Journal Pre-proof Five decades of urologic pathology: the accelerating expansion of knowledge in renal cell neoplasia
Gregory T. MacLennan, Liang Cheng PII:
S0046-8177(19)30174-1
DOI:
https://doi.org/10.1016/j.humpath.2019.09.009
Reference:
YHUPA 4928
To appear in:
Human Pathology
Received date:
5 September 2019
Accepted date:
6 September 2019
Please cite this article as: G.T. MacLennan and L. Cheng, Five decades of urologic pathology: the accelerating expansion of knowledge in renal cell neoplasia, Human Pathology(2019), https://doi.org/10.1016/j.humpath.2019.09.009
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© 2019 Published by Elsevier.
Journal Pre-proof
Five decades of urologic pathology: the accelerating expansion of knowledge in renal cell neoplasia Gregory T. MacLennan1, Liang Cheng2
From 1Department of Pathology and Laboratory Medicine, Case Western Reserve University and
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University Hospitals Cleveland Medical Center, Cleveland, Ohio; and 2Department of Pathology
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and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
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Total number of text pages, 40; Number of tables, 0; Number of figures, 22.
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Running Head: Decades of Urologic Pathology
Total number of text pages, 60; Number of Tables, 0; Number of figures, 22.
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Competing interest: none
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Disclosure Statement: The authors declare that they have no conflicts of interest.
Authors for Correspondence: Liang Cheng, e-mail:
[email protected] or Gregory T. MacLennan, e-mail:
[email protected]
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Journal Pre-proof Abstract Those who are knowledgeable in cosmology inform us that the expansion of the universe is such that the velocity at which a distant galaxy is receding from the observer is continually increasing with time. We humbly paraphrase that as "The bigger the universe gets, the faster it gets bigger". This is an interesting analogy for the expansion of knowledge in the field of renal tumor pathology over the past 30 to 50 years. It is clear that a multitude of dedicated investigators have
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devoted incalculable amounts of time and effort to the pursuit of knowledge about renal
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epithelial neoplasms. As a consequence of the contributions of numerous investigators over
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many decades, the most recent World Health Organization classification of renal neoplasms
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includes about 50 well defined and distinctive renal tumors, as well as various miscellaneous and metastatic tumors. In addition, a number of emerging or provisional new entities are under active
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investigation and may be included in future classifications. In this review, we will focus on a
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number of these tumors, tracing as accurately as we can the origins of their discovery, relating relevant additions to the overall knowledge base surrounding them, and in some instances
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addressing changes in nomenclature.
Keywords: Kidney, renal tumors, classification, emerging new entity, history.
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Journal Pre-proof Those who are knowledgeable in cosmology inform us that the expansion of the universe is such that the velocity at which a distant galaxy is receding from the observer is continually increasing with time. We humbly paraphrase that as "The bigger the universe gets, the faster it gets bigger". This is an interesting analogy for the expansion of knowledge in the field of renal tumor pathology over the past 30 to 50 years. The authors have been charged with the enjoyable task of providing a synopsis of
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historical events chronicling developments in a field of genitourinary pathology over the past 50
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years. After some deliberation, we have chosen to discuss the rather remarkable transformation
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of the field of renal epithelial neoplasms during that era. Of course it is impossible to touch on
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these events without at least some passing mention of the knowledge that had been brought forward in the previous 150 years. Students of this history are referred to several remarkable
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publications [1-3]. Our efforts will focus on the field as it evolved after about 1970.
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The first renal neoplasm was reported nearly 200 years ago [1]. Thereafter, it became evident that a variety of different tumors could arise within the kidney. In 1952, renal cell
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carcinomas had been separated into two groups - clear cell or granular cell - depending upon
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their cytoplasmic staining characteristics [4]. By 1953, according to Dr. Lauren Ackerman in his influential textbook, Surgical Pathology [5], the inventory of "renal tumors" included perirenal lipoma, leiomyoma, liposarcoma, rhabdomyosarcoma, a ‘well-circumscribed mucin-producing adenocarcinoma of the cortex,’ (illustrated, and possible representing the earliest recorded image of mucinous tubular and spindle cell carcinoma), (Fig. 01) renal adenoma, Wilms tumor, and renal adenocarcinoma. Although Dr. Ackerman acknowledged that renal adenocarcinoma has ‘various patterns . . . granular . . . clear . . . papillary,’ it was his opinion that ‘it does not appear logical to make subdivisions in nomenclature; better to call it simply an adenocarcinoma of renal
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Journal Pre-proof tubule origin’; this had not changed by the time the 1964 version of his textbook appeared. Remarkably, Dr. Ackerman’s entire description of renal adenocarcinoma in the 1953 edition was encompassed within 30 lines of text. After that time, and particularly in the past 50 years, the list of renal neoplasms has grown extensively, and classification systems have become increasingly sophisticated as distinctive morphologic patterns in renal neoplasms have been recognized and correlated with
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clinical findings. Ancillary diagnostic tools, including electron microscopy,
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immunohistochemistry, cytogenetics, and molecular diagnostic techniques, made it possible to
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detect distinctions between various types of renal neoplasm; some tumors, such as Xp11
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translocation carcinoma and synovial sarcoma, are essentially defined by their molecular characteristics [6]. As a consequence of the contributions of numerous investigators over many
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decades, the most recent World Health Organization classification of renal neoplasms includes
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about 50 well defined and distinctive renal tumors, as well as various miscellaneous and metastatic tumors [7]. In addition, a number of emerging or provisional new entities are under
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active investigation and may be included in future classifications. In this review, we will focus
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on a number of these tumors, tracing as accurately as we can the origins of their discovery, relating relevant additions to the overall knowledge base surrounding them, and in some instances addressing changes in nomenclature. We will deliberately avoid descriptions of the various diagnostic pathologic features of these tumors, since this information is readily available in a number of excellent recently published textbooks. We will begin by discussing some benign epithelial neoplasms and some renal epithelial neoplasms with limited or perhaps no malignant potential. We will end by focusing upon selected malignant renal epithelial neoplasms.
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Renal epithelial neoplasms that are considered benign
Oncocytoma In the first AFIP fascicle devoted to renal pathology, published in 1957, tumors putatively derived from renal cortical epithelium were designated either adenoma or carcinoma,
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acknowledging the possibility that some such tumors were benign [8]. In the second AFIP
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fascicle, published in 1975, all renal tubular epithelial neoplasms were characterized as
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adenocarcinoma, in keeping with the authors’ opinion that adenomas simply represented early
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carcinomas [9].
Following an initial report in 1942 [10], followed by a few sporadic reports thereafter,
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interest in renal oncocytoma was stimulated by a report in 1976 suggesting that renal
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oncocytomas were relatively common, distinctly separable from renal carcinoma, and benign [11]. For several years, controversy concerning its malignant potential persisted [12]; the
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identification of chromophobe renal cell carcinoma in 1985 helped considerably in resolving this
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uncertainty [13]. Chromophobe renal cell carcinoma was so named because the predominant cell type had abundant pale flocculent cytoplasm that did not stain strongly with hematoxylin and eosin. In 1988 the same investigators acknowledged that most such tumors include components of cells with finely granular cytoplasm that stains darkly with hematoxylin and eosin, and in fact some of these tumors were composed entirely of these cells, and hence were designated "eosinophilic variant of chromophobe renal cell carcinoma"[14]. This variant has significant morphologic overlap with oncocytoma. Although it is certainly possible to distinguish these entities using sophisticated techniques, making this distinction using readily available routine
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Journal Pre-proof diagnostic tests has proven to be a somewhat difficult exercise, resulting in a plethora of USCAP abstracts and peer-reviewed publications.
Papillary adenoma Criteria for the definition of papillary adenoma of the kidney were refined over a period of several decades [15]. It was observed in 1938 that renal tumors less than 3 cm in diameter
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rarely metastasized [16]. A subsequent study in 1950 documented metastases in 65 tumors less
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than 5 cm in diameter [17]; nonetheless, tumors less than 3 cm were still classified as adenomas.
