`
`\dvancex in Ana/antic Pathology
`Vol. 6, No. I, pp, 1—11
`3 1999 Lippincott Williams & Wilkins, Inc., Philadelphia
`
`Benign Tumors and Tumor-Like Lesions of the Adult Kidney
`Part I: Benign Renal Epithelial Neoplasms
`
`*Saverio Ligato, M.D., Jae Y. R0, M.D., Ph.D., Pheroze Tamboli, M.D., TMahul B. Amin, M.D.,
`and Alberto G. Ayala, MD.
`
`Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; Department of Pathology,
`Guthrie Clinic, Sayre, Pennsylvania; and TDepartment of Pathology, Emory University Hospital, Atlanta, Georgia
`
`
`
`Summary: The spectrum of renal neoplasms has expanded in recent years, Although
`most of the work taking place in this field has concerned malignant neoplasms of the
`kidney, there have been significant improvements in our knowledge of benign renal
`tumors and tumor-like lesions, especially in renal cell adenoma, renal oncocytoma, and
`renal angiomyolipoma. Awareness and knowledge of these benign lesions is important
`because they are often included in the differential diagnoses of malignant tumors, with
`which they may be confused both clinically and pathologically. The authors review the
`topic of benign renal neoplasms and tumor—like lesions that occur in adults, empha-
`sizing some of the newly described aspects of these lesions. Key words: Kidney—
`Benign neoplasms—Tumor-like lesions—Adult—Renal oncocytoma—Renal adeno—
`ma—Renal angiomyolipoma
`
`
`The frequency with which benign epithelial and mes—
`enchymal tumors and tumor-like conditions of the kid-
`ney occur relative to other cancers is difficult to estimate
`from reports in the literature. This is because many of
`these conditions are asymptomatic and are only found
`incidentally during surgery or at autopsy. In addition,
`these lesions are often relatively small and, conse-
`quently, are difficult to detect. Benign lesions can arise
`from any of the cell types within or around the kidney,
`and are classified as shown in Table 1.
`
`Part One of this two-part article discusses benign ep-
`ithelial neoplasms. Part Two (to be published in a sub—
`sequent issue) will present and discuss the wide spectrum
`of benign mesenchymal neoplasms and tumor-like le—
`sions of the kidney.
`
`RENAL CELL “ADENOMA”
`
`The existence of renal cell adenoma as a distinct
`pathologic entity is controversial and the criteria for its
`
`Received June 12, 1998; accepted June 16, 1998.
`* Address correspondence to Jae Y. R0. M,D., Ph.D., Department of
`Pathology, The University of Texas M. D. Anderson Cancer Center,
`1515 Holcombe Boulevard, Box 85. Houston, TX 77030.
`
`diagnosis are debatable. There are no reliable radiologic,
`gross, histopathologic, histochemical,
`immunologic,
`cytogenetic, or ultrastructural criteria that enable the
`physician to accurately distinguish renal cell carcinoma
`from renal cell adenoma. This distinction has tradi-
`
`tionally been based on tumor size (1). In a large series
`of renal cortical neoplasms discovered at autopsy, Bell
`found that only 3 of 65 tumors (4.6%) measuring
`less than 3 cm in diameter had metastasized (I). There—
`fore, although the 3 cm cutoff was not absolute in
`separating benign tumors from malignant tumors, Bell
`arbitrarily classified cortical neoplasms less than 3 cm
`in diameter as renal cell adenomas. Subsequently, and
`not surprisingly, several cases of renal cortical neo-
`plasms that were less than 3 cm in diameter and that
`demonstrated local
`invasion or metastasis were docu-
`mented (2—5). Medeiros and Weiss reported an example
`of a 0.5 cm-diameter, nuclear grade 4, sarcomatoid
`renal carcinoma found incidentally during a nephrec—
`tomy performed for refractory pyelonephritis (6).
`Aizawa and colleagues reported a renal conical neo-
`plasm 0.8 cm in diameter with distant metastasis (7).
`Medeiros and Weiss (6) and Bennington (8) concluded
`that all renal cell neoplasms should be considered as
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`2
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`S. LIGATO ET AL.
