Surgical Diseases of the Kidney
NORMAL ANATOMY
In the adult, the normal kidney weighs about 115 to 155 g in women and 125 to 170 g in men. Anatomically, the kidneys are composed of an outer cortex and an inner medulla that has 8 to 18 pyramids. The base of each pyramid is at the corticomedullary junction, and the apex forms a papilla where the collecting ducts open into the renal pelvis. The minor calyces receive the papillae and in turn join to form the major calyces that are the dilated upper portion of the ureter in the renal pelvis. Histologically, the components of the kidney include glomeruli, tubules, blood vessels, and interstitium.
Maldevelopment and Nonneoplastic Cystic Diseases
Johann D. Hertel
Peter A. Humphrey
Helen Liapis
The developmental abnormalities and benign cystic diseases of the kidney that are most likely to be seen by the surgical pathologist are presented here.
I. DEVELOPMENT ABNORMALITIES
A. Renal dysplasia is seen in malformed kidneys where there is abnormal differentiation of metanephric elements. Most cases are unilateral and sporadic, but a wide variety of genetic diseases, malformation syndromes, and chromosomal disorders have been linked to renal dysplasia (Stocker JT, Dehner LP, Husain AN, eds. Stocker and Dehner’s Pediatric Pathology, 3rd ed. Philadelphia: Wolters Kluwer/Lippincott Williams and Wilkins, 2011). Bilateral renal dysplasia is less frequent and is associated with renal failure at birth. Renal dysplasia is a common cause of an abdominal mass mimicking neoplasia in children <1 year of age but can also be diagnosed in older children and adults. There is an association with congenital urinary tract obstruction in about 50% of cases.
B. Grossly, multicystic dysplasia is characterized by a slightly enlarged kidney, or a small and irregularly cystic kidney (e-Fig. 20.1)* Aplastic dysplasia is typified by a small, solid remnant of the kidney. Segmental dysplasia occurs when the collecting system is duplicated; microscopically, there are immature tubules or ducts surrounded by collarettes of condensed mesenchyme (e-Fig. 20.2), and islands of immature-appearing cartilage (e-Fig. 20.3), cysts of varying sizes that have a flattened epithelial lining, and islands of normal glomeruli and renal tubules between the dysplastic areas. Rare cases of Wilms tumor and renal cell carcinoma (RCC) have been reported in multicystic dysplastic kidneys.
II. NONNEOPLASTIC CYSTIC DISEASES
A. Autosomal dominant polycystic kidney disease (ADPKD) is an autosomal dominant disease with complete penetrance but highly variable expressivity. The disease results from a defective copy of the PKD1 gene in 85% to 90% of cases (on chromosome 16p13.3) or PKD2 gene in 10% to 15% of cases (on chromosome 4q22.1). The genes encode polycystin-1 and polycystin-2, respectively, the loss of which causes failure to appropriately assemble cilia in the renal tubules. While the defect is present in utero and initiates cyst formation, a second mutation is required for cyst enlargement (J Am Soc Nephrol. 2007;18:1374). The disease typically manifests in adulthood (mean age of onset 30 years), although there are ADPKD cases manifesting in the neonatal period which usually present with glomerular cysts (Arch Pathol Lab Med. 2010;134:583). Clinically, ADPKD presents with renal failure, hypertension, hematuria, and flank pain. ADPKD is a systemic disease; the connective tissue abnormality is also associated with liver and pancreatic cysts, intracranial aneurysms, and mitral or aortic insufficiency.
Macroscopically, the involved kidney is dramatically enlarged with loss of its reniform structure (e-Fig. 20.4). About 1% to 3% of nephrons are affected by cysts which are usually large and oval in shape, distributed throughout the medulla and cortex, and involve any part of the nephron. The cysts are typically sac-like structures containing fluid ranging from clear and yellow to brown and turbid. The cysts vary in size from a few millimeters to several centimeters in maximal dimension. Microscopically, the cysts are lined with columnar, cuboidal, or flattened epithelium (e-Fig. 20.5) surrounded by a thickened basement membrane layer, and micropapillary hyperplasia (e-Fig. 20.6) and small intracystic polyps may be present. Some studies have suggested an association between ADPKD and RCC but none has shown a definitive increased risk of malignancy (Clin J Am Soc Nephrol. 2009;4:1998). In the end stage, the kidney is hugely enlarged and shows severe interstitial fibrosis, chronic inflammation, and severely thickened vessels, although the glomeruli appear relatively unaffected.
