Principles and Practice of·
`
`nco ogy
`
`Derek Raghavan, MBBS, PhD, FRACP, FACP
`Chief, Departments of Solid Tumor Oncology
`and Investigational Therapeutics
`Roswell Park Cancer Institute and
`Professor of Medicine and Urology
`State University of New York at Buffalo
`Buffalo, New York
`
`Howard I. Scher, MD
`Chief, Genitourinary Oncology Service
`Associate .Attending Physician
`Division of Solid Tumor Oncology
`Department of Medicine
`Memorial Sloan-Kettering Cancer Center
`New York, New York
`
`Steven A. Leibel, MD
`Vice Chairman and Clinical Director
`Attending Radiation Oncologist
`Department of Radiation Oncology
`Memorial Sloan-Kettering Cancer Center
`New York, New York
`
`Paul Lange, MD, FACS
`Professor and Chair .
`Department of Urology
`University of Washington
`Seattle, Washington
`
`With 226 Additional Contributors
`
`r Lippincott - Raven
`
`_ , P U B L
`
`I S H E R S
`
`Philadelphia • New York
`
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`

`- 1
`
`Developmental Editor: Eileen Wolfberg Jackson
`Project Editor: EUen M. Campbell
`Production Manager. C11TCn Erlichman
`Production Coordinator: MaryClare Malady
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`Indexer. Steve Sorenson
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`Primer: Courier Book Company/Westford
`
`Copyright Cl I 997 by Lippincott-Raven Publishm. All rights reserved. This book is
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`Materials appearing in this book prepareed by individuals as part of their official duties
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`
`Library of Congress Cataloging-in-Publication Data
`Principles and practice of genitourinary oncology I Derek Raghavan ...
`[et al.] ; with 226 additional contributors.
`p. cm.
`Includes bibliographical references and index.
`ISBN 0-397-51458-1 (alk. paper)
`I. Raghavan, Derek.
`I. Genitourinary organs- Cancer.
`I. Urogenital Neoplasms. WJ 160 P9573 1996)
`(DNLM:
`RC280.U74P746 1996
`616.99'26-dc20
`DNLM/DLC
`for Library of Congress
`
`96-8893
`CIP
`
`Care has been taken to confirm the accuracy of the information presented and 10
`describe generally accepted practices. However, the authors, editors, and publisher are
`not responsible for errors or omissions or for any consequences from application of the
`information in ibis book and make no warranty, express or implied, with respect to the
`contents of the publication.
`The authors, editors, and publisher have exerted every effort t.o ensure that drug
`selection and dosage set forth in this text are in accordance with current
`recommendations and prac1ice at the time of publication. However, in view of ongoing
`research, changes in government regulations, and the constant flow of information
`relating to drug therapy and drug reactions, the reader is urged to check the package
`insert for each drug for any change in indications and dosage and for added warnings
`and precautions. Th.is is panicularly imponant when the recommended ageot is a new
`or infrequently employed drug.
`Some drugs and medical devices presented in this publication have Food and Drug
`Administration (FDA) clearance for limited use in restricted research settings. It is the
`responsibility of the health care provider to ascertain the FDA status of each drug or
`device planned for use in their clinical practice.
`
`9 8 7 6 5 4 3 2 I
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`Prindpl•s and Pracria of Genitourinary Oncology, edited by
`Derek Raghavan, Howard I. Scher, S1even A. Leibel. and Paul H.
`Lange. Lippincott-Raven Publishers. Philadelphia, 0 1997.
`
`CHAPTER 77
`
`Pathology of Renal Cancers
`
`Lavvrence D. True and David Grignon
`
`Although this chapter focuses on malignancies, benign tumors
`are discussed whe n relevant to the diffe rential pathologic diag(cid:173)
`nosis. Because an accurate pathologic diagnosis evolves from
`an accurate diffe remial diagnosis, charl s are provided thal list
`lhe differenti al d iagnostic considerations of lumors based on
`both gross and microscopic featu res. Furthennore, because :ic(cid:173)
`curale distinction of poorly differentiated tumors is best done
`by characterizing antigens expressed by the tumor cells, the
`immunohistochemical profiles of selected tumors is provided.
`lnfonnation is given concerning the genetic fea tures of renal
`cell carcinomas.