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`TABLE 1. Classification of benign epithelial and
`mesenchymal neoplasms and tumor—like conditions of the
`adult kidney
`
`Benign Epithelial Neoplasms
`Renal cell “adenoma"
`Renal oncocytoma
`Metanephric (embryonal) adenoma
`Nephrogenic adenofibroma
`Benign Mesenchymal Neoplasms
`Angiomyolipoma
`Capsuloma
`Leiomyoma
`Juxtaglomerular cell tumor
`Renomedullary interstitial cell tumor (medullary fibroma)
`Hemangioma
`Lymphangioma
`Lipoma
`Myxoma
`Neurogenic tumors
`Neurofibroma
`Perineurioma
`Benign fibrous histiocytoma
`Adult variant of mesoblastic nephroma
`Solitary fibrous tumor
`Tumor-Like-Lesions
`Xanthogranulomatous pyelonephritis
`Malakoplakia
`Tubular hyperplasia
`Cysts including multilocular cysts (cystic nephroma)
`lntravascular papillary endothelial hyperplasia (Masson's tumor)
`Rosai-Dorfman disease
`Cystic hamartoma of the renal pelvis
`Adenomatoid metaplasia of the epithelium of Bowman's capsule
`Fibroepithelial polyp
`Adrenal rests
`
`small adenocarcinomas that have the potential to metas-
`tasize.
`
`Several experts believe that the term “renal cell ade-
`noma” is useful only when referring to small cortical
`tumors incidentally found at autopsy, that size is not a
`reliable criterion for distinguishing between a benign and
`malignant renal cortical tumor, and that microscopic fea—
`tures, particularly the nuclear grade, should be evaluated
`in small neoplasms (2—6,9,10). At
`the Diagnosis and
`Prognosis of Renal Cell Carcinoma 1997 Workshop.
`sponsored by the Union lntemationale Contre 1e Cancer
`(UICC) and the American Joint Committee on Cancer
`(AJCC), it was agreed to refer to all lesions measuring
`less than 5 mm in diameter and having morphology simi-
`lar to low grade papillary renal cell carcinoma as “renal
`adenomas” (11). These are considered to be benign be-
`cause they are seen much more frequently than papillary
`carcinoma and lack its extensive genetic abnormalities.
`The incidence of renal adenomas smaller than 5 mm in
`diameter is about 20% in autopsy series, whereas only
`about 4,500 new cases of papillary renal cell carcinoma
`are detected in the United States each year, indicating
`
`Arlmnres in Anatomic Pathology. V01. 6. No. 1, January. [999
`
`that only a few of these small adenomas evolve into
`papillary renal cell carcinomas (12).
`
`Incidence and clinical features
`Renal adenomas are usually found incidentally during
`surgery or at autopsy, with an incidence of 7.2% to 22%
`in individuals older than 40 years of age (12,13). They
`may present as small cortical subcapsular lesions, and are
`significantly more common in individuals with ischemic
`kidneys and in smokers (14).
`
`Radiologic findings
`The ultrasound pattern of a renal adenoma is that of a
`small homogeneous tumor of low echogenicity. located
`in the renal cortex. On renal angiograms, they show neo-
`vascularity and numerous irregular disorganized vessels
`similar to those seen in renal cell carcinoma.
`
`Gross appearance
`Renal adenomas—defined by a low grade tubulo-
`papillary histology and size smaller than 5 mm—are
`characteristically small white or gray nodules located in
`the cortex, most being less than 3 mm in diameter. They
`are usually single but may be multiple and bilateral.
`Rarely, the multifocality may be so prolific that it
`is
`labeled as “renal adenomatosis” (15). These tumors
`tend to be found more often in patients with end-stage
`renal disease or chronic renal damage secondary to hy—
`pertension, which may be evidenced grossly by small
`and contracted kidneys.
`
`Histopathology
`Most adenomas are well circumscribed, and may or
`
`may not possess a fibrous capsule. They have a tubular or
`tubulo-papillary architecture (Fig. l), and are composed
`of a homogenous population of cells with uniform nuclei.
