Chapter

Primary Malignant Renal Parenchymal 5.4 Epithelial Neoplasms in Adults

Raymond Oyen, Hendrik Van Poppel, Tania Roskams

Contents Introduction Introduction ...... 595 Primary malignant renal epithelial neoplasms account Primary Malignant Renal Epithelial Neoplasms ...... 596 for 3% of adult [1]. US, CT and MRI all Renal Cell of the Clear Cell Type ...... 596 contribute to the increased detection of all types of re- Pathology ...... 596 nal parenchymal mass lesions, including those that re- Imaging ...... 602 Ultrasound ...... 602 quire surgery and those where surgery has to be avoid- Computed Tomography ...... 602 ed. Malignant tumors are detected at earlier stages. Ear- Magnetic Resonance Imaging ...... 604 lier detection and more accurate diagnosis improve the Papillary Renal Carcinoma or Chromophilic Cell Carcinoma 605 cure rate of renal carcinoma. Radiological characteriza- Pathology ...... 605 tion of these tumors from their benign masses (i.e., an- Imaging ...... 607 giomyolipoma and complicated ) is a continuous Ultrasound ...... 607 challenge and an essential prerequisite for appropriate Computed Tomography ...... 608 management [2]. Radical nephrectomy is the treatment Magnetic Resonance Imaging ...... 608 of choice, regardless of size.Alternative treatment strat- Chromophobic Renal Carcinoma ...... 609 egies are available now, in particular for smaller tumors Pathology ...... 609 (<4 cm), and include open or laparoscopic tumorecto- Imaging ...... 610 my, partial nephrectomy, radiofrequency ablation, and Ultrasound ...... 610 cryotherapy [3–6]. Computed Tomography ...... 610 Understanding the underlying gross pathology and Magnetic Resonance Imaging ...... 610 histological correlates provides an essential substrate Collecting (Bellini) Duct Renal Carcinoma ...... 610 for explaining the radiological characteristics of these Pathology ...... 610 masses. Many pathologists still rely on hematoxylin- Imaging ...... 611 Ultrasound ...... 611 and eosin-stained preparations of surgical specimens to Computed Tomography ...... 611 achieve the histological diagnose of renal cell carcino- ma (RCC) [7, 8]. From clinicopathological observations, Unclassified Renal Carcinoma ...... 612 it has been observed that a neoplasm may change its Observations on Sarcomatoid Neoplasms ...... 612 pattern of differentiation in time and that it does not Pathology ...... 612 necessarily retain the phenotype of its presumed pro- Imaging ...... 613 Ultrasound ...... 613 genitor cell. Thus it can be explained that in the past, Computed Tomography ...... 613 lectin and immunohistochemical studies using markers Magnetic Resonance Imaging ...... 613 for different parts of the adult renal tubular system Observations on Renal ...... 613 yielded conflicting results regarding the proximal ver- sus distal tubular origin of renal cell tumors. Further- Observations on Renal ...... 613 more, renal cell may be composed of ad- Pathology ...... 613 Imaging ...... 615 mixtures of clear and granular cells or clear and chro- Ultrasound ...... 615 mophilic cells. Such observations would suggest that a Computed Tomography ...... 615 transition between phenotypes occurs during progres- Magnetic Resonance Imaging ...... 615 sion. Indications for Lesional Biopsy ...... 615 During the last decades, it has become increasingly clear that the initiation and progression of solid tumors Summary ...... 616 is governed by alterations of genes that control growth References ...... 616 and differentiation. Tumor development is based on 596 Raymond Oyen, Hendrik Van Poppel, Tania Roskams

specific and separate molecular mechanisms in differ- gression. Furthermore, the absence of the typical radio- ent cells, and therefore they are almost completely dif- logical features warrants additional investigation to ex- ferent. There is a specific combination of chromosomal clude lesions for which surgery should be avoided (i.e., and mitochondrial DNA alterations marking distinct benign lesions, metastases, lymphoma). types of tumor genes or putative tumor suppressor genes [9]. of the Clear Cell Type