`
`EPITHELIAL NEOPLASMS
`
`Principles of Pathologic Classification
`
`The classification of renal epithelial tumors has traditionally
`been based on the cytologic and architectural patterns of growth.
`This approach is generally used in North America (see Table
`77-1 ). T hoenes and colleagues ' have proposed a system that is
`based on lhe cytoplasmic features of cells; this system has
`gained acceptance in Europe. Kovacs2 presented a scheme
`based on cytogenetic features. These sc hemes are summarized
`in Table 77-2.
`An assumption of these c lassifications is that cells in a given
`tumor have a common phenotype; however, many LUmors belie
`this assumption. Some renal cell carcinomas are composed of
`mixtures of clear cells, granular cells, and spindle cells, and
`mixed collecting duct-transitional cell carcinomas have been
`reported.3 The proporlion of cells of different histologic type
`comprising tumors may be prognostically important."
`
`Rena l Cell Carcinoma, Usual Type
`
`More than 90% of solid epithelial renal tumors are of the
`usual type. Although most cases occur sporadically, a small
`percentage of cases have a hereditary association (e.g., von Hip(cid:173)
`pel-Lindau disease, tuberous sclerosis, adult polycystic kidney
`disease). Hereditary tumors tend to fie mul tifocal and bilateral,
`in contrast with sporadic tumors, which tend to have a single
`
`focus and be unilateral. However, the histology of hereditary
`and sporadic tumors is identical. Both sporadic and familial
`tumors have simiJar cycogenetic changes, the most frequent of
`which are deletions within 3p. The von Hippel-Lindau locus
`has been mapped to 3p25. In add ition, most renaJ carcinomas
`have deletions within 3pl2-14.2.5- 9 Fluorescent in situ hybridi(cid:173)
`zation has demonstrated ploidy heterogeneity within tumors. 10
`Renal cell carcinomas have a highly variable gross appear(cid:173)
`ance. Typically, they are large, lobul ated masses !hat distort the
`kidney and bulge into perinephric fat (Fig. 77-1), which i.s not
`necessarily indicative of extracapsular invasion. A fibrous pseu(cid:173)
`docapsule gives these tumors a sharply circumscribed appear(cid:173)
`ance. The cut surface is variegated yellow (indicating eilher
`necrosis or the high lipid content of clear tumor cells or macro(cid:173)
`phages) Lo red-brown (indicating a granular cell component).
`Necrosis, hemorrhage, cystic change, and fibros is are frequent.
`Some cystic rumors resemble a multilocular cyst. Gross inva(cid:173)
`sion of the renal vein or vena cava occurs in as many as 40%
`of cases. 11
`Hiswlogically, the usual renal cell carcinoma is composed
`predominantly of clear, lipid-rich cells (Fig. 77-2). Variable
`numbers of eosinophilic (granular) and. rarely, spindle cells
`may be present. Tumors composed predominantly of spindle
`cells are classified as sarcomatoid carcinomas (discussed later).
`T he ratios of cell types may be of prognostic value4
`; an in(cid:173)
`creased proportion of s pindle cells portends a poorer prognosis.
`Typically, tumor cells grow as sheets or confl uent nests wid1
`a prominent sinusoidal vascular patte rn. Other pallems (e.g.,
`tubular, alveolar, papillary) may be present.
`The most common grading scheme is a four-point system
`based on nuclear features. 12 Grade I nuclei are small, round, and
`hyperchromatic, without observable nucleoli. Grade 2 nuclei a.re
`large, with an open chromatin pattern and s mall nucleoli. Grade
`3 nuclei have large, prominent nucleoli. Grade 4 nuclei are
`large and pleomorphic with marked atypia and hyperchromasia.