B. Autosomal recessive polycystic kidney disease (ARPKD) is an autosomal recessive disease with complete penetrance due to mutations in both copies of the PKHD1 gene encoding for fibrocystin. Fibrocystin is a transmembrane protein expressed in cilia in many organs including the kidney, liver, and pancreas; how precisely fibrocystin mutations cause ciliary dysfunction and subsequently cyst formation is still under investigation (since the mutant proteins causing cyst formation in ADPKD and ARPKD are localized to cilia, the proposal to classify cystic kidney diseases as ciliopathies is currently favored by some investigators). ARPKD usually develops in utero causing oligohydramnios and in utero renal failure, but it may present later in childhood or adulthood (Clin J Am Soc Nephrol. 2010;5:972); in any event, progressive renal failure leads to end-stage renal disease during the first decade of life. Pulmonary hypoplasia secondary to oligohydramnios is a common cause of mortality in the perinatal period. ARPKD is also associated with congenital hepatic fibrosis, and the pancreas can also be involved resulting in pancreatic failure. Macroscopically (e-Fig. 20.7), the kidneys are symmetrically enlarged and generally maintain their reniform appearance. The kidney has a sponge appearance caused by innumerable small, smooth lined cysts throughout the cortex and medulla. The cysts are typically cylindrical (as opposed to the spherical cysts seen in ADPKD) and about 1 mm to 2 mm in size; fusiform dilatations of the collecting ducts run radially through the cortex and medulla. Microscopically, the kidneys show ectatic dilated collecting ducts (e-Fig. 20.8). The cysts are generally lined by a single cell layer of cuboidal epithelium, although areas of hyperplasia may be seen.
C. Medullary sponge kidney is usually asymptomatic unless complicated by urinary tract infection, nephrolithiasis, or hematuria. The condition is typically detected radiologically during examination of an adult for stones. The kidney is not
enlarged. Microscopically, there is ectasia of the papillary collecting ducts in the renal medulla, with intraluminal microliths commonly observed.
D. Medullary cystic kidney disease (MCKD) complex is an autosomal dominant adult onset kidney disease. The specific gene abnormality has not been identified but has been mapped to 1q22 for MCD type I and to 16p13 for MCD type II by gene linkage analysis. Both types have a similar phenotype, although MCD type II has an earlier age of onset (fourth decade) than MCD type I (seventh decade). Both MCD I and II present as progressive nephropathy and progress to endstage renal disease. Macroscopically, the kidneys appear normal to shrunken but maintain their reniform appearance. On sectioning, numerous small corticomedullary cysts are seen. Microscopically, the kidney shows focal tubular atrophy and dilatation with cyst formation caused by disintegration of the tubular basement membrane. The cysts are typically at the corticomedullary junction, few in number, small, and lined by columnar, transitional, or metaplastic squamous epithelium. The renal parenchyma reveals a modest interstitial lymphocytic infiltrate and fibrosis indistinguishable from other tubulointerstitial processes.
E. Nephronophthisis is a hereditary disease of childhood and early adulthood with gross and microscopic pathology indistinguishable from MCD. Some investigators view juvenile nephronophthisis and MCD as part of the same disease complex. The disease is caused by mutations in at least 12 different nephrocystins—a mutation in any of which leads to a loss of cilia function and development of cystic renal disease. Grossly and microscopically, the findings are nonspecific and similar to those found in MCD.
F. Simple renal cysts, or retention cysts, are asymptomatic incidental findings seen on abdominal imaging. Simple renal cysts affect approximately 7% to 10% of the general population and are increasingly common with advancing age. Surgical pathologists typically see tissue only if there is suspicion of malignancy or if there are symptoms (such as pain, hematuria, or infection). On imaging and by gross examination, the cysts are usually unilateral, and unilocular, but can be bilateral and multiple. The size of the cysts can vary dramatically. Microscopically, the cysts have a flattened epithelial lining.