`There is scant granular cytoplasm, resulting in a high
`nuclear-to-cytoplasmic ratio, and a “basophilic” appear-
`ance on low power microscopy (Fig. 1A). They demon—
`strate a low nuclear grade with absent or infrequent in—
`conspicuous nucleoli. A renal adenoma with a high
`nuclear grade, equivalent to Fuhrman's nuclear grade 3
`0r 4. should be classified as a renal cell carcinoma. Renal
`adenomas with tubulopapillary architecture and clear cy-
`toplasm are extremely rare, and should probably be clas-
`sified as renal cell carcinoma. Any lesion, even one
`smaller than 5 mm, that has the histologic appearance of
`conventional (clear cell) renal cell carcinoma, chromo-
`phobe renal cell carcinoma, or collecting duct carcinoma
`should be considered a carcinoma (see below).
`
`DNA ploidy analysis
`Using image analysis, Banner and colleagues retro-
`spectively quantitated DNA on 59 renal cortical neo—
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`BENIGN TUMORS OF THE KIDNEY
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`(A) renal cell “adenoma" showing a well circumscribed proliferation of small tubules. At this low power of microscopy the tubules exhibit
`FIG. I.
`a basophilic appearance because of high nuclear—to—cytoplasmic ratio. (B) renal cell ”adenoma" showing a well circumscribed proliferation of short
`papillary processes.
`
`plasms that were 5 cm or less in diameter. They inves—
`tigated whether the traditional 3 cm size distinction be-
`tween small “benign” and large “malignant” tumors
`was substantiated by a difference in the tumors’ DNA
`content (16). The results of their study showed an in—
`crease in the number of nondiploid cell lines with an
`increase in tumor size and nuclear grade. Of the 59 tu-
`mors studied, 27% were nondiploid, and, interestingly.
`none of the 5 tumors smaller than 3.0 cm and only one of
`the 13 tumors smaller than 4.0 cm contained nondiploid
`cell lines. In a flow cytometric study of 55 patients with
`stage I renal cell carcinoma, Grignon and colleagues in-
`cluded ll patients with tumors smaller than 5.0 cm and
`found that only 27% (3 of 55) were nondiploid (17).
`These studies suggest that as renal cortical neoplasms
`increase in size, nondiploid cell lines emerge. These data
`are less valuable in the context of renal adenoma because
`
`the studies by Banner and colleagues and Grignon and
`colleagues defined renal cell carcinoma according to the
`guidelines of the 1997 consensus conference (1 l).
`
`Cytogenetic analysis
`Cytogenetic analyses of renal adenomas show triso-
`mies of chromosomes 7 and 17, and loss of the Y chro-
`mosome. Similar and additional numeric chromosomal
`
`alterations are seen in papillary renal cell carcinoma,
`suggesting that the progression of renal adenomas to
`papillary renal cell carcinoma depends on the develop—
`ment of additional chromosomal abnormalities (18,19).
`
`Concluding statements regarding renal adenoma
`In conclusion, when strictly defined,
`the term renal
`cell adenoma applies only to tubulopapillary lesions of
`10W nuclear grade smaller than 5 mm, and, therefore, is
`frequently an autopsy diagnosis. In surgical pathology
`specimens, a tumor of any size exhibiting a clear cell,
`
`chromophobe, or collecting duct histology should be
`considered as conventional (clear cell). chromophobe, or
`collecting duct renal cell carcinoma, respectively. Small
`tubulopapillary tumors (that is, those smaller than 3 cm)
`may be considered to be “renal cortical neoplasms of
`low malignant potential.”
`
`RENAL ONCOCYTOMA
`
`Renal oncocytoma is a renal epithelial neoplasm that
`was first described by Zippel in 1942 (20). However, it
`was not until 1976 that the benign nature and excellent
`prognosis of this tumor was demonstrated by Klein and
`Valensi in a series of 13 cases (2]). A subsequent report
`supported their findings (22). The cell of origin of on—
`cocytoma appears to be the intercalated cell of the cor-
`tical portion of the collecting tubule (23—26), although
`some older studies also support an origin from the proxi-
`mal renal tubular cells (21,25), while still others show
`origin from either segment of the nephron.
