artigo tumor de Wilms

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Educational Case
Educational Case: Wilms Tumor
(Nephroblastoma)
Taylor E. Anderson, BA1 and Richard M. Conran, MD, PhD, JD1
The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME),
a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and
Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and
a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.
Keywords
pathology competencies, organ system pathology, kidney, renal neoplasia, Wilms tumor, nephroblastoma, abdominal mass,
pediatric tumors
Received September 06, 2018. Received revised November 30, 2018. Accepted for publication December 03, 2018.
Primary Objective
Objective UTK1.4: Wilms Tumor: Describe the clinical and
pathologic features and molecular basis for Wilms tumor and
list the histologic features that are important to recognize in
determining prognosis, and the etiology of Wilms tumor as part
of different syndromes.
Competency 2: Organ System Pathology; Topic UTK: Kid-
ney; Learning Goal 1: Renal Neoplasia.
Patient Presentation
A 3-year-old male presents to the clinic with his mother who has
noticed a rapidly growing mass in the left side of his abdomen. She
has also noticed a pink tinge to his urine and noted that he often cries
with urination. On physical examination, the physician palpated a
large left-sided abdominal mass with smooth, regular margins that
did not cross the midline. The rest of the physical examination was
unremarkable. Ultrasound and contrast-enhanced computed tomo-
graphy (CT) scans of the abdomen were ordered.
Questions/Discussion Points, Part 1
What Is the Differential Diagnosis for an Abdominal
Mass in a Young Child?
The differential diagnosis for an abdominal mass in a young child
consists of disorders of renal origin (neoplastic, nonneoplastic),
cysts of other abdominal organs (mesenteric, omental, choledo-
chal), other neoplasms (neuroblastoma, teratoma, hepatoblas-
toma), or congenital (developmental) abnormalities.1
Diagnostic Findings, Part 2
Imaging
Ultrasound revealed an 8 � 7 cm well-defined mass of hetero-
geneous echogenicity arising from the left kidney. Heteroge-
neity is due to hemorrhage and necrosis. On CT scan, a large
mass with low-density areas signifying tumor necrosis was
seen. There was no evidence of nodal or hepatic metastasis.
The right kidney was unremarkable.
Pathologic Examination
The left kidney was resected (Figure 1). On gross examination,
a lobulated tan mass with surrounding pseudocapsule is visua-
lized arising from the left kidney. It appears as a heterogenous
1 Eastern Virginia Medical School, Norfolk, VA, USA
Corresponding Author:
Richard M. Conran, Eastern Virginia Medical School, 700 West Olney, Norfolk,
VA 23501, USA.
Email: conranrm@evms.edu
Academic Pathology
Volume 6: 1–4
ª The Author(s) 2019
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mass with prominent foci of necrosis and hemorrhage. Tissue
submitted for histological examination demonstrates a mixed
pattern of blastemal, stromal, and epithelial elements (Figure 2).
Questions/Discussion Points, Part 2
What Is the Diagnosis Based on the Clinical, Imaging,
Gross and Histological Findings?
The clinical (left-sided abdominal mass), imaging (8 � 7 cm het-
erogenous echogenic mass on ultrasonography), gross (lobulated
tan heterogenous mass), and histological findings (mixed pattern of
blastemal, stromal, and epithelial elements) are consistent with a
diagnosis of Wilms tumor (WT; nephroblastoma).
Describe the Gross and Microscopic Pathologic Features
of Nephroblastoma
Grossly, the mass may appear as a large, bulging, tan-white
lobulated, homogenous mass that is sharply demarcated from
the renal parenchyma (Figure 3) or as a heterogeneous mass
with necrosis and hemorrhage, as in this case (Figure 1).2
Wilms tumor typically occurs unilaterally, but in 5% to 10%
of cases the malignancy appears bilaterally, either simulta-
neously or one after the other. Microscopically, the classic
WT is a combination of blastemal, stromal, and epithelial
elements (mixed tumor; Figure 2). Neoplasms containing all
elements are commonly referred to as triphasic tumors.