G. Acquired cystic kidney disease occurs in the setting of chronic hemodialysis. The cysts are generally asymptomatic and are seen as incidental findings on abdominal imaging. On gross examination the kidney is normal to shrunken and shows multiple smooth-lined cysts filled with clear fluid. Microscopically, the cysts are generally lined by flattened cuboidal epithelium (e-Fig. 20.9), although hyperplastic and even dysplastic epithelium has been reported; in this setting, however, no criteria presently exist for separating a region of hyperplastic epithelium from a microscopic papillary RCC.
H. Cysts can be associated with malformation syndromes including tuberous sclerosis and von Hippel-Lindau (VHL) disease (see section on renal cell carcinoma). Tuberous sclerosis complex is autosomal dominant and caused by mutations in TSC1 (on chromosome 9q; encodes for hamartin) or TSC2 (on chromosome 16p; encodes for tuberin). Renal angiomyolipomas (discussed later) and cortical cysts are common. These distinctive cysts vary in size and are lined by hyperplastic epithelium with eosinophilic cytoplasm, with multilayering and papillary growth seen.
SUGGESTED READINGS
Agarwal MM, Hemal AK. Surgical management of renal cystic disease. Curr Urol Rep. 2011;12: 3-10.
Bonsib SM. The classification of renal cystic diseases and other congenital malformations of the kidney and urinary tract. Arch Pathol Lab Med. 2010;134:554-568.
Eknoyan G. A clinical view of simple and complex renal cysts. J Am Soc Nephrol. 2009;20:1874-1876.
Gascue C, Katsanis N, Badano JL. Cystic diseases of the kidney: Ciliary dysfunction and cystogenic mechanisms. Pediatr Nephrol. 2010;26(8):1181-1195.
Gunay-Aygun M, et al. Correlation of kidney function, volume and imaging findings, and PKHD1 mutations in 73 patients with autosomal recessive kidney disease. Clin J Am Soc Nephrol. 2010;5:972-984.
Lennarz JK, Spence DC, Iskandar SS, Dehner LP, Liapis H. Glomerulocystic kidney one hundred-year perspective. Arch Pathol Lab Med. 2010;135:583-605.
Rosetti S, Harris PC. Genotype-phenotype correlations in autosomal dominant and autosomal recessive polycystic kidney disease. J Am Soc Nephrol. 2007;18:1374-1280.
Wilson PD, Goilav B. Cystic disease of the kidney. Annu Rev Pathol. 2007;2:341-368.
Pediatric Renal Neoplasms
Jason A. Jarzembowski
Frances V. White
I. INTRODUCTION. There are approximately 500 pediatric renal neoplasms diagnosed each year in the United States, the majority of which are unique to children or occur only rarely in adults (Table 20.1). Protocols for specimen processing, the staging system, and differential diagnosis differ from that of adult tumors. At present, the majority of pediatric renal tumors in the United States are centrally reviewed by the Children’s Oncology Group (COG), and procurement of snap-frozen tumor for molecular studies has become important for placement of patients in specific treatment protocols (Pediatr Dev Pathol. 2005;8:320).
II. GROSS EXAMINATION AND TISSUE SAMPLING. A radical nephrectomy is the usual specimen. In cases of bilateral nephroblastoma, partial resections (kidney-sparing procedures) are performed. Pretreatment biopsies may be obtained for unresectable
tumors; however, intraoperative biopsies are discouraged due to the risk of tumor spillage unless the diagnosis will alter operative management.