`Nuclear grade, which corre lates with mitotic activity, has signif(cid:173)
`icant prognostic power, independent of tumor stage. The grade
`assigned is that of the highest grade withi n the tumor, even if
`it is only focal. Nuclear inorphometry is potentially a more
`re liable way of grading renal carcinomas. 13
`Pathologic staging of resection specimens, using the TNM
`system of the Un ion lntemalionale Conire le Cancre, is based
`
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`800
`
`I CHAPTER 77
`
`TABLE 77-1. Histologic classification of kidney tumors
`according to the modified WHO scheme
`
`TABLE 77-2. Classification schemes of renal epithelial
`j tumors
`
`Epithelial tumors of renal parenchyma
`Adenoma, including oncocytoma
`Carcinoma
`Usual renal cell carcinoma
`Other histologic types
`Epithelial tumors of renal pelvis
`Transitional cell papilloma
`Transitional cell carcinoma
`Squamous cell carcinoma
`Adenocarcinoma
`Undifferentiated carcinoma
`Nephroblastic tumors
`Nephroblastoma (Wilms' tumor)
`Mesoblastic nephroma
`Multilocular cystic nephroma (multilocular cyst)
`Nonepithelial tumors
`Benign
`Angiomyolipoma
`Fi bro ma
`Hemangioma
`Others, including leiomyoma, lipoma, and neurilem(cid:173)
`moma
`Malignant
`Sarcoma
`Miscellaneous tumors
`Juxtaglomerular cell tumor
`Others, including neuroblastoma, carcinoid, and teratoma
`Secondary (metastatic} tumors, including lymphoma
`Unclassified tumors
`Tumor-like lesions
`Renal blastema, persistent or massive
`Renal dysgenesis
`Cysts
`Xanthogranulomatous pyelonephritis
`Malakoplakia
`Others
`
`WHO
`(Mostofi, 1981}
`
`Thoenes et al,
`19861
`
`Adenoma
`Renal cell
`carcinoma
`Clear cell
`Granular cell
`Spindle cell
`Others
`Collecting duct
`Chromophobe cell
`
`Renal cell
`carcinoma
`Clear cell
`Chromophil
`Eosinophil
`Basophil
`Chromophobe
`Typical
`Eosinophil
`Collecting duct
`Oncocytoma
`
`Kovacs, 19932
`
`Papillary tumor
`Ade no ma
`Carcinoma
`Nonpapillary
`carcinoma
`Chromophobe
`carcinoma
`Oncocytoma
`
`on both gross and microscopic findings . Gross data include
`tum or size (the size threshold distinguishing TL and T 2 tumors
`is 2.5 cm in greate st dimension), invasion of perinephric tissues,
`involvement of extrarenal organs (e:g., lymph nodes, adrenal
`gland), and invasion of the renal vein, vena cava, or both. Micro(cid:173)
`scopic invasion of vessels is irrelevant for staging. Invasion of
`perinephric fat requires histologic confirmation that tumor cells
`extend beyond the kidney parenchyma and the tumor pseudo(cid:173)
`capsule, if present
`Stage is the best predictor of tumor behavior. 11 Mhrkers of
`cell proliferation, including mitotic activity, expression of pro(cid:173)
`liferating ce ll nuclear antigen or the Ki-67 epitope, and S-phase
`fraction of cells, determined by flow cytometry, correlate with
`grade and survival but do not consistently provide prognostic
`information of value beyond that provided by stage and
`grade. 14- 16
`
`Mostofi FK. Histological typing of kidney tumours. World
`Health Organization, Geneva, 1981.
`
`Adenoma
`
`The d is tinction between adenoma and carcinoma is an unre(cid:173)
`solved but significant issue, because many small lesions are
`
`FIG. 77-1 . The typical gross appearance
`of renal cell carcinoma is a large tumor
`mass with cystic areas admixed with
`bridging bands of fibrous tissue, and
`more solid areas of renal cell carcinoma,
`which are multifocally yellow as a result
`of the clear cell component of this tui:nor.
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`P AT HOLOGY O F RENAL C ANCERS
`
`I 801
`
`FIG. 77-2. The most common histologic
`pattern of clear cell-type renal cell carci(cid:173)
`noma consists of cells with a clear cyto(cid:173)
`plasm as a result of the high content of
`lipid, which is extracted during tissue pro(cid:173)
`cessing. Note the fine network of capillar(cid:173)
`ies between the nests of tu mor cells. This
`tumor is classified as Fuhrman's grade 2
`because of the small nuclei and infrequent
`nucleoli.
