kidney tumor
DESCRIPTION
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Kidney >
Wilms' TumorSynonyms: Nephroblastoma, Embryoma, Carcinosarcoma, Adenomyosarcoma, Adenosarcoma
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Definition
Pediatric renal neoplasm that recapitulates renal embryogenesis at the morphologic and molecular levels.
Clinical Features
Primarily infants: o 50% aged <3 years o 90% aged <6 years1–3 o exceptionally congenital4
Occasionally adolescent5 or adult6–8 No sex predilection Presentation:
o classically an abdominal mass felt by the mother when handling the child
o rarely: hematuria and pain hypertension (caused by renin secretion)9 symptoms related to traumatic rupture sudden death from tumor embolism10
o may be proteinuria due to tumor-associated glomerular disease in the non-neoplastic kidney11
Associated Abnormalities
Urogenital congenital abnormalities: o particularly if Wilms' tumor:
occurs during first year of life involves both kidneys
Other malignancies, such as: o osteosarcoma o botryoid rhabdomyosarcoma o retinoblastoma o hepatocellular carcinoma o neuroblastoma12–15
Pathogenesis
A neoplastic process that faithfully recapitulates embryogenesis at morphologic and molecular levels16–18
A putative precursor lesion and expression of WT1 gene in some extrarenal cases19,20
Risk factors
Can occur in monozygous twins and other familial settings21 Orientals>whites>blacks
Conditions with Increased Risk
Definitely increased: o Wilms–aniridia genital anomaly–retardation (WAGR) syndrome o omphalocele–macroglossia (Beckwith–Wiedemann syndrome) o hemihypertrophy o Denys–Drash syndrome22–25
Possibly increased: o renal and genital malformations o cutaneous nevi and angiomas o trisomy 18 o Klippel–Trenaunay syndrome o neurofibromatosis
o Bloom syndrome o cerebral gigantism26–29
Gross Pathology
Kidney: o classic location o both equally affected o synchronous or metachronous bilateral involvement in 5–10%30–32
Extrarenal sites include: o retroperitoneum o sacrococcygeal region o testis o uterus (sometimes presenting as a cervical polyp) o inguinal canal o mediastinum19,33–38
Some have arisen within a teratoma Usually:
o solitary o well circumscribed o rounded o soft consistency
Size variable (median 550 g) Cut section:
o predominantly solid and pale gray or tan o often:
cystic change, necrosis, and hemorrhage (Figs 1–4
Fig. 1: A gross appearance of Wilms' tumor. The lesion has a variegated appearance.
Fig. 2: A gross appearance of Wilms' tumor. The lesion has a variegated appearance.
Fig. 3: A gross appearance of Wilms' tumor. The lesion is more homogeneous and nodular than in Figs 1 and 2.
Fig. 4: A gross appearance of Wilms' tumor. The lesion has extensive areas of infarct-like necrosis.
)
a lobular pattern due to fibrous septationo multicentric foci in 7%
Spread
Advanced cases: o local in perirenal soft tissues o may involve adrenal glands, bowel, liver, vertebrae, and paraspinal region
(may result in spinal cord compression)39 o commonly invasion of the renal vein o rare and late – extension into the renal pelvis or ureter:
the resulting polypoid masses protruding into the pyelocalyceal system may resemble botryoid rhabdomyosarcoma40
Metastases
In regional lymph nodes in 15% Most common sites of distant metastases are lungs, liver, and peritoneum Several other organs can be involved, including CNS41 Bone metastases in only 1%
Histopathology
Three major components: o undifferentiated blastema o mesenchymal (stromal) tissue o epithelial tissue42–44
Usually: o all three components, but proportions vary
Some tumors: o biphasic o monophasic (monomorphous)
Blastematous areas: o extremely cellular o small round-to-oval primitive cells o cytoplasm:
usually scanty sometimes oncocytoid appearance
o growth pattern: may be:
diffuse nodular cordlike (serpentine) basaloid (with peripheral palisading)
o Mesenchymal elements:
usually a spindle cell fibroblast-like configuration may be differentiation toward various cell types, particularly
smooth and skeletal muscle45 sometimes predominate almost to the exclusion of other
components46o Predominantly rhabdomyosarcomatous tumors involving the renal pelvis
or supernumerary ureteropelvic structures: acquire morphologic features similar to those of botryoid
rhabdomyosarcoma47–49 sometimes seen in the opposite kidney to that with typical Wilms'
tumor50o Epithelial component:
embryonic tubular (and sometimes glomerular) structures that closely recapitulate the appearance of normal developing metanephric tubules (and glomeruli) 51–54 Figs 5 and 6
Fig. 5: Microscopic appearance of Wilms' tumor. Low-power microscopic view showing a combination of blastema, stroma, epithelial tubular formation, and immature glomeruli.
