5.4

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Introduction

Primary malignant renal epithelial neoplasms account for 3% of adult malignancies [1]. US, CT and MRI all contribute to the increased detection of all types of renal parenchymal mass lesions, including those that require surgery and those where surgery has to be avoided. Malignant tumors are detected at earlier stages. Ear- lier detection and more accurate diagnosis improve the cure rate of renal carcinoma. Radiological characterization of these tumors from their benign masses (i.e., angiomyolipoma and complicated cysts) is a continuous challenge and an essential prerequisite for appropriate management [2]. Radical nephrectomy is the treatment of choice, regardless of size. Alternative treatment strategies are available now, in particular for smaller tumors (<4 cm), and include open or laparoscopic tumorecto- my, partial nephrectomy, radiofrequency ablation, and cryotherapy [3–6].

Understanding the underlying gross pathology and histological correlates provides an essential substrate for explaining the radiological characteristics of these masses. Many pathologists still rely on hematoxylin- and eosin-stained preparations of surgical specimens to achieve the histological diagnose of renal cell carcinoma (RCC) [7, 8]. From clinicopathological observations, it has been observed that a neoplasm may change its pattern of differentiation in time and that it does not necessarily retain the phenotype of its presumed pro- genitor cell. Thus it can be explained that in the past, lectin and immunohistochemical studies using markers for different parts of the adult renal tubular system yielded conflicting results regarding the proximal ver- sus distal tubular origin of renal cell tumors. Further- more, renal cell carcinomas may be composed of ad- mixtures of clear and granular cells or clear and chromophilic cells. Such observations would suggest that a transition between phenotypes occurs during progression.

During the last decades, it has become increasingly clear that the initiation and progression of solid tumors is governed by alterations of genes that control growth and differentiation. Tumor development is based on

Chapter

Contents

Introduction . . . 595

Primary Malignant Renal Epithelial Neoplasms . . . 596

Renal Cell Carcinoma of the Clear Cell Type . . . 596

Pathology . . . 596

Imaging . . . 602

Ultrasound . . . 602

Computed Tomography . . . 602

Magnetic Resonance Imaging . . . 604

Papillary Renal Carcinoma or Chromophilic Cell Carcinoma 605 Pathology . . . 605

Imaging . . . 607

Chromophobic Renal Carcinoma . . . 609

Pathology . . . 609

Imaging . . . 610

Collecting (Bellini) Duct Renal Carcinoma . . . 610

Pathology . . . 610

Imaging . . . 611

Unclassified Renal Carcinoma . . . 612

Observations on Sarcomatoid Neoplasms . . . 612

Pathology . . . 612

Imaging . . . 613

Observations on Renal Adenoma . . . 613

Observations on Renal Oncocytoma . . . 613

Pathology . . . 613

Imaging . . . 615

Indications for Lesional Biopsy . . . 615

Summary . . . 616

References . . . 616

Primary Malignant 5.4

Renal Parenchymal

Epithelial Neoplasms in Adults

Raymond Oyen, Hendrik Van Poppel, Tania Roskams

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specific and separate molecular mechanisms in different cells, and therefore they are almost completely different. There is a specific combination of chromosomal and mitochondrial DNA alterations marking distinct types of tumor genes or putative tumor suppressor genes [9].

Primary Malignant Renal Epithelial Neoplasms The morphological classification of renal cell neoplasm in adults relies on three essential criteria: (1) the aspect of the tumor cells (i.e., clear cells, chromophilic cells [basophilic or eosinophilic], chromophobic cells, on- cocytes, collecting duct cells, and sarcomatoid or fusi- form cells); (2) the architecture (solid [acinar], tubulopapillary, tubular, tubulocystic); and (3) nuclear grade, based on increasing numbers of nuclear and nucleolar atypia. Based on these morphological criteria, classification of the majority of renal cell neoplasms is feasible, with few exceptions only. This morphology-based classification is now supported by cytogenetic analysis. Five major groups of malignant renal epithelial neoplasms are distinguished (Table 1) [10–13].

Tumor genesis is driven by genetic changes including not only classic point mutations, but also deletions re- moving entire genes, as well as gross chromosomal abnormalities at specific sites in the genome. Molecular cytogenetic techniques enable the identification of ge- netically homogeneous groups of malignant renal parenchymal tumors. Each subgroup is characterized by a combination of genetic changes affecting different sites within the chromosomal and mitochondrial DNA [16].

Careful analysis of CT and/or MR images allows for preoperative characterization of the histological subtypes in the majority of cases. The criteria include size, shape, location, number, contrast enhancement pattern (including the angiographic or corticomedullary phase), presence and site of hemorrhage and necrosis, patency of renal vein, and lymph node status. Categorizing neoplasms may be helpful in designing appropriate thera- peutic strategies and predicting the likelihood of pro-

gression. Furthermore, the absence of the typical radiological features warrants additional investigation to exclude lesions for which surgery should be avoided (i.e., benign lesions, metastases, lymphoma).

Renal Cell Carcinoma of the Clear Cell Type Pathology

The clear cell subtype is the most common subtype, ac- counting for approximately 70%–80% of RCCs. It is also referred to as classic or conventional RCC. The majority occurs sporadically as a solitary tumor and is randomly distributed in the renal cortex. There is a male predominance (1.5–2 : 1). Multicentricity in the same kidney occurs in approximately 4% of cases, whereas bilaterality occurs in 0.5%–3%. Synchronous (75%) or metachronous multifocality may occur. Multicentricity and bilaterality are often associated with conditions such as von Hippel-Lindau disease [17]. Clear cell carcinomas can become very large but the frequency of small lesions has increased because of earlier detection with US, CT and MRI.

RCC of the clear cell type protrudes from the renal cortex as a rounded, bosselated mass. The interface of the tumor with the kidney is usually well demarcated.

Yet the presence of a clear pseudocapsule depends on the nuclear grading: well-differentiated lesions are more likely to have such a pseudocapsule. Rarely, RCC may be diffusely infiltrative and then become difficult to distinguish from urothelial carcinoma or other infiltrating tumors.