`
`being detected with increasingly sensitive techniques. ln a large
`autopsy series, small cortical epithelial lesions were found in
`2 1 % of patients; frequency increased with age, from 10% in 21-
`to 40-year-old patients to 40% in 70- to 90-year-old patients. 17
`Adenomas have other clinical associations. Those w ith a papil(cid:173)
`lary histology are often multiple and are associated with papil(cid:173)
`lary carcinoma. 18 Many patie nts with acquired cystic disease
`develop adenomas. Papillary adenomas have characteristic cy(cid:173)
`togenetic changes: trisomy 7 and 17 and loss of the Y chromo(cid:173)
`some. 18
`Grossly, the adenoma is sharply circumscribed and yellow(cid:173)
`tan to gray; it protrudes from the cortical surface. Histologically,
`the tumor has a tubulopapillary architecture and lacks a capsule,
`merging with adjacent renal parenchyma. Cells have an eosino(cid:173)
`philic to basophil ic cytoplasm and small, uniform nucle i (Fig.
`77-3). When clear tumor cells are present, the tumor should be
`regarded as a carcinoma, regardless of size.
`
`Investigators have used different pathologic criteria to distin(cid:173)
`guish adenoma from carcinoma. Size is not a sufficiently spe(cid:173)
`cific c riterion, because small tumors (as small as 0.5 cm in
`diameter) have metastasized. 19 Some authors restrict the diag(cid:173)
`nosis of adenoma to small lesions composed of closely packed
`tubules and papillae with small, uniform cuboidal cells hav ing
`nuclei of uniform size and shape and virtually absent mitoses.20
`Others recommend diagnosing such tumors as "small renaJ epi(cid:173)
`thelial neoplasms of low malignant potential. " 21 Adenoma
`should not be diagnosed by fi ne needle aspiration biopsy, be(cid:173)
`cause sampling may not be representative.
`
`Papillary Renal Cell Carcinoma
`
`As many as 10% of renal cell carcinomas are papillary var(cid:173)
`iants; according to Kovacs and Kovacs" 8 criteria, more than
`
`FIG. 77-3. A typical adenoma is not en(cid:173)
`capsulated and has a complex papillary tu(cid:173)
`bular architecture of cells with scanty baso(cid:173)
`philic cytoplasm and a high nuclear(cid:173)
`cytoplasmic ratio but minimal nuclear
`atypia. No mitoses are seen.
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`802
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`I Ci V\PTER 77
`
`75% of the tumor must have a papillary architecture. The cells
`are typically chrnmophi lic (either eosinophilic or basophilic);
`clear cells are rare. Tumors that meet these patho logic c riteria
`have specific cytogenetic changes: trisomy or tetrasomy of 7
`and 17 and loss of the Y chromosome.2 Papillary adenomas
`have the same cytogenetic changes. No abnonnalities of 3p
`have been found in these lesions. In ~ddition, abnonnalities of
`chromosomes 12, 16, and 20 may be found and may mark the
`development of malignancy.2
`Grossly, papillary renal cell carcinoma is well circumscribed,
`brown, soft, and friable, with central cystic change. The cystic
`change is often no t a result of necrosis, which is uncommon.
`These wmors are often multifocaJ and are associated with small,
`papillary adenomas. The predominant histologic pattern is pap(cid:173)
`ilJary; small cuboidaJ or columnar cells of low cytologic grade
`line fibrovasc ular stalks which contain foamy hi stiocytes.
`Psammoma bodies may be present. Although these tumors have
`been associated with a better prognosis than the usual renal cell
`carc inoma, at least some of these tumors may behave aggres(cid:173)
`sively.22·23
`
`Oncocytoma
`
`Oncocytoma, ftrst reported in 1976, accounts for fewer than
`5% of solid renal tumors in adults.24 The most controversial
`aspect of this tumor concerns its malignant potential. The debate
`has been confused by the use of different pathologic crite(cid:173)
`ria.24-27 In studies using strict criteria, renal oncocytomas be(cid:173)
`haved in a unifonnJy benign nature. Cytogenetic studies also
`support distinguishing this tumor from the usual renal cell carci(cid:173)
`noma. The most frequent abnormality associated with oncocy(cid:173)
`toma is trisomy 17. Abnormalities in mitochondrial DNA have
`been found; 3p deletions are not presenr.28
`Grossly, the oncocytoma is a sharply c ircumscri bed, nonen(cid:173)
`capsulated tumor with a central stellate scar, wh ich may be
`inconspicuous in small tumors (Fig. 77-4). Oncocytomas are a
`uniform tan-brown or mahogany brown. Histologically, onco(cid:173)
`cytomas are composed of a pure population of round or cuboidal
`
`cells with coarse, granular, eosinophilic cytoplasm (Fig. 77-5).
