Editing Wilms' tumor (section)

== Pathogenesis ==
[[File:Wilms tumor.jpg|thumb|Cut section showing two halves of a nephroblastoma specimen. Note the prominent septa subdividing the sectioned surface and the protrusion of tumor into the renal pelvis, resembling botryoid rhabdomyosarcoma.]]
[[File:Part of whole slide image of a Wilms' tumor of the kidney.jpg|thumb|Low magnification micrograph of a Wilms' tumor infiltrating the renal parenchyma. It shows the characteristic triphasic pattern consisting of tubules, solid sheets of small round cells, and stroma. [[H&E stain]]. The surrounding renal parenchyma is more eosinophilic (pink) than the rather grey tumor stroma.]]
Wilms' tumor has many causes, which can broadly be categorized as syndromic and non-syndromic. Syndromic causes of Wilms' tumor occur as a result of alterations to genes such as the [[Wilms Tumor 1]] (WT1) or Wilms Tumor 2 (WT2) genes, and the tumor presents with a group of other signs and symptoms.<ref name=":3" /> Non-syndromic Wilms' tumor is not associated with other symptoms or pathologies.<ref name=":3">{{Citation|last=PDQ Pediatric Treatment Editorial Board|title=Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®): Health Professional Version|date=2002|url=https://www.ncbi.nlm.nih.gov/books/NBK65842/|work=PDQ Cancer Information Summaries|publisher=National Cancer Institute (US)|pmid=26389282|access-date=2018-11-26}}</ref> Many, but not all, cases of Wilms' tumor develop from nephrogenic rests, which are fragments of tissue in or around the kidney that develop before birth and become cancerous after birth. In particular, cases of bilateral Wilms' tumor, as well as cases of Wilms' tumor derived from certain genetic syndromes such as [[Denys-Drash syndrome]], are strongly associated with nephrogenic rests.<ref name=":3" /> Most nephroblastomas are on one side of the body only and are found on both sides in less than 5% of cases, although people with Denys-Drash syndrome mostly have bilateral or multiple tumors.<ref>{{cite journal | vauthors = Guaragna MS, Soardi FC, Assumpção JG, Zambaldi L, Cardinalli IA, Yunes JA, de Mello MP, Brandalise SR, Aguiar S | s2cid = 205860918 | title = The novel WT1 gene mutation p.H377N associated to Denys-Drash syndrome | journal = Journal of Pediatric Hematology/Oncology | volume = 32 | issue = 6 | pages = 486–8 | date = August 2010 | pmid = 20562648 | doi = 10.1097/MPH.0b013e3181e5e20d }}</ref> They tend to be encapsulated and vascularized tumors that do not cross the midline of the abdomen. In cases of [[metastasis]] it is usually to the lung. A rupture of Wilms' tumor puts the patient at risk of [[hemorrhage|bleeding]] and peritoneal dissemination of the tumor. In such cases, surgical intervention by a surgeon who is experienced in the removal of such a fragile tumor is imperative.{{citation needed|date=June 2020}}

Pathologically, a triphasic nephroblastoma comprises three elements:<ref name="PopovSebire2016">{{cite book|last1=Popov|first1=Sergey D.|last2=Sebire|first2=Neil J.|last3=Vujanic|first3=Gordan M.|title=Wilms' Tumour – Histology and Differential Diagnosis|year=2016|pages=3–21|doi=10.15586/codon.wt.2016.ch1|pmid=27512769 |isbn=9780994438119 |s2cid=78834136 |url=https://discovery.ucl.ac.uk/id/eprint/10026140/ }}</ref>
* [[blastema]]
* [[mesenchyme]] (stroma)
* [[epithelium]]

Wilms' tumor is a malignant tumor containing [[metanephric blastema]], stromal and epithelial derivatives. Characteristic is the presence of abortive tubules and glomeruli surrounded by a spindled cell stroma. The stroma may include striated [[muscle]], [[cartilage]], [[bone]], fat tissue, and fibrous tissue. Dysfunction is caused when the tumor compresses the normal kidney parenchyma.{{citation needed|date=April 2021}}

The mesenchymal component may include cells showing rhabdomyoid differentiation or malignancy ([[rhabdomyosarcoma]]tous Wilms).{{citation needed|date=April 2021}}

Wilms' tumors may be separated into two prognostic groups based on pathologic characteristics:{{citation needed|date=April 2021}}
* ''Favorable'' – Contains well developed components mentioned above
* ''[[Anaplastic]]'' – Contains diffuse anaplasia (poorly developed cells)

