Renal Neoplasms

John N. Eble

David J. Grignon

A diverse array of tumors can arise in the human kidney. In this chapter, these will be covered using an approach that has become a standard one in dealing with this group of tumors. The classification of epithelial tumors of the kidney has in particular undergone substantial progress in the last two decades with major contributions from genetic typing of renal cell carcinomas (RCCs). The role of genotyping and ancillary tools, in particular immunohistochemistry, in correctly classifying these tumors is highlighted in the section on Renal Cell Carcinoma. In 2012, the International Society of Urologic Pathology (ISUP) updated the 2004 World Health Organization (WHO) classification of these tumors; the modified classification is highlighted in Table 30.1 (1). The first section will cover those tumors that characteristically are associated with the pediatric population. This is a somewhat arbitrary designation, as most tumors can develop over a wide age range. This is followed by coverage of neoplasms in the more traditional categories of epithelial, mesenchymal, and other categories. Specific discussions of etiology and pathogenesis are dealt with in each of the sections on individual tumors, rather than as a freestanding section, as is used elsewhere in this text. The purpose of this chapter is to familiarize the reader with the tumor types encountered in the human rather than to provide a comprehensive diagnostic reference, which is better handled in more comprehensive textbooks and monographs.

PEDIATRIC NEOPLASMS

Wilms Tumor

Clinical Findings and Epidemiology

More than 80% of renal tumors of childhood are Wilms tumor (nephroblastoma) (1,2). Neonatal Wilms tumor is rare. Most Wilms tumor occurs in children between the ages of 2 and
4 years (3). It is uncommon in the first 6 months of life and after 6 years of age. It is slightly more common in girls than in boys (3). It is bilateral in about 5% of cases (4). Wilms tumor may be associated with hemihypertrophy and aniridia and with genital anomalies, such as cryptorchidism and hypospadias (5). Patients with Beckwith-Wiedemann syndrome and Denys-Drash syndrome have an increased risk of developing Wilms tumor (5,6). Wiedemann-Beckwith syndrome is related to abnormalities on chromosome 11p15 and characterized by multiple craniofacial anomalies, abdominal wall defects, and tumors of the genitourinary tract, liver, adrenal gland, and central nervous system among other abnormalities. Denys-Drash syndrome, due to mutations of the WT1 gene, is also associated with a congenital nephropathy and disorders of sexual development. Wilms tumor is rare in adults (3). Wilms tumor is believed to arise from embryonic tissues called nephrogenic rests that fail to undergo normal involution (7).

TABLE 30.1 Modified 2004 WHO classification of renal tumors

Renal cell tumors
	Clear cell renal cell carcinoma
		Multilocular cystic clear cell renal cell carcinoma
	Papillary renal cell carcinoma Chromophobe renal cell carcinoma Carcinoma of the collecting ducts of Bellini (collecting duct carcinoma) Renal medullary carcinoma Translocation-associated carcinomas Mucinous tubular and spindle cell carcinoma Tubulocystic carcinoma Clear cell papillary renal cell carcinoma Acquired cystic disease-associated carcinoma Carcinoma associated with neuroblastoma Papillary adenoma Oncocytoma
Metanephric tumors
	Metanephric adenoma Metanephric adenofibroma Metanephric stromal tumor
Nephroblastic tumors
	Wilms tumor (nephroblastoma) Cystic partially differentiated Wilms tumor (nephroblastoma)
Mesenchymal tumors
	Occurring mainly in children
		Clear cell sarcoma Rhabdoid tumor Congenital mesoblastic nephroma Ossifying renal tumor of infancy
	Occurring mainly in adults
		Angiomyolipoma
			Epithelioid angiomyolipoma
		Leiomyosarcoma (including the renal vein) Angiosarcoma Solitary fibrous tumor Rhabdomyosarcoma Osteosarcoma Leiomyoma Hemangioma Lymphangioma Schwannoma Juxtaglomerular cell tumor Renomedullary interstitial cell tumor
Mixed mesenchymal and epithelial tumors
	Cystic nephroma
		Pediatric Adult
	Mixed epithelial and stromal tumor Synovial sarcoma
Neuroendocrine tumors
	Carcinoid Neuroendocrine (small cell) carcinoma Primitive neuroectodermal tumor Neuroblastoma Pheochromocytoma
Hematopoietic and lymphoid tumors
	Lymphoma Leukemia Plasmacytoma
Germ cell tumors
	Teratoma Choriocarcinoma
Metastatic tumors

Pathology

GENETICS

The development of Wilms tumor has been linked to mutations of the WT1 and WT2 genes located on chromosome 11 at 11p13 and 11p15.5, respectively (8,9).

GROSS

Wilms tumor often is greater than 5 cm in diameter, with an average size of 10 cm (3). The cut surface is typically solid, soft, and gray or pink, with a texture and appearance resembling brain tissue. The tumor is usually circumscribed by a pseudocapsule formed of compressed renal and perirenal tissues. Cysts are common, as are foci of hemorrhage and necrosis (Fig. 30.1). Predominantly cystic Wilms tumor that contains blastema and other Wilms tumor tissues in its septa is called cystic partially differentiated nephroblastoma (10).

MICROSCOPIC

Histology remains the most important prognostic indicator of Wilms tumor (11). Wilms tumor is typically composed of a mixture of blastema, epithelium, and stroma; sometimes one or two of these components are absent (Fig. 30.2) (12). Stromal and epithelial predominant Wilms have an excellent prognosis (13). Blastema consists of densely packed small cells randomly arranged in sheets. Blastemal cells have dense nuclei, frequent mitotic figures, and inconspicuous cytoplasm. Aggregates of blastema commonly form serpentine, nodular, and diffuse patterns that have sharp borders with the stromal component.

FIGURE 30.1 Wilms tumor. A large, pale, bulging mass in a small kidney.