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The recognition of oncocytoma as a neoplasm with benign behavior, regardless of size, only
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partially resolved the dilemma [11]. In other types of renal epithelial neoplasms, it remained impossible to distinguish renal adenomas from adenocarcinoma on the basis of light microscopy,
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histochemical stains, or electron microscopy. Papillary adenomas, in particular, could not be
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distinguished from papillary renal cell carcinoma even with the use of cytogenetic and comparative genomic hybridization studies [18-21].
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Whereas more than 20% of persons over the age of 20 harbor papillary renal neoplasms
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less than 5 mm in diameter, and only about 4500 new cases of papillary renal cell carcinoma are diagnosed each year, it seems evident that the growth potential for tumors less than 5 mm in diameter is quite limited [15]. On the other hand, tumors larger than 5 mm have shown growth potential exceeding that of the remaining 90%. On the basis of these data, it was proposed that papillary adenoma of the kidney should be defined as a neoplasm having papillary, tubular or tubulopapillary architecture, a diameter less than or equal to 5 mm, and no histologic resemblance to clear cell, chromophobe or collecting duct renal cell carcinoma [22]. This definition garnered widespread acceptance and approval for approximately the next 17 years.
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Journal Pre-proof Currently, renal papillary adenoma is defined as an unencapsulated renal neoplasm with papillary or tubular architecture, composed of cells of low ISUP nucleolar grade and measuring ≤ 15 mm in greatest dimension. As noted, prior to 2015, the upper limit of size acceptable for a diagnosis of papillary adenoma was ≤5 mm. The size cutoff was increased in 2015, based on analyses of the malignant potential of small renal masses. Evidence indicates that for each 1-cm increase in tumor size, the incidence of synchronous metastases increases 22%. Combined
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experience in nephrectomies performed at Mayo Clinic and Memorial Sloan-Kettering Cancer
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Center demonstrates that of 519 renal tumors <2 cm in diameter, none had synchronous
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metastases, and none developed asynchronous metastases following surgical excision of the
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primary tumor. Similar findings were reported from Fox Chase Cancer Center [23-25]. It has additionally been suggested that such tumors should lack histologic resemblance to clear cell,
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chromophobe, or collecting duct renal cell carcinoma. The importance of distinguishing between
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small papillary and clear cell neoplasms was noted many decades ago, and the importance of this
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distinction was reinforced by reports of small clear cell renal carcinomas with metastases.
Renal epithelial neoplasms with limited or perhaps no malignant potential
Multilocular cystic renal neoplasm of low malignant potential Multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) is an uncommon renal tumor that was until recently designated multilocular cystic renal cell carcinoma.
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Journal Pre-proof The first report of a multilocular cystic renal tumor with a component of clear cells appeared in 1928, followed by another in 1957 [26, 27]. Although the designation of "multilocular cystic renal cell carcinoma" first appeared in a publication in 1982 in a Radiology journal [28], the pathologic features of this tumor were not well documented until the publication of a report in 1991 of a small series of carefully analyzed cases, which indicated that multilocular cystic renal neoplasms with very limited components of clear cells are distinguishable from and
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should be classified separately from ordinary renal cell carcinoma [29]. Further experience with
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this neoplasm led to the proposal that it should be defined by the following criteria: it has a
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fibrous pseudocapsule; it is composed entirely of cysts and septa with no expansile solid nodules;
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the septa should contain aggregates of epithelial cells with clear cytoplasm that are indistinguishable from the tumor cells that compose grade 1 renal cell carcinoma [30] [Fig. 02].
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If necessary, the epithelial nature of the tumor cell clusters can be confirmed by their
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immunoreactivity to antibodies against cytokeratin and EMA; immunostains for histiocytic markers are negative [30]. The proper diagnosis hinges on strict adherence to the diagnostic
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criteria for this entity. The tumor was considered sufficiently well characterized to be listed as a
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distinct renal epithelial neoplasm in the 2004 WHO classification of renal tumors as multilocular cystic renal cell carcinoma [21]. VHL gene mutations are identifiable in about 25% in MCRNLMP, and there is no difference in the status of chromosome 3p deletion between low grade clear cell RCC and MCRNLMP, supporting the concept that MCRNLMP is a subtype of clear cell RCC [31-33]. There are no reports of recurrence or metastasis of MCRNLMP [34-37]. In recognition of the apparently very indolent biologic behavior of this tumor, it was listed as a distinct renal epithelial
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Journal Pre-proof neoplasm in the 2016 WHO classification of renal tumors under the name multilocular cystic renal neoplasm of low malignant potential [7].
Clear cell papillary renal cell carcinoma Although originally described in 2006 as one of two unique tumors typically arising in end-stage kidneys, with and without acquired cystic change [38], it is now known that the
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majority of clear cell-papillary renal cell carcinomas (CCPRCC) arise sporadically [39],
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accounting for up to 4.3% of resected kidney tumors, occurring about equally in males and
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females, and comprising the 4th most common renal tumor [40-45].[Fig. 03]
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In contrast to conventional clear cell RCC and papillary RCC, CCPRCC lacks the VHL 3p25 deletion and also lacks VHL gene mutations, VHL promoter hypermethylation, trisomies of
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chromosomes 7 and 17, and loss Y chromosome, although low copy number gains of
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chromosomes 7 and 17 have been reported in a small number of cases [44, 46]. No mutations of KRAS, NRAS,BRAF, PIK3CA, ALK, ERBB2, DDR2, MAP2KI, RET OR EGFR genes were
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found.
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detected in a recent study [47]. Currently, no specific characteristic genetic abnormality has been
More than 90% of CCPRCCs are stage pT1 at presentation [39]. A single patient with sarcomatoid change in a CCPRCC had a fatal outcome [46]. Of several hundred reported cases of conventional CCPRCC [39, 44, 46, 48], no patient has reportedly died from or suffered recurrence of this neoplasm, leading some to propose that CCPRCC be renamed "clear cell papillary neoplasm of low malignant potential"[46].
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Journal Pre-proof Malignant renal epithelial neoplasms
Clear cell renal cell carcinoma It is difficult to summarize succinctly or adequately the advances that have been made in the past 50 years with respect to the knowledge we have gained concerning this cancer, the most common form of renal cell carcinoma. The literature in this field is diverse and voluminous, and
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the reader is referred to the previously mentioned historical papers, review articles and standard
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textbooks for specific information. From a broad perspective, it should be borne in mind that at
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least until the mid-1970s it was unclear whether renal epithelial tumors should be subclassified at all. As previously noted, Dr. Lauren Ackerman had observed in his 1953 textbook that renal
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adenocarcinoma has ‘various patterns . . . granular . . . clear . . . papillary...’ It was his opinion
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that ‘it does not appear logical to make subdivisions in nomenclature; better to call it simply an
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adenocarcinoma of renal tubule origin’; his opinion had not changed by the time the 1964 version of his textbook appeared. As previously noted, in the second AFIP fascicle, published in
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1975, all renal tubular epithelial neoplasms were characterized as adenocarcinoma, reflecting the
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authors’ opinion that adenomas simply represented early carcinomas. Remarkably, in 1976, two landmark publications established that relatively common tumors - specifically, oncocytoma and papillary renal cell carcinoma, could be classified separately from the general category of "renal adenocarcinoma"[11, 49]. Since that time, a number of other renal tumors have been shown to be distinct from clear cell renal cell carcinoma (ccRCC), most notably the conventional variant of chromophobe carcinoma, clear cell papillary renal cell carcinoma, and some forms of translocation carcinoma, as will be discussed later. Reports by numerous investigators have established that more than 90% of cases of ccRCC have characteristic cytogenetic abnormalities
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Journal Pre-proof that involve loss of genetic material from the short arm of chromosome 3 (3p) and mutations in the VHL gene. In the mid-1980s, several studies established that ccRCC is characterized by loss of chromosome 3p sequences [50-53]. In the early 1990s, investigators discovered and clarified the relationship between ccRCC and alterations in the von Hippel-Lindau disease tumor suppressor gene, and presented evidence that the gene causing von Hippel-Lindau disease has an important and specific role in the etiology of sporadic renal cell carcinomas [54-56]. The
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identification of distinctive karyotypic alterations in papillary carcinoma in 1991 reinforced the
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distinction of the two most common types of renal cell carcinoma [20]. Because ccRCC and
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papillary renal cell carcinoma collectively account for the great majority of renal cell
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carcinomas, with the largest outcome databases, data for these types of renal cancer have been used traditionally to develop valid grading and staging systems for renal carcinoma. Grading and
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staging will be discussed separately in this review.