When one component consists of more than two-thirds of
a tumor, the term monophasic tumor is used. The triphasic
tumor is the most frequent pattern followed by the blastema-
predominant pattern (Figure 4). Blastemal cells are the least
differentiated and consist of primitive small round blue
cells. The epithelial component ranges from primitive
rosette-like structures to tubules or glomerular-like struc-
tures. The stromal component appears as densely packed
undifferentiated mesenchymal cells interspersed with loose
cellular myxoid regions or contain heterologous elements
(skeletal muscle, cartilage, and bone).3
Figure 1. Kidney sectioned in half showing a hemorrhagic tan-white
8 � 7 cm necrotic mass compressing the non-neoplastic renal par-
enchyma (arrowheads).
Figure 2. Triphasic tumor composed of blastema (B), epithelial ele-
ments (tubules) (T), and stroma (S). H&E, Intermediate power.
Figure 3. The bisected kidney demonstrates a large, tan-white, bul-
ging, well-demarcated tumor compressing the normal renal
parenchyma.
Figure 4. Blastema-predominant Wilms tumor composed of small
round blue cells (B) intermixed with single tubule (T) and stromal
elements (S). H&E, Intermediate power.
2 Academic Pathology
Marlinson borges
Marlinson borges
Marlinson borges
Marlinson borges
What Histological Finding Is Classified as Unfavorable
Histology?
The presence of diffuse anaplastic histology, observed in
approximately 5% of WTs, would correlate with a poor prog-
nosis. Three features define anaplasia: prominent cytologic
atypia (nuclear diameter greater than 3 times the size of the
adjacent nuclei), hyperchromasia, and atypical mitotic figures
(Figure 5). Anaplasia classified as “unfavorable histology” cor-
relates with TP53 mutations and resistance to chemotherapy.4
What Is the Epidemiology of Wilms Tumor in the
United States?
Wilms tumor has an incidence of 1 in 10 000 children in the
United States.4,5 It is the most prevalent primary renal tumor and
the most common intra-abdominal solid tumor of childhood.
Wilms tumor is the fourth most common malignancy in the pedia-
tric population in the United States. Peak incidence is between
ages 2 and 4 with 80% of cases presenting before age 5.6
Describe the Molecular and Developmental
Abnormalities Associated With Wilms Tumor
Both inherited and sporadic forms of WT can arise. Mutation
involving inactivation of the WT1 tumor suppressor gene locus
on chromosome 11p13 often is a predisposing factor. Wilms
tumor 1 protein normally functions as a transcriptional activa-
tor of genes that are involved in differentiation of renal and
gonadal cells. It is a primary regulatory componentduring
kidney development that governs the transition from mesench-
ymal cells to epithelial cells.7
Define “Nephrogenic Rests”
Nephrogenic rests (NRs) are abnormal areas of embryonic tis-
sue that persist beyond 36 weeks of development and may be
either perilobar or intralobar and are thought to be a precursor
lesion for WT (Figure 6).3,4 Nephrogenic rests are observed in
approximately 25% to 40% of unilateral WT cases and 100% of
bilateral WT cases. Perilobar NRs occur peripheral to the renal
lobules and have been associated with the Beckwith-
Wiedemann syndrome. Intralobar NRs are found within the
central part of the lobule and have been associated with WAGR
and Deny-Drash syndromes.8
What Syndromes Are Associated With Wilms Tumor?
Wilms tumors associated with syndromes account for approx-
imately 10% of all cases.4 WAGR syndrome is one such syn-
drome consisting of WT, aniridia, genital anomalies
(cryptorchidism, hypospadias, etc), and mental retardation.4,6
Approximately one-third of individuals with WAGR syndrome
will develop WT over the course of their lifetime. This syn-
drome is characterized by germline deletion of chromosome
11p13 which carries the WT1 and PAX6 genes coding for WT
and aniridia, respectively. Another syndrome increasing the
risk of developing WT is Denys-Drash syndrome consisting
of pseudohermaphroditism and progressive glomerulonephritis
leading to renal failure. This syndrome is caused by altered
DNA-binding properties of the zinc finger region of the WT1
protein due to a dominant negative missense mutation. Wilms
tumor is seen in these patients only when there is biallelic
inactivation of WT1. Beckwith-Wiedemann syndrome is
another instance of increased risk of development of WT and
occurs due to loss of function of the WT2 gene on chromosome
11p15. This syndrome is characterized by macroglossia,
omphalocele, organomegaly, genitourinary anomalies, and
increased risk of abdominal tumors. Genes present in the
11p15.5 region are normally subjected to imprinting, so only
one of the 2 parental alleles are expressed. The phenotype and
predisposition to tumorigenesis are specific to the type of
imprinting abnormality that is seen in the affected individual.