On section, clear cell RCCs have a yellowish-golden appearance, due to the abundant cytoplasmic lipid content, mucolipids (Figs. 1–5). Thus the cells are markedly similar to that of the proximal convoluted tubules. The typical lesion is composed of varying mixtures of cells with clear and/or granular cytoplasm in nonpapillary formations, often arranged in sheets of broad trabecu- lae, separated by a richly vascular fibrous stroma with thin-walled blood vessels (owing to high levels of vascular growth factors) (solid growth pattern), around central spaces to resemble tubules (tubular growth pattern), or line cyst-like spaces (cystic growth pattern).

Occasionally, areas with tubulopapillary or papillary growth may also be observed. Granular cells are eosinophilic and the granules correspond to mitochondria.

The granular cells usually have a higher nuclear grade compared with the clear cells, and necrosis and hemorrhage are even more likely to be present. The surface of predominantly granular cell tumors is brown because of the phospholipid content of the numerous cytoplasmic organelles. Predominant granular RCCs are most often single tumors with a male predominance (2 : 1). Many high-grade RCCs of the clear cell type contain granular Table 1.Classification of renal epithelial neoplasms (Heidelberg

Classification) [14, 15]

Malignant renal epithelial neoplasms

Renal carcinoma conventional (clear cell) type Papillary renal carcinoma

Chromophobic carcinoma Collecting duct carcinoma Medullary carcinoma Unclassified renal carcinoma Benign renal epithelial neoplasms

Adenoma

Metanephric adenoma Oncocytoma

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Chapter 5.4 Primary Malignant Renal Parenchymal Epithelial Neoplasms in Adults 597

Fig. 1. ATypical RCC of the clear cell type protruding from the renal cortex as a rounded, bosselated mass. The interface of the tumor and the kidney is well demarcated. Note the eccentric hemorrhagic necrosis of the tumor.BContrast-enhanced CT, early vascular phase and Cnephrographic phase in two different patients. Ir- regular, hypervascular peripheral rim and predominant eccentric necrosis are typical features. Note retroperitoneal lymph adenopa- thy with similar characteristics as the primary tumor (C).DAxial T1-weighted and ET2-weighted image in another patient. The tumor is almost isointense on the T1-weighted image; the eccentric necrosis and the irregular border are clearly visible on the T2- weighted image, an almost exclusive feature for this histological subtype of RCC.FAxial T1-weighted image with fat saturation and after IV contrast: nodular and hypervascular border and with eccentric necrosis

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cell components. In some tumors, a highly malignant spindle cell or sarcomatous transformation may be observed. Areas of necrosis, cystic degeneration, hemorrhage and calcification (sometimes even with ossifica- tion) are seen. Extensive necrosis occurs predominantly in fast-growing neoplasms of high-grade malignancy.

Distinct areas of fat may be present as well [18, 19]. The latter is most frequently seen with extensive calcification. In practice, a calcified, fat-harboring lesion should be considered a RCC until proven otherwise. Angiom- yolipomas, in general, do not contain calcifications. In RCC, cystic changes may be so predominant that the tumor resembles a benign cystic mass. Approximately 10% of clear cell RCC is completely cystic [20]. Cystic RCCs tend to be large, rounded or polylobular lesions.

They tend to be solitary and predominately on the right side (75%), more frequently in the interpolar area.

There is a clear male predominance (2:1).

RCC extends in the venous system in 4%–9% of cases and is associated with worse characteristics.

The cytogenetic abnormality characterizing clear cell RCC is the deletion of the short arm of chromosome 3 (–3p), which is present in 96% of sporadic as well as in hereditary cases, and is considered as the trigger genetic event in the tumor development. Trisomy 5q occurs in 50% of cases. Additional chromosomal abnormalities are acquired during progression (–14q, –8p, –9, –6q, trisomy 7) and the frequency increases with the cytologi- cal grade and size of the tumor. The frequency of deletion of 14q increases with the presence of metastases (no metastases –14q: 30%; with metastases –14q: 73%).

The loss of the Y chromosome has been observed in 26% of nonpapillary RCC in males. This figure is consis-

Fig. 2A–C.Smaller RCCs of the clear cell type (2–3 cm), one protruding outside the renal border and sharply demarcated (A), the other with intrarenal origin (B). Note again the typical eccentric necrosis of both tumors. The contrast-enhanced CT (C, same pa-

tient as in B) in the early corticomedullary phase shows the intrarenal lesion with its eccentric necrosis. This lesion was hypodense in the nephrographic phase (not shown) and could have been er- roneously interpreted as a cyst or complicated cyst

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Fig. 3A–H.Bilateral synchronous renal cell carcinoma of the clear cell type.AUS: slightly hyperechoic lesion at the lower pole of the right kidney (arrow). There is only some vascularity at the implan- tation base. B Contrast-enhanced CT, early corticomedullary phase, showing the typical characteristics of a classic clear cell carcinoma: peripheral hypervascular border of viable tumor and ec- centric hypodense area due to necrosis (arrow).CAt the lower pole of the left kidney, an almost isoechoic mass lesion is seen on ultra-

sound (arrow).DOn color-Doppler ultrasound low-resistance flow (0.60) is found in the lesion, suggesting its malignant nature.

EAgain, the characteristics of this classic clear cell RCC are clearly shown on the vascular phase of the contrast-enhanced CT (arrow).

F–HAxial (F,G) and coronal (H) T2-weighted images from the same patient illustrating the irregular viable peripheral border and the necrosis of both lesions in the lower pole of the kidneys

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Fig. 3G–H.

Fig. 4A–D.Multifocal metachronous renal cell carcinoma, clear cell type in the left kidney, after right radical nephrectomy, 16 months earlier. US shows a necrotic lesion in the upper pole of the left kidney (A), whereas another one is isoechoic with a hypoechoic rim

(B).C,DOn MRI, axial (C) and coronal (D) T2-weighted images, both lesions have almost similar signal characteristics, with extensive necrosis extending to the pseudocapsule of the lesions

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tent with that of other types of malignant tumors aris- ing in elderly patients. It has been reported to be the only genetic abnormality in tumors as small as 1 mm in diameter, as well as in tumors up to 8 cm in diameter with metastatic growth. The loss of the 3p segment is a highly specific chromosomal anomaly occurring early on in the development of RCC.