Papillary renal cell carcinoma
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In 1976, the notion of subclassifying renal tumors based at least partly on architectural
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appearance was introduced by the publication of an article describing "papillary renal cell carcinoma" [49]. The distinction between clear cell carcinoma and papillary carcinoma was further reinforced by cytogenetic studies reported in 1991, documenting specific karyotypic changes in papillary renal tumors that were different from those that had been previously identified in clear cell renal cell carcinoma [20]. Papillary renal cell carcinoma (PRCC) is the second most common type of renal cell carcinoma, accounting for up to 18.5% of all renal epithelial neoplasms [57]. The great majority of cases occur sporadically, but some develop in members of families with hereditary PRCC, an
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Journal Pre-proof inherited renal cancer characterized by mutations in the MET oncogene at 7q31 and by a predisposition to develop multiple bilateral papillary renal tumors [58]. When multiple papillary tumors are found in patients without a family history of renal tumors, each papillary tumor arises independently; multifocality is not the result of intrarenal metastasis [59]. In patients with hereditary papillary renal cancer, it has been estimated that each kidney may harbor as many as 3400 separate microscopic papillary tumors [60].
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As experience with PRCC grew, it was increasingly recognized that there is a good deal
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of morphologic heterogeneity in histologic grade and cytoplasmic quality (eosinophilic or
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basophilic) in renal cancers with papillary architecture [61]. Based on studies of morphology,
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immunohistochemical staining, growth kinetics, clinicopathologic staging parameters and patient survival data, it was proposed that PRCC could be subclassified into two morphologic variants,
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which were designated types 1 and 2 (PRCC1 and PRCC2) [62].
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The practicality of subtyping PRCC was noted by some investigators to be complicated by the fact that a clear-cut distinction is difficult in some cases; specifically, although various
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series of cases included readily categorized PRCC1 and PRCC2 cases, significant proportions of
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cases were difficult to categorize precisely on the basis of their morphology, molecular profiles and/or immunoprofiles [63-65]. Specifically, some papillary tumors exhibit nuclear features typical of PRCC1 but cytoplasmic features typical of PRCC2, and some are composed of mixtures of cells of generally low nuclear grade but with substantial variations in cytoplasmic characteristics. In short, it seems that up to 47% of PRCC cases do not meet the well-accepted histologic criteria for either PRCC1 or PRCC2, and such tumors have been variously designated "mixed, unclassified, overlapping or not otherwise specified (NOS)" [64, 65].
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Journal Pre-proof Furthermore, an oncocytic low grade variant of PRCC has been identified, composed predominantly of tumor cells with oncocytic cytoplasm and round, non-overlapping low-grade nuclei with inconspicuous nucleoli, and a linear arrangement toward cell apices. [Fig. 04] These tumors resemble PRCC1 molecularly, with similar gains of chromosomes 7 and 17, and clinically, exhibiting indolent behavior, and a good prognosis [66, 67]. More recently, these tumors were redefined as a distinct subset of papillary renal neoplasm with reversed polarity.[68]
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Immunohistochemically, they are positive for GATA3 and cytokeratin 7 with variable AMACR
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stainings. KRAS mutations are present in the majority of these tumors.
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Alternative classifications and suggested classifications of PRCC have been published
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recently. Based on comprehensive molecular characterization of 161 PRCCs, the Cancer Genome Atlas Research Network showed that PRCC1 and PRCC2 are different types of renal
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cancer. PRCC1 is associated with MET alterations. Multiple molecular clusters were described
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within the PRCC2 group. PRCC2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-anti-oxidant response element
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(ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct
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subgroup of type 2 papillary renal cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase [69]. Even taking into consideration the fact that the TCGA study included tumors that were not conventional PRCCs (specifically, translocation carcinomas and fumarate-hydratase-deficient carcinomas were included in the study and the report), it seems clear that PRCC2, rather than being homogeneous, represents a heterogeneous group of tumors that require further study. A recent study employing several immunohistochemical stains (CA9, GATA3, and ABCC2), miRNA expression and copy number variation analysis, provided evidence in support
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Journal Pre-proof of subclassifying PRCC into 4 subtypes, designated PRCC1, PRCC2 and two new subtypes PRCC3 and PRCC4/OLG (the latter representing the oncocytic low grade variant of PRCC noted above). PRCC1, PRCC2 and PRCC3 each have unique staining signatures. The different PRCC subtypes had different clinical characteristics, providing additional support for the proposed subclassification [64]. Taken as a whole, it seems that the process of proper subclassification of papillary renal
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cell carcinoma is continually evolving, and there is more to be learned in future studies.
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Hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma
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Initial reports of this tumor appeared in 2001 [70, 71]. Rare cases of an aggressive renal carcinoma occur in the setting of an autosomal dominant tumor syndrome associated with germline
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mutations in the fumarate hydratase gene at chromosome 1q42; this syndrome is known as the
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hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome [71]. Patients with this syndrome typically develop cutaneous leiomyomas [Fig. 05 A and B] and females also develop
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uterine leiomyomas. The syndrome is also characterized by a predisposition to developing renal
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cell carcinoma, and less frequently, uterine leiomyosarcoma [70-73]. Approximately one third of patients with the syndrome develop renal cell carcinoma. [Fig. 05 C and D] Germline mutations of the fumarate hydratase (FH) gene at chromosome 1q42 is the underlying genetic abnormality. Biallelic inactivation of the fumarate hydratase (FH) gene in FHmutated cells results in accumulation of fumarate, which reacts spontaneously, via protein succination, with the cysteine sulfhydryl group of proteins to form S-2(2-succino)-cysteine (2SC). These accumulations modulate the activity of various transcription factors, notably HIF1a, NRF2, and AMPK, resulting in increased proliferation and resistance to apoptosis [74-76].
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Journal Pre-proof All confirmed HLRCC tumors demonstrate diffuse and strong nuclear and cytoplasmic 2SC immunostaining, a finding not present in a wide range of other renal carcinoma types. In addition, positive nuclear and cytoplasmic 2SC staining correlate well with the presence of FH germline mutation. Somatic inactivation of the remaining FH allele is found in HLRCC renal cancers, consistent with the role of FH as a tumor-suppressor gene. Its loss of function in the tumor cells corresponds to strong 2SC staining, whereas adjacent renal parenchyma maintains a wild-type
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allele and does not show 2SC immunoreactivity [74].
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Following reports of loss of FH immunostaining in HLRCC associated tumors, a study was
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conducted to ascertain the status of 2SC and FH immunostaining in a large number of high grade
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unclassified RCCs, unclassified RCCs with papillary pattern, and type 2 papillary RCCs [77]. One fifth of renal cancers initially diagnosed as "unclassified RCC, high grade" or "unclassified RCC
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with papillary pattern" were found to have deficient FH immunostaining, almost invariably
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accompanied by FH mutations as well as strong 2SC immunoreactivity. A small minority (0.5%) of tumors previously diagnosed as papillary RCC, and 3% of tumors previously diagnosed as type
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2 papillary RCC showed FH deficiency by immunostaining and FH mutations [77]. Evaluation of
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both FH and 2SC immunostaining status seems warranted in cases exhibiting the morphologic and clinical features noted above.
HLRCC-RCC is a lethal disease with rapid aggressive growth and early metastasis even when the tumor is small [72]. The majority of patients present with advanced stage disease and succumb to their cancers. Consequently, recognition of the characteristic features of this tumor are important not only in managing the affected patient, but in counselling and follow-up of family members. Aggressive excision of even small tumors in syndromic patients is warranted.
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Journal Pre-proof Chromophobe renal cell carcinoma In 1955, Dr. Pierre Masson, then working in Montreal, Quebec, published a surgical pathology textbook, written in French. The English translation of the book was published in 1970 [78]. It is essentially an atlas describing various tumors that he had encountered in his practice, accompanied by short dissertations about these tumors. The illustrations are hand-drawn by an artist named Constantin, and Dr. Masson laments that, to his intense regret, Constantin's early
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death forced him to replace the drawings with photomicrographs, which he considered a poor
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substitute. The section on renal tumors is rather fascinating in the context of our review. Dr.