`These cytoplasmic featurd are the result of abundant mitochon(cid:173)
`dria. An organoid growth pattern is typical, particularly in asso(cid:173)
`ciation with the scar. Solid, alveolar, or tubular patterns may be
`seen. Nuclei are round and of uniform size, with small, central
`nucleoli. Scallered cells with enlarged, atypical hyperchromatic
`nuclei are often present; this is considered a degenerative fea(cid:173)
`ture. Mitoses are not seen. According to some authors, the find(cid:173)
`ing of even a single mitosis excludes the diagnosis of oncocy(cid:173)
`toma. Extension into perinephric fat has been found in rare
`tumors th at had a benign clinical course.27
`Oncocytomas, by defin.ition, are not graded. T he possibility
`that a subset of oncocytomas with a high nuclear grade has
`mali gnant potential has been raised.26 However, the study on
`which this observation is based failed to apply strict criteria to
`dertning oncocyto'mas; the category "pink cell (or, granular,
`eosinophilic cell) tumors" of the kidney includes not only onco(cid:173)
`cytorna but also chromophobe cell carcinoma and eosinophilic
`papillary renal cell carcinoma.
`The minimal diagnostic criteria for oncocytoma include a
`characteristic gross appearance, a pure population of oncocytes,
`and the absence of mitoses. To satisfy these criteria, sampling
`should be thorough; at least one block of tissue per centimeter of
`maximum wmor dimension should be analyzed. The diagnosis
`should probably not be made either by frozen section or fi ne
`needle aspiration biopsy because of sampling limitation s.
`
`Cystic Renal Carcinoma
`
`Cysti c renal lesions have a variety of associations with renal
`cell carcinoma. Cystic degeneration is not uncommon in renal
`cell carc inoma; as many as 15% of renal cell carcinomas are
`radiographically cystic.29 Usually, the presence of cystic change
`presents a greater problem to the radiologist than to the patholo(cid:173)
`gist. However, in some cases, the identification of diagnostic
`tumor ti ssue may be problematic because of the paucity of
`tumor cells, which may be of low grade.
`Cystic renal carcinomas are characterized by variably sized,
`noncommuni cating cysts separated by irregular, thick, fibrous
`
`FIG. 77-4. The typical o ncocytoma is a
`round, circumscribed, tan-to-brown mass
`with a central stellate scar.
`
`J
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`PATHOLOGY OF RE-"IAL CANCERS
`
`I 803
`
`FIG . 77-5. Oncocytoma tumor cells form
`small nests in a fibrous, variably edema(cid:173)
`tous , myxoid stroma. The brown color of
`the gross tumor and the granular eosino(cid:173)
`philia seen mic roscopically result from the
`high content of mitochondria. Typical on(cid:173)
`cocytoma cells have large nuclei with
`prominent nucleoli.
`
`septae. The septae usually show marked hyalinization and may
`contain calcifications or foci of ossification. The tumor cells
`that line the cysts may be markedly attenuated or absent. Nests
`of tu mor cells can be fo und within the septae; tl1ese are most
`often of the c lear cell type. A uniloc ular variant has a thick
`irregular fibrous wall and a lining of tumor cells wh ich may be
`clear or granular. Characteristically, tl1ere are papillary cxcres(cid:173)
`censes; the papillae are covered by clear or granular cells.
`In cases resul ting fro m cystic necrosis of a previous ly solid
`rumor, the cyst contains hem orrhage and necrotic tissue. The
`cyst wall is thickened and irregular. These cases may be difficult
`to d iagnose because an epithelial lining is often absent. Any
`cystic mass in the kidney that contains hemorrhagic or.necrotic
`material s hould be suspected to be malignant and should be
`extens ively sampled.
