Kidneys, Adrenals, and Retroperitoneum

Imaging Techniques

Procurement of renal tissue for cytology has been performed with the aid of intravenous pyelography, selective renal angiography, and fluoroscopy, as well as after excretory urography. Ultrasonically guided FNA has become the preferred method because it permits the point of entry, angle of incident path, and depth of the needle to be defined in absolute terms. The lesion is located with ultrasound and its position relative to surface landmarks memorized. CT can also be used and has the advantage of being able to localize small lesions accurately by verifying the position of the needle tip in a lesion, but it lacks the speed and greater scanning flexibility of ultrasound. FNA is performed after local anesthesia, with the patient in a prone or decubitus position, using a guiding needle with a stylet, a 20-gauge spinal needle, or a 22-gauge Chiba needle (see Chapter 21 ). Immediate cytologic assessment of specimen adequacy is desirable and may require several passes with the needle until an adequate specimen has been procured. The contents of the needle and syringe are rinsed into a tissue culture solution (RPMI 1640), if tissue should be required for immunocytochemistry, molecular studies or cell block analysis, or flow cytometry. It is our practice to make cell blocks on all FNA specimens, tissue permitting. For ultrastructural studies, the needle is rinsed directly into glutaraldehyde.

Complications of FNA are extremely rare and range from 0% to 4%, in comparison with a reported incidence of serious surgical complications of 1.6–8% in patients undergoing open renal biopsy. Abscess formation following therapeutic cyst aspiration or bleeding after aspiration has occasionally been reported. Needle tract seeding is extremely rare to non­existent. Other complications from renal aspiration may include arteriovenous fistula, bile peritonitis, colon perforation with abscess, and urinoma.

Anatomy and Histology

In an adult, the paired kidneys, located on either side of the great vessels and overlying the lower thoracic and upper lumbar vertebrae (T12 to L3), measure up to 13 cm in length and have an average weight of 150–160 g. They are surrounded by perirenal adipose tissue and lie within Gerota's fascia. The left kidney is bounded anteriorly by the pancreas, left adrenal, stomach, splenic flexure of the colon, jejunum, and posteroinferior border of the spleen. The right kidney's anterior relationships are with the right adrenal, the posterior surface of the liver, and the hepatic flexure of the colon. Knowledge of the anatomic relationships of the kidneys with other organs is essential for interpretation of percutaneous renal aspirations because the trajectory of the needle tip may result in procurement of parenchymal cells from these organs.

The kidney is composed of the cortex and the medulla. The medulla comprises 8–18 renal pyramids, or lobes, which contain radial striations caused by the straight part of the collecting ducts or uriniferous tubules and their accompanying blood vessels. The uriniferous tubules converge on to the apex, or papilla, of a minor calyx that is continuous with one of two or more major calyces of the renal pelvis, which continues distally as the ureter. The glandular portion of the kidney resides within the cortex and is composed of a secretory portion, or nephron (derived from metanephrogenic blastema), which unites with the excretory duct system (derived from the wolffian duct). The nephron begins at the renal corpuscle with Bowman's capsule and is continuous with the proximal convoluted tubule, the descending and ascending loops of Henle, and the distal convoluted tubule. The renal corpuscle comprises the glomerulus, a tuft of blood capillaries supplied by an afferent and an efferent, and an efferent arteriole that invaginates and invests itself of the inner (visceral) layer of Bowman's capsule. The visceral epithelial cells adhere closely to the endothelial cells and on ultrastructural analysis demonstrate fine processes or pedicels that project on to the basement membrane separating the endothelial cells from the epithelial cells. The outer parietal layer of Bowman's capsule is continuous with the proximal convoluted tubule, whose epithelium consists of a single layer of cells with abundant eosinophilic cytoplasm, a larger nucleus, and a microvillous brush border. The descending (thin) loop of Henle is lined by pale, flat squamous epithelium, whereas the epithelium lining the ascending limb is cuboid and stains more darkly. The epithelium of the distal convoluted tubule is lower, stains less intensely with hematoxylin and eosin, and contains more cells on cross-section than the proximal convoluted tubule. Microvilli can be seen by electron microscopy on the luminal surface. The cells of the collecting ducts are cuboid and well defined, with a dark nucleus and clear cytoplasm. The collecting ducts contain mitochondria-rich cells, known as principal cells, that possess apical invaginated cytoplasmic vesicles and the enzyme carbonic anhydrase C. A subgroup of principal cells contains an anion exchange protein, also known as band 3 protein. The cells of the larger collecting ducts are tall and columnar.