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Masson provided four illustrations, labeled 5.21 through 5.24. Astute readers are invited to
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"diagnose" these tumors as they see fit. Nonetheless, Figure 5.21, which Dr. Masson labeled "True" hypernephroma, or better, oncocytoma, bears several striking resemblances to
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chromophobe renal cell carcinoma - specifically, it exhibits a tumor with prominent sharply
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demarcated cell membranes and abundant cytoplasm (which Masson described as "finely granular and vacuolated, very acidophilic"). Dr. Masson observed that "the nuclei are relatively
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small and very chromophilic".) On close inspection, a number of these small dark irregular
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nuclei have distinct perinuclear halos. He observed that the tumor is "traversed by scattered capillaries, sometimes with a thick wall, sometimes provided with a hyaline collagen sheath". He specified that "It only contains traces of fat and glycogen." It is interesting to note that, by the nomenclature he applied, even Dr. Masson found the precise nature of the tumor somewhat enigmatic. We speculate that this may have been the first published illustration of chromophobe renal cell carcinoma. [Fig. 06] Chromophobe cells were described in 1974, in chemically-induced renal tumors in rats [79]. Chromophobe renal cell carcinoma was first reported in 1985; its name was derived from
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Journal Pre-proof the morphologic similarity between the predominant tumor cells in the human tumor to those comprising the experimentally-produced rat kidney tumor [13]. Following the initial description of the typical form of this tumor in 1985, an eosinophilic variant was described in 1988 [14]. Genomic studies indicate that chromophobe renal cell carcinoma arises from cells of the distal nephron [80]. Most cases arise sporadically. Some are associated with a germline mutation of FLCN in the autosomal-dominant cancer predisposition Birt-Hogg-Dube syndrome,
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characterized by hair follicle fibrofolliculomas, (mainly on the face and neck), and a
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predisposition to develop bilateral multifocal renal tumors as well as pulmonary cysts that can
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give rise to spontaneous pneumothorax [81]. Chromophobe renal cell carcinoma comprises
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approximately 34% of the renal neoplasms that occur in patients with this syndrome; other tumors in such patients are oncocytoma (7%), ccRCC (9%), and tumors with features that
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resemble a mixture of oncocytoma and chromophobe carcinoma (50%). Another hereditary
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predisposition to development of chromophobe renal cell carcinoma results from a germline mutation of PTEN in Cowden syndrome [82]. Chromophobe renal cell carcinoma accounts for
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4.9% of surgically excised renal epithelial neoplasms. It has been shown conclusively by multi-
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platform genomic analyses to be a disease entity that is distinct from clear cell renal cell carcinoma, sharing little cell lineage or genomic characteristics with that cancer [80]. The genetic abnormality most consistently observed in chromophobe renal cell carcinoma has been loss of one copy of the entire chromosome for most or all of the chromosomes 1, 2, 6, 10, 13, 17 and 21 (in 86% of cases), as well as losses of various other chromosomes (at frequencies varying from 12-58% of cases) [80, 83]. About half of cases of the eosinophilic variant of chromophobe renal cell carcinoma do not share the same chromosomal abnormalities as the classic type, and indeed a few of such cases show no copy number alterations at all,
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Journal Pre-proof suggesting a degree of genomic heterogeneity that distinguishes the histopathology-based classifications [80]. About half of cases of the eosinophilic variant of chromophobe renal cell carcinoma do not share the same chromosomal abnormalities as the classic type, and indeed a few of such cases show no copy number alterations at all, suggesting a degree of genomic heterogeneity that distinguishes the histopathology-based classifications [80]. The International Society of Urologic Pathologists has recommended that chromophobe
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renal cell carcinoma should not be graded [84].
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Collecting duct carcinoma
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The notion that renal carcinoma could originate in collecting duct epithelium was initially proposed in two case reports, one published in 1979 [85], and the other in 1982 [86]. Upon
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review, the 1979 case does not fit well as a case of collecting duct carcinoma. Remarkably, upon
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review, the 1982 case describes clinical and morphologic features that can be considered classic for renal medullary carcinoma, and we will return to that case later.
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The first formal and well accepted description of collecting duct carcinoma was
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published in 1986 [87]. This neoplasm arises in the principal cells of the collecting ducts of Bellini. It accounts for less than 1% of renal malignancies. It is a highly aggressive renal carcinoma with a poor prognosis. A diagnosis of collecting duct carcinoma is challenging. It is notable that recent experience with aggressive high grade renal cancers has shown that as many as 25% of cancers previously diagnosed as collecting duct carcinoma are in fact examples of fumarate hydratasedeficient renal cell carcinomas (FH-deficient RCCs) [88]. These tumors are addressed more fully in the section on hereditary leiomyomatosis and renal cell carcinoma-associated renal cell
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Journal Pre-proof carcinoma. A diagnosis of collecting duct carcinoma is most confidently rendered after exclusion of metastatic adenocarcinoma, urothelial carcinoma of the pelvicalyceal system, renal medullary carcinoma and FH-deficient renal cell carcinoma. Descriptions of the process of working through these differential difficulties are available in the literature. The reported molecular changes in collecting duct carcinoma are markedly variable and limited, and no distinctive molecular mechanism or pathway has been proposed for collecting
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duct carcinoma [89].
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Renal medullary carcinoma
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Earlier we alluded to a report in 1982 of a patient with a renal cancer that was thought possibly to have arisen in collecting duct epithelium [86]. The patient was a 22 year old black
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man with a 4 cm mass in the mid portion of the right kidney. He underwent right nephrectomy.
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His tumor exhibited unusual morphology, and was seen in consultation by a number of consultants, including a very highly respected genitourinary pathologist at the AFIP, who
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proferred a diagnosis of "poorly differentiated carcinoma with papillary and glandular features
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and with extension to perinephric fat. Carcinoma of the duct of Bellini?" Despite aggressive treatment, the patient deteriorated rapidly, developed widespread metastases, and died less than 3 months after his nephrectomy. The photomicrographs provided in the paper are entirely consistent with renal medullary carcinoma, and we speculate that this may have been the first published case of renal medullary carcinoma, based on the constellation of clinical and pathologic findings. It is of interest that the case was seen in consultation by one of the coauthors of the landmark paper on this renal tumor, published in 1995 [90].
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Journal Pre-proof In 1995, physicians at the Armed Forces Institute of Pathology published their findings related to a newly recognized renal cancer that they named renal medullary carcinoma [90]. They provided details of renal cancers from 34 patients that they had seen in the previous 22 years. Renal medullary carcinoma (RMC) is an uncommon highly aggressive renal malignancy. It is believed to arise in the terminal collecting ducts and their adjacent papillary epithelium. Its occurrence is very strongly associated with sickle cell hemoglobinopathies, so it has been
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postulated that the above-noted epithelium suffers chronic ischemic damage related to sickling
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erythrocytes, and that RMC originates in a setting of chronic regenerative proliferation of this
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damaged epithelium [90].
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Most reported patients with RMC are in their second and third decades of life, with an age range of 5 to 58 years of age and a mean age at diagnosis of approximately 20 years. The
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male-to-female ratio is at least 2:1, and for reasons that are enigmatic, about 75% of tumors
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occur on the right and 25% occur on the left [90]. The patients are most commonly of African ancestry, but individuals of Central and South American and Mediterranean ancestry are also at
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risk for RMC. In reported cases in which sickle cell status was known, 87% had sickle cell trait
07]
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(HbAS), 9% had hemoglobin SC disease (HbSC), and 4% had sickle cell disease (HbSS). [Fig.
Loss of expression of SMARCB1 (INI1), a nuclear transcription regulator encoded on chromosome 22, is a feature of renal medullary carcinoma [88]. This is due to loss of heterozygosity or hemizygous deletions at the SMARCB1 locus, and in rare instances, loss of chromosome 22 [91]. In one study, inactivation of the SMARCB1 gene was shown to be due to interchromosomal balanced translocations [92]. In the same study, whole exome sequencing
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Journal Pre-proof showed that RMC has no other recurrent genetic alterations and an overall stable genome, underscoring the oncogenic potency of SMARCB1 inactivation [92]. Some investigators have adopted the stance that loss of SMARCB1 immunostaining and documentation of hemoglobinopathy by history and/or appropriate laboratory studies and evidence of diffuse sickling within the tumor stroma and blood vessels are necessary criteria in making a diagnosis of RMC [88]. The rare tumors that exhibit RMC-like histology, SMARCB1-
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deficient immunophenotype, and aggressive clinical features but arising in patients in whom
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sickle cell trait or disease has been rigorously excluded, are designated as renal cell carcinoma,
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unclassified, with medullary phenotype [7, 88].