The epithelium of Wilms tumor usually consists of small tubules or cysts lined by columnar or cuboidal cells. Occasionally, it forms stubby papillae superficially resembling glomeruli or has mucinous, squamous, neural, or endocrine differentiation (12,14).

The stroma of Wilms tumor is variable and may differentiate toward almost any type of mesenchymal tissue. Nondescript myxoid and fibroblastic spindle cell stroma is most common, but smooth muscle, skeletal muscle, fat, cartilage, and bone are present in some tumors (12,14). When diffuse differentiation toward skeletal muscle occurs, the term fetal rhabdomyomatous nephroblastoma is applied (15,16). There is evidence that these are more resistant to chemotherapy (16). Complex combinations of differentiated epithelium and stroma are sometimes present. The term teratoid Wilms tumor has been applied to these (17,18). These tumors are also resistant to preoperative chemotherapy (18).

FIGURE 30.2 Wilms tumor. Typical triphasic histology with epithelial, blastemal, and mesenchymal elements. In this case, the mesenchymal component is primitive and undifferentiated.

FIGURE 30.3 Wilms tumor. Focus of anaplasia in a Wilms tumor with nucleomegaly, hyperchromasia, and multipolar mitotic figure.

The most important pathologic prognostic feature is the presence or absence of anaplasia (19,20,21). Anaplasia is defined as the combination of cells with enlarged hyperchromatic nuclei (at least three times as large as typical blastemal nuclei in both axes and having obvious hyperchromasia) and multipolar mitotic figures (Fig. 30.3). Recognition of anaplasia requires proper fixation, sectioning, and staining. The criteria for abnormal hyperdiploid mitotic figures are stringent; not only must there be structural abnormalities but the mitotic figure must also be enlarged as evidence of hyperploidy. Enlarged nuclei in skeletal muscle fibers in the stroma of Wilms tumor are not evidence of anaplasia.

Treatment and Outcome

The progress in the treatment of Wilms tumor is one of the great success stories of oncology. Most cases are treated with surgery and dactinomycin and vinblastine chemotherapy with relatively low toxicity (11). Mortality declined approximately 10% per decade throughout the past century. This owes in large part to the efforts of the National Wilms Tumor Study (NWTS). From the results of the NWTS, Wilms tumor has been classified as having either favorable or unfavorable histology, depending on whether or not anaplasia is present. Approximately 2% of Wilms tumors in patients under 2 years of age have anaplasia, and this increases to 13% in children over age 5 years (9). The staging scheme for Wilms tumor and other pediatric renal malignancies differs somewhat from that used for RCC (Table 30.2) (22). Currently, the overall survival for patients diagnosed with Wilms tumor is approximately 90% (3,11).

Congenital Mesoblastic Nephroma

Clinical Findings and Epidemiology

Congenital mesoblastic nephroma makes up less than 3% of renal neoplasms in children; it is the predominant renal neoplasm in the first 3 months of life and is uncommon after 6 months (23,24). The births of patients with congenital mesoblastic nephroma often are complicated by polyhydramnios and prematurity. The presenting finding is almost always
an abdominal mass. Congenital mesoblastic nephroma was first recognized in 1966 (25), and subsequent studies have shown it to be a morphologically distinct tumor with a good prognosis (24).

TABLE 30.2 Staging system for renal tumors of childhood

Stage I
	Tumor is limited to the kidney or surrounded by a fibrous capsule (pseudocapsule) Tumor can protrude into the renal pelvis or ureter Intrarenal vessel involvement can be present
Stage II
	Viable tumor penetrates into perirenal fat but not to the surgical resection margin Viable tumor infiltrates the soft tissue of the renal sinus Viable tumor infiltrates blood or lymphatic channels outside of the kidney but is completely resected Viable tumor infiltrates the renal pelvis or ureter wall Viable tumor infiltrates adjacent organs or vena cava, but is completely resected
Stage III
	Viable or nonviable tumor extends beyond the resection margins Any abdominal lymph nodes are involved Tumor ruptures before or intraoperatively (irrespective of other criteria) Tumor has penetrated through the peritoneal surface Tumor implants are present on the peritoneal surface. Tumor thrombi are present at resection margins of vessels or the ureter (or removed piecemeal by the surgeon) Tumor has been surgically biopsied (wedge biopsy) prior to preoperative chemotherapy or surgery
Stage IV
	Hematogenous metastases (lung, liver, bone, brain, etc.) or lymph node metastases outside the abdominopelvic region
Stage V
	Bilateral renal tumors at diagnosis (each side substaged as above)

Pathology

GENETICS

Congenital mesoblastic nephroma has genetic similarities to infantile fibrosarcoma with the t(12;15)(p13.q35) translocation common to both (26,27).

GROSS

Congenital mesoblastic nephroma is usually large relative to the infant’s kidney. The external surfaces of the tumor and kidney are smooth, and the renal capsule and renal pelvis and caliceal system are stretched over the tumor. Congenital mesoblastic nephroma may be spherical or bosselated. The cut surface resembles leiomyoma: firm, whorled or trabeculated, and pale (28). There is no true capsule. The tumor usually mingles with the surrounding kidney and may extend into perinephric soft tissue. Invasion of the renal vein occurs occasionally. Cysts, necrosis, and hemorrhage may be found occasionally, particularly in cases that are cellular on microscopic examination.

FIGURE 30.4 Congenital mesoblastic nephroma. The tumor is composed of bland, spindle-shaped cells growing in an infiltrative manner; note the invasion between entrapped normal structures.

MICROSCOPIC

Bolande (29) described the classic pattern of congenital mesoblastic nephroma: a moderately cellular neoplasm composed of interlacing bundles of spindle cells with elongate nuclei, usually infiltrating renal and perinephric tissues (Fig. 30.4). In the classic pattern, there is usually either one mitotic figure per 10 high-power fields or less (28). Some tumors contain small islands of cartilage or foci of extramedullary hematopoiesis.

