic White populations (6.1%).<ref>{{cite journal | vauthors = Batai K, Harb-De la Rosa A, Zeng J, Chipollini JJ, Gachupin FC, Lee BR | title = Racial/ethnic disparities in renal cell carcinoma: Increased risk of early-onset and variation in histologic subtypes | journal = Cancer Medicine | volume = 8 | issue = 15 | pages = 6780–6788 | date = November 2019 | pmid = 31509346 | pmc = 6826053 | doi = 10.1002/cam4.2552 }}</ref>

== References ==
<references />

== External links ==
{{Medical resources|ICD10=C64 [https://icd.who.int/browse10/2019/en#/C64-C68]}}
{{Urologic neoplasia}}
{{Tumor morphology}}

{{DEFAULTSORT:Renal Cell Carcinoma}}
[[Category:Kidney cancer]]