`Carci nomas may arise in benign cystic disease of the kidney,
`including acquired cystic disease, adu lt polycystic kidney dis(cid:173)
`ease, and s imple unilocular cortical cysts.30•31 Tumors in simple
`cysts are typically small, solid, yellow nodules wiiliin U1e cyst
`wa ll. Histologically, most such tumors are composed of clear
`cells and have a low nuclear grade. The prognosis with these
`lesions is good.
`
`Collecting Duct (Bellini's Duct) Carcinoma
`
`Tl1is rare epithelial tumor, which was first recognized in
`1976, tends to occur at a younger age than the usual renal cell
`carcinoma.22·32·33 Many patients have a family history of can(cid:173)
`cer.33 Collecting duct rumors are located in the medulla, are
`gray-whi te, and show an infiltrative growth pattern. Necrosis
`is frequent. His to logically, collecting duct carcinomas typically
`have a m ixed papillary and infiltrati ve tubular arch itecture.
`There is pronounced stromal desmoplas ia. Often, tumor cells
`diffusely invade rena l parenchyma, trapping normal renal struc(cid:173)
`tures. Nuclear atypia is marked and mitoses are frequent. Dys(cid:173)
`plasia or carcinoma in situ may be found in the collecting ducts.
`Tumors have also been described in which this pattern is associ(cid:173)
`ated wi th a trans itional cell carcinoma.3 The common e mbryo] -
`
`ogic derivation of the collecting duct and renal pelvis is a histo(cid:173)
`gene tic basis for this event. A sarcomatoid variant has also been
`described.34 These tumors have a very aggress ive course. Of
`18 patients, 10 died o f metastatic disease within 2 years; the
`median survival was 22 months.33
`Recently, Davis and colleagues35 have reported as "renal
`mcdullary carcinoma" a highly mal.ignant tumor that occurs
`almost exclusively in individuals with sickle cell disease or trait
`and that shares ilie following pathologic features with collecting
`duct carcinoma: des moplastic stroma, marked nuclear atypia,
`in s itu neoplasia in the calyceal epithelium, and a medullary
`location. The authors consider it different, however, from col(cid:173)
`lecting duct carcinoma because of its distinctive histologic fea(cid:173)
`tures, including a reticular, yolk sac-like histology. General
`acceptance of renal medullary carcinoma as a new tumor type
`awaits confinnatory reports.
`
`Chromophobe Cell Carcinoma
`
`Chromophobe cell carci.noma, first reported in 1985, repre(cid:173)
`sents fewe r than 5% of renal cell carcinomas.36•37 This tumor
`warrants distinction from oilier variants because of its unique
`morphology and cytogenetic features and the possibility of mis(cid:173)
`diagnosing it as an oncocytorna. Many cases of "malignant
`oncocytoma" actually represent chromophobe cell carcinoma.
`Cy to genetically, there is loss of cilromosomes 1, 2, 6, 10, l 3,
`17, 2 1 and of sex chromosomes; no loss of 3p has been fo und.38
`Grossly, the tumor is circumscribed and tan to brown. Areas
`of necrosis and hemorrhage may be fou nd. No cenrral scar,
`which is characteristic of oncocytoma, is seen. Microscopically,
`there are two patterns. In the classic type, the cells are volumi(cid:173)
`nous, wiili a finely reticular, pale, eosinophilic cy toplasm,
`which tends to condense along the cell membrane, producing
`a perinuclear halo. The .eosinophilic type is characterized by
`smaller cells with a denser, finely granular, eosinophilic cyto(cid:173)
`plasm and a less conspicuous perinuclear halo.