`
`Incidence and clinical features
`
`Renal oncocytoma is found in 3—7% of all renal cor—
`tical
`tumors, with many of the reported cases having
`been originally diagnosed as renal cell carcinoma and
`retrospectively re-classified (22,26,27). Renal oncocy-
`toma usually occurs in men, with a male to female ratio
`of 2—321. It generally occurs in older patients, with a
`peak incidence in the seventh decade of life. In the ma-
`jority of cases it is asymptomatic or is discovered inci-
`dentally, but may cause gross or microscopic hematuria,
`pain, or weight loss. It sometimes presents as a palpable
`mass (26).
`There is controversy surrounding this tumor’s poten-
`
`Advances in Almmmir PHI/trilogy. Val. 6. No.
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`I. Jmmmjt. I999
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`4
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`S. LIGATO ET AL.
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`
`
`FIG. 2. Gross example of renal oncocytoma. Well circumscribed
`neoplasm with central scar. (Reproduced, with permission, from Amin
`MB, Crotty TB. Tickoo SK. Farrow GM. Renal oncocytoma: A reape
`praisal of morphologic features with clinicopathologic findings in 80
`cases. (Reprinted, with permission, from Am J Surg Put/10! 1997;21:
`1—12. Copyright © 1997, by Lippincott-Raven Publishers.)
`
`tial for malignancy, primarily because metastases have
`been reported (28—34). However, the authors believe that
`this tumor, if strictly defined, is truly a benign neoplasm,
`and that several of the reported cases with adverse out-
`comes actually involved chromophobe renal cell carci—
`nomas that were mistakenly classified as oncocytoma
`(26).
`
`Radiologic findings
`It is not possible to definitively differentiate renal on-
`cocytoma from renal cell carcinoma by imaging tech—
`niques. Certain imaging characteristics. however, may
`suggest renal oncocytoma. On ultrasonograms, oncocy—
`tomas may appear as an isoechoic, hypoechoic, or hy—
`perechoic, heterogeneous or homogeneous solid mass
`with a well circumscribed border. A central scar is a
`
`helpful clue but unfortunately is seen in only 6.750% of
`cases. It is also not a specific feature, as 5—10% of chr0-
`mophobe renal cell carcinomas also exhibit a central
`scar. The angiographic features suggestive of renal 0n-
`Cocytoma include: I) a spoke—wheel configuration of the
`feeding arteries (present in 17—80% of cases); 2) a ho-
`mogenous capillary nephrogram phase (present in 71%
`of cases); 3) a lucent rim sign (that is, a sharp and smooth
`margin with a fibrous capsule, seen in 76% of cases); and
`
`Advance: in Anatomic Pullwlogy, Vol. 6. No. I. January. [999
`
`4) absence of a clearly pathologic vasculature. Unfortu-
`nately, renal cell carcinoma may have the same appear-
`ance (35). Experience with magnetic resonance imaging
`(MRI) is still limited.
`
`Gross appearance
`Renal oncocytomas have a distinctly different gross
`appearance when compared with the typical macroscopic
`appearance of conventional (clear cell) renal cell carci-
`nomas. They are well circumscribed and may have a
`lobulated cut surface that exhibits a characteristic ma-
`
`hogany-brown color, a result of lipochromes in the mi-
`tochondrial membranes (Fig. 2). Although the vast ma-
`jority of tumors are well circumscribed, they may occa-
`sionally grossly involve the perinephric adipose tissue
`(26,34,36). Larger tumors may have a stellate central
`scar, but some smaller tumors also possess this feature.
`These tumors may occasionally show cystic changes, fo-
`cal hemorrhage, or (very rarely) calcifications. Necrosis
`may be seen secondary to vasculitis, sickle cell anemia,
`or sepsis (36), although this is rare. The presence of
`extensive hemorrhage and macroscopic necrosis in renal
`tumors should always raise the suspicion of renal cell
`carcinoma, as these features are absent or inconspicuous
`in even the largest oncocytomas.
`Renal oncocytomas average 6 cm in diameter, with a
`range of 0.6—15 cm. They can be as large as 20 cm, and
`may weigh as much as 2,300 g (22,27). Although most of
`these tumors are typically single and unilateral, cases of
`multicentric (29) and bilateral oncocytomas (28) have
`been described.