Primary Malignant Renal Epithelial Neoplasms Pathology

The morphological classification of renal cell neoplasm The clear cell subtype is the most common subtype, ac- in adults relies on three essential criteria: (1) the aspect counting for approximately 70%–80% of RCCs. It is also of the tumor cells (i.e., clear cells, chromophilic cells referred to as classic or conventional RCC. The majority [basophilic or eosinophilic], chromophobic cells, on- occurs sporadically as a solitary tumor and is randomly cocytes, collecting duct cells, and sarcomatoid or fusi- distributed in the renal cortex. There is a male predom- form cells); (2) the architecture (solid [acinar], tubulop- inance (1.5–2:1). Multicentricity in the same kidney oc- apillary, tubular, tubulocystic); and (3) nuclear grade, curs in approximately 4% of cases, whereas bilaterality based on increasing numbers of nuclear and nucleolar occurs in 0.5%–3%. Synchronous (75%) or metachro- atypia. Based on these morphological criteria, classifi- nous multifocality may occur. Multicentricity and bilat- cation of the majority of renal cell neoplasms is feasible, erality are often associated with conditions such as von with few exceptions only. This morphology-based clas- Hippel-Lindau disease [17]. Clear cell carcinomas can sification is now supported by cytogenetic analysis. Five become very large but the frequency of small lesions major groups of malignant renal epithelial neoplasms has increased because of earlier detection with US, CT are distinguished (Table 1) [10–13]. and MRI. Tumor genesis is driven by genetic changes including RCC of the clear cell type protrudes from the renal not only classic point mutations, but also deletions re- cortex as a rounded, bosselated mass. The interface of moving entire genes, as well as gross chromosomal ab- the tumor with the kidney is usually well demarcated. normalities at specific sites in the genome. Molecular Yet the presence of a clear pseudocapsule depends on cytogenetic techniques enable the identification of ge- the nuclear grading: well-differentiated lesions are netically homogeneous groups of malignant renal pa- more likely to have such a pseudocapsule. Rarely, RCC renchymal tumors. Each subgroup is characterized by a may be diffusely infiltrative and then become difficult combination of genetic changes affecting different sites to distinguish from urothelial carcinoma or other infil- within the chromosomal and mitochondrial DNA [16]. trating tumors. Careful analysis of CT and/or MR images allows for On section, clear cell RCCs have a yellowish-golden preoperative characterization of the histological sub- appearance, due to the abundant cytoplasmic lipid con- types in the majority of cases. The criteria include size, tent, mucolipids (Figs. 1–5). Thus the cells are markedly shape, location, number, contrast enhancement pattern similar to that of the proximal convoluted tubules. The (including the angiographic or corticomedullary phase), typical lesion is composed of varying mixtures of cells presence and site of hemorrhage and necrosis, patency with clear and/or granular cytoplasm in nonpapillary of renal vein, and lymph node status. Categorizing neo- formations, often arranged in sheets of broad trabecu- plasms may be helpful in designing appropriate thera- lae, separated by a richly vascular fibrous stroma with peutic strategies and predicting the likelihood of pro- thin-walled blood vessels (owing to high levels of vascu- lar growth factors) (solid growth pattern), around cen- tral spaces to resemble tubules (tubular growth pat- Table 1. Classification of renal epithelial neoplasms (Heidelberg tern), or line -like spaces (cystic growth pattern). Classification) [14, 15] Occasionally, areas with tubulopapillary or papillary Malignant renal epithelial neoplasms growth may also be observed. Granular cells are eosino- Renal carcinoma conventional (clear cell) type philic and the granules correspond to mitochondria. Papillary renal carcinoma The granular cells usually have a higher nuclear grade Chromophobic carcinoma Collecting duct carcinoma compared with the clear cells, and necrosis and hemor- rhage are even more likely to be present. The surface of Unclassified renal carcinoma predominantly granular cell tumors is brown because of Benign renal epithelial neoplasms the phospholipid content of the numerous cytoplasmic Adenoma organelles. Predominant granular RCCs are most often Metanephric adenoma single tumors with a male predominance (2:1). Many Oncocytoma high-grade RCCs of the clear cell type contain granular Chapter 5.4 Primary Malignant Renal Parenchymal Epithelial Neoplasms in Adults 597

Fig. 1. A Typical RCC of the clear cell type protruding from the re- nal cortex as a rounded, bosselated mass. The interface of the tu- mor and the kidney is well demarcated. Note the eccentric hemor- rhagic necrosis of the tumor. B Contrast-enhanced CT,early vascu- lar phase and C nephrographic 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). D Axial T1-weighted and E T2-weighted image in another patient. The tu- mor 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. F Axial T1-weighted image with fat saturation and after IV contrast: nodular and hypervascular border and with ec- centric necrosis 598 Raymond Oyen, Hendrik Van Poppel, Tania Roskams

cell components. In some tumors, a highly malignant spindle cell or sarcomatous transformation may be ob- served. Areas of necrosis, cystic degeneration, hemor- rhage and calcification (sometimes even with ossifica- tion) are seen. Extensive necrosis occurs predominantly in fast-growing neoplasms of high-grade . Distinct areas of fat may be present as well [18, 19]. The latter is most frequently seen with extensive calcifica- tion. 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 tu- mor 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 cas- es 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 genet- ic event in the tumor development.Trisomy 5q occurs in 50% of cases. Additional chromosomal abnormalities are acquired during progression (–14q, –8p, –9, –6q, tri- somy 7) and the frequency increases with the cytologi- cal grade and size of the tumor. The frequency of dele- tion 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 pro- tient as in B) in the early corticomedullary phase shows the intra- truding outside the renal border and sharply demarcated (A), the renal lesion with its eccentric necrosis. This lesion was hypodense other with intrarenal origin (B). Note again the typical eccentric in the nephrographic phase (not shown) and could have been er- necrosis of both tumors. The contrast-enhanced CT (C, same pa- roneously interpreted as a cyst or complicated cyst Chapter 5.4 Primary Malignant Renal Parenchymal Epithelial Neoplasms in Adults 599

Fig. 3A–H. Bilateral synchronous renal cell carcinoma of the clear sound (arrow). D On color-Doppler ultrasound low-resistance flow cell type. A US: slightly hyperechoic lesion at the lower pole of the (0.60) is found in the lesion, suggesting its malignant nature. right kidney (arrow). There is only some vascularity at the implan- E Again, the characteristics of this classic clear cell RCC are clearly tation base. B Contrast-enhanced CT, early corticomedullary shown on the vascular phase of the contrast-enhanced CT (arrow). phase,showing the typical characteristics of a classic clear cell car- F–H Axial (F, G) and coronal (H) T2-weighted images from the cinoma: peripheral hypervascular border of viable tumor and ec- same patient illustrating the irregular viable peripheral border centric hypodense area due to necrosis (arrow). C At the lower pole and the necrosis of both lesions in the lower pole of the kidneys of the left kidney, an almost isoechoic mass lesion is seen on ultra- 600 Raymond Oyen, Hendrik Van Poppel, Tania Roskams

Fig. 3G–H.