A detailed histological analysis of entire kidneys failed to detect any microscopic precursor lesions with the notable exception of some hereditary cases. Micro- scopic precursor lesions are characterized by suscepti- bility to develop multiple or bilateral carcinomas, and are associated with a germ line balanced translocation involving the chromosome 3p13–14.2 region. In familial clear cell carcinomas not associated with von Hippel- Lindau disease, the genetic abnormalities include trans- locations t(3;8) and t(3;6). In von Hippel-Lindau disease, clear cell carcinomas are bilateral (frequently showing a cystic growth pattern) and associated with cystic lesions (lined by clear or sometimes granular cells) [17]. Such tumors develop in approximately 25%–55% of von Hippel-Lindau patients. Lesions tend

to be bilateral and multicentric, are often associated with cysts and angiomyolipomas, and occur at an earlier age than sporadic RCC. The genetic defect is situated on segment 3p (3p25–26) and codes for a protein that links with elongins) and is found in over 50% of indi- viduals with von Hippel-Lindau disease. The gene of von Hippel-Lindau disease is muted in the great majority of sporadic clear cell carcinomas.

RCCs are often associated with cysts. In most cases, the cyst is a cortical retention cyst, but associations with both acquired and hereditary polycystic disease have been well documented. The renal neoplasms associated with acquired polycystic kidney disease in patients on chronic hemodialysis generally occur after dialysis for several years (mean, 3.5 years) and the frequency of RCC varies directly with the primary renal disease pro- cess and both the duration of dialysis and the incidence of cysts.

Fig. 5A–D.Clear cell carcinoma invading the left renal vein.A,B Precontrast CT showing a large necrotic tumor in the lower pole of the left kidney (A) and a widened and left renal vein (B).CThe thrombus extends in the inferior vena cava (arrow); the implanta-

tion base of the carcinoma is visible (arrowheads) on this contrast- enhanced CT.DThe nephrectomy specimen shows the tumor and the extension to the major veins

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Imaging Ultrasound

There is nothing specific about the US diagnosis of typical clear cell RCC: lesions may be isoechoic, hypoechoic, hyperechoic or complex (Figs. 3, 4). Areas of necrosis may be present, yet sometimes hardly recognizable. Cal- cifications may be present as well. It is estimated that the small RCC (<3 cm), in almost 50% of the cases, is isoechoic. This explains why many lesions are invisible on US. Isoechoic lesions can only be detected when the inner or outer renal outline is deformed. Furthermore, isoechoic lesions may mimic normal anatomic structures or anatomic variants such as hypertrophy of the septal cortex (Bertin’s column). Color or power Doppler may be helpful in such cases to illustrate the normal vasculature in the suspicious area. Whenever there is any doubt about the diagnosis, further imaging with CT is warranted.

With hyperechoic lesions, the differential diagnosis includes angiomyolipoma (AML) and other rare benign and malignant tumors. Angiomyolipomas are rare in males, and therefore, as a rule, hyperechoic masses in males warrant further investigation. Some features may be helpful in distinguishing hyperechoic RCC from AML. Cystic areas due to hemorrhage or necrosis are almost never seen in AML; a hypoechoic rim or halo encircling the lesion is a feature of RCC. The vascular pattern on power Doppler has been suggested to add important information to gray-scale US findings for differential diagnosis of small solid renal lesions [21]. Be- cause of considerable overlap in the vascular pattern between AML and RCC, this criterion is not very useful in the individual patient. Since lesion discrimination is essential for further management, a plain CT scan is proposed to enable the detection of intralesional fat.

Whatever the echogenicity of the renal mass lesion, low resistive flow (resistive index <0.6) is more likely to be found in RCC than AML [22].

On US, the cystic clear cell RCC may appear almost completely cystic. Most often, however, diffuse wall thickening, or mural nodular thickening and multiple internal echoes will be seen. Mural nodes virtually exclude the radiological diagnosis of a benign neoplasm.

These protrusions are most commonly found near the implantation base of the mass in the kidney. Searching for these protrusions is far more important than putting efforts in measuring the actual size of the lesion. At times (numerous and thick) septations are present.

Then, the multicystic RCC resembles a benign neoplasm known as the benign multilocular cystic nephroma [23]. This benign neoplasm is very rare (virtually nonexistent) in adult males: a multilocular cystic mass in adult males, therefore, must be considered as a clear cell RCC. In middle-aged women, however, the radiolo-

gist may be faced with the differential diagnosis between a benign multilocular cystic nephroma and RCC. There are no reliable criteria to distinguish these two types of renal masses. Multilocular cystic nephroma is characteristically situated in the upper pole of the kidney and tends to protrude into the renal hilum, even into the collecting system. This lesion is almost always solitary and unilateral and the cysts multiloculated. On color Doppler, in clear cell cystic RCC, the septations are well vascularized, whereas in multilocular cystic nephroma there is almost no vascularity in the septations.

Both lesions are considered as surgical lesions (i.e., indication for surgical intervention).

Computed Tomography

On plain CT series, the lesions are iso-, hypo-, or hyper- attenuation masses compared to the renal parenchyma;

a heterogeneous appearance is a common feature of larger lesions [24]. Coarse calcifications may be present at the periphery of the lesion, near the center, or calcifications may be spread throughout the lesion.

In the arterial phase (corticomedullary phase) after intravenous injection of iodinated contrast, at least three-quarters of the clear cell RCCs are hypervascular, while approximately 20% appear almost isovascular and only few are hypovascular [25]. The enhancement pattern is heterogeneous with a somewhat patchy and nodular pattern in the periphery encircling unenhanced areas (Figs. 1–3). In the venous (nephrographic) and/or excretory phase, RCCs become hypodense compared to the renal parenchyma, the thick peripheral rim remaining clearly visible.