MiT family translocation renal cell carcinoma
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In the early to mid-1990s, there were a number of reports of renal adenocarcinomas in
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children and adults in which translocations involving the short arm of the X chromosome were identified [93-95]. These reports stimulated an extraordinary expansion of our knowledge
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regarding renal carcinomas defined by specific translocations.
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Tumors in this class of renal cell carcinomas are characterized by gene fusions involving TFE3 or TFEB, two members of the MiT family of transcription factors [93, 94]. Translocation renal cell carcinomas (TRCCs) that are associated with Xp11 translocations harbor gene fusions involving TFE3, and those with t(6;11) translocation harbor a MALAT1-TFEB gene fusion. The t(6;11) TRCCs are less common than Xp11 TRCCs. Renal carcinoma accounts for less than 5% of pediatric renal neoplasms. Half or more of pediatric renal cell carcinomas are translocation renal cell carcinomas [96]. Translocation carcinoma accounts for between 1 and 4% of adult renal cell carcinomas [97].
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Journal Pre-proof Xp11 TRCCs are defined by a variety of chromosome translocations, all of which involve a breakpoint at Xp11.2, and all of which result in the fusion of any one of multiple translocation partners with the TFE3 transcription factor gene at this locus, triggering oncogenic activation of the TFE3 transcription factor [93, 94]. Known TFE3 fusion partners include ASPSCR1 (ASPL), PRCC, SFPQ1 (PSF), NONO, CLTC, PARP14, LUC7L3, DVL2, and KHSRP [98]. Of these, the most common are the ASPSCR1-TFE3 (also known as ASPL-TFE3) TRCC that results from a
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t(X;17)(p11;q25) translocation [99], and the PRCC-TFE3 TRCC, resulting from a
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t(X;1)(p11;q21) translocation [100]. [Fig. 08A]
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Although the majority of patients with TRCC are less than 50 years old, patients up to 79
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years of age have been reported [101]. Translocation carcinoma occurs with approximately equal
prior chemotherapy treatment [102].
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frequency in males and females, and in some patients its development has been associated with
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Only about 50 cases of t(6;11) TRCC have been reported. It is characterized by a t(6,11)(p21;q12) translocation that results in fusion of the 5ʹ portion of the Alpha gene with the
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transcription factor gene TFEB at 6p21[103]. [Fig. 08B]
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TFE3 rearranged tumors involve the Xp11.2 gene locus and fall into one of three general categories: Xp11 PEComas [Fig. 08C], Xp11 RCCs, and melanocytic Xp11 RCCs [104-106]. [Fig. 08D] The number of patients with documented followup after treatment for the various types of translocation carcinoma is limited [107, 108]. Regarding TFE3 TRCCs, there are notable clinical differences between PRCC-TFE3 TRCC and ASPSCR1-TFE3 TRCC [108]. TFE3 TRCC patients who present with distant metastases usually have ASPSCR1-TFE3 TRCC, and usually die of cancer or exhibit disease progression. More than two-thirds of ASPSCR1-TFE3 TRCCs
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Journal Pre-proof have metastatic cancer in regional lymph nodes; despite this, in the absence of concurrent distant metastases, the great majority of these patients achieve long-term freedom from disease. Only about a third of PRCC-TFE3 TRCCs have positive nodes at presentation. However, PRCC-TFE3 TRCC occasionally recurs as late as 20-30 years after surgery, requiring long-term follow-up [108]. The specific type of TFE3 TRCC appears to have no significant impact on outcome; only older age or advanced stage at presentation are predictive of death from cancer [108]. Overall,
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cancer-specific survival for patients with TFE3-rearranged renal cell carcinoma is similar to the
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survival of patients with conventional ccRCC, but worse than the survival of patients with
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papillary RCC.
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The t(6;11) TRCCs are generally confined within an intact pseudocapsule and usually present at stage pT1 or pT2. Of about 50 reported t(6;11) TRCCs, 11 patients were known to
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have metastatic cancer and of these, 4 were known to have died [107].
Succinic dehydrogenase-deficient renal cell carcinoma
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A subset of tumors occur in the setting of germline mutations of SDHA, SDHB, SDHC,
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SDHD and SDHAF2. These include pheochromocytomas/paragangliomas, gastrointestinal stromal tumors (GISTs), renal cell carcinomas, and pituitary adenomas. Tumors associated with germline mutations of SDHB, SDHC, SDHD and SDHAF2 show loss of immunostaining for SDHB, but retain positive staining for SDHA, whereas tumors associated with SDHA mutation show loss of immunostaining for SDHB, but also show loss of staining for SDHA. In 2010, a morphologically unique renal tumor occurring in a patient with a germ-line mutation and somatic loss of the wildtype SDHB allele was reported [109]. [Fig. 09] In 2011, it was reported that renal carcinomas related to SDH mutation could be identified by loss of immunohistochemical (IHC) staining for
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Journal Pre-proof SDHB [110], and later that year it was reported that SDH-deficient renal cell carcinomas had distinctive morphologic features that could prompt IHC staining for SDHB, with the premise that loss of staining could prompt definitive genetic testing [111]. In recent years, more than 60 renal neoplasms arising in the setting of germline SDH mutation have been reported, with mutation frequencies approximately as follows: SDHB - 81%; SDHC - 9%; SDHD - 5%; SDHA - 5% [110]. The molecular abnormality that defines SDH-deficient renal cell carcinomas is double-hit
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inactivation of one of the SDH genes, and this is an event that occurs only rarely, if ever, in the
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absence of a germline mutation [110]. With this in mind, all patients with SDH-deficient renal cell
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carcinoma should be offered genetic testing, and surveillance for other SDH-deficient neoplasms
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(e.g., paraganglioma, pituitary adenoma, SDH-deficient gastrointestinal stromal tumor) should be initiated.
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SDH-deficient renal cell carcinoma is estimated to account for about 0.05% to 0.2% of
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renal neoplasms [110].
Patients whose SDH-deficient renal cell carcinomas are uniformly low grade and lack
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coagulative necrosis have about a 90% likelihood of a good outcome. Tumors that exhibit
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coagulative necrosis, grade 3 nucleoli or sarcomatoid change have a guarded prognosis, with metastasis in up to 70% of cases [110].
Tubulocystic renal cell carcinoma The morphologic features of a single example of this rare distinctive renal neoplasm were described in 1955 by Dr. Pierre Masson in his textbook, Tumeurs Humaines. He designated the lesion “Bellinian epithelioma”, because he regarded it as a neoplasm originating in the collecting ducts of Bellini [78]. [Fig. 10] In his capacity as a world-renowned consultant at Mayo Clinic
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Journal Pre-proof over a period of more than 30 years, Dr. George Farrow collected 13 rather unusual renal tumors, from Mayo Clinic surgical files and referred consultation cases. [Fig. 11] Of these 13 tumors, in hindsight, 8 were tubulocystic carcinomas, and 5 were mucinous tubular and spindle cell carcinomas. Of course, by the mid to late 1990s, neither of these entities had been defined, and so Dr. Farrow regarded them as tumors belonging to a spectrum of "low grade collecting duct carcinomas". Dr. Farrow included 8 tumors from his collection in a poster presented at a meeting
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of the USCAP in 1994 [112]. The precise mix is unknown at this point. He included illustrations
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of the gross and microscopic appearance of one or more of the tubulocystic carcinomas in the
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AFIP Atlas of Tumor Pathology, Series III, in 1994, under the rubric "renal cell carcinoma,
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collecting duct type" [113]. [Fig. 12 and Fig. 13] An expanded series of cases was presented at a USCAP meeting in 1996, but regrettably that series included 3 conventional high grade
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collecting duct carcinomas [114]. The first detailed report of the clinical and pathological details
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of Dr. Farrow’s cases (excluding the 3 high grade collecting duct carcinomas) was published in 1997 [115]. Although the neoplasms were clearly unlike any type of renal tumor that had
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previously been described in peer-reviewed publications, it was unclear at that point what name
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they should be given. Because these tumors were entirely composed of tubules and duct-like structures, showed areas of hobnail change, and had immunohistochemical characteristics similar to classic collecting duct carcinoma (ie., immunopositivity for 34βE12 and UEA-1), it was hypothesized that they were of collecting duct origin, and that they represented the low grade end of a spectrum of findings in collecting duct carcinoma; hence they were named "low grade collecting duct carcinoma". [Fig. 14] It was emphasized that although the neoplasm had some features suggestive of collecting duct origin, it was distinctly different from classic collecting duct carcinoma in many ways.