Fig. 4A–D. Multifocal metachronous renal cell carcinoma, clear cell (B). C, D On MRI, axial (C) and coronal (D) T2-weighted images, type in the left kidney, after right radical nephrectomy, 16 months both lesions have almost similar signal characteristics, with exten- earlier. US shows a necrotic lesion in the upper pole of the left kid- sive necrosis extending to the pseudocapsule of the lesions ney (A), whereas another one is isoechoic with a hypoechoic rim Chapter 5.4 Primary Malignant Renal Parenchymal Epithelial Neoplasms in Adults 601

Fig. 5A–D. Clear cell carcinoma invading the left renal vein. A, B tion base of the carcinoma is visible (arrowheads) on this contrast- Precontrast CT showing a large necrotic tumor in the lower pole of enhanced CT. D The nephrectomy specimen shows the tumor and the left kidney (A) and a widened and left renal vein (B). C The the extension to the major veins thrombus extends in the inferior vena cava (arrow); the implanta- tent with that of other types of malignant tumors aris- to be bilateral and multicentric, are often associated ing in elderly patients. It has been reported to be the on- with cysts and angiomyolipomas, and occur at an earli- ly genetic abnormality in tumors as small as 1 mm in di- er age than sporadic RCC. The genetic defect is situated ameter, as well as in tumors up to 8 cm in diameter with on segment 3p (3p25–26) and codes for a protein that metastatic growth. The loss of the 3p segment is a high- links with elongins) and is found in over 50% of indi- ly specific chromosomal anomaly occurring early on in viduals with von Hippel-Lindau disease. The gene of the development of RCC. von Hippel-Lindau disease is muted in the great major- A detailed histological analysis of entire kidneys ity of sporadic clear cell carcinomas. failed to detect any microscopic precursor lesions with RCCs are often associated with cysts. In most cases, the notable exception of some hereditary cases. Micro- the cyst is a cortical retention cyst, but associations with scopic precursor lesions are characterized by suscepti- both acquired and hereditary polycystic disease have bility to develop multiple or bilateral carcinomas, and been well documented. The renal neoplasms associated are associated with a germ line balanced translocation with acquired polycystic kidney disease in patients on involving the chromosome 3p13–14.2 region. In familial chronic hemodialysis generally occur after dialysis for clear cell carcinomas not associated with von Hippel- several years (mean, 3.5 years) and the frequency of Lindau disease, the genetic abnormalities include trans- RCC varies directly with the primary renal disease pro- locations t(3;8) and t(3;6). In von Hippel-Lindau dis- cess and both the duration of dialysis and the incidence ease, clear cell carcinomas are bilateral (frequently of cysts. 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 602 Raymond Oyen, Hendrik Van Poppel, Tania Roskams