Cytology of the Normal Kidney

Normal renal parenchymal components, which usually derive from the renal cortex, may be aspirated during FNA of the kidney ( Fig. 28-1 ). Glomeruli may occasionally be aspirated. These are large, sharply demarcated, multilayered clusters of epithelial and endothelial cells, which may be continuous with a short segment of proximal convoluted tubules ( Fig. 28-2 ). The proximal convoluted tubules make up most of the substance of the renal cortex and have abundant granular but ill-defined eosinophilic cytoplasm and large oval nuclei. At high power (×400), careful examination may reveal small, inconspicuous nucleoli ( Fig. 28-1 ). Unlike their histologic counterpart, brush borders cannot be seen in cytologic smears. The cells of Henle's loop and the distal convoluted tubules are much smaller than cells from the proximal tubules. Distal convoluted tubules may be removed intact, appearing as multilayered tubules or cast-like structures. Distal convoluted tubular epithelium is flatter, with more numerous and conspicuous nuclei than the cells of the proximal tubules. Dark cytoplasmic granules may be demonstrated on Romanowsky stains in cells most probably derived from the ascending loop of Henle or distal convoluted tubules. The cells of the collecting tubules of the medulla are cuboid and sharply defined ( Fig. 28-2 ).

Renal Cysts

Cysts of the kidney are among the most common mass lesions to be aspirated, their incidence in three large consecutive FNA series ranging in frequency from 15% to 43%. Renal cysts may be congenital or acquired, the former resulting from disordered embryogenesis involving cystic enlargement at various sites of the renal tubular system. The diagnosis of congenital cysts rests largely on evidence of genetic transmission, the age of the patient, associated congenital abnormalities, and the gross and microscopic features of the renal cysts.

Congenital Cysts

Polycystic disease of the kidney may be of the infantile or adult type, both being inherited forms of cystic disease, usually involving both kidneys. Numerous thin-walled unilocular cysts of various sizes lined by flattened epithelial cells involve the renal parenchyma and contain clear fluid. The adult form is usually clinically silent until the fourth decade of life, when patients may present with gradual onset of renal failure. The disorder may occasionally be manifested clinically as lithiasis, flank pain caused by bleeding into a cyst, or ureteral obstruction caused by a blood clot.

Fine-needle aspiration results in variable amounts of clear or pale amber fluid containing a few foamy macrophages.

Xanthogranulomatous Pyelonephritis

Xanthogranulomatous pyelonephritis (XPN) is an uncommon chronic inflammatory kidney disease associated with recurrent urinary tract infections, flank pain, and a non-functioning renal mass or kidney on intravenous pyelography that may mimic a carcinoma. Renal calculus is frequently associated.

Clinically, patients present with symptoms related to renal pain, hematuria, a flank mass, or recurrent urinary tract infections, with the most common organisms cultured being Escherichia coli , Pseudomonas , and Proteus .

Xanthogranulomatous pyelonephritis may be difficult to distinguish from a hypovascular renal tumor by intravenous pyelogram or arteriography. Plain abdominal films may reveal renal enlargement and staghorn calculi, a retrograde pyelogram may show hydronephrosis or staghorn calculi, and a partially or totally non-functioning kidney may be demonstrated by renal scans. Sease and coworkers described four patients with XPN and characteristic ultrasound findings supportive of abscess formation, as well as FNA findings supportive of XPN. A preoperative diagnosis of XPN can spare a patient a radical nephrectomy; a partial nephrectomy may be the procedure of choice if involvement of the kidney is only focal. Two reports have described erroneous preoperative FNA diagnosis of “clear cell carcinoma” and “hypernephroma” in two patients with XPN. Histologic study may show focal or diffuse replacement of renal parenchyma by sheets of histiocytes with foamy or granular or eosinophilic cytoplasm and small, regular nuclei that may mimic renal adenocarcinoma. Necrosis, multinucleated cells, cholesterol clefts, and lymphocytes are commonly seen.