`These rumor cells grow in a solid pattern with a capillary-rich
`stroma. Histochemical staining with Hale's colloidal iron shows
`
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`804
`
`I CHA PTER 77
`
`intense blue cytoplasmic reactivity; thi s result is no t seen in usual
`renal cell carcinoma or in oncocytoma. N uclei vary from small ,
`round , and hyperchromatic to large with clumped chromatin and
`prominent nucleoli. Ultrastructurally, the cells contain abundant
`microvesicles and variable numbers of mitochondria. The re(cid:173)
`ported cases of chromophobe cell carcinoma behaved in a man(cid:173)
`ner similar to that of usual renal cell carcinoma. 37
`
`Sarcomatoid Renal Cell Carcinoma
`
`As many as 5% of renal tumors in adults are sarcomatoid
`re nal cell carcinomas. A lthough their clinical presentation is
`similar to that of usual re nal cell carcinoma, sarcomatoid renal
`cell carcinomas often are of higher stage at diagnosis. 39Ao
`G rossly, this tumor is often a gray-white , infiltrating mass
`tha t is often contiguous w ith a usual renal ceU carc inoma. Histo(cid:173)
`logicaJly, sarcomatoid renal cell carcinoma is composed of ma(cid:173)
`lignant spindle ce lls that can mimic virtually any his tologic type
`of sarcoma.4 Tumor cells are often arranged as poorly formed,
`inte rlacing fascicles. Cytologically bizarre tumor cells and atyp(cid:173)
`ical mitoses are frequent. A lthough osteoid or chondroid mate(cid:173)
`rial may be present, a diagnosis of osteosarcoma or chondrosar(cid:173)
`coma s hould not be made. When no epithelial component can
`be found, evidence of epithelial differentiation should be sought
`by special studies (e.g., immunohistochemical localization of
`keratin to tumor cells, ultrastructural identification of desmo(cid:173)
`somes).41 Because sarcomatoid differentiation of carcinoma is
`more common than pure sarcoma of the kidney, malignant spin(cid:173)
`dle cell tumors of the kidney should be presumed to be carc ino(cid:173)
`mas until proven otherwise. Clinically, these tumors are highly
`maJ ignant. In one series, the 5-year survival rate was 19%.
`Adjuvant chemothe rapy may improve surv ivaJ.40
`
`Transitional Cell Carcinoma
`
`o r the kidney are similar .to that of transitional cell tumors in
`the urinary bladde r.42 Mosf transitional cell carcinomas are .low(cid:173)
`grade, noninvasive papillary neoplasms; invasive, high-grade
`tumors are less frequent. Rarely, these tumors have other histo(cid:173)
`logic components, including, in order of frequency, squamous,
`glandul ar, and sarcomatoid elements. Because of their low cyto(cid:173)
`logic grade and the diffic ulty of visuali zing and biopsying the
`re nal pelves and calyces, these tumors can be clinically and
`pathologically challenging to diagnose. As in the bladder, tumor
`s tage is of greatest prognostic power.43 Low grade and absence
`of aneuploid or tetraploid cell populations are indepe nde nt pre(cid:173)
`dictors of a good prognosis for low-stage tumors.44 For tumors
`that a but re nal parenchyma, distinguishing intraductal extension
`of tumor from renal parenchymal invasion probably is also of
`prognostic importance.45
`in frequently, re nal transitional cell carcinomas grow as solid
`masses that infiltrate the renal parenchyma and lack a papillary
`component (Fig. 77-6). The differential diagnosis of such a
`diffu se ly infiltrative tumor includes lymphoma and re nal cell
`carcinoma. Immunohistochemical characte rization of the tumor
`can help make the distinction. Transitional ce ll carcinomas are
`characterized by ex pression of high-molecular-weight keratins
`and o f keratin 20.46
`As in the urinary bladder, squamous cell carcinoma and ade(cid:173)
`nocarcinoma of the renal pelvis occur, although rarely. More
`often, squamous a nd glandular differentiation occur as compo(cid:173)
`nents of a transitional cell carcinoma. P ure sq uamous cell carci(cid:173)
`noma has distinctive clinical associations (i.e., renal calculi and
`a history of recurrent upper urinary tract infections). These tu(cid:173)
`mors have the same histology as their counterparts in the blad(cid:173)
`der. Patterns of adenocarci.noma of urothelium include papil(cid:173)
`lary, glandular, and muci.nous w ith signet ring formation.
`Differentiation from metastatic carcinoma can be diffic ult but
`can be aided by immunohistoc hemical studies. The prognosis
`associated with these tumors is poor.
`
`Neuroendocrine Neoplasms
`
`A pproximately 5 % of primary renal tumors are transitional
`cell carcinomas. These tumors originate in renal pelvic urothe l(cid:173)
`ium. The histology and biology of transitional cell carci nomas
`
`Primary ne uroendocri.ne tumors of the kidney are very rare.