Fig. 6: Microscopic appearance of Wilms' tumor. High-power view showing blastema, stroma, and immature tubular formations.
)
differentiation can be so pronounced that may be tumor analogs of nearly all segments of normal nephron55
these tubular structures can be small and round, simulating the rosettes of neuroblastoma
features favoring tubules over basal lamina are: a lumen single cell layer distinct basal lamina surrounding fibromyxoid stroma42
exceptionally, marked hydropic changes in the tubular epithelium56
o Papillonodular type: grossly evident projections extend from the septa into the cyst
lumina57 appearance on low power may be fibroadenoma like58
o May be focal or extensive anaplastic features o Possible additional features:
ciliated, mucinous, squamous, or transitional epithelium42,59 (Fig. 7
Fig. 7: Mucinous epithelium in Wilms' tumor.
)
endocrine cells of various types59 renin-producing cells;60 neuroepithelium, neuroblasts, and mature ganglion cells61,62 (Fig.
8
Fig. 8: Neural differentiation in Wilms' tumor. Several neuron-like structures with prominent dendritic extensions are well appreciated in this slide, stained with the Del-Rio Hortega technique. (Courtesy of Dr Hugo Cejas, Cordoba, Argentina)
)
neuroglia63 adipose tissue cartilage, bone, and hematopoietic cells59
o Occasionally, foci of renal cell carcinoma64,65
Special Stains and Immunohistochemistry
Immunohistochemical profiles of various components mirror those of their counterparts in the developing kidney, including highly specialized compounds such as transport mediators66,67
o blastematous elements show only: focal positivity for vimentin
o epithelial elements react for: keratin EMA various lectins various components of basement membrane66,68
o mesenchymal elements show reactivity consonant with their morphologic appearance such as:
positivity for myogenin and desmin in rhabdomyoblastomatous foci69
o neural elements (when present) are reactive for: neuron-specific enolase glial fibrillary acidic protein S-100 protein70
Type I insulin-like growth factor receptors: o have been found o may be responsible for:
increased proliferation inhibition of differentiation71–73
Electron microscopy
Cells closely resemble those of developing metanephros74,75 Features in poorly differentiated neoplasms of this region that favor the diagnosis
of Wilms' tumor include: o well-developed cell junctions o microvillous differentiation o a layer of thick, flocculent coating around the cell surface74,76 (a dense
lamina formed of highly sialylated neural cell adhesion molecules)77
Diagnosis
Extensive skeletal muscle component: o invariably seen in young children o bilateral in >50% of cases83
Diagnostic cytology: o limited role o advocated for subsets of patients, such as those with stage IV disease84 o all three major cell components of the tumor can be recognized85
Teratoid Wilms' tumor: o sometimes diagnosed o when the variety of tissues present blurs the distinction between Wilms'
tumor and teratoma42,86,87
Other Investigations
Intravenous pyelogram: o an intrarenal mass that displaces and distorts the pelvis
Ultrasonography, CT scan, and MRI: o define tumor extent
Several potential tumor markers:78 o include increased circulating levels of:
hyaluronic acid79 acquired von Willebrand's factor (may be associated with severe
coagulopathies)80 inactive renin81 erythropoietin82
o none is specific or consistently present
Differential Diagnosis
Select up to 2 differential diagnoses to compare with Wilms' Tumor
Nephroblastomatosis and Nephrogenic Rests (View full diagnosis)
Mesoblastic Nephroma (View full diagnosis)
Clear Cell Sarcoma [Kidney] (View full diagnosis)
Rhabdoid Tumor [Kidney] (View full diagnosis)
Multicystic Nephroma (View full diagnosis)
Intrarenal Neuroblastoma and Peripheral Neuroectodermal Tumor (View full diagnosis)
Metanephric Stromal Tumor (View full diagnosis)
Mesoblastic nephroma
Wilms' tumor is only exceptionally congenital (a point of great importance in the differential diagnosis with mesoblastic nephroma)4
Small round cell tumors, including neuroblastoma
Can be confused with Wilms' tumors in which the blastematous component predominates
Lung metastases in a child with a retroperitoneal neoplasm strongly favors a diagnosis of Wilms' tumor over neuroblastoma (conversely, the presence of bone metastases suggests a diagnosis other than Wilms' tumor because they occur in only 1% of the cases)
Multicystic nephroma and renal cell carcinoma
The differential diagnosis of predominantly epithelial Wilms' tumors42,65
Staging/Grading
Stage: o main criteria used:
capsular invasion rupture at surgery extrarenal vein invasion tumor implants lymph node metastases distant metastases bilaterality88
Staging is fraught with pitfalls: o tumor ‘capsule’ (or pseudocapsule) can be confused with renal capsule o renal sinus and surgical margins may be difficult to evaluate o renal vein may retract considerably, giving a false impression (when
invaded) that tumor is present at the margin o important for sections to be taken from:
renal sinus junction between tumor and normal kidney tumor capsule uninvolved renal parenchyma
