4. Dr. Max Wilms
The German surgeon
who first described WT
WILMS TUMOUR
(NEPHROBLASTOMA)
5. Wilms’ Tumor
• Epidemiology
– Second most common pediatric solid abdominal
tumor, most common renal malignancy
– Presents between age 1-5; most commonly age 3
6. Clinical Presentation
• No tumor-specific symptoms
• Most common presentation is painless
abdominal mass
• Physical Exam
– Smooth, palpable large abdominal mass
– Hematuria – 30%
– Associated congenital abnormalities – 25%
7. Genetics
• Wilms’ tumor was one of the original
examples in Knudson’s two-hit model of
cancer development
• Tumor supressor genes
– WT1 – 11p13 – WAGR, DDS
– WT2 – 11p15 – BWS
10. Tumorigenesis
• Wilms tumor is thought to rise
from a foci of persistent
metanephric cells called
nephrogenic rests
– These normally occur in 1%
of newborn kidneys and
regress in early childhood
• Multiple foci of nephrogenic
rests is called
nephroblastomatosis
– Present in 35% of kidneys
with unilateral Wilms and
almost 100% of bilateral
Wilms
– Need for continued
surveillance after
nephrectomy
14. Diversity of
• cell and tissue types
• stages of
differentiation
Triphasic appearance
• epithelial lineage
• blastemal,
• stromal,
All 3 Favourable
histology
Monophasic & Biphasic lesions
• are relatively uncommon
15. • Small
• Closely packed cells
• High N:C ratio
• Little/no evidence of differentiation
• toward epithelial or stromal cell types
• at the light microscopic level.
• Nuclei
• usually round or oval
• with moderately coarse chromatin
• mold to each other.
• Nucleoli relatively inconspicuous.
The blastemal cells
17. Tubular differentiation
most frequent epithelial pattern.
Ranges from vague hints at tubular formation in blastemal foci to highly
differentiated tubules resembling nephronic elements in mature kidneys.
19. Skeletal muscle is the most common heterologous cell type and it usually attains a
high degree of differentiation
20. • only criterion of “unfavorable histology” in
WTs
ANAPLASTIC NUCLEAR CHANGES
21. The features of anaplasia include
(a) markedly
enlarged tumor cell
nuclei with
increased
chromatin content
and
(b) multipolar or
obviously
polyploid mitotic
figures - the most
unequivocal
criterion for
polyploidy
22. • WT1 protein
– blastema and epithelial components - positive
– stroma negative
Immunohistochemistry
23. WT blastemal cells
• Desmin Positive
• Negative for other muscle markers
a characteristic feature
shared with desmoplastic small round-cell tumor.
• Vimentin ±
• Cytokeratin ±
24. Wilms Tumor
• Staging
– I – limited to kidney, completely resected
– II- outside kidney, completely resected
– III – confined to abdomen
– IV – hematogenous mets
– V – bilateral initial/during treatment
28. variable
• tough, whorled appearance
resembling leiomyoma,
• cellular CMNs are more
frequently soft, friable tumors
• Hemorrhage, necrosis, and
cyst formation
sectioned surface
29. • CMN is generally categorized into
a) “classic,” fibromatosis-like subtype &
b) “cellular,” infantile fibrosarcoma (IFS)-like subtype.
MICROSCOPIC APPEARANCE
30. 1) Relatively low cell density
2) Low to moderate no. of mitotic figures
3) Long tongues of tumor extending radially into
adjacent kidney and soft tissue
• are usually small
Classic Congenital Mesoblastic Nephroma
31. 1. Densely packed spindle cells with
2. High mitotic rate.
• Predominant or exclusive pattern in 66% of CMN
specimens.
• Border
• can be interdigitating
• eventually develop a pushing border.
• Attain very large size
Cellular Congenital Mesoblastic Nephroma
32. 1) WT
2) Metanephric stromal tumor
3) Clear-cell sarcoma of the kidney
4) Rhabdoid tumor
DIFFERENTIAL DIAGNOSIS
33. • AGE - first 3 months
• Cellular composition
• Diversity of cell types and tissue patterns
• Blastemal foci ab in CMN
• Skeletal muscle never seen in CMN
• Nodules of entrapped cartilage and squamous pearls may occur in
CMN and should not be taken as evidence for WT.