Nephrographic phase scans enable greater lesion detection and better characterization of small renal masses than corticomedullary scans only. Nephrographic phase series should be obtained when only monophasic scanning is used to detect small renal masses [26].

Intralesional necrosis is virtually always present and is frequently characterized by its eccentric location: the necrosis extends to the periphery, most often at the op- posite side of the renal parenchyma. Tumor necrosis is independent of the size of the lesion. Therefore, tumor necrosis is the key criterion for imaging-based lesion characterization. Extension into major renal veins and inferior vena cava may occur (Fig. 5).

On plain CT series, most cystic RCCs are hypodense [23]. Typically, the content has attenuation numbers ranging between 10 and 30 Hounsfield units (HU). After IV injection of contrast, the thick wall of cystic RCC en- hances with mural nodes, near the renal parenchyma (Figs. 6–8). Calcification in a cystic renal mass is not as important in diagnosis as is the presence of associated enhancing soft tissue elements [27]. It may be impos- sible to differentiate septate cystic RCCs from multiloc-

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Fig. 6A–C.Cystic renal cell carcinoma.AContrast-enhanced CT shows a predominately cystic mass in the left kidney. The mural nodes (arrow) exclude the diagnosis of a benign mass.B,CThe outer surface of the tumor is smooth (B), but at cross-section, the inner surface is irregular (C)

Fig. 7A–F.Cystic renal cell carcinoma, clear cell type.APrecontrast CT shows a rounded mass lesion in the right kidney, with cystic portions.BThe contrast-enhanced CT shows the multinodular enhancing mass and the anterior cyst-like component.C,DThe lesion is isointense on T1-weighted image (C), and heterogeneous on T2- weighted image (D).EContrast-enhanced MR with fat saturation displays the heterogeneity of the tumor including a solid area with necrosis and a cyst-like area. Note the striking resemblance with the contrast enhanced CT in B.FThe surgical specimen after nephron-sparing surgery shows the heterogeneity of this renal cell carcinoma of the clear cell type

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ular cystic nephroma. Both neoplasms may have very similar features on CT (Fig. 9). Therefore, secondary signs (gender, location, protrusion in renal hilum, regional lymph nodes, and renal vein patency) may contribute to the radiological diagnosis.

Thrombosis of the renal vein is expected in approximately 10% of cases of cystic RCC. Regional lymph node metastases are detected in 10% of patients at the time of diagnosis. Few patients will have ipsilateral or contralateral adrenal metastases at the time of presentation.

Magnetic Resonance Imaging

Similar to CT, the key to the MR diagnosis of clear cell RCC is the presence of necrosis. Necrosis is hypointense on predominately T1-weighted images and hyperintense on predominately T2-weighted images, and is easily recognized without further intravenous injection of contrast (Figs. 3, 4).

After intravenous administration of contrast, the enhancement pattern is comparable to that of CT: enhanc-

ing viable tumor enveloping a hemorrhagic–necrotic, nonenhancing area, which extends to near the pseudocapsule [28].

On MRI cystic RCCs tend to be isointense on T1- weighted images, with extensive hyperintense areas on T2-weighted images [23]. As with CT, the peripheral nodules of viable tissue may be hardly recognizable (Figs. 7, 9). The enhancement pattern again is similar to that of CT lesions [29].

Fig. 7C–F.

Fig. 8A–C.Cyst-like papillary carcinoma, type A.AThis contrast- enhanced CT shows a cystic mass lesion with a hardly recogniz- able mural node at the anterior surface (arrow).B,CThe opened surgical specimen shows the yellowish tumor in the deep area of the cyst (B) and the nodular tumor at the implantation base on the kidney (C)

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Papillary Renal Carcinoma or Chromophilic Cell Carcinoma Pathology

Papillary RCC constitutes approximately 10%–15% of all RCCs and are predominant among tumors smaller than 3 cm. The current definition is based on the histological finding of vascularized connective tissue stalks invested by neoplastic cells [30]. Nevertheless, at contrast-enhanced imaging studies, virtually all papillary carcinomas are hypovascular. Some investigators require that the papillary areas compose at least 50% (or Fig. 9A, B.Cystic renal cell carcinoma, clear cell type. Axial (A) and coronal (B) T2-weighted images of an almost completely cystic and multilocular renal cell carcinoma. The intralesional protrusions are more readily visible on the axial image, whereas the septations are better recognized on the coronal image. Such a lesion should not be confused with benign multilocular cystic nephroma

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even 70%) of the tumor. There is male-female ratio of approximately 2.5–5 : 1. The mean age is in the 6th decade, but there is a wide age range. The rate of calcification is reported to be higher than in clear cell RCC.

Two subgroups can be distinguished. Type B (one- quarter of cases) consists of multicentric lesions

(100%), often bilateral (two-thirds), usually with one large mother lesion (approximately 3 cm in diameter) and with other multiple, small daughter lesions (ranging from microscopic to subcentimeter size) (Figs. 10, 11) [31, 32]. The largest lesion shows a complete or at least partial exorenal growth. Multicentricity may occur

Fig. 10A–G.Papillary RCC carcinoma (chromophilic cell carcinoma).AHypovascular mass with extrarenal growth at the anterior surface of the right kidney on the contrast enhanced CT, vascular phase.B–DAnother patient with a slightly hyperechoic mass at the lower pole of the left kidney with some calcifications (US in B), isodense and with some coarse calcifications on the precontrast CT (C) and without increased attenuation on contrast-enhanced CT

(D). The attenuation numbers though increase from 25 to 46 HU, suggesting a solid hypovascular tumor, rather than an avascular cyst.E,FThe nephrectomy specimen of the first patient shows a mother lesion (E) and multiple daughter lesions (E,F).GA nephrectomy specimen of another patient with multifocal papillary carcinoma is shown. Note the grayish aspect of the tumors, some of them protruding from the kidney; other smaller lesions are flat

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either synchronously ipsilateral or contralateral to the largest lesion, or both iso- and contralateral to the largest tumor, with an almost equal frequency. Pathological examination often reveals more tumoral (small microscopic) foci than suspected by imaging. The other type (type A, three-quarters of cases), is more aggressive, and constitutes a single and usually bulky tumor, either multinodular solid or almost completely cystic, with a ratio of approximately 2 : 1.