Later, a second, more common, pattern was recognized. This pattern is densely cellular and composed of polygonal cells. Mitotic figures are present in the range of 8 to 30 per 10 high-power fields. Cysts are common in this pattern. Rather than being infiltrative, the borders usually are “pushing.” This pattern is called cellular congenital mesoblastic nephroma (28,30). Often both the classic and cellular patterns are mixed in the same tumor.

Congenital mesoblastic nephroma is usually not difficult to diagnose when age and histology are considered. The major differential diagnostic consideration is Wilms tumor with stromal predominance, especially if it has been treated preoperatively with chemotherapy. Identification of blastema, which does not occur in mesoblastic nephroma, usually resolves the issue. Also, the sharply circumscribed borders of Wilms tumor contrast with the infiltrative borders of mesoblastic nephroma.

Treatment and Outcome

Almost all are cured by surgical resection (24). Recurrence and adverse outcome are rare and have mainly occurred in patients older than 3 months when the tumor was discovered. Congenital mesoblastic nephroma has infiltrative borders that the surgical pathologist must carefully study because recurrence may occur if resection is incomplete. Metastasis is exceptional (31,32). It has been suggested that the cellular pattern is prone to recur. Because it is the more common pattern and the great majority of patients are cured, any such tendency must be small, and age and completeness of resection are the prime risk factors.

Clear Cell Sarcoma of Kidney

Clinical Findings and Epidemiology

Clear cell sarcoma occurs in the same age range as Wilms tumor and makes up approximately 6% of renal neoplasms in children (33,34). Most patients are between 1 and 3 years old, and about two thirds are male. Only three cases of bilateral clear cell sarcoma are described, and these may represent metastases rather than two primaries (34).

Pathology

GENETICS

A common translocation t(10;17)(q22;p13) has been identified in some cases (35). This results in fusion of the YWHAE and FAM22 genes (35).

GROSS

Clear cell sarcoma usually is large, is well circumscribed, and often weighs more than 500 g (33). The cut surfaces of clear cell sarcoma have a variable appearance: Some are homogeneous, gray, and lobular; others are variegated and composed of firm gray whorled tissue with light pink soft areas. In some, an abundance of extracellular mucin imparts a glistening slimy appearance. Approximately 33% of tumors have cysts ranging from a few millimeters to several centimeters in diameter.

MICROSCOPIC

The typical appearance of clear cell sarcoma at low magnification is of a monotonous sheet of cells with pale cytoplasm. At higher magnification, the cells are recognized to be organized in cords separated by branching septa composed of spindle cells with dark nuclei and of small blood vessels. The cells of the cords have pale cytoplasm and indistinct cytoplasmic membranes (Fig. 30.5). Although the cytoplasm of the cord cells is pale, it usually is not clear in the same way as that of clear cell RCC, and clarity of cytoplasm is not key to making the diagnosis. Nuclear features are key to the diagnosis. The chromatin is finely dispersed, and the nucleoli are small and inconspicuous. This differs from the dark nuclei of blastema in Wilms tumor and the prominent nucleoli typical of rhabdoid tumor. Another helpful feature is the infiltrative border in which renal tubules are frequently surrounded by sarcoma; this contrasts with the circumscribed border typical of Wilms tumor. Confusing variations on the classic pattern occur—including spindle cell, cystic, hyaline sclerosis, and palisading (12,33). In such cases, generous sampling often reveals areas in which the pattern of cords and septa indicates the correct diagnosis. Other helpful points that distinguish clear cell sarcoma of the kidney from Wilms tumor include the following: blastema does not occur in clear cell sarcoma, heterologous elements such as cartilage or muscle do not occur in clear cell sarcoma, clear cell sarcoma is neither multicentric nor bilateral, and sclerotic stroma is uncommon in Wilms tumor before therapy. Rarely, clear cell sarcoma contains foci in which the cells have prominent nucleoli, resembling those of rhabdoid tumor of the kidney; in other areas, patterns typical of clear cell sarcoma often clarify the diagnosis.

FIGURE 30.5 Clear cell sarcoma of the kidney. The tumor is composed of small, uniform spindle cells with scant pale cytoplasm growing in cords.

Rhabdoid Tumor of the Kidney

Clinical Findings and Epidemiology

Rhabdoid tumor is the most aggressive renal neoplasm of childhood and metastasizes widely to cause death in the majority of patients within 3 years of the time of diagnosis (38,39). The NWTS median age at diagnosis is 11 months, and few rhabdoid tumors occur after 3 years. Boys predominate over girls in a ratio of 3:2 (39). Embryonal tumors of the central nervous system (40) and paraneoplastic hypercalcemia (41) occasionally are associated with rhabdoid tumor of the kidney.

Pathology

GENETICS

Almost all cases studied have been found to have a mutation or deletion of the SMARCB1/INI1 gene located at chromosome 22q.11 (42).

GROSS

Rhabdoid tumor is less well circumscribed than Wilms tumor or clear cell sarcoma. Most tumors are located in the center of the kidney, and it is usual for the renal sinus (the space formed by the medial concavity of the kidney containing fat, loose connective tissue, vascular structures, the renal pelvis, and proximal ureter) and pelvis to be infiltrated (39). The parenchyma of rhabdoid tumor is usually light tan or yellow-gray, solid, and friable with foci of necrosis and hemorrhage.