`
`Histopathology
`The neoplasm is composed exclusively of uniform
`polygonal cells arranged in nests or organoid pattern
`(Fig. 3), though coalesced nests may impart a solid ap-
`
`
`
`FIG. 3. Renal oncocytoma exhibiting an organoid "archipelagi-
`nous" pattern. The nests of tumor are composed of uniform polygonal
`cells with small. round or oval nuclei. with smooth nuclear contours
`and finely dispersed chromatin.
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`BENIGN TUMORS OF THE KIDNEY
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`5
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`FIG. 4. Renal oncocytoma with a tubulocystic pattern.
`
`pcarance. Another architectural feature of oncocytoma is
`a lubulocystic pattern (Fig. 4). The organoid “archipe-
`laginous,” 0r island—like, arrangement of tumor cells is
`the most frequently observed pattern. The nests may be
`joined by interanastomosing cords and trabeculae, with a
`prominent trabecular pattern being evident in rare in-
`stances. A mixed pattern of nested and tubulo-cystic ar-
`chitecture is frequently seen, with nested areas being
`predominant. The nests of cells are surrounded by a dis-
`tinct reticulin framework and are set within a loose
`
`edematous or myxoid stroma that is sometimes hyalin-
`ized. Occasionally, a cylindromatous appearance with
`hyaline deposits of type IV collagen (37) can be seen.
`The oncocytes characteristically contain abundant eo—
`sinophilic granular cytoplasm because of their increased
`numbers of mitochondria. The mitochondria are demon—
`
`strable by electron microscopy and use of Sudan black B
`stain. Cytoplasmic clearing may be seen, especially in
`nests trapped in the central scar. This clearing is never as
`prominent as in conventional (clear cell) carcinoma; also
`absent is the peripheral accentuation of cytoplasm seen
`in chromophobe renal cell carcinomas. The nuclei are
`usually small, round or oval. with distinct nuclear con-
`tours and finely dispersed chromatin (Fig. 3). Nucleoli
`may be prominent (in approximately 50% of cases), in-
`conspicuous, or absent. Binucleated cells and, some-
`times, multinucleated cells may be seen. Cytoplasmic
`inclusions are sometimes seen. A unique feature of on-
`cocytoma is the presence of “clones,” or zones of atypia
`in which hyperchromatic pleomorphic nuclei with
`smudged and degenerated chromatin can be seen, super—
`ficially making an alarming picture. In a rare case this
`degenerative change may be fairly extensive. Mitoses are
`virtually absent, and atypical mitoses are impermissible
`(26,30).
`Certain worrisome “atypical” features may be seen in
`
`oncocytomas, but these need to be viewed in the context
`of the entire morphologic presentation, i.e., the lesion
`should otherwise have typical architectural, cytoplasmic,
`and nuclear features of oncocytoma. These features in-
`clude perinephric fat
`invasion (Fig. 5), hemorrhage,
`minimal microscopic necrosis, microvascular invasion,
`and rare mitoses (26,34). Atypical features that can rule
`out a diagnosis of oncocytoma include gross involve-
`ment of the renal vein, gross or prominent microscopic
`necrosis, extensive papillary architecture, foci of conven-
`tional (clear cell) carcinoma, sarcomatoid dedifferentia-
`tion, and frequent or atypical mitoses (26).
`Histologically, the main differential diagnostic consid-
`erations include renal cell carcinomas with eosinophilic
`granular cytoplasm, such as chromophobe renal cell car—
`cinoma, granular variant of conventional (clear cell) car—
`cinoma, papillary carcinoma, and collecting duct carci-
`noma (38,39). The latter two are characterized by a tu—
`bulopapillary architecture and are therefore easily ruled
`out, while the granular variant of conventional (clear
`cell) carcinoma has a high nuclear grade and frequent
`mitoses. Tumors in which oncocytoma is a diagnostic
`consideration should be extensively sampled, as even
`small foci of conventional (renal cell) carcinoma would
`warrant the diagnosis of renal cell carcinoma. The pres-
`ence of concurrent conventional (clear cell) carcinoma
`has been reported, and in one series its incidence was
`fairly common, with 22.6% of cases having concurrent
`carcinoma (36,40). Tumors with features of both renal
`oncocytoma and renal cell carcinoma, called “congeners
`of oncocytoma,” have also been described (41).