Abscess of the Kidney

Both intrarenal and perinephric abscesses can be accurately localized and aspirated under ultrasound guidance. At the time of aspiration, if turbid fluid or pus is aspirated, a Gram stain of the smears and cultures for microbacteriologic study are obtained. In the majority of cases, Gram-negative organisms are isolated. In many instances, surgery can be avoided and percutaneous drainage may be all the treatment that is required.

Angiomyolipoma

Angiomyolipomas are fairly uncommon benign tumors that are composed of a mixture of mature tissue components comprising mature adipose tissue, tortuous thick-walled blood vessels, and fascicles of smooth muscle. They were generally regarded as hamartomas or benign mesenchymomas. However, angiomyolipomas are now considered to belong to a family of neoplasms with perivascular epithelioid differentiation, now referred to as PEComas. Despite a strong association between angiomyolipomas and tuberous sclerosis, fewer than 40% of patients with angiomyolipomas demonstrate features of tuberous sclerosis complex (cutaneous lesions, retinal phakomas, angiomas, and cerebellar neoplasm). Patients with tuberous sclerosis may have multiple small and bilateral angiomyolipomas. Patients who present with solitary tumors are frequently younger women who show no stigmata of tuberous sclerosis. The presenting symptom is usually flank or abdominal pain or a palpable mass. The tumors are generally large, with a mean diameter of 9.4 cm. Despite their characteristic radiologic appearance on CT and ultrasound, they may be confused preoperatively with RCC on intravenous urogram.

Cytology.

The leiomyomatous component is composed of single cells and clusters of mesenchyme-like cells, which may vary in size and shape but are usually small with ample but indistinct delicate cytoplasm ( Fig. 28-3A ). The overlapping nuclei may appear to form syncytial groups because cell borders may not be visible. Nuclear chromatin may vary from finely to coarsely granular. Some cells may show prominent nucleoli. HMB-45 reactivity has been demonstrated in the leiomyomatous component of angiomyolipoma as well as in lymphangioleiomyomatosis. Also, angiomyolipoma stains for melan A (A103) and smooth muscle actin. The vascular component is characterized by thick-walled blood vessels lined by endothelial cells ( Fig. 28-3B ). This component may not be seen on cytology but may be demonstrated in cell block preparations. The fatty component is composed of mature adipose tissue, which may be abundant. Areas of fat necrosis containing histiocytes and multinucleated giant cells may be found.

The pitfalls in diagnosis are as follows:

• The pleomorphic mesenchymal or smooth muscle cells of angiomyolipoma may be so atypical that they are confused with the sarcoma or sarcomatoid component of sarcomatoid RCC.

• In an atypical pattern that may be seen, highly cellular areas have a predominantly round cell pattern that may be confused with a granular cell RCC.

Key Features of Angiomyolipoma

• Variable admixture of mature adipose tissue, tortuous thick-walled blood vessels, and fascicles of smooth muscle

• The leiomyomatous component may comprise spindle or round cells with granular cytoplasm

• The leiomyomatous component is positive for smooth muscle actin and melanoma markers such as HMB-45 and melan A (A103) and negative for PAX8.

Oncocytoma

Oncocytomas are composed of oncocytes, which are large epithelial cells with abundant eosinophilic cytoplasm. Oncocytomas were originally identified by Hamperl in the salivary gland in 1931, and were previously recognized in the thyroid and parathyroid. They were recognized in the kidneys in 1976, when Klein and Valensi reported on 14 patients with oncocytic tumors and emphasized their benign behavior. These tumors are regarded as variants of renal adenomas, derived most likely from the mitochondria-rich principal cells of collecting duct of medullary origin. Although they may become large, they generally show no tendency to invade or metastasize. The reported average incidence is 5% of all renal neoplasms; they occur predominantly in men, with a peak incidence in the sixth to eighth decades of life.

The gross features of this neoplasm are characteristic; they include a well-demarcated, well-encapsulated tumor that is a mahogany color or reddish brown on the cut surface. The tumors range in size from several millimeters to 25 cm in diameter, with a median diameter of 8 cm. A central fibrous scar is often seen. Tumors are usually solitary; however, they may be bilateral or multicentric.

The tumor may be composed of nests or cords of oncocytic cells separated by edematous stroma. Typical cells are polygonal, with round or oval, hyperchromatic nuclei and minimal pleomorphism ( Fig. 28-4 ). Binucleated cells may frequently be seen. Lieber and colleagues described six cases that metastasized and led to the ultimate demise of the patients. These tumors were characterized by nuclei that showed greater nuclear pleomorphism than in the usual oncocytoma.