TABLE 20.1 Pediatric Renal Neoplasms: Percentages and Age Distribution
Tumor
Mean age
Pediatric renal neoplasms (%)
Age distribution (y)
Classic mesoblastic nephroma
7 d
1
0-2
Cellular mesoblastic nephroma
4 mo
3
0-2
Malignant rhabdoid tumor
18 mo
2
0-3
CCSK
2 y
4
0-9; rare after 9 y of age
Nephroblastoma
36.5 mo (boys)
42.5 mo (girls)
85
0-10; rare in first 3 mo and after 10 y of age
Metanephric stromal tumor
2 y
Rare
0-15
Ewing sarcoma / PNET
28 y
Rare
0-18+
Papillary RCC
10 y
<5
1-18+
Translocation carcinomas
Wide range
<5
1-18+
Metanephric adenoma
41 y
Rare
5-18+
Renal medullary carcinoma
22 y
Rare
11-18+
Angiomyolipoma
50 y
Rare
17-18+
Synovial sarcoma
37 y
Rare
18
PNET, primitive neuroectodermal tumor; RCC, renal cell carcinoma; CCSK, clear cell sarcoma of kidney. Compiled from References in Suggested Readings
Pediatric renal tumors are often large, friable tumors that bulge beyond the normal renal contour. The capsule should be carefully examined for sites of rupture and inked before incised. The initial plane of section is taken to demonstrate the relationship of tumor to the capsule and renal sinus. At this point, fresh tissue from each tumor nodule, nephrogenic rests, and normal kidney is snap frozen for protocol studies. Tissue may also be taken for cytogenetics, flow cytometry, and electron microscopy, depending on clinical history. Following initial cuts to facilitate fixation, overnight fixation is recommended before histologic sampling to decrease tumor friability and capsule retraction. Tissue for histology should be mainly taken from the tumor’s periphery, as histology of the interface between tumor and renal parenchyma is often important in identifying the type of tumor. Each separate tumor nodule should be sampled, with at least one section per centimeter of tumor diameter. Sections should also demonstrate the relationship of tumor to the capsule and the renal sinus. The hilum is a common route of tumor spread, necessitating adequate sampling of this area as well. Ureteral and vascular margins, hilar lymph nodes, nephrogenic rests, and normal kidney are also sampled. Tumor sections are mapped, using either a diagram or photograph of the specimen; mapping is necessary for nephroblastoma, as the presence of diffuse versus focal anaplasia alters type of treatment (Arch Pathol Lab Med. 2003;127:1280). III. DIAGNOSTIC FEATURES OF PEDIATRIC RENAL TUMORS. Pediatric renal neoplasms are notorious for their variable histologic patterns, which often show overlap between the various entities; thus, there should be careful examination of the tumor-kidney interface for pattern of infiltration, which is characteristic for each tumor type. Correct diagnosis depends on knowledge of both classic and variant histology, along with adequate sampling and correlation of the microscopic findings with patient age and other clinical information. While immunohistochemical studies may be useful for establishing the diagnosis (e.g., for INI1 in rhabdoid tumor) or for excluding a diagnosis in specific cases, immunohistochemical stains are usually not needed. Molecular studies can also be used to confirm specific diagnoses (Table 20.2).
A. Nephroblastoma (Wilms tumor) and nephrogenic rests. Nephroblastoma (Wilms tumor) accounts for 85% of pediatric renal tumors. Most patients present before 10 years of age, with a peak between 2 and 5 years. Rare examples have been reported in adults (J Clin Oncol. 2004;22:4500). The tumor is more common in children of African descent than of other races and is slightly more common in girls than boys.
Although genetic abnormalities have been identified in only a minority of nephroblastomas, multiple genetic abnormalities and syndromes are associated with the tumor. Abnormalities of WT1 on chromosome 11p13, a gene involved in renal and gonadal development, occurs in aniridia and genital anomalies syndrome (WAGR), Denys-Drash, and Frasier syndromes, all associated with a high risk for nephroblastoma. Molecular alterations of imprinted genes at the WT2 locus on chromosome 11p15 are associated with Beckwith-Wiedemann syndrome, which has an increased risk for nephroblastoma. Both WT1 and WT2 locus gene alterations are found in a minority of sporadic tumors. About 1% of patients with nephroblastoma have a family history of nephroblastoma; two familial genes, FWT1 and FWT2, have been identified in this setting in which the disease shows autosomal dominant transmission with variable penetrance (Curr Opin Pediatr. 2002;14:5). Other molecular alterations that are associated with tumor progression or aggressiveness have been identified; TP53 is implicated in progression to anaplastic nephroblastoma, and loss of heterozygosity of 1p and 16q is associated with poor prognosis in favorable histology nephroblastoma (J Clin Oncol. 2005;23:7312 and J Clin Oncol. 2006;24:2352).