===Molecular biology and related conditions===
Mutations of the ''[[WT1]]'' gene which is located on the short arm of [[chromosome 11]] (11p13) are observed in approximately 20% of Wilms' tumors, the majority of them being [[Heredity|inherited]] from the [[germline]], while a minority are acquired [[Somatic (biology)|somatic mutations]].<ref>{{cite journal | vauthors = Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH | s2cid = 29092372 | title = Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus | journal = Cell | volume = 60 | issue = 3 | pages = 509–20 | date = February 1990 | pmid = 2154335 | doi = 10.1016/0092-8674(90)90601-A }}</ref><ref>{{cite journal | vauthors = Huff V | title = Wilms tumor genetics | journal = American Journal of Medical Genetics | volume = 79 | issue = 4 | pages = 260–7 | date = October 1998 | pmid = 9781905 | doi = 10.1002/(SICI)1096-8628(19981002)79:4<260::AID-AJMG6>3.0.CO;2-Q }}</ref> In addition at least half of the Wilms' tumors with mutations in WT1 also carry acquired somatic mutations in [[CTNNB1]], the gene encoding the proto-oncogene [[beta-catenin]].<ref>{{cite journal | vauthors = Maiti S, Alam R, Amos CI, Huff V | title = Frequent association of beta-catenin and WT1 mutations in Wilms tumors | journal = Cancer Research | volume = 60 | issue = 22 | pages = 6288–92 | date = November 2000 | pmid = 11103785 | url = http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11103785 }}</ref> This latter gene is found on short arm of [[chromosome 3]] (3p22.1).

Most cases do not have mutations in any of these genes.<ref name="pmid18311776">{{cite journal | vauthors = Ruteshouser EC, Robinson SM, Huff V | title = Wilms tumor genetics: mutations in WT1, WTX, and CTNNB1 account for only about one-third of tumors | journal = Genes, Chromosomes & Cancer | volume = 47 | issue = 6 | pages = 461–70 | date = June 2008 | pmid = 18311776 | pmc = 4332772 | doi = 10.1002/gcc.20553 }}</ref>

{| class="wikitable"
! Syndrome Name
! Associated Genetic Variant
! Risk for Wilms tumor
! Description of Syndrome
|-
|[[WAGR syndrome]] (Wilms tumor, aniridia, genital anomalies, retardation)
|Gene deletion that includes both ''[[WT1]]'' and ''[[PAX6]]''
|45–60%
|Characterized by Wilms tumor, [[aniridia]] (absence of iris), [[hemihypertrophy]] (one side of body larger than the other), genitourinary abnormalities, ambiguous genitalia, intellectual disability.<ref name=Dome2015>{{cite journal | vauthors = Dome JS, Graf N, Geller JI, Fernandez CV, Mullen EA, Spreafico F, Van den Heuvel-Eibrink M, Pritchard-Jones K | title = Advances in Wilms Tumor Treatment and Biology: Progress Through International Collaboration | journal = Journal of Clinical Oncology | volume = 33 | issue = 27 | pages = 2999–3007 | date = September 2015 | pmid = 26304882 | pmc = 4567702 | doi = 10.1200/JCO.2015.62.1888 }}</ref>
|-
|[[Denys–Drash syndrome|Denys-Drash syndrome (DDS)]]
|''[[WT1]]'' (exon 8 and 9)
|74%
|Characterized by kidney diseases since birth leading to early-onset kidney failure, ambiguous genitalia (intersex disorders).<ref name=Dome2015/>
|-
|[[Beckwith–Wiedemann syndrome|Beckwith-Wiedemann Syndrome]]
|Abnormal regulation of chromosome 11p15.5
|7%
|Characterized by macrosmia (large birth size), [[macroglossia]] (large tongue), [[hemihypertrophy]] (one side of the body is larger), other tumors in body, [[omphalocele]] (open abdominal wall) and [[Organomegaly|visceromegaly]] (enlargement of organs inside abdomen).<ref name=Dome2015/>
|}

An association with [[H19 (gene)|H19]] has been reported.<ref name=Coorens2019>Coorens THH, Treger TD, Al-Saadi R, Moore L, Tran MGB, Mitchell TJ, Tugnait S, Thevanesan C, Young MD, Oliver TRW, Oostveen M, Collord G, Tarpey PS, Cagan A, Hooks Y, Brougham M, Reynolds BC, Barone G, Anderson J, Jorgensen M, Burke GAA, Visser J, Nicholson JC, Smeulders N, Mushtaq I, Stewart GD, Campbell PJ, Wedge DC, Martincorena I, Rampling D, Hook L, Warren AY, Coleman N, Chowdhury T, Sebire N, Drost J, Saeb-Parsy K, Stratton MR, Straathof K, Pritchard-Jones K, Behjati S (2019) Embryonal precursors of Wilms tumor. Science 366(6470):1247-1251</ref> H19 is a [[long noncoding RNA]] located on the short arm of [[chromosome 11]] (11p15.5).