MICROSCOPIC

Rhabdoid tumor consists of medium or large polygonal cells with abundant eosinophilic cytoplasm and round nuclei with thick nuclear membranes and large nucleoli. The cells are arranged in diffuse sheets (Fig. 30.6). The name was given because the cytoplasm often bears a superficial resemblance to that of differentiating rhabdomyoblasts. The resemblance is
spurious, and if there is definite differentiation toward skeletal muscle, the tumor is not a rhabdoid tumor. The cytoplasm commonly contains a large eosinophilic inclusion that forces the nucleus to one side. At the ultrastructural level, these inclusions are composed of whorled microfilaments (39). A variety of rare patterns have been recognized, including sclerosing, epithelioid, spindle cell, lymphomatoid, vascular, pseudopapillary, and cystic (39). These are usually mixed with the typical pattern and with each other and retain the characteristic nuclear features. It is important to recognize that a number of other primary kidney tumors including medullary carcinoma and RCC can have rhabdoid-like cells (43).

FIGURE 30.6 Rhabdoid tumor. The tumor is composed of a sheet of loosely cohesive cells having vesicular nuclei with prominent nucleoli. Many of the cells have fibrillar eosinophilic cytoplasmic inclusions.

SPECIAL STUDIES

These tumors do not express muscle markers and are positive for vimentin. Loss of INI1 expression can be demonstrated by immunohistochemistry in these tumors (44).

Metanephric Adenoma

Clinical Findings and Epidemiology

The rare tumor known as metanephric adenoma has now been described in detail (47,48,49,50,51,52). Epithelial neoplasms of the kidney are rare in children, but among them metanephric adenoma is the most common. It occurs at all ages but is most common in middle age, with a 2:1 female preponderance. Approximately 50% of metanephric adenomas are incidental findings, with others presenting with polycythemia, abdominal or flank pain, mass, or hematuria. The relationship, if any, of metanephric adenoma to other families of renal neoplasms has been debated. They do not have the chromosomal gains characteristic of papillary renal neoplasia (53), and some consider them to be related to Wilms tumor (52). Metanephric adenoma is part of a family of neoplasms that includes the even rarer metanephric adenofibroma (54) and metanephric stromal tumor (55). The 2004 WHO classification places these tumors in a family by themselves (1).

Pathology

GENETICS

Gains of chromosome 19 have been detected in some cases by comparative genomic hybridization in one study (56) but not in another (57). In another report, the presence of a tumor suppressor gene at chromosome 2p13-21 was detected (58). Most recently, BRAF mutations were detected in 90% of 29 cases studied (59).

GROSS

Metanephric adenoma is well circumscribed, gray or pale tan, and solid or lobular, and its size ranges up to 15 cm. Small cysts and calcifications can be present.

MICROSCOPIC

Metanephric adenoma is composed of small, uniform, round tubules embedded in a loose stroma. It is sharply circumscribed and can have a fibrous capsule. At first glance, Wilms tumor usually comes to mind. Nuclei are small and uniform with absent or inconspicuous nucleoli and scant cytoplasm (Fig. 30.7). Papillary or microcystic architectures are less common. Psammoma bodies are common, as are hemorrhage and necrosis. Wilms tumor stroma and blastema are not found in metanephric adenoma.

SPECIAL STUDIES

Metanephric adenoma cells usually react with antibodies to WT1 (49,51). It is usually nonreactive or only weakly reactive for cytokeratin 7 and epithelial membrane antigen (48,51). The majority do not express alpha-methylacyl-CoA racemase (AMACR) (60).

Treatment and Outcome

Cases reported to date have not recurred or metastasized. There have been two cases with an associated papillary RCC described
that developed metastases (61,62). Fewer than a handful of metanephric adenomas have been associated with psammoma bodies or even epithelial cells in lymph nodes draining the kidney with the metanephric adenoma; the nature of this process is unclear (63).

FIGURE 30.7 Metanephric adenoma. The tumor is composed of small uniform cells with scant cytoplasm and forms regular round tubules.

Translocation Carcinomas

Over the last several years, a family of renal carcinomas that contain various translocations involving Xp11.2 has been identified (64,65). All of these translocations resulted in gene fusions involving TFE3. This family of carcinomas was classified as Xp11 translocation carcinomas in the 2004 WHO classification (1). Subsequently, carcinomas with a t(6;11) producing a fusion with the TFEB gene have been identified (66). Since TFE3 and TFEB are members of the MiTF/TFE family of transcription factor genes, some authors have grouped these together as MiT-related RCCs (67).

Clinical Findings and Epidemiology

Although carcinomas make up less than 5% of renal tumors in children (68,69), translocation carcinomas appear to make up at least 20% to 50% of pediatric renal carcinomas (70,71,72). Translocation carcinomas also occur in adults although their frequency remains unclear (73). Some patients have had histories of chemotherapy for other conditions (71).

Pathology

GENETICS

This group of tumors includes several translocations that result in different gene fusions. These include t(X;1)(p11.2.q21) with PRCC-TFE3 gene fusion, t(X;1)(p11.2;p34) with PSF-TFE2 fusion, inv(X)(p11;q12) with NONO-TFE3 fusion, t(X;17) (p11.2.q25) with ASPL-TFE3 fusion, t(X;17)(p11.2;q23) with CLTC-TFE3 fusion, and t(6;11)(p21;q13) with Alpha-TFEB fusion (67).

GROSS

Translocation carcinomas are typically nondescript solid tanyellow neoplasms, often with foci of hemorrhage and necrosis.

MICROSCOPIC

Xp11.2 translocation carcinomas often have large areas of papillary architecture in which the papillae are covered by cells with abundant clear or pale cytoplasm (Fig. 30.8). However, they also have an alveolar or nested architecture, and cells with eosinophilic cytoplasm are common. Psammoma bodies are common and may be quite numerous. There are subtle variations in morphology among carcinomas with the different Xp11 translocations.

The t(6;11) translocation carcinomas consist of nests and microscopic cysts composed of polygonal cells with pale or eosinophilic cytoplasm. Papillae are uncommon. A distinctive component consists of cells with small amounts of cytoplasm and denser chromatin arranged around nodules of hyaline material in large acini. At low magnification, these resemble rosettes (74).