The insulin-like growth factor-2 gene expression has the
Figure 5. The large hyperchromatic cells (arrowheads) and atypical
mitotic figure (red arrow) are demonstrative of anaplasia in a
nephroblastoma. H&E, Intermediate power.
Figure 6. Nephrogenic rest. Persistent foci of embryonic cells
(arrowheads) are present within the renal parenchyma. H&E, Inter-
mediate power.
Anderson and Conran 3
greatest correlation with tumor predisposition in Beckwith-
Wiedemann syndrome.
What Other Neoplasms Are in the Differential?
Other renal tumors include congenital mesoblastic nephroma,
clear-cell sarcoma, and rhabdoid tumor.5,7 Other small round
blue cell tumors of childhood that should be considered include
neuroblastoma and primitive neuroectodermal tumor. Hepato-
blastoma is another malignancy in the differential. Differential
diagnosis is based on clinical and imaging findings. Diagnosis
is based on pathologic features.
What Are Therapeutic Options After Diagnosis of
Wilms Tumor?
Most patients can be cured of WT. Tumor staging is a surgical
and pathological designation; most commonly the North
American National Wilms Tumor Study Group staging sys-
tem is used. In the United States, surgical resection is the first
step in treatment and staging and will be followed by che-
motherapy and radiotherapy if indicated.7 Protocol in other
countries involves primary treatment with chemotherapy to
decrease the risk of intraoperative rupture and hemorrhage
and to reduce the disease stage at the time of surgical resec-
tion. Stage I disease is limited to the kidney with the capsule
intact and can be removed completely. Stage II disease indi-
cates tumor has extended locally beyond the kidney capsule
but is completely excised. Stage III WT is designated for
tumors that cannot be completely excised. After surgery, there
is residual nonhematogenous tumor that may include positive
hilar or periaortic lymph nodes or positive margins at location
of excision. Stage III also includes suspected peritoneal con-
tamination following tumor rupture or surgical biopsy. Pres-
ence of distant tumor deposits such as lung, liver, or bone
involvement qualifies as stage IV disease. Stage V WT is
defined as bilateral renal tumors at the time of diagnosis. Each
tumor is staged separately.9
Teaching Points
� An unidentified mass in an infant can be of renal (55%),
gastrointestinal (15%), pelvic (15%), adrenal (10%), or
hepatobiliary (5%) origin.
� Wilms tumor is the most common renal malignancy in
children with an incidence of 1 in every 10 000 children.
� Wilms tumor is primarily a sporadic disease, but it can
be associated with several congenital syndromes
including WAGR syndrome, Denys-Drash syndrome,
and Beckwith-Wiedemann syndrome.
� Diagnosis of WT requires histological confirmation,
and staging is determined by the anatomic extent of
the tumor.
� Therapeutic options at presentation, based on stage, con-
sist primarily of surgical resection followed by adjuvant
chemotherapy or radiation therapy in patients with more
advanced disease.
� Diffuse anaplasia is an adverse prognostic feature
in WT.
Acknowledgment
Figures 1 to 4 were obtained during the scope of US government
employment for Dr Conran.
Declaration of Conflicting Interests
The author(s) declare no potential conflicts of interest with respect to
research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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3. Charles V, Charles B. Renal tumors of childhood. Histopathology.
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4. Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic
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5. Lowe LH, Isuani BH, Heller RM. Pediatric renal masses: Wilms
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6. Waseem M. Pediatric rounds: a 4-year-old boy with constipation
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