• Bilaterality - WT
• Presence of NRs - WT
Congenital Mesoblastic Nephroma Vs
Wilms Tumor
43. Myxoid & sclerosing
pattern
In 30 % MPS progressively
accumulates in tumor cells
& eventually degenerates.
As the cell producing
mucoid material disappear
, mucin production ceases,
mucoid material becomes
denser, eosinophilic &
hyaline appearance
Replacement of cords with
hyaline sclerosis – chicken
wire appearence
49. Rhabdoid tumor of kidney(RTK)
– young infants
– 13 months
– Associated with medulloblastoma, hypercalcemia,
neurovascular hamartoma
50. Rhabdoid tumor
– Microscopic
• Monomorphic neoplasm involving the medullary region
• Tumor – kidney jn ill defined
• Imp clue to dx is Aggressiveness can spread to adjacent
vessels , soft tissues & lymphatic space
51. Gross- RTK
-Yellow grey or light tan
with indistinct border
--Lack of encapsulation
- Renal sinus & renal pelvis
commanly involved
-Necrosis & hemorrhage
commmon
52. RTK - Microscopy
-Cells are relatively large ,
round or polygonal with
abundant eosinophilic
/amphophilic cytoplasm
- Cytoplasmic inclusions
charecteristic features:
eosinophilic &
homogenous
Nucleus- Large & vesicular
, prominant nucleoli
Sometimes nuclei mimics
RS cells
53. RKT - IHC
Loss of INI 1 protein
-Vementin
- Co expression of
cytokeratin & epithelial
membrane antigen is
frequently observed
55. • 6% of pediatric renal neoplasms
• more common than RTK, CCSK, or CMN.
• von Hippel-Lindau syndrome
– predisposed to develop clear-cell (conventional) RCC.
• Tuberous sclerosis
– Both RCC and Epithelioid Angiomyolipoma
• Staging - American Joint Committee on Cancer criteria
• Same as adult RCC
RENAL CELL CARCINOMAS IN CHILDREN
56. – comprises the majority of pediatric RCCs.
– association with prior exposure to chemotherapy identified
– Gross resemble conventional (clear-cell) renal carcinomas
• tan-yellow and often necrotic and hemorrhagic.
– often have nested architecture
– cells with granular eosinophilic cytoplasm.
– characteristically underexpress epithelial markers ( CK, EMA)
Xp11.2 TRANSLOCATION RENAL CELL
CARCINOMAS
57. Miscellaneous Pediatric renal tumors
• Metanephric stromal tumor
– Presents grossly as a fibrous lesion centered in the
renal medulla that contains smooth-walled cysts.
– Neoplastic cells are spindle shaped, with
onionskin cuffing around entrapped tubules
– Reactive to CD34
– Surgical excision is curative
58. Metanephric adenofibroma
• Previously termed nephrogenic adenofibroma
• A biphasic tumor
– An epithelial component similar to that of metanephric
adenoma admixed with a bland spindle cell stroma
59.
60. Benign tumor consisting of vessels(angio),
smooth muscle(myo), and fat(lipo)
Angiomyolipomas present in 25% to 50% of
patients with tuberous sclerosis
◦ TS caused by loss-of-function mutations in the
TSC1 or TSC2 tumor suppressor genes
◦ The clinical importance of angiomyolipoma is due
largely to their susceptibility to spontaneous
hemorrhage
Angiomyolipoma
Its common name is an eponym, referring to Dr. Max Wilms, the German surgeon (1867–1918) who first described this kind of tumor.[2]
can arise anywhere in the cortex or medulla,
usually compressing and distorting renal parenchyma around its margin.
Rarely renal surface
exophytic tumors
connected by a narrow pedicle
may mimic extrarenal WT.
Pelvicalyceal lumen
Polypoid masses
may occur either as
extensions from the intrarenal mass or
separate tumors arising within the pelvic wall.
Generally, however, there is relatively little variation in histologic appearance from region to region within the same tumor.
in the same fashion as do the nuclei of small-cell carcinoma of the lung
Epithelial differentiation in WT produces a variety of cell types and degrees of differentiation, as listed in Table 43.4. Most of these recapitulate events in normal nephrogenesis (homologous differentiation). Others are foreign to the normal kidney at any stage of development (heterologous differentiation).
most frequent epithelial pattern.