The t(X;17)(p11.2;q25) translocation carcinomas are composed of cells with abundant clear cytoplasm forming papillae and large nests. These tumors also produce prominent hyaline nodules and contain many psammoma bodies (75,76).

FIGURE 30.8 Xp11.2 translocation carcinoma. The tumor is composed of clear cells forming papillary and solid architectures. Note the large calcification.

There are also very rare tumors considered to belong to this family that produce visible melanin pigment (77,78). These have been reported under the term “melanotic Xp11 translocation renal cancer” (77).

SPECIAL STUDIES

Translocation carcinomas with gene fusions involving TFE3 typically show a positive intranuclear reaction with antibody to TFE3 protein (79). Carcinomas with gene fusions involving TFEB typically show positive intranuclear reactions with antibody to TFEB. Xp11 translocation carcinomas characteristically fail to mark or mark weakly with antibodies to epithelial markers, such as epithelial membrane antigen and cytokeratins (64,73,80). Expression of cathepsin-K is present in both TFE3- and TFEB-related carcinomas (74,81). t(6;11) carcinomas are frequently positive for HMB45 and melan-A (66,74). The hyaline nodules typical of the t(6;11) and t(X;17) tumors react with antibodies to type IV collagen. Ultrastructurally, despite the expression of melanocytic markers, melanosomes or premelanosomes are not present in the t(6;11) carcinomas (74).

Carcinoma Associated With Neuroblastoma

Roughly two dozen children and young adults have been diagnosed with RCC after surviving neuroblastoma in the first 2 years of life (84). In 1999, Medeiros et al. (85) published an account of four survivors of neuroblastoma who had histologically distinctive renal tumors and suggested that they constituted a distinct clinicopathologic entity; subsequently, another series of similar tumors in neuroblastoma survivors
was published (86). A few similar looking tumors have also been reported in children treated with chemotherapy for other tumors (87).

Clinical Findings and Epidemiology

The patients had neuroblastoma at the usual age; two of them received neither radiation nor chemotherapy. They were diagnosed with RCC at ages ranging from 5 to 14 years. In one patient, the RCC metastasized to the lymph nodes and liver.

Pathology

GENETICS

There is no information on the genetics of these tumors.

GROSS

The majority tumors have ranged in diameter from 35 to 80 mm; the 20 small tumors in the patient with multiple and bilateral tumors ranged from 1 to 24 mm. Two tumors were invasive of renal capsule, renal vascular system, or peripelvic lymphatics.

MICROSCOPIC

The best-documented postneuroblastoma carcinomas of the kidney contain majority populations of cells with abundant eosinophilic cytoplasm that sometimes is reminiscent of the cytoplasm in oncocytomas (Fig. 30.9). The cells grow in both papillary and solid patterns. Psammoma bodies are infrequently present, as are small clusters of foamy histiocytes. The nuclei often are medium sized and have irregular contours. Nucleoli are easy to find, corresponding to nuclear grade 3. A few mitotic figures are usually present.

SPECIAL STUDIES

All tumors studied have reacted with antibodies to epithelial membrane antigen, vimentin, and cytokeratin Cam 5.2.

ADULT NEOPLASMS EPITHELIAL NEOPLASMS

Papillary Adenoma

Clinical Findings and Epidemiology

All classifications of renal tumors include adenoma as an entity (1,10,88), although criteria for distinguishing adenoma from carcinoma in the kidney remain a significant and unresolved issue in surgical pathology. With increasing numbers of small tumors, including many under 1 cm, being detected with new imaging technology, resolution of this issue is important (89,90,91). Small cortical epithelial lesions have been found in 7% to 37% of kidneys in autopsy series (92,93,94). Eble and Warfel (95) evaluated a series of 400 consecutive autopsies in which the kidneys were carefully sectioned and examined; in 83 instances (21%), epithelial cortical lesions were identified. The frequency increased with age (10% in 21- to 40-year-olds vs. 40% in 70- to 90-year-olds). Similar tumors frequently develop in patients on long-term hemodialysis, and papillary adenomas have been reported in up to one third of patients in association with acquired cystic disease (96,97). These are believed to be the precursors of carcinoma in this patient group (96,98)

Pathology

GENETICS

Papillary adenoma has similar cytogenetic changes to papillary carcinoma with trisomy 7 and 17 (99).

GROSS

Papillary adenoma is currently defined as being 5 mm or less in size (1,10). Tumors as small as 1 mm are identifiable with the naked eye. It is well circumscribed, yellow to gray, and located in the cortex. Most are single, but it is not rare for multiple adenomas to be present.

MICROSCOPIC

Adenoma is usually tubular, papillary, or tubulopapillary in architecture, with most corresponding to the chromophilbasophil cell type described by Thoenes et al. (88). The cells have round to oval nuclei with stippled or clumped chromatin, and nucleoli are inconspicuous. Cytoplasm is usually scant and amphophilic to basophilic (Fig. 30.10). Lesions formed by cells with more abundant eosinophilic cytoplasm occur. Nuclear grade is not currently a criterion. All solid clear cell tumors are considered to be clear cell RCC irrespective of size.

SPECIAL STUDIES

The immunohistochemical profile of papillary adenoma is similar to that of papillary RCC including expression of AMACR (98).

Treatment and Outcome

Reliable criteria for distinguishing adenoma from carcinoma remain elusive (50). In 1950, Bell (100) classified all tumors less than 3.0 cm in diameter as adenoma, despite the fact that metastases developed from 3 of 65 tumors (4.6%) in this size range. Small cortical clear cell tumors have repeatedly demonstrated malignant behavior, confirming that size alone is not a reliable diagnostic criterion (101). We agree that these tubulopapillary tumors are the most clearly identified benign
tumor of cortical epithelium and consider all lesions composed of clear cells to be malignant regardless of size (1,10).