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Journal Pre-proof Following the publication of the paper on low grade collecting duct carcinoma in 1997, there was a good deal of interest in collecting and analyzing more of such cases. By 2004, 29 cases had been assembled, including Dr. Farrow's original 8 cases and 21 additional cases, and these were presented at a USCAP meeting under the new name of "tubulocystic carcinoma" [116]. That is the name that has endured. Gene expression profiling demonstrates that the molecular signature of tubulocystic
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carcinoma is distinct from those of papillary, clear cell and chromophobe carcinomas [117].
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Tubulocystic carcinoma and collecting duct carcinoma are unrelated from a molecular
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perspective [118].
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The diagnosis of tubulocystic renal cell carcinoma should be restricted to tumors with the classic histologic features [119]. [103][Fig. 15] Cases of tubulocystic carcinoma with purely
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classic morphology are distinctive and lack the full spectrum of genetic and
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immunohistochemical features that are classically seen in papillary renal cell carcinoma [120]. Cases with extensive papillary architecture, or with areas of poorly differentiated solid and
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papillary elements, or resembling t(6,11) translocation renal cell carcinoma should not be
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diagnosed as tubulocystic carcinoma.
Mucinous tubular and spindle cell carcinoma As recounted in the section on tubulocystic carcinoma, Dr. George Farrow had collected five examples of this tumor by the mid-1990s. In 1997, the clinical and pathologic features of these tumors, along with 8 cases of tubulocystic carcinoma, were reported for the first time in peer-reviewed literature under the name of "low grade collecting duct carcinoma". [Fig. 16] Four similar cases were reported in 2001, described as "low grade myxoid renal epithelial neoplasms"
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Journal Pre-proof [121], and five more patients with similar tumors in 2002 as "low-grade tubular-mucinous renal neoplasms" [122]. It was recognized as a distinctive new renal neoplasm in the 2004 WHO Blue Book under the name "mucinous tubular and spindle cell carcinoma" [123]. [103][Fig. 17] The senior author of the 2001 article [121] reviewed selected slides from Dr. Farrow's "low grade collecting duct" cases and confirmed that "the five cases are identical to the mucinous tubular and spindled renal tumor which will be included in the upcoming WHO renal tumor
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classification" (personal communication, Dr. Pedram Argani to Dr. GTM).
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Despite morphologic similarities to papillary renal cell carcinoma in some cases, the
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gains of chromosomes 7 and 17 and loss of Y chromosome that are characteristic of papillary
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RCC are not seen in mucinous tubular and spindle cell carcinoma [124]. Alterations in the Hippo pathway are present in mucinous tubular and spindle cell carcinoma but are not seen in papillary
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renal cell carcinoma [125]. Cytogenetic analyses and comparative genomic hybridization studies
15, 18 and 22 [126].
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have revealed multiple genetic alterations that include losses of chromosome 1, 4, 6, 8, 9, 13, 14,
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These tumors are generally of low pathologic stage at the time of excision, and most
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tumors with classic histologic findings behave in an indolent fashion. However, high nuclear grade and sarcomatoid change in isolated cases have been associated with fatal outcomes [127].
Acquired cystic disease-associated renal cell carcinoma The incidence of acquired cystic kidney disease (ACKD) in the dialysis population is proportional to dialysis interval, with close to 100% of patients affected by 10 years of dialysis. Patients with ACKD are especially prone to the development of carcinoma, with an incidence of 3–7% and a risk that increases with the duration of dialysis, approaching 100 times that of the
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Journal Pre-proof general population [38]. The biological basis for increased renal carcinogenesis in ESRD is undefined. Depressed immunity, excessive free radical production related to inflammation, impaired antioxidant defenses and deposition of oxalate crystals have been postulated. The renal cell carcinomas that arise most commonly in a setting of ACKD are, in descending order of frequency, acquired cystic disease-associated renal cell carcinoma (ACDRCC) (36%), clear cell papillary renal cell carcinoma (23%), clear cell renal cell carcinoma
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(18%), papillary renal cell carcinoma (15%), and chromophobe renal cell carcinoma (5%) [38].
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Of these tumors, only ACD-RCC, by definition, occurs only in patients with ACKD.
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About 80% of ACD-RCC specimens show abundant intratumoral calcium oxalate
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crystals within luminal structures and in the stroma [128]. Intratumoral calcium oxalate deposition is a feature that appears to be restricted to tumors arising in a background of ACKD.
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[Fig. 187]
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The earliest report of renal cell carcinoma with abundant oxalate crystals appeared in 1998 [129]. The characteristics of ACD-RCC were subsequently described more fully in large
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series of cases in 2005 and 2006 [38, 130].
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Studies indicate that ACD-RCC arises from cells of the proximal nephron [131]. Gains in chromosomes 3, 7, 16, 17 and the sex chromosomes are noted with high frequency in ACD-RCC [128, 132]. The prognosis for acquired cystic disease-associated renal cell carcinoma is generally favorable, since it tends to have an indolent behavior, and constant medical surveillance of dialysis patients facilitates diagnosis at an early stage. However, when sarcomatoid or rhabdoid morphology is identified, it often portends a poor outcome [38, 133].
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Journal Pre-proof
Emerging and/or provisional renal epithelial neoplasms
Oncocytic renal cell carcinoma occurring after neuroblastoma More than 30 cases of renal cell carcinoma arising in children who survived neuroblastoma in childhood have been reported in the past 40 years [134, 135]. Although the
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great majority were exposed to chemotherapy and/or radiation therapy, at least two never had
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either exposure, raising the possibility that the etiology of such cancers may lie in an underlying
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genetic relationship or susceptibility. Tumors arising in this clinical setting have included
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conventional carcinomas, such as clear cell RCC, papillary RCC, MiT family RCC, and SDHBdeficient RCC, as well as an enigmatic subset of tumors with prominent oncocytoid cytoplasm,
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that has been designated oncocytic RCC post-neuroblastoma (ORCC-PNB). [Fig. 19]This subset
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is included in the category of emerging/provisional renal cell carcinomas [135-137]. The interval between a diagnosis of neuroblastoma and of ORCC-PNB ranges from 3 to 38 years, and age at
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diagnosis of ORCC-PNB ranges from 8 to 40 years. Further studies of more cases of these
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tumors is needed to clarify whether they represent a distinct entity with unique molecular abnormalities [135].
Thyroid-like follicular carcinoma of the kidney The first reports of a primary renal neoplasm bearing a striking resemblance to follicular carcinoma of the thyroid appeared in 2006 and 2009 [138, 139]. [Fig. 20] To date, 39 cases have been reported. Despite exhibiting some striking resemblances to thyroid tissue or thyroid neoplasia, no history of thyroid cancer has been noted previously, concurrently or subsequently,
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Journal Pre-proof and immunostains that are typically positive in thyroid tissue are negative in these tumors. Additional study of these tumors is needed for more definitive classification [140].
ALK rearrangement-associated renal cell carcinoma There are recent reports of fewer than 20 cases of renal cell carcinomas characterized by translocations resulting in fusion of a variety of genes with the anaplastic lymphoma kinase
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(ALK) gene, occurring in children with sickle cell trait and adults without sickle cell trait [141,
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142]. Further studies of more cases of these tumors is needed to clarify whether they represent a
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distinct entity with unique molecular abnormalities. Detection of the ALK rearrangement can be
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of critical importance in the management of a patient with metastatic cancer.