On section, the surface of papillary RCC varies in col- or from light gray to golden yellow. The color depends

on the amount of lipid-laden macrophages in the stroma. Tumor necrosis may liberate large amounts of lipid, and cholesterol crystals may form. Intralesional hemorrhage and necrosis are observed in many cases (half to two-thirds) [33].

Adrenal metastases or distant metastases may be seen at the time of diagnosis in type A papillary carcinoma. Invasion of the renal vein or liver metastases is only rarely seen. Lymph node and distant metastases are rare in type B papillary carcinoma.

Multiple, nephrogenic, cyst-like precursor lesions are often seen in the apparently normal part of the tumor- bearing kidney. The potential role of reactivation of nephrogenic rests or regeneration of tubules is investi- gated in the etiogenesis of tubulopapillary neoplasms.

Detailed examination shows multifocal and bilateral development of papillary renal cell tumors in nearly all cases. The carcinomas are usually low stage, with 85% of cases pT1 and only 12% in pathologic pT3.

Papillary neoplasm has only recently been found to have a unique constellation of cytogenetic abnormalities [34, 35]. There is evidence that there is a benign precursor lesion (tubulopapillary adenoma). Regardless of size, both the adenoma and the carcinoma tend to show a loss of the Y chromosome. In papillary renal adenomas, the anomalies are further characterized by trisomy of chromosomes 7 and 17 (+7; +17). The finding that this constant combination of alteration of three chromosomes (–Y, +7 and +17) occurs in very small as well as in large tumors suggests stability of these genetic changes during growth. In papillary RCC the same abnormalities can be found along with other abnormalities (+3q; +8; +12; +16; +20). Most of these tumors show invasive or metastatic growth. Some tumors may acquire complex genetic alterations early during their growth, while others undergo changes at a later stage of development only. Thus it can be explained that papillary renal cell tumors of different size may have a different aggressive biological behavior or, in other words, that the size of papillary tumors does not correlate with their actual biological behavior.

On US, type B papillary RCCs are hypoechoic masses in approximately 60% of cases, or isoechoic or hyperechoic (approximately 20% each) (Fig. 10) [36]. Calcifica- tions are reported in a minority of cases (less than 20%). As can be expected from the gross morphology, almost 40% of papillary RCCs are avascular on color Doppler US (i.e., no intralesional flow detectable).

Solid type A papillary RCCs appear as a hypoechoic, isoechoic or even as a hyperechoic mass. Cystic lesions Fig. 10G

Fig. 11.Rarely, a papillary carcinoma develops intrarenally. On radiological studies, it mimics other tumors, anatomic variants and pseudotumors

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have a complex US pattern, 25% appearing as avascular on color Doppler US.

In type B papillary RCC, all lesions are isodense on unenhanced CT series (Fig. 10). Sometimes calcifications may be seen. These tumors are hypovascular compared to the renal parenchyma on corticomedullary and de- layed-phase images and sharply marginated [31, 32, 37], resembling cortical cysts. Enhancement of renal neoplasms is time-dependent and may not be evident in hypovascular lesions analyzed during the early corticomedullary phase [24]. Therefore, measuring attenuation numbers is essential to prove enhancement and thus to differentiate between a cortical cyst and a papillary RCC. Multiple measurements in different phases with similar parameters (same area, same slice thickness, same pixel area) are required [24]. An increase in the attenuation numbers of at least 20 HU between unenhanced and enhanced series is conclusive for contrast enhancement and, therefore, for a solid lesion (Fig. 10).

When no plain CT is available, and CT is only performed during a late venous phase, as in many screen- ing examinations, attenuation numbers over 70 HU in- dicate contrast enhancement and reliably allow differentiation between a cyst and a solid (vascularized) lesion [36, 38, 39].

Particularly with multifocal papillary RCC the differential diagnosis with renal metastases and lymphoma may be difficult. At times, this may be an indication for percutaneous ultrasound or CT-guided biopsy to differentiate between a surgical renal neoplasm and nonsurgical metastases or lymphoma.

On unenhanced CT, type A papillary RCC is isodense or slightly hypodense. Calcifications are generally punctiform and located near the periphery of the tumor. Af- ter IV contrast, the majority of the mass becomes hypodense compared to the renal parenchyma; few tumors are isodense (Fig. 8). All lesions are hypodense on late- phase images and all have a sharp border. The solid lesions show areas of necrosis near the center, unlike carcinomas of the clear cell type that show eccentric necrosis. Lymph node metastases, adrenal metastases and distant metastases may occur. Soft tissue metastases (i.e., corpus cavernosum) may be the presenting symptom. Invasion of the renal vein or liver metastases are not frequently seen at the time of diagnosis.

On MR, these tumors appear hypointense or isointense (three-quarters) on T1-weighted images and hypoin-

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tense on T2-weighted images in all tumors (Fig. 12). All lesions are hypovascular to the renal parenchyma after administration of gadolinium [40]. Here again, appropriate measurement of the lesion signal intensities be- fore and after contrast injection is essential. Larger papillary RCCs show heterogeneous signal intensities (Fig. 13).

Chromophobic Renal Carcinoma Pathology

Chromophobic carcinoma is a relatively recently (1985) described neoplasm characterized ultrastructurally by cells with abundant cytoplasm. The cells may be related to the normal intercalated cells (type B) of the collecting duct [41]. This subgroup accounts for about 4%–5% of renal cell neoplasms and its median incidence is in the 6th decade (range, 31–75 years). The lesions are most frequently located near the pole of the kidney (Fig. 14).

For some reason, the tumor is more frequently observed in rather young females (40–50 years) and in old males.

Chromophobic cell carcinoma tends to be large, ranging from 1.3 to 22 cm (mean diameter 8 cm) in their great- est dimension (Fig. 14) [41, 42].

Grossly, it resembles conventional RCC: they are well circumscribed and solitary, with a gray to brown appearance and typically lacking hemorrhage or necrosis [42, 43]. Most tumors are pathologic stage pT2 or pT3 at the time of resection. Some are associated with conventional RCCs.