FIGURE 30.10 Papillary adenoma. A small papillary lesion merges imperceptibly with adjacent normal tubules; the cells have small uniform nuclei without significant atypia.

Treatment of small cortical epithelial tumors is determined on clinical grounds. A therapeutic decision should not be based on frozen section, which is associated with both false-positive and false-negative results (102). With the popularity of partial nephrectomy for small tumors, the issue of frozen section is less pressing (103,104). Small tumors are also increasingly being managed by surveillance (91,105). Surveillance generally consists of sequential imaging studies (every 3 to 6 months) with reduced frequency if the lesion is slow growing. Intervention is indicated with rapid growth, patient preference, or improvement in the patient’s other medical condition(s) if that was the major reason for surveillance.

Oncocytoma

Clinical Findings and Epidemiology

In 1976, Klein and Valensi (106) described a subset of renal tumors in adults composed of oncocytes and having an apparently benign clinical course. This observation, subsequently, was confirmed by several other groups (107,108,109). Oncocytoma accounts for approximately 4% of renal tumors in adults. Most occur in adults older than age 50 years, with a male-to-female ratio of 2:1. They are most often detected as incidental findings, although oncocytoma may present with hematuria or a palpable mass. They are usually sporadic, but oncocytoma or oncocytoma-like tumors can develop as part of the Birt-Hogg-Dubé syndrome (110). The Birt-Hogg-Dubé syndrome, due to mutation of the FLCN gene, is characterized by skin lesions (trichofolliculomas, trichodiscomas, and acrochordons), lung cysts (with increased risk of pneumothorax), and the development of renal tumors.

Radiologic studies may suggest the diagnosis of oncocytoma, although they are not specific. Typical angiographic features include a sharp, smooth margin with the capsule, thereby creating a lucent rim; vasculature without marked disarray, with no pooling of contrast material or arteriovenous shunting; homogeneous capillary pattern, giving a density similar to normal renal parenchyma; and feeding arteries in a spokewheel pattern (111). Radiologic studies are, however, not reliable in making a specific diagnosis of oncocytoma (112,113).

Pathology

GENETICS

Cytogenetic studies have supported the view that oncocytoma is a distinct renal neoplasm. These tumors have a mosaic pattern of normal and aberrant karyotypes and consistently lack abnormalities in the 3p region. The most common abnormality detected is loss or partial loss of chromosome 1 (114,115,116). Less frequently, translocations involving chromosome 11 are described (117,118).

GROSS

Oncocytoma is well circumscribed, homogeneous, and tan brown or mahogany brown (Fig. 30.11). It sometimes is bilateral or multifocal (119,120), and rarely, innumerable lesions (ranging from 1 to 2 mm up to several centimeters) are present, a process that has been termed oncocytomatosis or oncocytosis (121,122). There may be areas of hemorrhage, but necrosis is absent. A stellate central zone of edematous connective tissue is common in large tumors, but in smaller tumors, it may be absent. Any tumor with a variegated appearance should be extensively sampled before making a diagnosis of oncocytoma; for this reason, the definitive diagnosis of oncocytoma at frozen section is discouraged.

MICROSCOPIC

Renal oncocytoma is composed of cells with abundant intensely eosinophilic and coarsely granular cytoplasm. Focal cytoplasmic vacuolization and clearing occur in up to 15% of cases (109). The cells are cuboidal to columnar and are arranged in well-defined nests that are closely packed peripherally but often are separated by a loose stroma near the center of the tumor (Fig. 30.12). Tubule formation is common and can predominate in a minority of cases (109). Cysts also occur occasionally and rarely are large enough to be grossly visible.
Cysts may be associated with hemorrhage. Necrosis is absent. Nuclei are regular and round to oval, with granular chromatin and central nucleoli. The presence of cells with bizarre pleomorphic nuclei is well recognized and believed to be degenerative (Fig. 30.13). Mitotic figures are absent or rare, at most. Evidence suggests that oncocytoma originates from the intercalated cell of the collecting duct (123,124). Distinguishing oncocytoma from chromophobe RCC is important because the latter may show malignant behavior.

FIGURE 30.11 Oncocytoma. The tumor is well circumscribed and solid with a golden brown color and central patch of edematous stroma.

FIGURE 30.12 Oncocytoma. Characteristic histology of oncocytoma, with uniform cells having abundant eosinophilic cytoplasm arranged in well-defined nests and tubules, some of which are becoming microcystic. Note the appearance of the nests in loose, fibrous connective tissue; this pattern is almost pathognomonic for oncocytoma.

SPECIAL STUDIES

Oncocytoma contains low molecular weight cytokeratin but does not contain vimentin (125,126). Cytokeratin 7 is expressed intensely by a few scattered single cells or small groups of cells (125,126). The tumor does not express the RCC antigen (127). The tumors are c-kit (CD117) positive with a membrane pattern (128). Hale colloidal iron stain is negative (positive in chromophobe carcinoma) (129). Some authors will allow staining limited to the luminal surface if tubules are present (109,130). Ultrastructurally, the cells are filled with mitochondria (131).

Renal Cell Carcinoma

Classification

Today the term renal cell carcinoma connotes a group of neoplasms having a common origin from the epithelium of the renal tubules but having distinct morphologic and genetic features. Until the mid-1980s, RCC was most often classified by its cytoplasmic appearance as clear cell or granular cell type (132). In 1976, Mancilla-Jimenez et al. (133) described a subset of papillary tumors that they believed were derived from the collecting ducts (ducts of Bellini). Then, in 1985, the Mainz group reported the first cases of a subtype with distinctive morphologic features that they called the chromophobe type (134). In 1986, Thoenes et al. (88) proposed a new classification of renal cell neoplasms that recognized collecting duct carcinoma and chromophobe cell carcinoma as well as clear cell RCC and chromophil RCC, also known as papillary RCC. Papillary, chromophobe, and collecting duct carcinomas made up 15% to 20% of renal cell neoplasms in surgical series, whereas clear cell RCC accounted for about 70%, with a few rarities and unclassified tumors making up the remainder. These efforts began the development of the currently employed classification system (1,10). Genetic studies validated these approaches to classification by discovering genetic abnormalities that are characteristic for each of the diagnostic groups. The most recent classifications have reaffirmed these changes and have added several newer entities (1,10). In 2012, the ISUP met and updated the 2004 WHO classification to recognize advances since its development. A modified WHO classification is presented in Table 30.1. In the following sections, each of the currently recognized types of RCC is discussed; there are many other described variants that at this point have not been judged to have sufficient evidence to recognize them as distinct. These are not dealt with in this Chapter.