TABLE 20.2 Common Molecular Derangements in Pediatric Renal Neoplasms
Tumor
Cytogenetic abnormality
Implicated genes
Protein role
Related assay(s)
Nephroblastoma
Deletions or mutations involving 11p13, 11p15, or Xq11.1
WT1, WT2, WT3, WTX
Zinc-finger DNA-binding protein; tumor suppressor genes
IPOX for WT1
Cellular mesoblastic nephroma
t(12;15)(p13;q25)
ETV6-NTRK3
Receptor tyrosine kinase
RT-PCR, FISH
Ewing sarcoma/PNET
Translocations of 22q11, usually t(11;22) (q24;q12)
EWS-FLI1
Transcriptional activator
RT-PCR, FISH; IPOX for CD99 or FLI-1
Synovial sarcoma
t(X;18)(p11;q11)
SYT and SSX1, 2, or 4
Chromatin remodeling, transcriptional regulation, β-catenin signaling pathways
RT-PCR, FISH
CCSK
t(10;17), del 14q
Undetermined
Undetermined
Karyotyping
Malignant rhabdoid tumor
Deletions or mutations involving 22q11.2
hSNF5/INI1
Chromatin remodeling and transcriptional regulation
IPOX for INI1 and cytokeratin
Translocation carcinomas
t(X;1)(p11.2;q34)
t(X;1)(p11.2;q25)
t(X;1)(p11.2;q21)
t(6;11)(p21;q12)
ASPL-TFE3
PSF-TFE3
PRCC-TFE3
Alpha-TFEB
Transcriptional activators
Karyotyping, IPOX for TFE and cathepsin K
Renal medullary carcinoma
Constitutional 11p15.5 mutation; possible 22q11.2 involvement
HBB
hSNF5/INI1
Hemoglobin S
Chromatin remodeling and transcriptional regulation
IPOX for INI1
Angiomyolipoma
9q34, 16p13.3, 5q mutations
TSC1, TSC2
Tumor suppressor genes
Constitutional karyotype
IPOX, immunoperoxidase; RT-PCR, reverse transcription-polymerase chain reaction; FISH, fluorescence in situ hybridization; PNET, primitive neuroectodermal tumor; CCSK, clear cell sarcoma of kidney. Compiled from References in Suggested Readings.
Nephroblastomas are usually solitary masses; however, 10% are multicentric and 5% are bilateral at presentation (e-Fig. 20.10). The cut surface is typically pale gray and friable and may be hemorrhagic or cystic. Stromal-predominant tumors often have a myomatous appearance. The tumor is derived from nephrogenic blastema and is composed of varying proportions of blastemal, epithelial, and stromal elements (e-Fig. 20.11). Nephroblastomas have a pushing border surrounded by a fibrous pseudocapsule; one exception, however, is the diffuse blastemal type, which infiltrates adjacent renal parenchyma. Other blastemal types include serpentine, nodular, and basaloid patterns. Epithelial differentiation includes tubular, papillary, and glomeruloid patterns; squamous cell, mucinous, and neural differentiation can also occur. The stroma may be primitive mesenchyme or show differentiation into skeletal muscle or, less frequently, smooth muscle, adipose tissue, and cartilage. Tumors with prominent heterologous elements are sometimes referred to as teratoid Wilms tumor.
Nephroblastomas are designated favorable or unfavorable on the basis of the presence and distribution of anaplasia rather than type of differentiation. Anaplasia is defined by the presence of bizarre or multipolar mitotic figures and large hyperchromatic nuclei (three times the size of other tumor nuclei) (e-Fig. 20.11F). Focal anaplasia is defined as one or more focal areas of anaplasia surrounded by nonanaplastic tumor and limited to the kidney. Anaplasia that does not meet the definition of focal is considered diffuse anaplasia. Anaplasia in a biopsy is also considered diffuse. Approximately 5% of tumors have diffuse anaplasia, which is the sole criterion for unfavorable histology. The incidence of anaplasia is higher in posttreatment nephrectomies (J Clin Oncol. 2006;24:2352).