The chromophobic carcinoma has a solid architecture, with large cellular blocks and only limited stroma.

The lesion consists of large cells, the pale cytoplasm crowded with microvesicles and a variable number of mitochondria, and a fairly typical perinuclear halo. The cells contain little or no glycogen or lipids, but stain with Hale’s acid iron colloid, which allows differentiation from oncocytomas. The electron microscopic findings are unequivocal, with cytoplasm containing numerous 150- to 300-nm microvesicles.

Cytogenetic analysis shows a combination of allelic losses, which do not occur in other types of epithelial neoplasms [44]. These genetic losses involve seven chromosomes including –1 (100%); –2 (95%); –6 (80%);

–10 (86%); –13 (95%); –17 (70%); and –18 (21%). DNA analysis of one case revealed allelic losses at chromo- some 3p, 5q and 17 with variable frequency and in a combination, which does not occur in other types of kidney tumors. Along with this chromosomal loss, there are rearrangements in the mitochondrial DNA that are under further investigation.

Follow-up studies have suggested that chromophobic carcinoma has a more favorable prognosis compared to the classic RCC. Nevertheless it can be highly aggressive and must certainly be considered malignant. A sarcomatous transformation of chromophobic cells is only rarely seen.

Fig. 13A, B.Multinodular papillary carcinoma, type A. T1-weighted (A) and T2-weighted MR (B) showing a multinodular mass lesion in the right kidney. This mass lacks the typical eccentric necrosis

of the clear cell type. The nodule in the left adrenal gland was proven to be an adenoma

Fig. 12A–C.Papillary carcinomas, type B.AT2-weighted MR show- ing bilateral tumors, hypointense with hyperintense areas (arrow- heads) in this 36-year-old male. Bilateral nephrectomy was per- formed.BTwo lesions of the right kidney, one solid and one with hemorrhagic necrosis.CTypical multifocal papillary carcinoma on the cut surface of the left kidney

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Chromophobic carcinomas are hypo- or isoechoic and heterogeneous or hypovascular on color Doppler.

Chromophobic RCCs are homogeneously isodense on unenhanced CT images. Tiny punctiform calcifications may be observed near the periphery. All lesions appear homogeneous and hypovascular on contrast-enhanced CT and are sharply demarcated (Fig. 14A, B). Necrosis is not seen and metastases or invasion of the renal vein in general do not occur [45].

Since this subtype is rather rare, experience with MR is limited. The lesion is isointense on T1-weighted images and hypointense on T2-weighted images. A hyperintense peripheral rim may be seen on heavily T2-weighted images. After administration of contrast there is hy- povascularity of the lesion compared to the renal parenchyma.

Collecting (Bellini) Duct Renal Carcinoma Pathology

Bellini duct RCC, a rare tumor, constitutes less than 1%

of primary malignant renal parenchymal epithelial neoplasms. Bellini duct carcinomas appear to be aggressive, often with metastatic disease at manifestation and rap- id progression despite surgery, with an almost uniformly fatal outcome [46]. Hematuria is the most common symptom. Since this variant seems to originate in the medulla and has a predominately tubular configura- tion, a collecting duct dedifferentiation is suggested.

The cells contain the higher molecular weight keratin characteristic of the collecting ducts compared with the low molecular weight keratins of renal tubular epitheli- Fig. 14A–C. Chromophobic renal cell carcinoma. Hypovascular mass lesions in the left kidney (A) and in the right kidney on the parasagittal reformatted contrast-enhanced CT (B). The masses are solid with a grayish aspect at cross section (C). In general, these lesions are solitary and have already large dimensions at the time of detection. Compared to chromophilic cell carcinomas (papillary carcinoma), chromophobic cell carcinomas are solitary and larger (larger than 3 cm)

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Chapter 5.4 Primary Malignant Renal Parenchymal Epithelial Neoplasms in Adults 611 um. The mass is usually localized to the renal medulla,

with distortion of the pelvicaliceal system and often with infiltration into the adjacent renal cortex. The shape of the kidney is usually more or less preserved (Fig. 16C) [47]. The tumors are generally firm and white or grayish (not yellow) because of an accompanying de- smoplasmic reaction (usually no necrosis or hemorrhage) (Fig. 16). Extension into the renal vein does not occur. Very rarely only, the tumors are cystic with endo- phytic papillary projections. The intermingling of clear cells, basophilic and eosinophilic cells contribute to a fairly typical aspect. The tumoral architecture is usually tubulopapillary. In general, there is considerable pleo- morphism, especially in the invasive component, and mitotic figures are frequent. Associated atypical changes are often seen in adjacent collecting duct epithelium.

The small number of these that have been studied by genetic methods showed monosomies of chromosomes 1, 6, 14, 15 and 22 [48]. Chromosome 3p, 7, 17 and Y ab- normalities were not encountered.

A variant of collecting duct carcinoma, called medullary carcinoma, has been identified in patients suffering from sickle cell trait [49, 50].

The tumor is slightly hypoechoic or almost isoechoic, poorly marginated, and typically centrally located on US.

Bellini duct RCC appears homogeneous and isodense compared to the renal parenchyma on unenhanced CT.

After intravenous contrast administration, the tumor is hypovascular [51] (Fig. 15A, B). There may be central low attenuation areas, due to the extensive reactive fibrotic reaction (not necrosis), which accompanies the infiltrative growth of this neoplasm, rather than necrosis or hemorrhage.

Fig. 15A–C.Collecting (Bellini) duct renal cell carcinoma.ACon- trast-enhanced CT, excretory phase. Infiltrating tumor in the left kidney with hypodense areas. Note that the renal shape is largely preserved.BIn the upper pole, the tumor mimics a predominately cystic carcinoma. The hypodense areas are not due to hemorrhage

or necrosis, but are explained by reactive fibrosis. Note retroperitoneal lymph node metastases.CNephrectomy specimen of a sim- ilar case (right kidney) with infiltrating fibrotic tumor involving the upper half of the kidney

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Unclassified Renal Carcinoma

There is an increasing number of renal carcinomas, which are not readily classified. They may be observed in patients treated for carcinomas during childhood.