Ranges from
vague hints at tubular formation
in blastemal foci to
highly differentiated tubules
resembling nephronic elements in mature kidneys.
Immature myxoid and spindled mesenchymal cells are present in most specimens
Skeletal muscle is the most common heterologous cell type and usually attains a high degree of differentiation The presence of skeletal muscle in WT must not be confused with renal rhabdoid tumor. Although the term fetal rhabdomyomatous nephroblastoma is sometimes used to describe WTs with abundant skeletal muscle (19,20), we are not enthusiastic about the use of subdesignations for WT patterns. Only subtypes with distinctive clinical or biologic implications deserve separate designations.
.” Anaplasia is almost never seen in WT diagnosed during the first year and is rare in the second year of life. Its relative frequency increases after that age, and it is found in approximately 10% of WTs diagnosed after age 5 years. Anaplastic nuclear change is the only criterion of “unfavorable histology” in WTs, and all WTs lacking this feature are designated as having “favorable histology.”
We have considered as anaplastic the few WT specimens in which polyploid mitotic figures were found in the absence of severe nuclear gigantism.
Immunohistochemistry has been used productively in studies of WT biology and differentiation but, to date, has limited usefulness in diagnosis. The diversity of cell lines and degrees of differentiation imparts a correspondingly varied profile of immunohistochemical results. Blastemal cells may yield either positive or negative results for vimentin and cytokeratin, whereas various differentiating cell lines will give results according to their patterns of differentiation. Positive results for desmin with negative stains for other muscle markers have been suggested as a characteristic feature of WT blastemal cells and might prove helpful in distinguishing this entity from other undifferentiated tumors of childhood (24), although this feature is shared with desmoplastic small round-cell tumor. Immunoreactivity for WT1 protein is typically limited to the blastema and epithelial components of WT, with the stroma being negative (25). Hence, absence of labeling for WT1, particularly in a stroma-rich tumor, does not exclude the diagnosis of WT. Although WT1 immunoreactivity may help distinguish WT from PNET, one should be aware that desmoplastic small round-cell tumor (26) and other adult neoplasms, such as malignant mesothelioma, typically label for WT1. Hence, although useful, WT1 immunoreactivity cannot in and of itself establish or disprove a diagnosis of WT.
Blastemal cells may yield either positive or negative results for vimentin and cytokeratin, whereas various differentiating cell lines will give results according to their patterns of differentiation. Positive results for desmin with negative stains for other muscle markers have been suggested as a characteristic feature of WT blastemal cells and might prove helpful in distinguishing this entity from other undifferentiated tumors of childhood (24), although this feature is shared with desmoplastic small round-cell tumor.
Cellular histology, stage, and vascular invasion predict relapse
most common renal neoplasm in the first 3 months of life.
Sixty-two percent are diagnosed in the first 3 months of life, . Ninety percent are diagnosed in the first year.
Usually appears to have arisen deep within the parenchyma near the renal sinus.
Surgeons and pathologists must pay particular attention to the medial margin of the resection specimen in dealing with potential CMN specimensThis is no simple matter. The medial specimen margin is notoriously difficult to evaluate, and it is rarely possible to be certain that it is free of involvement by CMN.
These findings are too often present in cases with good outcome to serve as useful markers of adverse prognosis.
Some have a
Variable combinations of these patterns are occasionally seen, as the cellular pattern arises with a background of the classic pattern (Table 43.7). Recent molecular data confirm the distinctive natures of classic and cellular CMN (see subsequent discussion).
(Figs. 43.32, 43.33 and 43.34). The term classic is appropriate in the historic sense, but this is not the most common subtype of CMN. Tumors of the pure classic pattern are usually small, with nephrectomy specimens rarely exceeding 100 g.
Cartilage or other dysplastic changes may be found in the renal parenchyma adjacent to tumor, sometimes becoming surrounded by tumor.
. CMN of the cellular type can have an interdigitating border similar to that of classic CMN, but as they enlarge, most will develop a pushing border.
Cellular CMNs may attain very large size, with nephrectomy specimens sometimes exceeding 1 kg.