Cytology.

A monotonous population of polygonal single cells or small clusters of cells with defined cell borders is seen, as well as abundant eosinophilic cytoplasm. Nuclei are round to oval, single or multiple, and hyperchromatic or so clumped that they appear pyknotic ( Fig. 28-5 ).

Oncocytoma may be confused with a granular cell RCC and a chromophobe cell renal carcinoma (CCRC) (discussed below). Distinguishing features in favor of oncocytoma include consistently densely granular eosinophilic cytoplasm in all cells, in contrast to the eosinophilic variant of CCRC, which shows rare clear cells with reticulated cytoplasm and positive staining on Hale's colloidal iron. Oncocytomas are of low nuclear grade and usually diploid. Granular RCC usually has higher grade nuclei with prominent nucleoli. It may show focal areas of clear cells and may be aneuploid. Cytogenetics may be helpful to differentiate oncocytoma from RCC, because the former has no deletion of chromosome 3p (in contrast to RCC) and is usually a mosaic of normal karyotype and abnormal clones ( Table 28-2 ). Oncocytoma has no consistent karyotypic abnormality. A distinctive restrictive pattern of mitochondrial DNA has been found in oncocytomas. In addition, oncocytoma contains an anion exchange protein, also known as band 3 protein.

TABLE 28-2

Diagnostic Cytogenetic and Molecular Features of Common Renal Tumors

(From Tannenbaum and Madden 2006. )

Tumor	Features
Clear cell renal cell carcinoma	Loss of 3p; mutations/hypermethylations of VHL gene
Papillary renal cell carcinoma	Trisomies 7 and 17; loss of chromosome Y; MET mutations in familial and some sporadic cases; additional aberrations including gains of 3q, 8p, 12q, 16q, and 20q
Chromophobe renal cell carcinoma	Hypodiploidy, losses of chromosomes 1, Y, 6, 10, 13, 17, and 21
Renal oncocytoma	Losses of chromosomes I and Y, t(9;11)(p23;q13), t(5;11)(q35;q13)
Collecting duct carcinoma	Monosomies I, 6, 14, 15, and 22; loss of heterozygosity, 1q; minimal deletion at Iq32.1–32.2
Carcinoma with chromosomal aberrations	Xp11, t(X;I)(p11.2;q21), or t(X;17)(p11.2;q25)
Mucinous tubular and spindle cell carcinoma	Losses at chromosomes I, 4q, 6, 8p, 11q, 13, 14, and 15; gains at chromosomes 11q, 16q, 17, and 20q
Angiomyolipoma	TSC1 and TSC2 gene inactivation, frequent in cases with tuberous sclerosis but also in some sporadic angiomyolipomas
Wilms' tumor	Deletions of WT1 in WAGR syndrome and point mutations WT1 in Denys–Drash syndrome, WT2 gene involvement in Beckwith–Wiedemann syndrome, no consistent abnormalities in sporadic cases
Mesoblastic nephroma	t(12;15)(p13;q25) and ETV6–NTRK3 gene fusion – only in cellular variant
Rhabdoid tumor of the kidney	Inactivation of hSNF5/INII gene on chromosome 22

WAGR, Wilms' tumor, aniridia, genitourinary malformations, and mental retardation.

Immunocytochemistry.

Renal oncocytomas show immuno­positivity for parvalbumin, Ksp cadherin, PAX8, and C-KIT. This immunoprofile is similar to chromophobe RCC. However, CK-7 shows a differential staining pattern between chromophobe RCC and oncocytomas. In contrast to chromophobe RCC, in which CK-7 expression is noted in 50–100% of cases with a distinctive membrane accentuation, oncocytomas show only focal cytoplasmic staining occasionally in 8% of cases.

Key Features of Oncocytoma

• Benign tumor composed of oncocytic cells

• Abundant granular eosinophilic cytoplasm

• Round nuclei with small central nucleoli without any evidence of nuclear pleomorphism or mitotic activity

• Tumor cells can exhibit binucleation

• Positive for parvalbumin, Ksp, cadherin, PAX8 and C-KIT.