Such tumors contain an odd mixture of components, tumors with an unrecognizable architectural or cyto- logical pattern, or sarcomatoid carcinoma in which the original epithelium element cannot be identified or classified properly.

Observations on Sarcomatoid Neoplasms Pathology

The sarcomatoid RCC is a particularly poorly differentiated, anaplastic variant comprising approximately 1%

of cases and has an unfavorable prognosis. In fact, they represent a poorly differentiated, high-grade and invasive (infiltrative) type derived from any of the other cell types (clear cell, papillary, chromophobic, Bellini duct) [52]. They do no constitute a different subgroup per se;

any tumor of the histological subtypes may become sarcomatoid. Most frequently they are derived from the conventional clear cell carcinoma. The presence of clear, granular or chromophilic cell areas within spindle cell or sarcomatous RCC is an important distinguishing feature from true sarcomas. When the sarcomatoid por- tion predominates, the neoplasm appears firm and fibrous without hemorrhage or necrosis; the carcinoma part is heterogeneous with areas of necrosis and hemorrhage. The upper pole seems to be more often affect- ed than lower pole (ratio, 3 : 1). They are frequently bulky and advanced at presentation, with (atypical) distant metastases and may be inoperable (Fig. 16).

Fig. 16A–C.Sarcomatoid renal cell carcinoma. A Contrast-enhanced CT, nephrographic phase. Huge heterogeneous neoplasm at the lower pole of the left kidney. Soft tissue metastases in the subcutaneous fat of the anterior abdominal wall.BAxial T2- weighted MR showing similar imaging characteristics. Note that the tumor is predominately solid. Again the subcutaneous metas- tasis is clearly seen.CSurgical specimen showing the homogeneous solid mass extending of the surface of the left kidney

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Chapter 5.4 Primary Malignant Renal Parenchymal Epithelial Neoplasms in Adults 613 Imaging

Ultrasound

US shows a heterogeneous predominantly hyperechoic, isoechogenic or hypoechogenic mass. Calcifications may be seen quite often. The majority of sarcomatoid RCCs are hypovascular on color Doppler.

Sarcomatoid RCCs are iso- or hypodense on unenhanced scans. The tumors are heterogeneously hypervascular in the cortical phase. A hypodense and heterogeneous appearance is seen on late scans (Fig. 16A). Ne- crosis is always diffusely spread throughout the lesion, reaching the outer border of the lesion.

Lymph node metastases or adrenal or liver metastases are present in the majority of cases. These tumors may be very aggressive to adjacent organs (invasion of liver, spleen, pancreas, abdominal wall), and have atypical metastatic deposits.

The solid component of the lesion is either hypo- or isointense on T1-weighted images, heterogeneous and predominantly isointense on T2-weighted images (Fig. 16B). After Gd-DTPA administration, sarcomatoid RCCs are heterogeneously hypo- or hyperintense.

Observations on Renal Adenoma

For many years, size has been used as the main criterion to divide renal cell tumors into benign and malignant.

This assumption has been based largely on the work of Bell in 1950 [53]. He suggested that renal tumors of less than 3 cm in maximum diameter should be called adenomas, yet two of his adenomas metastasized! A generally used limit is 3 cm in diameter for diagnosing a well- differentiated renal cell tumor as an adenoma. However, tumors smaller than 3 cm with metastases have been described on several occasions. Furthermore, adenomas share many phenotypic features with RCCs. Therefore, all renal cell tumors should be considered as malignant.

The classic clear cell carcinoma and chromophobic RCCs develop as carcinomas, irrespective of grade and size. As already mentioned above, the natural history of papillary renal cell tumors is quite different from that of other types and their appearances are unique. Cortical adenomas are almost always papillary tumors, with a diameter less than or equal to 5 mm, and may transform to papillary carcinoma (Fig. 10) [54]. Tumors with a

constant combination of trisomy 7 and 17 as well as loss of the Y chromosome may be diagnosed as a papillary renal cell adenoma. Such tumors may reach a large size without any sign of malignancy, but malignant transformation accompanied by additional complex genetic alterations may occur in small adenomas. It is not the size, but the accumulation of genetic alterations, especially acquired trisomies 16, 12 or 20, that are associated with malignant behavior.

Observations on Renal Oncocytoma Pathology

Renal oncocytoma is a benign neoplasm and accounts for approximately 2%–5% of renal cell neoplasms [55].

Renal oncocytoma was first described by Klein and Va- lensi [56]. Incidental coexistence with RCC or angiomyolipoma has been reported. The majority remains asymptomatic and they are discovered incidentally.

Most patients are elderly with a median age of about 65 years and a male-female ratio of approximately 2.5 : 1. Contrary to RCC, there is no association with von Hippel-Lindau disease, tuberous sclerosis, or chronic dialysis. Oncocytomas are characteristically single, well demarcated, uniformly expansile masses occurring at any renal site (Fig. 17). Multiple oncocytomas have been reported (oncocytomatosis). Occasionally, oncocytomas become very large (i.e., giant oncocytoma). In one review, the average tumor diameter was 7.4 cm, but reported sizes range from 0.3 to 20 cm. Whatever the size, oncocytomas should be considered as a benign neoplasm.

The tumors are tan (Fig. 15A, B) because of the li- pochrome pigment associated with mitochondrial fill- ing of the cytoplasm, circumscribed, with or without a capsule and often surrounded by a rim of dilated blood vessels. Larger tumors tend to have a central myxoid-fibrotic stellate scar that can become calcified. Foci of hemorrhage are commonly seen, but cystic change and necrosis are unusual. The cells are arranged in solid, tubular, or trabecular rests. A predominant extrarenal growth can be expected in 50% of cases. Metastases or invasion of the renal vein do not occur.

Microscopically, cells have abundant, granular eosinophilic cytoplasm; no clear cytoplasm is seen. The tumor cells probably derive from intercalated cells (type A) from the collecting ducts. Nuclei are generally low grade (I or II) and uniform, but focal areas may have marked nuclear atypia (oncocytomas are not graded).