Nephrogenic rests are the precursor lesions of nephroblastoma (e-Fig. 20.10B and e-Fig. 20.12). Perilobar nephrogenic rests are located at the periphery of the renal lobule, are well demarcated from adjacent renal parenchyma, and have predominantly blastemal and epithelial elements. The cells in hyperplastic perilobar rests are cytologically identical to malignant tumor cells; however, rests tend to be ovoid in shape rather than spherical, and they are not surrounded by a tumor pseudocapsule. Intralobar nephrogenic rests can occur anywhere in the kidney and have a prominent stromal component that intermixes with normal renal parenchyma. The presence of multiple nephrogenic rests or nephroblastomas is consistent with nephroblastomatosis and increases the risk for tumor in the contralateral kidney, especially in infants. In diffuse hyperplastic perilobar nephroblastomatosis, the renal parenchyma is extensively replaced by nephrogenic tissue (e-Fig. 20.10C). The diagnosis is made by imaging studies and is treated without biopsy. Tumors that grow despite chemotherapy are removed with kidney-sparing surgical procedures (Pediatr Develop Pathol. 2009;12:237). Ectopic nephrogenic rests occur rarely (usually in the inguinal canal or intrapelvic sacrococcygeal regions) and can be associated with extrarenal nephroblastoma (J Pediatr Surg. 2009;44:e13).
Nephroblastomas with prominent cysts are designated cystic nephroblastomas. Multiloculated renal cysts with microscopic areas of nephroblastoma in the cyst walls, without any expansile septal mass, are designated partially differentiated cystic nephroblastomas (e-Fig. 20.10D). Multilocular cysts with only mature elements and no expansile nodules are designated cystic nephroma (CN) and, in children, are thought to represent end-stage differentiation of nephroblastoma (Semin Diagn Pathol. 1998;15:2, and Cancer. 1989;64:466). Familial and bilateral CN are associated with DICER1 mutations and pleuropulmonary blastoma (J Med Genet. 2010;47:863).
Following chemotherapy, biopsied or partially resected (usually bilateral) nephroblastomas are categorized according to histologically observed treatment effect (Pediatr Dev Pathol. 2005;8:320) (summarized in Table 20.3).
Most tumors will fall into the “intermediate” grade with subtotal necrosis and classic triphasic elements observed in the remaining viable tumor; under current protocols, these patients receive an additional 6 weeks of chemotherapy. Less frequently, tumors may show complete necrosis, in which case surgical resection can be performed without additional chemotherapy. Biopsy specimens demonstrating worrisome histologic features such as predominance of blastemal elements or anaplasia after initial treatment are switched to more aggressive chemotherapeutic regimens.
TABLE 20.3 Pathologic Staging of Nephroblastoma and Other Pediatric Renal Neoplasms
Stage
Pathologic criteria
I
Tumor limited to the kidney and completely resected
Intact renal capsule
No rupture or previous biopsy
Renal sinus vessels not involved
No evidence of tumor at or beyond margins of resection
II
Tumor completely resected
Tumor extends beyond the kidney, due to one of the following:
Penetration of the renal capsule
Extensive invasion of the soft tissue of the renal sinus
Tumor within blood vessels outside the renal parenchyma, including those of the renal sinus
No evidence of tumor at or beyond the margins of resection
III
Residual nonhematogenous tumor confined to the abdomen, as evidenced by:
Involvement of lymph nodes within the abdomen or pelvis
Penetration through the peritoneal surface
Tumor implants on the peritoneal surface
Tumor present at the margin of surgical resection
Tumor not resectable because of local infiltration into vital structures
Tumor spillage of any degree or disruption occurring before or during surgery
Tumor removed in more than one piece
Biopsy by any method prior to removal
IV
Hematogenous metastases (lung, liver, bone, brain, etc.)
Lymph node metastases outside the abdomen or pelvis
V
Bilateral renal involvement at diagnosis
Stage each side separately using above criteria
Modified from Pediatr Dev Pathol. 2005;8:320.
B. Metanephric tumors are well-differentiated nephroblastic tumors containing varying proportions of epithelial and stromal cells. Metanephric tumors are benign; however, both nephroblastoma and papillary RCC have been reported in tumors with epithelial elements.