Because most CMNs are managed by resection alone and the latter two entities are treated with aggressive and potentially dangerous regimens, the establishment of a correct diagnosis has exceptional clinical implications. It is uncommon for untreated WT to be composed predominantly of stromal cells, but rare examples do occur. In most of these, the presence of immature or mature skeletal muscle readily excludes the diagnosis of CMN. Embryonal metaplastic changes in nephrons surrounded by CMN cells are sometimes misinterpreted as tubular or papillary elements in a WT.
The most common errors in interpretation involve specimens removed after chemotherapy. Treatment often ablates the embryonal, proliferating elements of a WT but tends to spare stromal cells. The resultant appearances can readily be confused with CMN in some specimens. The following features are helpful in the differential diagnosis:
H/o prior therapy
AGE - first 3 months
The cellular composition
diversity of cell types and tissue patterns
Blastemal foci do not occur in a CMN, and
skeletal muscle is never seen.
Nodules of entrapped cartilage and squamous pearls may occur in CMN and should not be taken as evidence for WT.
The growth pattern
interdigitating, irregular border of CMN
sharp, pushing border
Bilaterality
presence of NRs
A diagnosis of CMN should be considered suspect in a patient who has received prior therapy, unless the clinical and other features are characteristic.
Most CMNs are diagnosed in the first 3 months, whereas WT is relatively uncommon at this age. Only 10% of CMNs are diagnosed after 1 year, and almost none are diagnosed after 2 years.
The cellular composition of the lesion is usually the most helpful feature. Most WTs express a diversity of cell types and tissue patterns. Blastemal foci do not occur in a CMN, and skeletal muscle is never seen. Nodules of entrapped cartilage and squamous pearls may occur in CMN and should not be taken as evidence for WT.
The growth pattern is helpful when the interdigitating, irregular border of CMN is present. However, cellular CMN often has a sharp, pushing border, similar to that of most WTs.
Bilaterality or the presence of NRs or both strongly favors WT.
Pediatric RCCs are staged using the same American Joint Committee on Cancer criteria applied to adult RCC.
Papillary RCC may overlap morphologically with epithelial-predominant WT or metanephric adenoma
RENAL CARCINOMAS IN CHILDREN
Renal cell carcinoma (RCC) comprises almost 6% of pediatric renal neoplasms, making it more common than RTK, CCSK, or CMN. RCC is discussed in detail in Chapter 42. All of the common RCCs of adulthood may occasionally affect the pediatric kidney, but the clinical and differential diagnostic considerations differ in this setting. Children with von Hippel-Lindau syndrome are predisposed to develop clear-cell (conventional) RCC. Children with tuberous sclerosis are at increased risk for developing both RCC and epithelioid angiomyolipoma, and immunohistochemical analysis may be needed to distinguish these two (93). As discussed previously, papillary RCC may overlap morphologically with epithelial-predominant WT or metanephric adenoma. Only those subtypes of RCC that preferentially affect children and young people are discussed here. Importantly, pediatric RCCs are staged using the same American Joint Committee on Cancer criteria applied to adult RCC.
The histologies of Xp11 translocation RCC associated with different TFE3 gene fusions may differ
Xp11.2 TRANSLOCATION RENAL CELL CARCINOMAS
RCCs with chromosome translocations involving Xp11.2 and resulting gene fusions involving the TFE3 transcription factor gene were officially recognized in the 2004 World Health Organization Renal Tumor Classification (94). Although this subtype of RCC is relatively uncommon on a percentage basis in adults, it most likely comprises the majority of pediatric RCCs. An association with prior exposure to chemotherapy has been identified (95).
One distinctive subtype bears a t(X;17)(p11;q25), which results in the identical ASPL-TFE3 gene fusion as was initially identified in alveolar soft part sarcoma (ASPS) (96), and has been designated the ASPL-TFE3 RCC (97). Other subtypes are listed in Table 43.8.
Xp11.2 translocation RCCs closely resemble conventional (clear-cell) renal carcinomas on gross examination, usually being tan-yellow and often necrotic and hemorrhagic.
Xp11.2 translocation RCCs often have nested architecture and often contain cells with granular eosinophilic cytoplasm. The histologies of Xp11 translocation RCC associated with different TFE3 gene fusions may dif