`Fewer than one dozen cases of intrarenal neuroblastoma and
`
`FIG. n -6. Transitional cell carcinoma has
`only a minimal component in the collecting
`system. It diffusely infiltrates renal paren(cid:173)
`chyma as an irre_gular, white-to-tan mass.
`
`West-Ward Exhibit 1042
`True-Raghavan 1997
`Page 008
`
`

`

`48 Carcino id
`pheoc hromocytoma have been reponed in adu lts. 47
`•
`tumors of the kidney are sometimes hormonally active and have
`caused Cushing 's syndrome49 and hyperglucagonemi a.50
`Grossly, carcinoids are usually weU circumscribed, solid, and
`tan. Rarely, carcinoid is a component of cystic teratorna.5 1 Al(cid:173)
`though typically following a benign course, some carcinoids
`have had a lethal course.52
`.
`Small cell undifferentiated carcinoma of the kidney is whi te
`to tun, with an infiltrative margin. Histologically, this lesion is
`composed of sheets of tuinor cells that have scanty cytoplasm,
`a fine chromatin pattern, and inconspicuous nucleoli. Because
`the histology is identical with that of small cell carcinoma of
`other sites (e.g., lung), the possibility of the tumor being a me(cid:173)
`tastas is should be excluded clinically. Tbe association of small
`cell undifferentiated carcinoma of the kidney with tbe renal
`pe lvis53 and with concurrent transitional cell carcinoma of the
`pelvis54 raises the possibility that these tumors originate in tran(cid:173)
`sitional epithelium. Differentiation froni other diffusely infiltra(cid:173)
`tive, small cell undifferentiated tumors can be made by immu(cid:173)
`nohistochemistry. These tumors are highly malignant; most
`patients die of tumor within l year of diagnos is.55·56
`All of these neoplasms have a neuroendocrine phenotype.
`Neurosecretory granules can be found ultrastrucnirall y, and im(cid:173)
`munoreactive neuron-specific enolase, chromogranin, and syn(cid:173)
`aptophysin can be localized to tumor cells.
`
`Juxtaglomerular Cell Tumor (Reninoma)
`
`Patients with this rare tumor of juxtaglomerular cells, which
`are the nom1al site of renin synthesis, present clinically with
`severe hypertension as a result of abnormal renin secretion. The
`tumor can be difficult to localize when small; some of these
`lesions are smaller than 0.3 cm in size.57 The histology is varied,
`although localization of immunoreactive renin to tu01or cells
`and ultrastructural identification of distinctive rhomboidal crys(cid:173)
`tals confirm the diagnosis. Not all cases of hyperreni nemia(cid:173)
`associated hypertension are caused by renal reninomas; exam(cid:173)
`ples of renin-secreling renal carcinoma have been reported.58
`Reninomas are not malignant.
`
`P ATHOLOGYOF REN AL CANCERS
`
`I 805
`
`NONEPITHELIAL AND MUL TlLINEAGE
`NEOPLASMS
`
`Angiomyolipoma
`
`Angiomyolipoma is a benign hamartoma composed of vary(cid:173)
`ing ratios of smooth muscle, fat, and blood vesse ls. About 50%
`of angiomyolipomas occur in patients with tuberous sclerosis;
`conversely, between 50% and 80% of patients with tuberous
`sclerosis develop one or more angiomyolipomas. Most patients
`with multifocal angiomyol ipoma have tuberous sclerosis; how(cid:173)
`ever, in sporadic cases, the tumor is usually unilateral and uni(cid:173)
`focal .
`Grossly, the tumor is circumscribed and not encapsulated. It
`is usually variegated yellow '(because of adipocytes) and tan
`(because of smooth muscle cells). Areas of hemorrhage and,
`less frequently, necrosis can be seen.
`The classic angiomyolipoma is composed of three cell types:
`smooth muscle cells, which grow as sheets of generally eosino(cid:173)
`philic cells that do not form fascicles; adipose tissue; and thick(cid:173)
`walled, dysmorphic blood vessels (Fig. 77-7). An abundant adi(cid:173)
`pocyte component imparts a distinctive radiologic and gross
`appearance; however, in some cases the adipocyte component
`is sparse or even absent. The diagnosis of these angiomyolipo(cid:173)
`mas can be difficult, both radiologicaJ