Renal Adenoma

Well-differentiated cortical glandular tumors <3 cm in diameter have been termed adenomas and have a very low propensity to metastasize. Most of the tumors are found incidentally at autopsy. These lesions are best imaged on CT. Because of their derivation from the proximal tubule and their morphologic similarity to RCC, most investigators now accept the view that these are in fact small RCCs with a low risk for metastases.

Metanephric Adenoma

Metanephric adenoma is a rare benign tumor with highly cellular epithelial elements composed of uniform primitive-appearing small blue cells. Metanephric adenoma can occur in children and adults, most commonly in the fifth and sixth decades. The majority of these tumors are detected incidentally, with few others presenting with abdominal mass, flank pain, or hematuria. These tumors range widely in size and usually measure between 3 and 6 cm in maximum dimension. They are usually well circumscribed with a grey or tan to yellow cut surface and may be soft or firm in consistency. Foci of necrosis and hemorrhage are common. Microscopically, they are composed of tightly packed small, uniform, round acini-like structures with an embryonal appearance. Long branching tubular structures are also commonly encountered. Almost half of these tumors also demonstrate cysts with blunt papillae protruding into them, which resemble immature glomeruli ( Fig. 28-6A–C ). Psammoma bodies are usually present. The cells of metanephric adenoma are monotonous, with small uniform round or oval nuclei with fine chromatin and scant cytoplasm. Mitotic figures are unusual. Immunostaining of metanephric adenoma has revealed variable results including positivity for CKs and vimentin. Positive intranuclear staining for WT1 is, however, a consistent finding, as is PAX8, based on the small numbers of neoplasms evaluated ( Fig. 28-6D,E ).

Hereditary Kidney Cancer

Kidney cancers may occur as sporadic or hereditary diseases; however, the hereditary forms offer insight into the genetic and molecular pathogenesis of the more common sporadic forms. Approximately 4% of kidney tumors occur as hereditary disorders and are characterized by multiple kidney tumors.

There are four well-defined hereditary kidney cancers: von Hippel–Lindau (VHL) clear cell renal carcinoma, hereditary papillary renal carcinoma (HPRC), Birt–Hogg–Dube, and hereditary leiomyomatosis RCC. The genetic features of these cancers will be discussed below.

Von Hippel–Lindau: Clear Cell Renal Carcinoma

Affected patients are at risk to develop bilateral renal tumors and benign renal cysts. Tumors are always clear cell RCC, hemangioblastomas of cerebellum and spine, retinal angiomas, endolymphatic sac tumors, pancreatic neuroendocrine tumors, and pheochromocytomas.

Genetics.

The patients evidence germ-line mutations of the VHL gene located at chromosome 3p25. The results of different mutations in the VHL gene manifest in different phenotypes of VHL diseases, including families at low risk and high risk for RCC.

The presence of an intact VHL gene product, pVHL, is essential in regulating a transcription factor known as hypoxia-inducible factor (HIF).

Malfunction of this pathway, which involves the polyubiquitylation of HIF-α for eventual proteasomal degradation, results in accumulation of HIF-α subunits, which bind to an HIF-β partner protein. This HIF heterodimer binds to specific DNA sequences and results in transcription of genes involved in acute or chronic adaptation to hypoxia, including vascular endothelial growth factor (VEGF), Glut-1, TGF-α/IGF, platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor (HGF), and erythropoietin as well as other genes regulating cell cycle and apoptosis ( Fig. 28-7 ). Loss of the remaining wild-type VHL allele results in renal cysts that are converted to RCC. Other mechanisms of VHL inactivation include methylation of the VHL promoter.

Sporadic RCC is associated with alterations of both VHL alleles, including mutations and loss of heterozygosity ( Fig. 28-8 ).

Understanding the VHL pathway has enabled development of therapies to target downstream genes activated by the HIF pathway, such as sunitinib, which has affinity for VEGF and platelet-derived growth factor (PDGF) receptors.

Birt–Hogg–Dube Syndrome

Birt–Hogg–Dube syndrome, originally described in 1977, is a rare autosomal dominant syndrome characterized by multiple cutaneous fibrofolliculomas, pulmonary cysts, and renal tumors. The associated kidney neoplasms include chromophobe RCC in 33% of cases, hybrid oncocytic RCC (50%), clear cell RCC, PRCC, and oncocytoma.

Genetics.