Mitotic activity is not seen, and foci of necrosis are un- common. Ultrastructural examination reveals numerous round mitochondria larger than the mitochondria of other renal cell neoplasms and with a membrane particularly rich in cristae.

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Fig. 17A–E.Oncocytoma.AOn fresh specimen, this tumor has a typical mahogany brownish color.B,CA central stellar scar may be present.DContrast-enhanced CT, cortical phase. Sharply demarcated and very smoothly outlined lesion at the upper pole of the right kidney and without central scar.EAxial T2-weighted MR (TR

= 4.3 ms; TE = 60 ms). Predominately hyperintense intrarenal lesion in the left kidney. The signal intensity, however, is lower than the content of the collecting system and some intralesional heterogeneity is observed. This was diagnosed as a tubulocystic variant of an oncocytoma

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Chapter 5.4 Primary Malignant Renal Parenchymal Epithelial Neoplasms in Adults 615 Cytogenetic studies show normal or abnormal kar-

yotypes including a translocation t(11q;13), or loss of chromosome 1 or Y. The development of oncocytoma is initiated by typical abnormalities of the mitochondrial DNA structure.

Most reported oncocytomas have a benign behavior, but local or distant metastases have been reported.

However, it is now felt that most, if not all, malignant oncocytomas described in the older literature are nonpapillary, papillary or chromophobic RCCs with eosinophilic granular cytoplasm. In addition, these tumors would be expected to display a deletion of 3p or trisomy 17 or mitochondrial alterations at genetic analysis. Yet oncocytomas may have the capacity to become malignant since they can contain chromophobic cells. This raises the possibility that oncocytomas and chromophobic carcinomas represent two ends of the same spectrum.

Most oncocytomas are slightly hypoechoic compared to the renal cortex on US. A central scar, reported as an an- echoic center, is only seen in the minority of cases.

Oncocytomas are homogeneous and isodense on unenhanced CT. The majority is isodense (75% of cases) on cortical phase images and hypodense on late scans (Fig. 17C). Although a central scar is commonly seen on gross morphology, it can only be expected to be detected in 50% of cases by CT. Furthermore, this scarring is not exclusive for oncocytoma [57–59]. A sharp and very smooth demarcation with the adjacent parenchyma is always seen. A predominant extrarenal location can be expected in 50% of cases.

Many authors focused on the possibility of differentiating oncocytoma and RCC based on CT criteria (or angiography) and that differences would become more apparent as tumors enlarge. On contrast-enhanced scans, homogeneous attenuation throughout the tumor and a central, sharply marginated stellate area of low attenuation were considered predictors of oncocytoma.

Any area of decreased attenuation in the tumor except for a stellate, central area was used as a predictor of carcinoma. Among oncocytomas larger than 3 cm in diameter, 67% exhibited criteria for oncocytoma and 33%

met the features of carcinoma; among smaller oncocytomas, the respective results were 82% and 18%. Among carcinomas larger than 3 cm in diameter, 84% fulfilled the criterion for malignancy and 16% were incorrectly

predicted to be oncocytomas; among smaller carcinomas, the respective results were 58% and 42%. There- fore, CT criteria used are poor predictors of the diagnosis of oncocytoma or carcinoma regardless of tumor size.

A likely explanation for the lack of homogeneity of oncocytomas on contrast-enhanced CT scans is an in- homogeneous perfusion as a result of ischemia. The pattern of growth of oncocytomas in which cells accu- mulate in more or less rounded, solid cell nests that become smaller, fewer, and farther apart toward the center of the tumor probably favors the ischemic events. Even- tually these ischemic tumor cells are replaced by fibro- blasts that give the classic gross specimen the pathologic and radiologic finding of a central scar. These same evolutionary changes of ischemia and fibrosis also occur in regions other than the center of an oncocytoma.

This is the most likely explanation for the observations of heterogeneity in the enhancement pattern of oncocytoma noted in several studies. In addition to hemorrhage and necrosis, ischemia must also be considered as a cause of low tumor attenuation.

Oncocytoma is isointense on T1-weighted images and hyperintense on T2-weighted images (Fig. 17D) [60].

After injection of contrast, lesions are iso- to slightly hypovascular compared to the renal parenchyma and without evidence of necrosis or hemorrhage. A central stellate may occasionally be seen.

Indications for Lesional Biopsy

Needle aspiration puncture or biopsy has a limited role in the evaluation of the renal mass in the CT/MR era and has been abandoned as a routine procedure. Biop- sy or needle aspiration has occasional value in the evaluation of the cystic indeterminate mass. In the setting in which a lesion is highly suspicious for neoplasm in a patient who is a very poor surgical risk, the technique could be performed to help establish a diagnosis and determine the treatment approach [61].

There are many occasions in which needle aspiration or biopsy is definitely indicated. These include differentiating a chronic abscess from a cystic carcinoma, differentiating a new primary renal neoplasm from a metastatic one in a patient who has had a previous primary tumor in another organ, and differentiating a primary renal neoplasm from renal lymphoma in a patient with lymphoma, particularly when the lesion does not re- gress with treatment whereas the rest of the disease does [62].

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Conclusion

General agreement exists in the current literature on the importance of early detection of renal parenchymal neoplasms since (a) small lesions grow and then large tend to metastasize, (b) early detection implies earlier treatment and improved survival rate, and (c) it im- proves the possibility of elective or mandatory renal- sparing surgery [63–65]. Besides earlier detection, sub- typing of RCCs may be valuable and useful for the sur- geon, especially in centers where elective nephron-sparing surgery is performed. In a study by Van Poppel et al.

[65], it has been shown that the most important require- ments for this surgery are: (1) tumor is easily resectable, and (2) selection of candidates is based not only on tumor size. Therefore, if a tumor is suspected of being a papillary RCC or when a renal lesion does not fit in any of the above categories, further studies and possibly biopsy are indicated to avoid surgery in nonsurgical lesions such as metastases and lymphoma.

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