Clinical Findings and Epidemiology

Clear cell RCC comprises a significant majority of RCCs and as such most of the following comments reflect largely on clear cell RCC. Features specific for specific types of RCC are presented
in the relevant sections below. The classic triad of presenting symptoms consists of hematuria, pain, and flank mass, a combination that is generally associated with advanced stage (135). However, approximately 40% of patients lack all of these and present with systemic symptoms. A common constellation is weight loss, abdominal pain, and anorexia, which may suggest carcinoma of the gastrointestinal tract (135). In up to 21% of patients, there is fever without infection (136,137). The erythrocyte sedimentation rate is elevated in approximately 50% of cases (138). Although blood erythropoietin levels are elevated in almost two thirds of patients (139,140), erythrocytosis occurs in less than 2% (140). Hypochromic anemia unrelated to hematuria occurs in about one third of cases (137). Systemic amyloidosis occurs in about 3% to 8% of patients with RCC and is of the AA type (141).

RCC occasionally causes paraneoplastic endocrine syndromes (142), which include pseudohyperparathyroidism, erythrocytosis, hypertension, and gynecomastia. Hypercalcemia occurs in the absence of bone metastases in approximately 10% of patients with RCC (137). Approximately 33% of patients are hypertensive (137); this is commonly associated with elevated renin concentrations (143). Typically, the blood pressure returns to normal after the tumor is resected. Gynecomastia may result from gonadotropin (144) or prolactin (145) production. RCC also is notorious for presenting as metastatic carcinoma of unknown primary, sometimes in unusual sites (146).

RCC occurs almost exclusively in adults, at rates of 10.0 and 4.8 per 100,000 among Caucasian males and females, respectively (147). The rates are significantly higher for African Americans at 11.5 and 5.7 per 100,000 (147). There is significant geographic and ethnic variation in RCC incidence with the lowest rates in Asian and Latin American countries (147,148). In the United States in 2012, approximately 64,770 new cases of cancer of the kidney and renal pelvis were diagnosed, and there were approximately 13,570 deaths attributed to these tumors (RCC accounts for approximately 80% to 90% of these) (149). In the first two decades of life, RCC is rare (68,69). Approximately 10% of cases occur before age 45 (150), but its incidence increases from that age to a peak in the sixth and seventh decades (151). Familial clusters of RCC are rare outside syndromes such as von Hippel-Lindau disease (152). In recent years, a variety of hereditary RCC syndromes have been described; however, overall, these account for a small proportion of tumors (153,154,155,156,157). The hereditary renal cell cancer syndromes are highlighted in Table 30.3.

As much as 30% of RCC is attributed to the carcinogenic effects of smoking (148,158). Obesity also is important, especially in women (148,158). Type 2 diabetes is also a risk factor in women (159). Environmental risk factors include phenacetin and acetaminophen use for long periods (160) and exposure to cadmium (161), petroleum products (161,162), and industrial chemicals (148,161). In most cases, the carcinogenic influence is unknown.

Between one third and one half of patients with von Hippel-Lindau disease develop RCC (156,157,163); metastasis occurs in approximately 50% of these and causes death in up to one half. Approximately 1% to 4% of patients with tuberous sclerosis develop RCC (155,157). Most have no recurrence, but a few cases with metastases have been documented (164). The association of autosomal dominant polycystic kidney disease with RCC is less well established (165). Acquired renal cystic disease in patients with chronic renal failure is also strongly associated with RCC (166,167).

TABLE 30.3 Hereditary renal cell carcinoma syndromes

Syndrome	Genetics	Pathology
Von Hippel-Lindau	VHL gene (3p25-26)	Cysts Clear cell RCC
Tuberous sclerosis	TSC1 (9q34) TSC2 (16p13)	Cysts Angiomyolipoma Clear cell RCC Papillary RCC Chromophobe RCC
Birt-Hogg-Dubé	FLCN (17p11.2)	BHD-associated RCC (so-called hybrid tumor) Clear cell RCC Papillary RCC
Hereditary leiomyomatosis and RCC	FH (1q42-43)	HLRCC-associated papillary RCC
Hereditary papillary RCC	MET (7q31)	Papillary RCC (type 1), papillary adenoma
Chromosome 3 translocation	Unknown	Clear cell RCC
Hereditary paraganglioma	SDHB (1p36) SDHC (1q21) SDHD (11q23)	SDHB-associated RCC Clear cell RCC

STAGING

Since there is minimally effective treatment for metastases, the extent of spread of RCC dominates the prognosis (168,169). At present, the American Joint Commission on Cancer tumor-node-metastasis system is recommended for use (170). Tumors confined by the renal capsule are in the most favorable category. Within the most favorable group, the size of the tumor is used to subdivide these into four categories having different prognoses (168,169). Invasion of perinephric or renal sinus adipose tissue defines the pT3a category (171,172). Also included in the pT3a category are tumors that grossly extend into the renal vein or its segmental (muscle-containing) branches. Although the tumor thrombus may extend beyond the site of transection of the renal vein, this is not considered a positive margin unless the thrombus is adherent to the vein wall at the edge. The pT3b and pT3c categories are defined by extension of tumor into the vena cava below or above the diaphragm, respectively. The ipsilateral adrenal is involved by direct invasion or metastasis in about 5% of radical nephrectomy specimens (173). Direct invasion of the adrenal gland is considered to be pT4 (174,175); metastatic involvement is staged as pM1. In 10% to 15% of cases, there is metastasis to regional lymph nodes without distant metastasis (176). However, most regional lymphadenopathy is caused by inflammatory or hyperplastic changes (177). Although radical nephrectomy with regional lymph node dissection has long been the standard operation for RCC, lymph node dissection contributes to accurate staging but does not impact survival (178).