Genetics
Type Name Comment
gene WT1Deletion of this zinc finger transcription factor located on 11p13
chromosome 11 11p13 and 11p15.5gene WT2 This gene located on 11p15.5 is deleted
syndrome WAGR Wilms tumor, iridia, genitourinary malformation and mental retardation
syndromeBeckwith-Wiedemann
syndromeHemihypertrophy, macroglossia, omphalocele and visceromegaly
Genetic loci predisposing to Wilms' tumor are: o WT1 (located in 11p13 and encoding a zinc finger transcription factor that
is expressed in the early development of the urogenital system)89–91 o WT2 (located in 11p15.5)92–95 o a relationship has been shown between the level of expression of these
genes and the microscopic features of the tumor96–99 Abnormalities in other chromosomes (1, 7q, 8, 12 and 16) have also been
encountered100–102 The genetic changes are identical in the various histologic components of the
tumor103 Mutations of p53 and/or overexpression of the protein:
o in 5% of cases o largely restricted to the anaplastic foci o carry an unfavorable prognostic connotation104
Management
Adolescents5 and adults6–8 o Investigate and treat according to the same guidelines used for pediatric
neoplasms105 Relatively standardized, largely through results of National Wilms' Tumor Study
instituted in 1969106–109 Depends on surgical and pathologic staging Nephrectomy and two-agent chemotherapy (actinomycin D and vincristine) for no
longer than 6 months without radiation therapy: o all stage I regardless of histology and stage II with ‘favorable histology’
(i.e. without anaplastic features)106 o nephrectomy via a wide transperitoneal route to allow visualization of the
opposite kidney and regional lymph nodes: during operation, examine the contralateral kidney, examine and
sample suspicious lymph nodes, and carefully explore other infradiaphragmatic structures
nephrectomy alone may be sufficient for small stage I, favorable-histology tumors in patients <2 years of age110,111
Other chemotherapeutic agents and radiation therapy: o added to tumors of higher staging
Biopsy followed by chemotherapy, with subsequent resection of remaining tumor:112
o bilateral Wilms' tumors Effects of chemotherapy and radiation therapy:
o more pronounced in blastematous than in mesenchymal or epithelial areas113–115
o do not seem to affect incidence of anaplasia115 o obtain a histologic diagnosis through laparotomy first because a high
percentage (up to 5%) of incorrect clinicoradiographic diagnoses116
Prognosis
Overall cure rate for unilateral tumor 80–90%117 A small percentage of long-term survivors develop a second malignant neoplasm:
o due to a genetic predisposition to neoplasia o secondary to therapy118
Prognostic Factors
Age:
o patients >2 years of age compared with those <2 years of age: significantly fewer metastases better 5-year survival rate119,120
Stage: o clinicopathologic staging is the most important o in stage I cases four features are associated with an increased rate of
relapse: an inflammatory pseudocapsule invasion of the renal sinus extensive infiltration of the renal capsule tumor infiltration of intrarenal vessels121
Size: o tumor mass (weight of excised specimen), especially for stage I tumors122
Anaplasia: o three criteria define anaplasia:
marked enlargement of nuclei within the blastemal, epithelial, or stromal cell lines (except skeletal muscle cells) to at least three times the diameter of adjacent nuclei of the same cell type
obvious hyperchromasia of the enlarged nuclei multipolar mitotic figures (Fig. 9
Fig. 9: Anaplastic (‘unfavorable histology’) Wilms' tumor. Marked pleomorphism with giant hyperchromatic nuclei and atypical mitoses.
)123
o in about 4% of cases o more common in blacks and older patients124 o very uncommon in patients <2 years of age (probably the reason for the
better prognosis for this age group) o sometimes found in metastases and not primary tumor o ‘focal’ anaplasia – only cases in which the above defined changes are
restricted to one or a few discrete loci within the primary tumor, with no anaplasia or marked nuclear atypia elsewhere125
o thorough tumor sampling (one section for each cm tumor diameter) for proper evaluation126
o less response to chemotherapy, especially when diffuse rather than focal (does not apply to stage I)127
Extensive tubular differentiation: o good prognostic sign (may also be true for extensive glomerular
differentiation)128,129 Skeletal muscle differentiation:
o said to be associated with a better prognosis when present in massive amounts130,131
Mucin production: o rare patients in whom mucin is detected in serum may have a poor
prognosis132 DNA ploidy:
o may give prognostic information133 p53 gene mutation:
o evaluated indirectly through the immunohistochemical detection of p53 protein overexpression (Fig. 10
Fig. 10: Anaplastic (‘unfavorable histology’) Wilms' tumor. Strong nuclear immunoreactivity for p53.
)
o correlates with the presence of anaplasia and therefore an unfavorable outcome134,135
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Wilms' Tumor
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