1. Metanephric stromal tumors (MSTs) occur throughout childhood, but most commonly in infancy (e-Fig. 20.13). Historically, these tumors were considered to be mesoblastic nephromas (MN) (discussed later) but are now considered a distinct entity. MST is usually solitary and extends out from the renal medulla as an unencapsulated mass that may be solid or cystic. The cut surface is firm and myomatous. Microscopically, the tumor is composed of spindled to stellate cells with indistinct cytoplasm. Under low-power microscopy, the tumor has a distinct nodular appearance due to alternating areas of hypocellularity and hypercellularity. The tumor is unencapsulated, and bands of tumor cells extend outward to entrap adjacent glomeruli and tubules, resulting in cysts and epithelial embryonal and juxtaglomerular
hyperplasia. Distinguishing features include concentric cuffs of spindled cells around blood vessels and renal tubules (“collarettes”) and angiodysplasia of arterioles with epithelioid transformation of smooth muscle. Heterologous elements such as cartilage and glial tissue are infrequently present (Am J Surg Pathol. 2000;24:917).
2. Metanephric adenofibromas (MAFs) occur in both children and adults. In children, the tumor has been reported as early as 5 months of age. MAFs are centrally located and contain varying proportions of stroma resembling MST as well as the epithelial nodules of metanephric adenoma. The peripheral stromal component merges with normal renal parenchyma in a manner similar to intralobar nephrogenic rests (see section on adult tumors) (Am J Surg Pathol. 2001;25:433).
3. Metanephric adenoma occurs most frequently in adults, although the tumor has been reported in children as young as 5 years of age (see section on adult tumors). In children, the main differential diagnosis is epithelial nephroblastoma. Unlike nephroblastoma, however, mitoses are rare, and there is no pseudocapsule, blastemal component, or vascular invasion. Immunohistochemical stains are helpful in distinguishing metanephric adenoma from papillary RCC, but not for distinguishing metanephric adenoma from epithelial nephroblastoma.
C. Mesoblastic nephroma (MN) is a distinct neoplasm of infancy which may present antenatally as fetal hydrops (e-Fig. 20.14). Tumors diagnosed in a child >2 years most likely represent MST, clear cell sarcoma of the kidney (CCSK), or other tumor. The tumors are unencapsulated, solitary, and they tend to infiltrate the renal sinus. Microscopically, they are characterized as cellular, classic, or mixed histology. Classic MN consists of intersecting fascicles of spindled cells resembling infantile fibromatosis. Long fascicles of tumor cells extend into the adjacent renal parenchyma, entrapping tubules and glomeruli and resulting in cysts and epithelial embryonal metaplasia. Dysplastic change with cartilage may be present in adjacent parenchyma. Consistent molecular abnormalities have not been identified with classic histology tumors. Cellular MN is composed of plump cells with vesicular nuclei, variable amounts of cytoplasm, and increased mitoses. The tumor has a well-demarcated interface with adjacent renal parenchyma, although it lacks a pseudocapsule. Cellular MN is histologically similar to infantile fibrosarcoma, both of which have the t(12;15)(p13;q25) chromosomal translocation that produces the fusion gene ETV6-NTRK3. Mixed MN contains both cellular and classic areas. MNs are treated by complete surgical resection, with adjuvant chemotherapy for positive margins. The recurrence rate is 5% to 10%, and the tumor rarely metastasizes, usually to lung (Adv Anat Pathol. 2003;10:243).