`Since the diagnosis of renal oncocytoma is made after
`excluding many features (lack of atypical mitosis, lack of
`clear cell areas with architecture of conventional [clear
`
`
`
`FIG. 5. Renal oncocytoma showing invasion into the perinephric
`adipose tissue.
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`Advance: in Alialomic Pathology. Vol. 6, No.
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`6
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`S. LIGATO ET AL.
`
`cell] carcinoma. lack of extensive papillary areas. lack of
`extensive or gross necrosis. lack of extensive pleomor-
`phism). it is recommended that generous samples of the
`tumor be taken before a diagnosis of oncocytoma is ren-
`dered. Needle core biopsies and fine needle aspiration
`biopsies are. therefore. better tools for excluding the di-
`agnosis of renal oncocytoma than for establishing it.
`
`DNA ploidy analysis
`Several studies have reported DNA ploidy analysis for
`renal oncocytomas. In one of these studies, the clinico-
`pathological and DNA flow cytometric characteristics of
`23 renal oncocytomas and 18 granular renal cell carci-
`nomas were compared (42). Twenty-two of the renal
`oncocytomas demonstrated diploid DNA content. and
`one showed near-diploid DNA aneuploidy. Of these pa-
`tients with renal oncocytoma.
`l7 had adequate follow-
`up, and none developed recurrence. metastasis. or died of
`disease. Seven of the granular renal cell carcinomas were
`DNA diploid. one was DNA tetraploid. and ten were
`DNA aneuploid. Two other studies (43,44) concur with
`these findings, but other authors have reported abnormal
`DNA ploidy in 30—50% of all renal oncocytomas exam-
`ined (45). Despite the demonstration of aneuploidy in
`these tumors. there is no apparent correlation between
`DNA ploidy and either disease-specific survival or tumor
`stage (46). In summary, DNA ploidy cannot be used to
`distinguish between renal oncocytomas and the other re-
`nal cell carcinomas, because typical renal oncocytomas
`may have abnormal
`tetraploid or aneuploid patterns
`(44,45). whereas some renal cell carcinomas may have
`diploid DNA content.
`
`Ultrastruclural findings
`Ultrastructurally. renal oncocytes are closely apposed
`and have many interconnecting tight junctions. The cy—
`toplasm has a paucity of different types of cell organelles
`except for mitochondria, which uniformly pack the cy-
`toplasm and impan the characteristic eosinophilic. finely
`granular appearance seen using light microscopy. These
`mitochondria show morphologic differences compared
`with mitochondria from normal cells. being larger and
`having a round shape with frequent stacking of cisterns.
`Both microvilli (supporting proximal tubule origin) and
`complex basal plasmalemmal interdigitations (indicating
`distal tubular origin) have been demonstrated. The pres—
`ence of significant lipid or glycogen in a renal neoplasm
`is not consistent with a diagnosis of renal oncocytoma.
`Although microvesicles may be present in oncocytoma
`in rare instances, they are much less consistent than in
`chromophobe renal cell carcinoma (47).
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`Atlwmrrx in Anatomic Pullwlngy. Vol. 6. No. 1. January. I999
`
`Cytogenetic findings
`Renal oncocytomas lack the specific chromosomal ab-
`normalities that characterize most conventional (clear
`cell) renal cell carcinomas. Recent studies suggest that
`oncocytomas may have two distinct cytogenetic changes:
`the loss of chromosomes 1 and Y (48,49) and the t (9:! l)
`(p32:q12) karyotypic anomaly (50). DNA analysis by
`restriction endonucleases shows a specific band of the
`mitochondrial genome (localized within the cytochrome
`c oxidase subunit 1 gene) to be present in all renal on-
`cocytomas examined and absent in all renal cell carci-
`nomas (50). This observation suggests that renal onco-
`cytomas represent a disease of mitochondrial DNA (50).