TABLE 30.4 Fuhrman nuclear grading system

Grade	Size (µm)	Shape	Chromatin	Nucleoli
1	<10	Round	Dense	Inconspicuous
2	15	Round	Open	Small, not visible with 10× objective
3	20	Round/oval	Open	Prominent
4	>20	Pleomorphic, multilobulated	Open, hyperchromatic	Macro

GRADING

In 1971, Skinner et al. (179) directed attention to the correlation between nuclear features and outcome. Currently, the Fuhrman et al. (180) grading system is most widely used (Table 30.4). Grade 1 and 4 tumors are least common, making up less than 10% of cases each; the middle grades each account for about 40% of cases (Fig. 30.14) (181). Numerous reports have documented that this grading system correlates well with survival in large series of patients with RCC (181,182,183,184). Actuarial, 5-year, disease-free survival ranges from around 90% for patients with grade 1 tumors to 18% for patients with grade 4 tumors (181,183,184). The highest grade found is the grade assigned, regardless of extent (181,182,183). Mitotic figures are not included in this system, but more than one per 10 high-power fields has adverse significance (182). The grading system has repeatedly been shown to be an independent prognostic factor for both clear cell and papillary RCC (181). Nuclear grading is part of almost all prognostic nomograms for RCC (185).

FIGURE 30.14 Clear cell renal cell carcinoma. A: Nuclear grade 1 tumor with small, uniform round nuclei and dense chromatin. B: Nuclear grade 2 carcinoma with slightly larger nuclei having more open chromatin and inconspicuous (at intermediate magnification, ×10 objective) nucleoli. C: Nuclear grade 3 neoplasm has large, open nuclei with prominent nucleoli (readily visible at intermediate magnification). D: Nuclear grade 4 carcinoma with large bizarre nuclei.

Areas resembling sarcoma are found in approximately 5% of RCCs (186,187). Grossly, these areas are often dense and white and contrast with the rest of the carcinoma (Fig. 30.15). Sarcomatoid areas have been found in association with all of
the types of RCC. Microscopically, these resemble fibrosarcoma or undifferentiated spindle cell sarcoma (Fig. 30.16) (188). Heterologous differentiation toward osteogenic sarcoma, chondrosarcoma, or rhabdomyosarcoma is uncommon occurring in only 1% to 2% of cases (186,188,189,190). Patients with even small foci of sarcomatoid carcinoma have a much worse prognosis than those whose tumors do not have such foci (186,188), so thorough sampling of areas with differing gross appearances (especially firm, whitish areas) is important in evaluating RCC.

FIGURE 30.15 Sarcomatoid renal cell carcinoma. The tumor is infiltrative with extensive necrosis; the sarcomatoid component is indicated by the fleshy gray-white areas (top left part of the tumor).

Treatment and Outcome

The primary treatment of RCC is surgery. In the past, partial nephrectomy was limited to patients with a single kidney or some other specific indication for nephron-sparing surgery (191); however, the last two decades have seen considerable literature supporting the performance of nephron-sparing surgery in a larger patient population. These studies have reported excellent long-term results, equivalent to radical nephrectomy, following partial nephrectomy for small tumors (192,193). Emerging data indicate that treatment by partial nephrectomy may improve outcome compared with radical nephrectomy due to a reduction in the developemt of chronic renal disease (193). The performance of partial nephrectomy has led to the increased use of frozen sections at the time of surgery, with the major role for frozen section being margin control and not diagnosis (194). Frozen-section interpretation of renal masses is associated with both false positives and false negatives, and we would not make an unequivocal diagnosis of oncocytoma or adenoma at the time of frozen section (102,195). Laparoscopic partial or radical nephrectomy is increasingly being performed (196,197). This can result in a morcellated specimen that may make pathologic staging and histologic classification challenging, but in most cases still possible (198,199). Most recently, the use of ablation procedures to treat small renal tumors has become popular with early results indicating equivalent cancer control to surgical approaches (200,201,202). Lastly, the role of surveillance as an option in selected patients is gaining interest (203,204,205). The latter two options have resulted in an increasing role for needle biopsy of renal masses (105,206,207). Interpretation of these biopsies can be challenging (208).

FIGURE 30.16 Sarcomatoid renal cell carcinoma. The tumor is composed of pleomorphic spindle-shaped cells arranged in poorly formed fascicles. Note the few residual clear cell renal cell carcinoma cells in the upper left.

For patients with spread of tumor into the renal vein, inferior vena cava, and even the right atrium, surgical resection remains the standard treatment option. Numerous studies have demonstrated the potential curability of such advanced disease (209).

RCC is notorious for its unpredictable clinical course. There are documented cases of spontaneous regression of metastases (210,211). Recurrence, a decade or more after nephrectomy, is found in more than 10% of those who survive so long (212,213), rising to 20% for patients living 20 or more years after surgical resection (212). The resistance of RCC to radiation and chemotherapy gives patients with remote metastases a poor prognosis with a median survival of 1 year (214). Treatment of metastatic disease in the last couple of decades has focused on biologic therapies with limited success (215). Currently, the role of targeted therapies is undergoing intense study with some optimism (216,217). In selected patients, resection of metastases may be beneficial (146,218).

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