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Eosinophilic solid and cystic renal cell carcinoma
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Eosinophilic solid and cystic renal cell carcinoma was initially identified in patients with tuberous sclerosis complex [143, 144]. The earliest reported patients were all females with a
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mean age of about 55 years, but in a more recently reported series of cases, this tumor has been
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identified in males as well as females, and in younger patients as well [145-148]. The tumors are arranged in solid nests or sheets, always with interspersed aggregates of lymphoctes and histiocytes, and psammoma bodies [Fig. 21]. All tumors harbor variably sized macrocysts and microcysts; cells lining the cysts often exhibit a prominent hobnail appearance. Tumors are composed of cells with voluminous eosinophilic cytoplasm and round to oval nuclei, with focally prominent nucleoli. Immunohistochemically, tumor cells are always PAX-8 and CK8/18 positive. The majority of these tumors have a CK20-positive/CK7 negative phenotype.
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Journal Pre-proof Renal cell carcinoma with angioleiomyoma-like stroma The first report of a renal neoplasm that appeared to have an epithelial component intimately admixed with smooth muscle appeared in 2000 [149]. Since then a number of additional studies of tumors exhibiting clear cell cytologic features and angioleiomyoma or leiomyoma-like stromal smooth muscle proliferation have appeared [150-153]. [Fig. 22] They lack chromosome 3 and VHL alterations, and are considered to be distinct from conventional
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precise nature of these tumors remains under investigation.
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clear cell renal cell carcinoma. They do not exhibit trisomies of chromosomes 7 or 17. The
Grading renal cell carcinoma
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"Grading is notoriously difficult to perform reproductively and depends heavily on
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experience and understanding of the criteria of the categories. The latter problem often means it is easier to invent one's own classification than to abide by another's."
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- Donald Skinner, MD, 1971
So stated Dr. Donald Skinner, a famous and influential genitourinary surgeon of his era [154]. Attempts to quantify the "degree of malignancy" in renal cancers, and ascertain its influence on prognosis, began in earnest in 1932 [155]. Cancer grading based on assessment of nuclear features was proposed initially in 1968 [156]. It has been well documented since then that nuclear features of renal cancers are of critical importance in predicting outcome [2, 57, 84]. Several grading systems that have been proposed in the past 50 years have fallen into disuse because they lacked sufficient validation or applicability to the currently accepted classification
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Journal Pre-proof of renal cell carcinomas. In an ideal grading system, significant outcome differences should be demonstrable between patients with different tumor grades, both univariately and after adjusting for important clinical and pathologic features. Until recently, the most widely used grading system was one proposed in 1982 by Fuhrman et al [157]. The validation, reproducibility and interpretation of the Fuhrman system drew substantial criticism [158, 159]. Consequently, the four-tiered WHO/International Society of Urologic Pathology (ISUP) grading system has been
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recommended for use in grading clear cell renal cell carcinoma and papillary renal cell
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carcinoma, cancers for which there is sufficient outcome data to allow the system to be used for
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predicting prognosis [84]. Grades 1-3 are defined by nucleolar prominence. Pronounced nuclear
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pleomorphism, tumor giant cells, and/or rhabdoid and/or sarcomatoid change are features of grade 4 tumors. Grade is assigned on the basis of these criteria within the single high-power field
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showing the highest nucleolar grade or greatest degree of nuclear pleomorphism. The
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WHO/ISUP grading system is not applicable for predicting outcome for renal cell cancers other than clear cell renal cell carcinoma and papillary renal cell carcinoma, due to a current paucity of
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outcome data for those tumors.
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Analysis of the utility of the WHO/ISUP system continues. One group of investigators did not find a statistically significant difference in outcome between patients with ISUP grade 1/2 and ISUP grade 3 tumors, perhaps, in part, because their data set did not include cases of multilocular cystic renal neoplasm of low malignant potential or cases of clear cell papillary RCC [160]. In contrast, others have found clear separation of cancer-free survival curves between the four grades of the WHO/ISUP system, and once again found evidence of its superiority over the now-abandoned Fuhrman grading system [161].
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Journal Pre-proof There has been some interest in further refining the accepted WHO/ISUP grading system by amalgamating defined grades with the presence or absence of tumor necrosis (defined as "homogeneous clusters and sheets of dead cells, or coalescing groups of cells forming a coagulum, containing nuclear and cytoplasmic debris"). Results of several studies have furnished evidence that combining these parameters for cases of clear cell RCC provides additional prognostic information as compared to use of only the WHO/ISUP nucleolar grade [158, 160,
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162].
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Staging renal cell carcinoma
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Tumor stage reflects the extent of anatomic spread and involvement of disease and is considered to be one of the most important factors in predicting the clinical behavior and
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outcome of renal cell carcinoma [57, 163]. Staging systems for renal cell carcinoma have been in
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use for nearly 50 years, and have been continually updated and improved. Since undergoing simplifications and refinements in 1992, the Tumor, Nodes, and Metastasis (TNM) staging
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system has become the predominant staging system for renal cell carcinoma. In 2017, the 8th
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edition of the AJCC Cancer Staging Manual was published [164]. Staging parameters for carcinomas arising in the kidney are provided, and definitions for Primary Tumor (T), Regional Lymph Nodes (N), and Distant Metastasis (M) are given. T1 and T2 tumors are localized to the kidney, and are defined by their greatest dimensions. T1 tumors are ≤ 7 cm, and are subclassified as T1a (≤ 4 cm) or T1b (> 4 cm but ≤ 7 cm). T2 tumors are > 7 cm, and are subclassified as T2a ( > 7 cm but ≤ 10 cm) or T2b (> 10 cm). T3 tumors extend beyond the renal parenchyma to involve major veins (renal vein or segmental branches, or vena cava), the pelvicalyceal system or perinephric tissues, but do not involve the ipsilateral adrenal and do not extend beyond Gerota’s
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Journal Pre-proof fascia. T3a tumors conform to this description but do not extend into the vena cava. T3b tumors extend into vena cava below the diaphragm and T3c tumors extend into vena cava above the diaphragm. T4 tumors invade the ipsilateral adrenal gland directly or invade beyond Gerota’s fascia. Lymph nodes submitted and uninvolved by tumor define N0; node involvement is staged N1. NX denotes absence of lymph nodes in the surgical specimen. Stage M1 denotes known
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distant metastases; M0 denotes absence of known distant metastases.
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Reflection and Summary
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It is clear that a multitude of dedicated investigators have devoted incalculable amounts of time and effort to the pursuit of knowledge about renal epithelial neoplasms. One ought to
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ponder the importance of their findings. What follows reflects only the ruminations of the
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authors, and some of our personal observations and opinions. We do not wish to speak for the reader, and of course we respect the fact that others may disagree with us, partially or entirely.
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Perhaps our observations will stimulate some lively and productive debates!
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The documentation of the benign nature of certain tumors, such as oncocytoma and papillary adenoma strikes us as tremendously important. Imagine the relief that a patient must experience when told that the much-feared kidney tumor just recently excised is benign! So to pursue that matter further, we wonder if sufficient clinical data will eventually accumulate that would allow pathologists and urologists to agree that multilocular cystic renal neoplasm of low malignant potential and clear cell papillary renal cell carcinoma no longer warrant the use of a name that implies the possibility of death from recurrence or metastasis - and simply state that these tumors are benign.
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Journal Pre-proof In reflecting upon Dr. Ackerman's premise that ‘it does not appear logical to make subdivisions in nomenclature; better to call it simply an adenocarcinoma of renal tubule origin’, it seems reasonable to ask ourselves whether the remarkable separation of renal tumors into an ever-increasing number of new neoplasms is a worthy exercise. We strongly believe that the accurate identification of HLRCC-RCCs is tremendously important not only in managing the affected patient, but in counselling and follow-up of family members. In a similar vein, accurate
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identification of SDH-deficient renal cell carcinomas may facilitate genetic evaluation and
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appropriate counselling for family members. Perhaps other examples of the importance of
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accurately identifying subsets of renal cell carcinoma can be brought forward. Regrettably,
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although we do not profess to be experts in the clinical management of renal cancer patients, it is our impression that the clinical options for treatment of renal cancer have lagged far behind our
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ability to identify new and fascinating variants of renal neoplasia. Similarly, it is a little unclear
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to us exactly how the clinicians currently use the carefully developed grading and staging parameters to make significant decisions on management of patients with renal cancer. Perhaps
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with increasing experience, innovative new clinical therapies will become more precisely
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applicable to treatments of the variants of renal cancer, and to cancers of variable grade and stage. Only the passage of time will answer that question.