The BHD gene occurs on the short arm of chromosome 17 at 17p11.2, and germ-line mutations of this gene have been found in the majority of the BHD kindreds evaluated. The BHD appears to function as a classic tumor suppressor gene, with retention of the mutated germ-line gene and loss of heterozygosity of the wild-type mutant allele. Multiple bilateral tumors with a diversity of histologic subtypes, including clear cell RCC, PRCC, oncocytomas, chromophobe RCCs, and hybrid tumors, predominate.

Cytology.

Hybrid oncocytic tumors comprise neoplasms containing both oncocytes and chromophobe cells with growth patterns resembling oncocytomas and chromophobe renal carcinoma. Adley and colleagues described a 48-year-old patient with multiple lung cysts and pneumothorax and multiple bilateral renal masses. FNA of the largest kidney mass and core biopsies of the other renal masses showed predominantly sheets of oncocytic cells with low nuclear-to-cytoplasmic ratio and uniform round euchromatic nuclei resembling oncocytoma. There were also rare intermixed clear cells with solid to trabecular growth pattern ( Fig. 28-9A–C ) consistent with hybrid renal oncocytic tumors. Focal areas resembled chromophobe RCC. Cells were positive for CD117 (C-KIT) and focally positive for CK-7 ( Fig. 28-9D ). The patient's family history was suspicious for BHD syndrome and she subsequently tested positive for BHD gene mutations. In patients who present with multiple kidney masses that demonstrate oncocytosis and foci of clear cells, a diagnosis of BHD should be considered.

Xp11.2 Translocation Renal Cell Carcinoma

Xp11.2 translocation RCC is a recently described distinct subtype of renal carcinoma that usually affects children and adolescents. Very few cases of this variant of renal cell carcinoma have been reported in adults. Xp11.2 translocation RCCs constitute approximately one-third of pediatric RCCs in comparison with conventional clear cell RCCs, which make up 15% of RCCs in children. Based on the limited data available so far, Xp11.2 translocation RCCs are believed to be rather indolent in behaviour even when diagnosed at advanced stages. However, there have been increasing recent reports of Xp11.2 translocation RCCs with aggressive clinical course in patients aged 16 years and older, which suggests that these lesions may be inherently more aggressive in adults than in children.

Genetics.

Xp11.2 translocation RCCs result from gene fusions between the TFE3 gene located on chromosome Xp11.2 and at least six different partners that have been reported so far. While the molecular identity of five of these six gene fusion partners of TFE3 are known, the identity of the sixth partner located on chromosome 3 is not yet known. The five known gene fusion partners of TFE3 are PRCC , ASPL , polypyrimidine tract-binding protein-associated splicing factor ( PSF ), non-POU domain-containing octamer-binding ( NONO ;p ^54nrb ), and clathrin heavy-chain (CLTC) genes, respectively, on chromosomes 1q21, 17q25, 1p34, Xq12, and 17q23. TFE3 is a member of the microphthalmia-associated transcription factor (MITF) family.

Cytology.

Xp11.2 translocation RCCs demonstrate fragments and sheets of tumor cells with clear and/or eosinophilic, granular, and voluminous cytoplasm ( Fig. 28-10A–C ). The nuclei of the tumor cells exhibit vesicular chromatin and prominent nucleoli. The tumors demonstrate the presence of psammoma bodies in 50–62% of the cases. The morphologic features demonstrated by XP11.2 translocation RCCs can however be heterogeneous based on the type of cytogenetic alteration of the tumor.

The most distinctive immunophenotypic features of Xp11.2 translocation RCCs is nuclear staining for the chimeric (mutant) TFE3 protein, which is absent in conventional clear cell and papillary RCCs. These tumors are usually positive for CD10, E-cadherin, alpha-methyl coenzyme A racemase (AMACR), PAX2 and PAX8, RCC antigen, variably positive for vimentin, and generally negative or weakly positive for AE1/AE3, CAM5.2, CK-7, EMA, and melanocytic markers (HMB-45, melan-A). Positive immunostaining for TFE3 protein is reported in 82–100% of the tumors.

Classification of Renal Tumors

Renal parenchymal tumors may be broadly classified as being derived from the proximal convoluted tubule (RCC), intercalated cells (chromophobe RCC), and principal cells (oncocytoma) of the collecting ducts, epithelial cells of larger collecting ducts of Bellini (collecting duct carcinoma, CDC), metanephric blastema (Wilms' tumor), or mesenchymal structures. Renal pelvic tumors are either epithelial (transitional cell carcinoma, TCC; squamous carcinoma; adenocarcinoma) or mesenchymal (sarcomas) in derivation ( Table 28-1 ).