Imaging gist may be faced with the differential diagnosis between a benign multilocular cystic nephroma and Ultrasound RCC. There are no reliable criteria to distinguish these two types of renal masses. Multilocular cystic nephro- There is nothing specific about the US diagnosis of typ- ma is characteristically situated in the upper pole of the ical clear cell RCC: lesions may be isoechoic, hypoecho- kidney and tends to protrude into the renal hilum, even ic, hyperechoic or complex (Figs. 3, 4).Areas of necrosis into the collecting system. This lesion is almost always may be present, yet sometimes hardly recognizable. Cal- solitary and unilateral and the cysts multiloculated. On cifications may be present as well.It is estimated that the color Doppler, in clear cell cystic RCC, the septations are small RCC (<3 cm), in almost 50% of the cases, is iso- well vascularized, whereas in multilocular cystic neph- echoic. This explains why many lesions are invisible on roma there is almost no vascularity in the septations. US. Isoechoic lesions can only be detected when the in- Both lesions are considered as surgical lesions (i.e.,indi- ner or outer renal outline is deformed. Furthermore, cation for surgical intervention). isoechoic lesions may mimic normal anatomic struc- tures or anatomic variants such as hypertrophy of the septal cortex (Bertin’s column). Color or power Doppler Computed Tomography may be helpful in such cases to illustrate the normal vasculature in the suspicious area. Whenever there is On plain CT series, the lesions are iso-, hypo-, or hyper- any doubt about the diagnosis, further imaging with CT attenuation masses compared to the renal parenchyma; is warranted. a heterogeneous appearance is a common feature of With hyperechoic lesions, the differential diagnosis larger lesions [24]. Coarse calcifications may be present includes angiomyolipoma (AML) and other rare benign at the periphery of the lesion, near the center, or calcifi- and malignant tumors. Angiomyolipomas are rare in cations may be spread throughout the lesion. males, and therefore, as a rule, hyperechoic masses in In the arterial phase (corticomedullary phase) after males warrant further investigation. Some features may intravenous injection of iodinated contrast, at least be helpful in distinguishing hyperechoic RCC from three-quarters of the clear cell RCCs are hypervascular, AML. Cystic areas due to hemorrhage or necrosis are al- while approximately 20% appear almost isovascular most never seen in AML; a hypoechoic rim or halo en- and only few are hypovascular [25]. The enhancement circling the lesion is a feature of RCC. The vascular pat- pattern is heterogeneous with a somewhat patchy and tern on power Doppler has been suggested to add im- nodular pattern in the periphery encircling unen- portant information to gray-scale US findings for diffe- hanced areas (Figs. 1–3). In the venous (nephrographic) rential diagnosis of small solid renal lesions [21]. Be- and/or excretory phase, RCCs become hypodense com- cause of considerable overlap in the vascular pattern pared to the renal parenchyma, the thick peripheral rim between AML and RCC, this criterion is not very useful remaining clearly visible. in the individual patient. Since lesion discrimination is Nephrographic phase scans enable greater lesion de- essential for further management, a plain CT scan is tection and better characterization of small renal mass- proposed to enable the detection of intralesional fat. es than corticomedullary scans only. Nephrographic Whatever the echogenicity of the renal mass lesion, low phase series should be obtained when only monophasic resistive flow (resistive index <0.6) is more likely to be scanning is used to detect small renal masses [26]. found in RCC than AML [22]. Intralesional necrosis is virtually always present and On US, the cystic clear cell RCC may appear almost is frequently characterized by its eccentric location: the completely cystic. Most often, however, diffuse wall necrosis extends to the periphery, most often at the op- thickening, or mural nodular thickening and multiple posite side of the renal parenchyma. Tumor necrosis is internal echoes will be seen. Mural nodes virtually ex- independent of the size of the lesion. Therefore, tumor clude the radiological diagnosis of a benign neoplasm. necrosis is the key criterion for imaging-based lesion These protrusions are most commonly found near the characterization. Extension into major renal veins and implantation base of the mass in the kidney. Searching inferior vena cava may occur (Fig. 5). for these protrusions is far more important than putting On plain CT series, most cystic RCCs are hypodense efforts in measuring the actual size of the lesion. At [23]. Typically, the content has attenuation numbers times (numerous and thick) septations are present. ranging between 10 and 30 Hounsfield units (HU).After Then, the multicystic RCC resembles a benign neo- IV injection of contrast, the thick wall of cystic RCC en- plasm known as the benign multilocular cystic nephro- hances with mural nodes, near the renal parenchyma ma [23]. This benign neoplasm is very rare (virtually (Figs. 6–8). Calcification in a cystic renal mass is not as nonexistent) in adult males: a multilocular cystic mass important in diagnosis as is the presence of associated in adult males, therefore, must be considered as a clear enhancing soft tissue elements [27]. It may be impos- cell RCC. In middle-aged women, however, the radiolo- sible to differentiate septate cystic RCCs from multiloc- Chapter 5.4 Primary Malignant Renal Parenchymal Epithelial Neoplasms in Adults 603

Fig. 6A–C. Cystic renal cell carcinoma. A Contrast-enhanced CT shows a predominately cystic mass in the left kidney. The mural nodes (arrow) exclude the diagnosis of a benign mass. B, C The 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. A Precontrast CT shows a rounded mass lesion in the right kidney, with cystic portions. B The contrast-enhanced CT shows the multinodular en- hancing mass and the anterior cyst-like component.C, D The lesion is isointense on T1-weighted image (C), and heterogeneous on T2- weighted image (D). E Contrast-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.F The surgical specimen after neph- ron-sparing surgery shows the heterogeneity of this renal cell car- cinoma of the clear cell type 604 Raymond Oyen, Hendrik Van Poppel, Tania Roskams

Fig. 7C–F.

ular cystic nephroma. Both neoplasms may have very ing viable tumor enveloping a hemorrhagic–necrotic, similar features on CT (Fig. 9). Therefore, secondary nonenhancing area, which extends to near the pseudo- signs (gender, location, protrusion in renal hilum, re- capsule [28]. gional lymph nodes, and renal vein patency) may con- On MRI cystic RCCs tend to be isointense on T1- tribute to the radiological diagnosis. weighted images, with extensive hyperintense areas on Thrombosis of the renal vein is expected in approxi- T2-weighted images [23]. As with CT, the peripheral mately 10% of cases of cystic RCC.Regional lymph node nodules of viable tissue may be hardly recognizable metastases are detected in 10% of patients at the time of (Figs. 7, 9). The enhancement pattern again is similar to diagnosis.Few patients will have ipsilateral or contralat- that of CT lesions [29]. eral 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 hyperin- tense on predominately T2-weighted images, and is eas- Fig. 8A–C. Cyst-like papillary carcinoma, type A. A This contrast- ily recognized without further intravenous injection of enhanced CT shows a cystic mass lesion with a hardly recogniz- contrast (Figs. 3, 4). able mural node at the anterior surface (arrow). B, C The opened surgical specimen shows the yellowish tumor in the deep area of After intravenous administration of contrast, the en- the cyst (B) and the nodular tumor at the implantation base on the hancement pattern is comparable to that of CT: enhanc- kidney (C) Chapter 5.4 Primary Malignant Renal Parenchymal Epithelial Neoplasms in Adults 605

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 protru- sions are more readily visible on the axial image, whereas the sep- tations are better recognized on the coronal image. Such a lesion should not be confused with benign multilocular cystic nephroma

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 histo- logical finding of vascularized connective tissue stalks invested by neoplastic cells [30]. Nevertheless, at con- trast-enhanced imaging studies, virtually all papillary carcinomas are hypovascular. Some investigators re- quire that the papillary areas compose at least 50% (or 606 Raymond Oyen, Hendrik Van Poppel, Tania Roskams

even 70%) of the tumor. There is male-female ratio of (100%), often bilateral (two-thirds), usually with one approximately 2.5–5:1. The mean age is in the 6th large mother lesion (approximately 3 cm in diameter) decade, but there is a wide age range. The rate of calcifi- and with other multiple, small daughter lesions (rang- cation is reported to be higher than in clear cell RCC. ing from microscopic to subcentimeter size) (Figs. 10, Two subgroups can be distinguished. Type B (one- 11) [31, 32]. The largest lesion shows a complete or at quarter of cases) consists of multicentric lesions least partial exorenal growth. Multicentricity may occur

Fig. 10A–G. Papillary RCC carcinoma (chromophilic cell carcino- (D). The attenuation numbers though increase from 25 to 46 HU, ma). A Hypovascular mass with extrarenal growth at the anterior suggesting a solid hypovascular tumor, rather than an avascular surface of the right kidney on the contrast enhanced CT, vascular cyst. E, F The nephrectomy specimen of the first patient shows a phase. B–D Another patient with a slightly hyperechoic mass at the mother lesion (E) and multiple daughter lesions (E, F). G A neph- lower pole of the left kidney with some calcifications (US in B),iso- rectomy specimen of another patient with multifocal papillary dense and with some coarse calcifications on the precontrast CT carcinoma is shown. Note the grayish aspect of the tumors, some (C) and without increased attenuation on contrast-enhanced CT of them protruding from the kidney; other smaller lesions are flat Chapter 5.4 Primary Malignant Renal Parenchymal Epithelial Neoplasms in Adults 607

on the amount of lipid-laden macrophages in the stro- ma. Tumor necrosis may liberate large amounts of lipid, and cholesterol crystals may form. Intralesional hemor- rhage 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 carci- noma. 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 de- velopment of papillary renal cell tumors in nearly all cases. The carcinomas are usually low stage, with 85% of Fig. 10G cases pT1 and only 12% in pathologic pT3. Papillary neoplasm has only recently been found to have a unique constellation of cytogenetic abnormal- ities [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 , the anomalies are further characterized by trisomy of chromosomes 7 and 17 (+7; +17). The find- ing 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 genet- ic changes during growth. In papillary RCC the same abnormalities can be found along with other abnormal- ities (+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 papil- lary renal cell tumors of different size may have a differ- ent aggressive biological behavior or, in other words, that the size of papillary tumors does not correlate with their actual biological behavior. Fig. 11. Rarely, a papillary carcinoma develops intrarenally. On ra- diological studies, it mimics other tumors, anatomic variants and pseudotumors Imaging either synchronously ipsilateral or contralateral to the Ultrasound largest lesion, or both iso- and contralateral to the larg- est tumor, with an almost equal frequency. Pathological On US, type B papillary RCCs are hypoechoic masses in examination often reveals more tumoral (small micro- approximately 60% of cases, or isoechoic or hyperecho- scopic) foci than suspected by imaging. The other type ic (approximately 20% each) (Fig. 10) [36]. Calcifica- (type A,three-quarters of cases),is more aggressive,and tions are reported in a minority of cases (less than constitutes a single and usually bulky tumor, either 20%). As can be expected from the gross morphology, multinodular solid or almost completely cystic, with a almost 40% of papillary RCCs are avascular on color ratio of approximately 2:1. Doppler US (i.e., no intralesional flow detectable). On section,the surface of papillary RCC varies in col- Solid type A papillary RCCs appear as a hypoechoic, or from light gray to golden yellow. The color depends isoechoic or even as a hyperechoic mass. Cystic lesions 608 Raymond Oyen, Hendrik Van Poppel, Tania Roskams

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

Computed Tomography

In type B papillary RCC, all lesions are isodense on un- enhanced 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 neo- plasms is time-dependent and may not be evident in hy- povascular lesions analyzed during the early corticome- dullary 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 at- tenuation numbers of at least 20 HU between unen- hanced 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 per- formed during a late venous phase, as in many screen- ing examinations, attenuation numbers over 70 HU in- dicate contrast enhancement and reliably allow diffe- rentiation between a cyst and a solid (vascularized) le- sion [36, 38, 39]. Particularly with multifocal papillary RCC the diffe- rential diagnosis with renal metastases and lymphoma may be difficult. At times, this may be an indication for percutaneous ultrasound or CT-guided biopsy to differ- entiate between a surgical renal neoplasm and nonsur- gical metastases or lymphoma. On unenhanced CT,type A papillary RCC is isodense or slightly hypodense.Calcifications are generally punc- tiform and located near the periphery of the tumor. Af- ter IV contrast, the majority of the mass becomes hypo- dense 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 le- sions show areas of necrosis near the center, unlike car- cinomas of the clear cell type that show eccentric necro- sis. Lymph node metastases, adrenal metastases and distant metastases may occur. Soft tissue metastases (i.e., corpus cavernosum) may be the presenting symp- tom. Invasion of the renal vein or liver metastases are not frequently seen at the time of diagnosis.

Magnetic Resonance Imaging

On MR, these tumors appear hypointense or isointense (three-quarters) on T1-weighted images and hypoin- Chapter 5.4 Primary Malignant Renal Parenchymal Epithelial Neoplasms in Adults 609

Fig.13A, B.Multinodular papillary carcinoma, type A. T1-weighted of the clear cell type. The nodule in the left adrenal gland was (A) and T2-weighted MR (B) showing a multinodular mass lesion proven to be an adenoma in the right kidney. This mass lacks the typical eccentric necrosis tense on T2-weighted images in all tumors (Fig. 12). All Grossly, it resembles conventional RCC: they are well lesions are hypovascular to the renal parenchyma after circumscribed and solitary, with a gray to brown ap- administration of gadolinium [40]. Here again, appro- pearance and typically lacking hemorrhage or necrosis priate measurement of the lesion signal intensities be- [42, 43]. Most tumors are pathologic stage pT2 or pT3 at fore and after contrast injection is essential. Larger pap- the time of resection. Some are associated with conven- illary RCCs show heterogeneous signal intensities tional RCCs. (Fig. 13). The chromophobic carcinoma has a solid architec- ture, with large cellular blocks and only limited stroma. The lesion consists of large cells, the pale cytoplasm Chromophobic Renal Carcinoma crowded with microvesicles and a variable number of mitochondria, and a fairly typical perinuclear halo. The Pathology cells contain little or no glycogen or lipids, but stain with Hale’s acid iron colloid, which allows differentia- Chromophobic carcinoma is a relatively recently (1985) tion from . The electron microscopic find- described neoplasm characterized ultrastructurally by ings are unequivocal, with cytoplasm containing nu- cells with abundant cytoplasm. The cells may be related merous 150- to 300-nm microvesicles. to the normal intercalated cells (type B) of the collecting Cytogenetic analysis shows a combination of allelic duct [41]. This subgroup accounts for about 4%–5% of losses, which do not occur in other types of epithelial renal cell neoplasms and its median incidence is in the neoplasms [44]. These genetic losses involve seven 6th decade (range, 31–75 years). The lesions are most chromosomes including –1 (100%); –2 (95%); –6 (80%); frequently located near the pole of the kidney (Fig. 14). –10 (86%); –13 (95%); –17 (70%); and –18 (21%). DNA For some reason,the tumor is more frequently observed analysis of one case revealed allelic losses at chromo- in rather young females (40–50 years) and in old males. some 3p, 5q and 17 with variable frequency and in a Chromophobic cell carcinoma tends to be large,ranging combination, which does not occur in other types of from 1.3 to 22 cm (mean diameter 8 cm) in their great- kidney tumors.Along with this chromosomal loss, there est dimension (Fig. 14) [41, 42]. are rearrangements in the mitochondrial DNA that are under further investigation. Follow-up studies have suggested that chromophob- ic carcinoma has a more favorable prognosis compared Fig. 12A–C. Papillary carcinomas, type B. A T2-weighted MR show- to the classic RCC. Nevertheless it can be highly aggres- ing bilateral tumors, hypointense with hyperintense areas (arrow- sive and must certainly be considered malignant. A sar- heads) in this 36-year-old male. Bilateral nephrectomy was per- formed. B Two lesions of the right kidney, one solid and one with comatous transformation of chromophobic cells is only hemorrhagic necrosis.C Typical multifocal papillary carcinoma on rarely seen. the cut surface of the left kidney 610 Raymond Oyen, Hendrik Van Poppel, Tania Roskams

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 (papil- lary carcinoma), chromophobic cell carcinomas are solitary and larger (larger than 3 cm)

Imaging

Ultrasound

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

Computed Tomography

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].

Magnetic Resonance Imaging

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 hyperin- tense peripheral rim may be seen on heavily T2-weight- ed images. After administration of contrast there is hy- povascularity of the lesion compared to the renal paren- chyma.

Collecting (Bellini) Duct Renal Carcinoma

Pathology

Bellini duct RCC, a rare tumor, constitutes less than 1% of primary malignant renal parenchymal epithelial neo- plasms.Bellini duct carcinomas appear to be aggressive, often with metastatic disease at manifestation and rap- id progression despite surgery, with an almost uniform- ly 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- Chapter 5.4 Primary Malignant Renal Parenchymal Epithelial Neoplasms in Adults 611 um. The mass is usually localized to the renal medulla, A variant of collecting duct carcinoma, called medul- with distortion of the pelvicaliceal system and often lary carcinoma, has been identified in patients suffering with infiltration into the adjacent renal cortex. The from sickle cell trait [49, 50]. 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- Imaging smoplasmic reaction (usually no necrosis or hemor- rhage) (Fig. 16). Extension into the renal vein does not Ultrasound occur.Very rarely only, the tumors are cystic with endo- phytic papillary projections. The intermingling of clear The tumor is slightly hypoechoic or almost isoechoic, cells, basophilic and eosinophilic cells contribute to a poorly marginated, and typically centrally located on fairly typical aspect. The tumoral architecture is usually US. tubulopapillary. In general, there is considerable pleo- morphism, especially in the invasive component, and mitotic figures are frequent. Associated atypical chang- Computed Tomography es are often seen in adjacent collecting duct . The small number of these that have been studied by Bellini duct RCC appears homogeneous and isodense genetic methods showed monosomies of chromosomes compared to the renal parenchyma on unenhanced CT. 1, 6, 14, 15 and 22 [48]. Chromosome 3p, 7, 17 and Y ab- After intravenous contrast administration, the tumor is normalities were not encountered. hypovascular [51] (Fig. 15A, B). There may be central low attenuation areas, due to the extensive reactive fi- brotic reaction (not necrosis), which accompanies the infiltrative growth of this neoplasm, rather than necro- sis or hemorrhage.

Fig. 15A–C. Collecting (Bellini) duct renal cell carcinoma. A Con- or necrosis, but are explained by reactive fibrosis. Note retroperi- trast-enhanced CT, excretory phase. Infiltrating tumor in the left toneal lymph node metastases. C Nephrectomy specimen of a sim- kidney with hypodense areas. Note that the renal shape is largely ilar case (right kidney) with infiltrating fibrotic tumor involving preserved. B In the upper pole, the tumor mimics a predominately the upper half of the kidney cystic carcinoma. The hypodense areas are not due to hemorrhage 612 Raymond Oyen, Hendrik Van Poppel, Tania Roskams

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 differen- tiated, anaplastic variant comprising approximately 1% of cases and has an unfavorable prognosis. In fact, they represent a poorly differentiated, high-grade and inva- sive (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 sar- comatoid. 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 .When the sarcomatoid por- tion predominates, the neoplasm appears firm and fi- brous without hemorrhage or necrosis; the carcinoma part is heterogeneous with areas of necrosis and hem- orrhage. 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) dis- tant metastases and may be inoperable (Fig. 16).

Fig. 16A–C. Sarcomatoid renal cell carcinoma. A Contrast-en- hanced 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. B Axial T2- weighted MR showing similar imaging characteristics. Note that the tumor is predominately solid. Again the subcutaneous metas- tasis is clearly seen. C Surgical specimen showing the homogene- ous solid mass extending of the surface of the left kidney Chapter 5.4 Primary Malignant Renal Parenchymal Epithelial Neoplasms in Adults 613

Imaging constant combination of trisomy 7 and 17 as well as loss of the Y chromosome may be diagnosed as a papillary Ultrasound renal cell adenoma. Such tumors may reach a large size without any sign of malignancy,but malignant transfor- US shows a heterogeneous predominantly hyperechoic, mation accompanied by additional complex genetic al- isoechogenic or hypoechogenic mass. Calcifications terations may occur in small adenomas.It is not the size, may be seen quite often. The majority of sarcomatoid but the accumulation of genetic alterations, especially RCCs are hypovascular on color Doppler. acquired trisomies 16, 12 or 20, that are associated with malignant behavior.

Computed Tomography Observations on Sarcomatoid RCCs are iso- or hypodense on unen- hanced scans. The tumors are heterogeneously hyper- Pathology vascular in the cortical phase. A hypodense and hetero- geneous appearance is seen on late scans (Fig. 16A). Ne- Renal oncocytoma is a benign neoplasm and accounts crosis is always diffusely spread throughout the lesion, for approximately 2%–5% of renal cell neoplasms [55]. reaching the outer border of the lesion. Renal oncocytoma was first described by Klein and Va- Lymph node metastases or adrenal or liver metasta- lensi [56]. Incidental coexistence with RCC or angiom- ses are present in the majority of cases. These tumors yolipoma has been reported. The majority remains may be very aggressive to adjacent organs (invasion of asymptomatic and they are discovered incidentally. liver, spleen, pancreas, abdominal wall), and have atypi- Most patients are elderly with a median age of about cal metastatic deposits. 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 Magnetic Resonance Imaging dialysis. Oncocytomas are characteristically single, well demarcated, uniformly expansile masses occurring at The solid component of the lesion is either hypo- or any renal site (Fig. 17). Multiple oncocytomas have been isointense on T1-weighted images, heterogeneous and reported (oncocytomatosis). Occasionally, oncocyto- predominantly isointense on T2-weighted images mas become very large (i.e., giant oncocytoma). In one (Fig. 16B). After Gd-DTPA administration, sarcomatoid review, the average tumor diameter was 7.4 cm, but re- RCCs are heterogeneously hypo- or hyperintense. ported sizes range from 0.3 to 20 cm.Whatever the size, oncocytomas should be considered as a benign neo- plasm. Observations on Renal Adenoma The tumors are tan (Fig. 15A, B) because of the li- pochrome pigment associated with mitochondrial fill- For many years, size has been used as the main criterion ing of the cytoplasm, circumscribed, with or without a to divide renal cell tumors into benign and malignant. capsule and often surrounded by a rim of dilated blood This assumption has been based largely on the work of vessels. Larger tumors tend to have a central myxoid-fi- Bell in 1950 [53]. He suggested that renal tumors of less brotic stellate scar that can become calcified. Foci of than 3 cm in maximum diameter should be called aden- hemorrhage are commonly seen, but cystic change and omas, yet two of his adenomas metastasized! A general- necrosis are unusual. The cells are arranged in solid, tu- ly used limit is 3 cm in diameter for diagnosing a well- bular, or trabecular rests. A predominant extrarenal differentiated renal cell tumor as an adenoma. However, growth can be expected in 50% of cases. Metastases or tumors smaller than 3 cm with metastases have been invasion of the renal vein do not occur. described on several occasions.Furthermore,adenomas Microscopically, cells have abundant, granular eosin- share many phenotypic features with RCCs. Therefore, ophilic cytoplasm; no clear cytoplasm is seen. The tu- all renal cell tumors should be considered as malignant. mor cells probably derive from intercalated cells (type The classic clear cell carcinoma and chromophobic A) from the collecting ducts. Nuclei are generally low RCCs develop as carcinomas, irrespective of grade and grade (I or II) and uniform, but focal areas may have size. As already mentioned above, the natural history of marked nuclear atypia (oncocytomas are not graded). papillary renal cell tumors is quite different from that of Mitotic activity is not seen, and foci of necrosis are un- other types and their appearances are unique. Cortical common. Ultrastructural examination reveals numer- adenomas are almost always papillary tumors, with a ous round mitochondria larger than the mitochondria diameter less than or equal to 5 mm, and may transform of other renal cell neoplasms and with a membrane par- to papillary carcinoma (Fig. 10) [54]. Tumors with a ticularly rich in cristae. 614 Raymond Oyen, Hendrik Van Poppel, Tania Roskams

Fig. 17A–E. Oncocytoma. A On fresh specimen, this tumor has a typical mahogany brownish color.B, C A central stellar scar may be present. D Contrast-enhanced CT, cortical phase. Sharply demar- cated and very smoothly outlined lesion at the upper pole of the right kidney and without central scar.E Axial T2-weighted MR (TR = 4.3 ms; TE = 60 ms). Predominately hyperintense intrarenal le- sion in the left kidney. The signal intensity, however, is lower than the content of the collecting system and some intralesional hetero- geneity is observed. This was diagnosed as a tubulocystic variant of an oncocytoma Chapter 5.4 Primary Malignant Renal Parenchymal Epithelial Neoplasms in Adults 615

Cytogenetic studies show normal or abnormal kar- predicted to be oncocytomas; among smaller carcino- yotypes including a translocation t(11q;13), or loss of mas, the respective results were 58% and 42%. There- chromosome 1 or Y.The development of oncocytoma is fore, CT criteria used are poor predictors of the diagno- initiated by typical abnormalities of the mitochondrial sis of oncocytoma or carcinoma regardless of tumor DNA structure. size. Most reported oncocytomas have a benign behavior, A likely explanation for the lack of homogeneity of but local or distant metastases have been reported. oncocytomas on contrast-enhanced CT scans is an in- However,it is now felt that most,if not all,malignant on- homogeneous perfusion as a result of ischemia. The cocytomas described in the older literature are nonpap- pattern of growth of oncocytomas in which cells accu- illary, papillary or chromophobic RCCs with eosino- mulate in more or less rounded, solid cell nests that be- philic granular cytoplasm. In addition, these tumors come smaller, fewer, and farther apart toward the center would be expected to display a deletion of 3p or trisomy of the tumor probably favors the ischemic events. Even- 17 or mitochondrial alterations at genetic analysis. Yet tually these ischemic tumor cells are replaced by fibro- oncocytomas may have the capacity to become malig- blasts that give the classic gross specimen the patholog- nant since they can contain chromophobic cells. This ic and radiologic finding of a central scar. These same raises the possibility that oncocytomas and chromo- evolutionary changes of ischemia and fibrosis also oc- phobic carcinomas represent two ends of the same cur in regions other than the center of an oncocytoma. spectrum. This is the most likely explanation for the observations of heterogeneity in the enhancement pattern of oncocy- toma noted in several studies. In addition to hemor- Imaging rhage and necrosis, ischemia must also be considered as a cause of low tumor attenuation. Ultrasound

Most oncocytomas are slightly hypoechoic compared to Magnetic Resonance Imaging the renal cortex on US.A central scar, reported as an an- echoic center, is only seen in the minority of cases. 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 Computed Tomography hypovascular compared to the renal parenchyma and without evidence of necrosis or hemorrhage. A central Oncocytomas are homogeneous and isodense on unen- stellate may occasionally be seen. hanced 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 Indications for Lesional Biopsy gross morphology, it can only be expected to be detect- ed in 50% of cases by CT. Furthermore, this scarring is Needle aspiration puncture or biopsy has a limited role not exclusive for oncocytoma [57–59].A sharp and very in the evaluation of the renal mass in the CT/MR era smooth demarcation with the adjacent parenchyma is and has been abandoned as a routine procedure. Biop- always seen. A predominant extrarenal location can be sy or needle aspiration has occasional value in the eval- expected in 50% of cases. uation of the cystic indeterminate mass. In the setting Many authors focused on the possibility of differen- in which a lesion is highly suspicious for neoplasm in a tiating oncocytoma and RCC based on CT criteria (or patient who is a very poor surgical risk, the technique angiography) and that differences would become more could be performed to help establish a diagnosis and apparent as tumors enlarge. On contrast-enhanced determine the treatment approach [61]. scans, homogeneous attenuation throughout the tumor There are many occasions in which needle aspiration and a central, sharply marginated stellate area of low at- or biopsy is definitely indicated. These include differen- tenuation were considered predictors of oncocytoma. tiating a chronic abscess from a cystic carcinoma, dif- Any area of decreased attenuation in the tumor except ferentiating a new primary renal neoplasm from a met- for a stellate, central area was used as a predictor of car- astatic one in a patient who has had a previous primary cinoma.Among oncocytomas larger than 3 cm in diam- tumor in another organ, and differentiating a primary eter, 67% exhibited criteria for oncocytoma and 33% renal neoplasm from renal lymphoma in a patient with met the features of carcinoma; among smaller oncocy- lymphoma, particularly when the lesion does not re- tomas, the respective results were 82% and 18%.Among gress with treatment whereas the rest of the disease carcinomas larger than 3 cm in diameter, 84% fulfilled does [62]. the criterion for malignancy and 16% were incorrectly 616 Raymond Oyen, Hendrik Van Poppel, Tania Roskams

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