D. Clear cell sarcoma of kidney (CCSK) represents 4% of pediatric renal tumors. It is a primitive mesenchymal neoplasm not associated with any consistent chromosomal or genetic abnormality, although t(10;17) and del(14q) are frequently seen (Arch Pathol Lab Medi. 2007;131:446). CCSK occurs usually from 1 to 4 years of age but is also seen in infants (including stillborns) and rarely in adults. It is a high-risk neoplasm, with a tendency for metastases (lung, bone, brain, and soft tissue) and late recurrence. Boys are affected more often than girls. The tumor is unilateral, solitary, well-circumscribed, and located in the renal medulla. Its cut surface is typically tan-gray and mucoid, although the surface may have a firm, whorled appearance (e-Fig. 20.15). Cysts are often present. Microscopically, areas with classic histology contain nests and cords of uniform polygonal to spindled cells that have ovoid nuclei with finely granular to vesicular chromatin, inconspicuous nucleoli, and indistinct cytoplasm, in a background of clear extracellular matrix. A delicate, arborizing fibrovascular network separates groups of tumor cells. The tumor interface is well circumscribed
under low-power microscopy; however, a pseudocapsule is not present, and tumor extends a short distance into adjacent parenchyma, entrapping tubules that may be cystic or have epithelial metaplasia. Almost all tumors have at least focal classic histology; however, numerous variant histologies including myxoid, sclerosing, cellular, epithelioid, palisading, spindle cell, pericytomatous, storiform, and anaplastic patterns may also be present and may predominate (e-Fig. 20.15). CCSK tumor cells are positive for vimentin and negative for epithelial markers. Although immunohistochemical stains may be useful in ruling out other tumors on an individual basis, there are no specific markers for CCSK (Am J Surg Pathol. 2004;24:4 and Virchows Arch. 2005;446:566).
E. Rhabdoid tumor of the kidney (RTK) is a highly aggressive malignant neoplasm of infancy, accounting for 2% of pediatric renal tumors (e-Fig. 20.16). Most patients present at <1 year of age with metastatic disease, and almost all patients present by 3 years. ˜10% to 15% of RTKs are associated with rhabdoid tumors of the central nervous system. Both renal and extrarenal infantile rhabdoid tumors contain molecular alterations of the hSNF5/INI1 gene at chromosome 22q11. Grossly, the renal tumor is pale tan, unencapsulated, and arises from the renal medulla. Multicentric or bilateral tumors are considered metastatic lesions. In areas of classic histology, there are sheets of discohesive tumor cells with large vesicular nuclei, prominent nucleoli, and abundant eccentric cytoplasm containing large eosinophilic inclusions. Ultrastructurally, these inclusions consist of whorls of intermediate filaments that are characteristic but not specific for the tumor. Cells with smaller nuclei and less cytoplasm may sometimes predominate. Variant histology includes sclerosing, epithelioid, spindled, and lymphomatoid patterns. Tumor cells have a polyphenotypic immunostaining pattern, with diffuse vimentin positivity and patchy positivity for other markers, including epithelial markers. There is absent nuclear staining for INI1 (Adv Anat Pathol. 2003;10:243, Am J Surg Pathol. 1989;1313:439, Am J Surg Pathol. 2004;28:1485).
F. Pediatric renal cell carcinoma (RCCs). Although pediatric RCCs bear a strong morphologic resemblance to their adult counterparts, they often possess unique clinical, pathologic, and genetic features that distinguish them from the adult versions (Adv Anat Pathol. 2003;10:243). The mean age at presentation is between 9 and 10 years, and the sentinel symptoms include a palpable mass, flank and/or abdominal pain, hematuria, polycythemia, and hypertension. Children tend to have a slightly better prognosis than adults, primarily due to their presentation at earlier stages; metastatic disease has a poor prognosis (<10% 5 year survival) in both groups.
1. In adults, clear cell RCC is the most common malignant epithelial renal neoplasm, but in children this tumor is less common and probably occurs only in patients with von Hippel-Lindau syndrome or another predisposing genetic background. The histopathologic features are identical to those in adult clear cell RCC (see section on adult neoplasms). Many previously reported/diagnosed cases of pediatric clear cell RCC are now thought to be associated with Xp11.2 translocations and therefore likely represent different entities (discussed later).
2. In children, papillary RCC is the most common malignant epithelial neoplasm of the kidney (Am J Surg Pathol. 1999;23:795). The histologic, molecular, and genetic findings are identical to those of the adult tumors. The tumor is microscopically composed of a single layer of columnar cells lining a papillary stalk, often with clusters of foamy macrophages, hemosiderin, and necrosis in the surrounding background. The neoplasm is often surrounded by a pseudocapsule with an associated lymphoid infiltrate. The tumor cells are strongly positive for CK7 and EMA expression, which can help differentiate papillary RCC from Wilms tumor and metanephric adenoma.
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