35
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Klein MJ, Valensi QJ. Proximal tubular adenomas of kidney with so-called oncocytic features. A clinicopathologic study of 13 cases of a rarely reported neoplasm. Cancer 1976;38:906-14.
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Lieber MM, Tomera KM, Farrow GM. Renal oncocytoma. J Urol 1981;125:481-5.
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Thoenes W, Storkel S, Rumpelt HJ, et al. Chromophobe cell renal carcinoma and its variants--a report on 32 cases. J Pathol 1988;155:277-87.
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Bennington JL. Cancer of the kidney-etiology, epidemiology, and pathology. Cancer
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Genes Chromosomes Cancer 1991;3:249-55. Presti JC, Jr., Moch H, Gelb AB, Huynh D, Waldman FM. Initiating genetic events in small renal neoplasms detected by comparative genomic hybridization. J Urol 1998;160:1557-61. [22]
Grignon DJ, Eble JN. Papillary and metanephric adenomas of the kidney. Semin Diagn Pathol 1998;15:41-53.
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carcinoma should be based on nucleolar prominence. Am J Surg Pathol 2011;35:1134-9. [160] Khor LY, Dhakal HP, Jia X, et al. Tumor Necrosis Adds Prognostically Significant Information to Grade in Clear Cell Renal Cell Carcinoma: A Study of 842 Consecutive Cases From a Single Institution. Am J Surg Pathol 2016;40:1224-31. [161] Dagher J, Delahunt B, Rioux-Leclercq N, et al. Clear cell renal cell carcinoma: validation of World Health Organization/International Society of Urological Pathology grading. Histopathology 2017;71:918-25.
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[164] Amin MB, Edge S, Greene FL, Byrd D. AJCC Cancer Staging Manual. 8 th ed. New
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Journal Pre-proof Figure Legends Fig. 01 A gross photo in a 1953 textbook that may represent the first published depiction of a mucinous tubular and spindle cell carcinoma of the kidney. From Ref. [5]
Fig. 02 Multilocular cystic renal neoplasm of low malignant potential. The delicate septa are lined by clear cells, and clear cells are present within the septa, but are not forming expansile
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nodules.
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Fig. 03 Clear cell papillary renal cell carcinoma (A-D). The tumor is sharply circumscribed and
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extensively cystic, but nodules of solid tumor are readily visible (A). A typical finding is the presence of areas of a densely and compactly arranged tubular structures (B), lined by cells with
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clear cytoplasm, whose nuclei are of low nuclear grade and are arranged at the apical end of the
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cells (C and D), similar to early secretory phase endometrium.
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Fig. 04 Papillary renal cell carcinoma, oncocytic variant (“papillary renal neoplasm with
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reversed polarity”). Tumor cells have relatively abundant cytoplasm, and round non-overlapping nuclei that are arranged linearly toward the cell apices and bear inconspicuous nucleoli (A and B).
Fig. 05 Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Male patient, age 48 years, with a history of metastatic renal cell carcinoma, was seen in a dermatology clinic regarding multiple red-brown firm dermal nodules. All six of his female siblings had undergone hysterectomy for leiomyomas. Sections shown here illustrate a dermal leiomyoma (A and B),
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Journal Pre-proof findings considered as probable evidence for HLRCC syndrome. Section from the renal cancer of the patient described in Fig. 05A and Fig 05B shows a papillary carcinoma, similar to conventional type 2 papillary renal cell carcinoma (A). However, many of the large nuclei exhibit very prominent inclusion-like orangiophilic or eosinophilic nucleoli, surrounded by a clear halo (C and D).
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Fig. 06 A renal tumor that may represent the first published depiction of a chromophobe renal
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cell carcinoma. From Ref. [78]
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Fig. 07 Renal medullary carcinoma (A and B). Medullary-based tumor in a 34-year-old African
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prominent stromal desmoplasia (B).
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American woman with sickle cell trait, presenting with hematuria (A). Infiltrative tumor solicits
Fig. 08 Translocation renal cell carcinoma. A: TFE3 [Xp11.2] translocation associated renal cell
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carcinoma showing tumor cells with voluminous clear cytoplasm and vesicular nuclei. Inset:
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The break-apart fluorescence in situ hybridization (FISH) assay showed a fused or closely approximated green-red signal pair (representing the uninvolved X chromosome) and another pair of split signals (white arrow). B: t(6;11) renal cell carcinoma (TFEB rearranged renal cell carcinoma). Two cell populations are evident: some with abundant clear cytoplasm, and a second cell population consisting of smaller cells with denser chromatin, clustered around nodules of hyaline basement membrane material, forming “pseudorosettes”. C: TFE3 translocationassociated perivascular epithelioid cell neoplasm (PEComa) of the kidney. D: melanotic translocation carcinoma shows consists of polygonal tumors cells with fairly distinct cell borders
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Journal Pre-proof and abundant clear to finely granular cytoplasm. Many cells contain brown-pigmented cytoplasmic granules.
Fig. 09 Succinate dehydrogenase-deficient renal cell carcinoma. Tumor infiltrates and surrounds native renal elements at the interface between tumor and normal kidney; microcysts are present. Tumor cells have small round low-grade nuclei. Cytoplasm is pale, eosinophilic, finely granular
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or flocculent.
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Fig. 10 A renal tumor that may represent the first published depiction of a tubulocystic
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carcinoma. From Ref. [78]
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Fig. 11 Dr. George Farrow in his office at Mayo Clinic, Rochester, MN, in the summer of 1995.
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Fig. 12 Gross photo of "Renal cell carcinoma, collecting duct type". From Ref [113].
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Fig. 13 Photomicrograph of "Renal cell carcinoma, collecting duct type". From Ref [113].
Fig. 14 A photomicrograph of one of the cases of tubulocystic renal cell carcinoma in Dr. George Farrow's collection of "low grade collecting duct carcinomas". From Ref. [115]
Fig. 15 Tubulocystic renal cell carcinoma Tumor is composed of cystic spaces of variable sizes with a “spider web” or “lace doily” appearance (A). Delicate septa lined by eosinophilic cells with “hobnail” appearance (B).
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Fig. 16 A gross (A) and photomicrograph (B) of one of the cases of mucinous tubular and spindle cell carcinoma in Dr. George Farrow's collection of "low grade collecting duct carcinomas". From Ref. [115]
Fig. 17 Mucinous tubular and spindle cell carcinoma. Round and closely packed elongated
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tubular structures filled and separated by “bubbly” mucin (A). The tumor-associated mucin
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shows positive staining with Alcian blue (B).
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Fig. 18 Acquired cystic kidney disease-associated renal cell carcinoma. A solid and cystic neoplasm is present in a background of extensive cystic change in this patient with a long-
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standing history of dialysis for renal failure (A). The tumor displays acinar architecture lined by
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tumor cells with prominent eosinophilic cytoplasm (B). Abundant oxalate crystals are
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demonstrable under polarized light, a unique property of this neoplasm (C).
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Fig. 19 Oncocytic renal cell carcinoma occurring after neuroblastoma. A: Tumor is solid and expansile; this example has prominent papillary architecture. B: Tumor cells have sharply defined cell membranes, and abundant eosinophilic granular cytoplasm. Nuclei are irregular, and many have prominent nucleoli.
Fig. 20 Thyroid follicular carcinoma–like carcinoma. This unusual renal neoplasm is remarkably reminiscent of a thyroid follicular neoplasm, set in a diffusely hyalinized fibrotic background.
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Journal Pre-proof Fig. 21 Eosinophilic solid and cystic renal cell carcinoma. The tumor shows solid and cystic architecture. Tumor cells have voluminous eosinophilic cytoplasm.
Fig. 22 Renal cell carcinoma with angioleiomyoma-like stroma. Stroma exhibits a smoothmuscle-like appearance and separates the neoplastic epithelial glandular structures, many of
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which are rimmed by a prominent layer of endothelial cells that mimic a myoepithelial cell layer.
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