Awareness of the radiologic appearance of a tumor is vital in the interpretation of renal FNAs, because most tumors display characteristic radiographic features.

Previously, RCC was most frequently detected initially by intravenous urography, on which it is characterized as a mass with decreased or heterogeneous staining quality, the latter often being caused by cystic degeneration or necrosis within the tumor. Currently, however, there are new and improved techniques for detection and staging of renal masses, in­cluding magnetic resonance tomography, CT imaging, and ultrasound.

Approximately 75% of RCCs are hypervascular and display characteristic arteriographic features that permit the diagnosis of RCC with a high degree of confidence. The 25% of RCCs that are hypovascular appear thus because they are extensively cystic or necrotic, arise within a cyst, or demonstrate a predominantly papillary architecture (PRCC). The differential diagnosis of a hypovascular renal mass also includes benign renal cysts, abscesses, oncocytoma, urothelial carcinoma (UC) of the renal pelvis, CDC of the renal medulla, renal lymphoma, XPN, sarcomatoid RCC, or metastatic renal neoplasms. Renal oncocytomas are well-encapsulated hypovascular masses, with a distinctive arrangement of internal vessels in a pattern like the spokes of a wheel. Angiomyolipomas may be differentiated by CT and ultrasound on the basis of their fat content; however, they are generally hypervascular and sharply demarcated from the uninvolved kidney.

Clear Cell (Conventional) Renal Cell Carcinoma

Renal cell carcinoma accounts for approximately 2% of all cancers and 60–65% of all renal epithelial neoplasms. It occurs more commonly in men than in women, with the peak age at presentation being in the sixth decade of life. It is predominantly a disease of adults, with few cases being reported in children or adolescents younger than 20 years. Non-random chromosomal changes on chromosomes 3p and 14q and gain of chromosome 5q22-qter and trisomy 7 are strong evidence in favor of a multistep carcinogenesis model involving tumor suppressor genes as well as proto-oncogenes in the evolution of RCC. The cytogenetics of hereditary RCC associated with VHL disease was described earlier (see above). However, somatic mutations or deletions or hypermethylations can be found in the VHL gene on chromosome 3p in 75–80% of sporadic tumors ( Fig. 28-8 ).

Recent cytogenetic and molecular studies have resulted in a revised classification of renal tumors ( Table 28-1 ) that has rendered much of the old literature on “renal carcinomas” obsolete, particularly that which deals with clear cell, granular cell, and sarcomatoid tumors.

Like renal adenoma, RCC derives from the proximal convoluted tubule, as evidenced ultrastructurally by the demonstration of a number of common characteristics, including a microvillous brush border and numerous elongated and unusually configured mitochondria.

The most common clinical presentation of RCC is hemat­uria, followed by flank pain and a palpable mass. As many as 25% of RCCs may be asymptomatic, with discovery of the tumor being incidental to a routine physical examination and unrelated radiologic study. Fever, anemia, a high erythrocyte sedimentation rate, or symptoms related to metastases, most frequently involving the lungs, bones, or central nervous system, may lead to detection of a hitherto undiagnosed primary RCC.

The average size of RCC at nephrectomy is 7.6 cm, with the majority of resected tumors measuring 3.1–8 cm. Tumors <3 cm in diameter rarely metastasize and, if well differentiated, encapsulated, and devoid of hemorrhage and necrosis, have been termed adenomas . This terminology has been a subject of much controversy, however, because these tumors are histogenetically and morphologically identical to RCC (see above). At the MD Anderson Cancer Center (MDACC), the term adenoma is not used for any clinically detected lesion, regardless of the size. The majority of RCCs are of the intermediate-size (>3 cm and <8 cm) category, in which prognosis on the basis of size cannot be predicted. Staging of RCC based on the extent of disease spread is widely adopted and prognostically significant. In the tumor, node, metastasis staging classification for RCC, size is the most important determinant of disease recurrence and death ( Table 28-3 ). Although stage I tumors (tumor confined to the kidney) accounted for 40% of total cases, 25% of patients have distant metastases (stage IV) at initial presentation, and approximately one-third of patients present with regional spread of tumor (stages II and III).