`
`Prognosis and therapy
`The prognosis of tumors classified using strict criteria
`is excellent. Although the majority of renal oncocytomas
`are benign. several early studies reported renal oncocy-
`tomas that showed a malignant course with distant me-
`tastasis (3 l—33). The cases with metastases may not have
`been true oncocytomas. and these studies have been criti-
`cized because they either failed to provide adequate
`documentation of metastasis or inadequately described
`the histologic sampling. gross appearance. and micro-
`scopic appearance of the tumors (Sl). Many of the re-
`ported metastasizing renal oncocytomas may have been
`chromophobe renal cell carcinomas with a predomi—
`nantly granular cytoplasm that were misdiagnosed be—
`cause of a lack of awareness of chromophobe renal cell
`carcinoma (26.51). Only two cases of renal oncocytoma
`using the currently accepted strict criteria have demon-
`strated metastasis ( 34). One patient developed metastases
`to the liver and bones l8 months after diagnosis and died
`with disease 6 months later (34). The other patient had
`metastasis to the liver that was diagnosed by needle bi-
`opsy at the time of surgery; however.
`the patient re-
`mained alive 58 months after metastasis. a fact that arv
`gues for the extremely low malignant potential of this
`tumor (34).
`Because there is no definitive preoperative method of
`identifying this tumor. surgical excision or nephrectomy
`remains the treatment of choice in the presence of ad-
`equate contralateral renal function. For patients with bi-
`lateral renal oncocytomas. parenchyma-sparing proce-
`dures can be used (26.35).
`
`METANEPHRIC (EMBRYONAL) ADENOMA
`
`To the authors' knowledge. the first repon of this tu-
`mor was made in the French literature in 1980 by Pages
`and Granier (52). They reported three cases that they
`referred to as “nephrogenic nephroma.“ ln I990. Wer—
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`BENIGN TUMORS OF THE KIDNEY
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`7
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`brouck and colleagues (53) described a rare renal epithe—
`lial tumor composed of an orderly array of small and
`uniform tubules with a rosette—like configuration, glo-
`meruloid structures, and inconspicuous stroma resem-
`bling the immature nephron, which they called an “em-
`bryonal adenoma.” In l99l, Nagashima and colleagues
`(54) reported two cases of a renal epithelial tumor re-
`sembling an immature nephron, and in 1992, Brisigotti
`and colleagues (55) reported a similar tumor in a young
`patient, calling the tumor “metanephric adenoma.” Re-
`cently (1995), Jones and colleagues described seven
`cases of metanephric adenoma and established its benign
`nature (56). In the same year, Davis and colleagues re-
`ported the experience of the Armed Forces Institute of
`Pathology, which had observed 50 cases of this uncom-
`mon renal tumor (57). In the current authors’ opinion, all
`of the reports mentioned above described the same
`clinico-pathologic entity.
`
`Incidence and clinical features
`This tumor accounts for much less than 1% of all renal
`
`neoplasms. It has been reported in many different age
`groups, in patients from 5 to 83 years of age, with a mean
`of 41 years of age. There is a slight predominance in
`females, with a female—to-male ratio of 2.5:]. It may be
`asymptomatic or manifest as abdominal fullness, ab-
`dominal or flank pain, or gross hematuria. In six cases,
`patients presented with polycythemia that regressed after
`the tumor was removed (57).
`Long term clinical follow-up (mean, 60 months;
`range, 13—199 months) in six cases revealed no recur—
`rence (56). However, not enough data exist to determine
`whether this is truly a benign neoplasm or one with a low
`malignant potential. Because of the difficulty of diagnos-
`ing this tumor preoperatively, the current treatment of
`choice is surgical removal.
`
`Radiologic findings
`Ultrasonograms, computed tomographic scans, and
`excretory urograms show that the tumor is a solid mass,
`frequently showing calcifications. It is poorly vascular-
`ized on renal arteriograms.
`
`Gross appearance
`Grossly metanephric adenoma is a single, unilateral,
`well encapsulated cortical neoplasm with sharply delin—
`eated margins (Fig. 6). In rare cases the tumor may be
`multifocal, but bilateral tumors have not been reported.
`The reported size ranges from 0.6 to 15 cm in diameter,
`with a mean of 5.5 cm. The cut surface shows a white or
`
`yellow, firm, homogenous, partially calcified solid mass
`that may have areas of cystic degeneration, with blood-
`
`
`
`FIG. 6. Metanephric (embryonal) adenoma. A well-circumscribed
`nodular mass involving the renal cortex and bulging into the perineph-
`ric fat. Hemorrhage related to intraoperative biopsy is present. (Re-
`printed, with permission, from Jones EC, Pins M, Dickersin GR. Young
`RH. Am J Surg Pathol 1995;19:615—626. Copyright © 1995, by Raven
`Press, Ltd.)
`
`filled spaces. Occasionally, hemorrhage and necrosis are
`seen (57).
`
`Histopathology
`When viewed microscopically, the tumor is usually
`surrounded by a capsule of cellular connective tissue and
`is composed primarily of a uniform sea of primitive
`nephronal epithelium reminiscent of the fetal metaneph-
`ric kidney (Fig. 7). This epithelium is composed of a
`single layer of uniform cuboidal-to—columnar cells ar—
`ranged in small, round, closely packed tubules, with ro—
`sette-like structures (Fig. 8). Occasionally, a papillary
`component may be present focally, sometimes with a
`glomeruloid appearance (Fig. 9). In rare instances, the
`tubules may be elongated, branched, or cystically dilated
`(Fig. 8). The epithelial cells have clear-to-pale staining
`scant cytoplasm, and large vesicular ovoid nuclei without
`pleomorphism, sometimes with inconspicuous nucleoli.
`Some solid areas with a blastema-like appearance may
`be seen, but these show the bland nuclear features typi-
`cally associated with metanephric adenomas. Mitotic fig-
`
`Advuuces in Anatomic Pathology, Vol. 6, No. 1, January. I999
`
`NOVARTIS EXHIBIT 2009
`Breckenridge V. Novattis, IPR 2017-01592
`Page 7 of11
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`NOVARTIS EXHIBIT 2009
`Breckenridge v. Novartis, IPR 2017-01592
`Page 7 of 11
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`S. LIGATO ET AL.
`
`
`
`FIG. 7. Metanephric (embryonal) adenoma. Low-power new show-
`ing an encapsulated tumor composed of a uniform sea of primitive
`nephronal epithelium.
`
`FIG. 9. Metanephric (embryonal) adenoma. Tubulcs with a glomcru-
`loid appearance (arrow) are seen focally.
`
`ures are usually absent (56). Calcospherites are typically
`present, often in the papillae and sometimes in the
`stroma. The stromal component is relatively inconspicu-
`ous and consists of spindle—shaped cells in a loose matrix
`with scattered calcifications and calcospherites; rare foci
`of metaplastic bone have also been described (56,57).
`Often, pans of the tumor regress, leaving behind fibrous
`scar tissue (57). Foci of necrosis and hemorrhage were
`present in three of the seven cases presented by Jones and
`colleagues (56). Immature blastema or nephrogenic rests
`are absent by definition. Invasion of renal capsule. pel-
`vis, and vascular-lymphatic spaces have not been re-
`ported.
`It is important to distinguish this tumor from Wilms‘
`tumor and “solid” papillary renal cell carcinoma
`(58.59). The distinction from Wilms’ tumor can be made
`because of a monophasic pattern, the absence of imma-
`
`_
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`
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`
`
`
`FIG. 8. Metanephric (embryonal) adenoma. Intermediate power
`showing closely packed small round tubules. with rosette-like struc-
`tures. lined by a single layer of uniform cuboidal to columnar cells.
`Some tubules are elongated. while others are branched.
`
`Arlrrmcex in Armnmn’r Pathology. Vol. 6, No. 1. January. I999
`
`ture blastema, and the lack of malignant nuclear features
`and mitoses. Papillary renal cell carcinomas with a
`“solid“ pattern show micronodules that may superfi-
`cially resemble the glomeruloid structures seen in meta-
`nephric adenoma, but the cells have more abundant cy-
`toplasm and show malignant nuclear features (58).
`
`Ancillary studies
`In one study. the tumor cells forming tubules were
`positive for vimentin, Leu 7, and 8-100 protein, and were
`conspicuously negative for keratin and epithelial mem-
`brane antigen (EMA), which are usually positive in nor—
`mal tubules and renal cell carcinomas (55). The tumors
`cell studied by Jones and colleagues were immunoreac-
`tive for cytokeratin in two of six cases, Leu 7 in three of
`five cases, EMA in one of six cases, vimentin in four of
`six cases, and muscle-specific antigen in one of six cases
`(56). The following stains were negative in all cases: