RСС: патологическая и молекулярная оценка мишеней

Ronald M. Bukowski , Robert A. Figlin, Robert J. Motzer (Eds). Renal cell carcinoma. Molecular targets and clinical applications. 3 Ed. Springer Science+Business Media New York (2015)

Evolution of the classification of renal cell carcinomas

Knowledge cannot be elaborated and transmitted in the form of isolated observations. For this reason, observations are grouped according to similar features, producing a classification. Classifications can differ depending on their objective and on changes in ways of thinking over time. In cancer, the evolution of knowledge reflects the pattern observed in the general evolution of human understanding, and accordingly cancer classifications are no more than a tool that require revision and re?nement from time to time based on the gradual increase in knowledge. The microscopic characterization of renal cell carcinoma (RCC) started in the mid-nineteenth century (1) with the controversy aroused by Grawitz’s hypothesis—in 1883, Grawitz stated that alveolar (clear cell) tumors, previously considered lipomas, originated in the neoplastic transformation of adrenal cortical residues into renal cortical. One year later, he confirmed his theory when he found ectopic adrenal cortex in the renal cortex. This theory was readily opposed by Sudek, who favored a renal tubular origin. The controversy between supporters and detractors of the Grawitz theory went on for decades. The term hypernephroma was introduced in 1909 and made reference to the adrenal origin. Support for the supposed adrenal origin started to grow weaker. Oberling et al.’s ultrastructural studies (2) finally brought the argument to a conclusion by demonstrating the tubular origin of RCC, in the proximal nephron.

Initial histological classifications

For a long time, the mechanical model of disease (according to which man is a complex “machine” and disease is a fault in the machinery) and the limited therapeutic modalities (practically only surgery) resulted in a classification with few histological subtypes. The first international classifications unified all the historical histological types under the common denomination of renal adenocarcinoma; this could be a clear cell or a granular cell carcinoma, its architecture could be tubular, papillary, or cystic, and its appearance was rarely sarcomatoid [3]. Nevertheless, quite soon attempts began to be made to distinguish histological subtypes on the basis of their origins from different parts of the nephron, with efforts to correlate them with different clinical evolutions. Thus, Thoenes et al. described the chromophobe renal cell carcinoma [4] morphologically different from the clear cell carcinoma and regarded as probably originating in the intercalated cells of the distal nephron [5]. Subsequently many possible histological variants were described, and attempts made to identify their origin from different areas of the nephron by means of immunohistochemistry. Many of these histological subtypes failed to show a correlation with the clinical evolution, however, bringing into doubt the utility of such morphological classifications. In the wake of these failures, chromosomal studies and developing knowledge of familial RCC syndromes helped to chance the scenario.

Chromosomal findings in familial renal cell carcinomas: impact on the pathology and therapy of sporadic cases

Approximately 2–3 % of RCCs occur within the context of a familial syndrome. These syndromes are characterized by early onset and/or multifocal/bilateral disease. Some are due to mutated or inactivated tumor suppressor genes and others to activated oncogenes. The recognition that each of these syndromes is associated with specific tumor phenotype, chromosomal changes, and gene alterations had a major impact on knowledge of RCC, and during recent years, various renal cancer syndromes have been characterized (Table 2.1).

Von Hippel–Lindau (VHL) Disease: This is the most frequent familial renal cancer syndrome, estimated to occur at rates of 1:36,000 to 1:45,500 population. It is associated with secondary VHL gene (3p25–26) changes. Missense mutations are the most common, but nonsense mutations, microdeletions/insertions, splice mutations, and large deletions also occur. The spectrum of clinical manifestations of VHL reflects the type of germline mutation [6].

Table 2.1. Hereditary renal cell carcinomas

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The typical renal manifestations of VHL disease are kidney cysts and clear cell renal cell carcinoma (ccRCC). Histological examination of macroscopically normal renal tissue may reveal several hundred independent tumors and cysts.

Hereditary papillary renal carcinoma (HPRC): Trisomy or tetrasomy 7, trisomy 17, and loss of chromosome Y are the most common chromosomal changes, with a germline-activating mutation in the MET proto-oncogene (7q31–34) which can cause papillary renal cell carcinoma type 1 (type 1 pRCC), with cuboidal cells with scanty basophilic cytoplasm and low-grade nuclei [7].

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC): Some families have a linkage to 1q42.3–q43 [8]. At the genetic level, a germline loss-offunction mutation in the fumarate hydratase (FH) gene is present, and the typical kidney pathology is a papillary renal cell carcinoma type 2 (type 2 pRCC) with eosinophilic cells and high-grade nuclei. Recently, however, tubular and solid patterns and the presence of large nucleoli with perinucleolar halos have been described [9].

The Birt–Hogg–Dubé syndrome (BHD): The BHD (FLCN) gene is located on 17q12-q11.2. It is associated with multiple cutaneous lesions (?brofolliculomas, trichodiscomas, and acrochordons) and with an increased risk of renal cancers of various histological types, especially chromophobe renal cell carcinoma (chRCC), oncocytoma, and hybrid oncocytoma–chromophobe renal cell carcinoma, although ccRCC and pRCC can also be present [10].

Tuberous sclerosis: The disease is associated with mutations in the TSC1 (9q34) and TSC2 (16p13) genes, leading to hyperactivation of the mTOR pathway. Although angiomyolipoma is the most characteristic kidney tumor in this syndrome, ccRCC and chRCC are also described [11].

Other familial syndromes are much more infrequent (Table 2.1).

Identification of the specific chromosomal and genetic alterations of the familial and hereditary syndromes as characteristics of the distinct histological subtypes of RCC has made it possible to confirm that a high percentage of the sporadic forms of these subtypes display the same genetic changes. The described morphological subtypes can be interpreted as an expression of specific genetic changes; accordingly, based on the morphology, distinct genetic pathways can be recognized. In view of the above considerations, additional entities were included in WHO’s 2004 classification [12] (Table 2.2), which combined morphological and genetic characteristics and began to recognize some variations with evidence of different immunophenotypes or molecular changes with clinical implications. Thus, when developing target therapies against different genetic pathways, the histological subtype can help in selection of the drug.

Table 2.2. Renal cell carcinoma classification

WHO histological subtypes

  • Clear cell renal cell carcinoma
  • Multilocular clear cell renal cell carcinoma
  • Papillary renal cell carcinoma
  • Chromophobe renal cell carcinoma
  • Carcinoma of the collecting ducts of Bellini
  • Renal medullary carcinoma
  • Xp11 translocation carcinomas
  • Carcinoma associated with neuroblastoma
  • Mucinous tubular and spindle-cell carcinoma
  • Renal cell carcinoma unclassified

Other entities

  • Tubulocystic carcinoma
  • Acquired cystic disease-associated carcinoma
  • Clear cell tubule-papillary carcinoma
  • Thyroid-like follicular carcinoma
  • Leiomyomatous renal cell carcinoma
  • Succinate dehydrogenase (SDHB) germline mutation-associated carcinoma
  • Anaplastic lymphoma kinase (ALK) translocation-associated carcinoma
  • Biphasic alveolosquamoid renal carcinoma cell carcinoma

Molecular pathways in renal cell carcinomas

Study of familial RCCs has identified the involvement of diverse molecular pathways, the main ones being those that mimic a hypoxic status [13], activating angiogenesis, and the mTOR pathway [14].

Pseudo-hypoxic pathways in renal cell carcinoma

VHL Pathway

The VHL gene (3p25.3) encodes the pVHL protein, which regulates HIF-α, a transcription factor involved in the response to oxygen changes. In the hypoxic situation, HIF is not degraded and activates several genes, including platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) that stimulate angiogenesis and inhibit tumor cell apoptosis [15]. In addition, it upregulates other growth factors (TGFα, EGFR, IGF) that stimulate autocrine cell growth or activate energy supply factors such as glucose transporter protein-1 (GLUT1) and erythropoietin.

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Fig. 2.1. Pseudo-hypoxic pathway. VHL loss with HIF-1α and HIF-2α accumulation and angiogenesis and proliferation increase

The mutation in 3p, present in 70–90 % of sporadic ccRCCs and less commonly in other subtypes, with inactivation of the VHL gene results in failure of the pVHLE3 ubiquitin ligase complex that mediates HIF degradation. This leads to accumulation of HIF-α and binding to HIF-1β, mimicking a hypoxia situation, and transcriptional activation of genes such as VEGF [16].

There are multiple forms of HIF-α, HIF-1α, and HIF-2α being those most commonly involved in RCC. Apoptosis is mediated by HIF-1α, and proliferation is mediated preferentially by HIF-2α, which displays elevated c-Myc activity, resulting in enhanced proliferation and resistance to replication stress [14, 17] (Fig. 2.1). Likewise, HIF-2α can inhibit p53 through a growth factor receptor AKT-MDM2 pathway, contributing to the survival of RCCs during standard treatments such as ionizing radiation or chemotherapy [18].

Krebs cycle and pseudo-hypoxic pathway

Fumarate hydratase pathway. The fumarate hydratase gene (FH) (1q42.3–q43) encodes the FH protein involved in the conversion of fumarate to malate in the Krebs cycle.

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Fig. 2.2. Pseudo-hypoxic pathway. The fumarate hydratase or succinate dehydrogenase mutation can produce a pseudo-hypoxic status similar to VHL gene loss

The mutation in 1q present in the HLRCC syndrome, featuring a pRCC similar to type 2 but with characteristic large nuclei with very prominent eosinophilic nucleoli like a “viral inclusion” [9], results in the accumulation of fumarate. The latter acts as a competitive inhibitor of the activity of HIF prolyl hydroxylases (HPH), which may result in HIF accumulation and pseudo-hypoxic status with all the deregulations characteristic of this situation [19] (Fig. 2.2).

Succinate Dehydrogenase Pathway. Succinate dehydrogenase consists of four different subunits. Their genes (SDHAF2-SD5-11q13.1, SDHB-1q23–25, SHDC-1q21–23, SDHD-11q23) are encoded in the nuclear DNA, and their proteins are assembled at the inner mitochondrial membrane to form mitochondrial complex 2 and catalyze the conversion of succinate to fumarate [20].

The autosomal germline mutations are the cause of the familial pheochromocytoma/ paraganglioma syndromes (PGL1–4), some of which present with gastrointestinal stromal tumors, and the genes SDHD and especially SDHB are associated with renal neoplasms of different histological features with eosinophilic cells [21].

The mechanism postulated to be responsible for these syndromes involves aberrant apoptosis, oxidative stress, and a pseudo-hypoxic pathway, similar to that observed with increased levels of fumarate [20].

Any pathway with HIF-α accumulation can upregulate the mammalian target of rapamycin or mTOR pathway.

mTOR is an intracellular serine/threonine protein kinase of 289 kDa belonging to the phosphatidylinositol kinase-related kinases coded in 1p36.2. It is involved in the monitoring of cellular nutrition, with effects on protein translation, angiogenesis, cell growth, and apoptosis [22]. mTOR exists in two multiprotein complexes: mTORC1 and mTORC2.

mTORC1 includes the regulatory associated protein of mTOR (RAPTOR). It can be activated by growth factors in the cellular membrane through Ras and PI3K and plays a role in the regulation of cell growth, proliferation, survival, and motility via the phosphorylation of S6K1 and 4E-BP1, which promote mRNA translations and ribosome biogenesis (Fig. 2.1) [23]. On the other hand, HIF-1α represses mTORC1, thereby promoting the release of mTORC2 [18].

mTORC2 is a rapamycin-insensitive companion of mTOR (RICTOR). Knowledge of its functions and control is more limited. Recently the finding that it can directly phosphorylate Akt indicates that mTORC2 may modulate cell survival [24].

HIF-1α seems to be regulated by mTORC1 and mTORC2, whereas HIF-2α expression is mTORC2 dependent but mTORC1 independent [25].

TSC1/TSC2 Pathway

The complex TSC1 (9q34) and TSC2 (16p13.3) is a negative-regulating Rheb/mTOR/p70S6K cascade [26] (Fig. 2.1). The TSC2 loss results in HIF-1α accumulation and pseudo-hypoxic pathway activation [27], which can explain the occasional association of angiomyolipoma with RCC in sporadic cases or in tuberous sclerosis [28].

c-MET pathway in renal cell carcinoma

The MET gene (7q31–34) is ampli?ed in some RCCs. c-MET is a member of the receptor tyrosine kinase family; its ligand is the hepatocyte growth factor (HGF). Both are upregulated after renal injury and tissue repair via PI3-AKT and PI3-RASErk. RCCs with a c-MET mutation presumably overactivate protein products of the MET gene, potentially driving uncontrolled growth [29] (Fig. 2.3).

The phosphate and tensin homologue deleted on chromosome 10 (PTEN) is involved in negatively regulating the Rheb/mTOR/p70S6K cascade via PI3K inhibition [22]. Individuals with a germline mutation of the PTEN gene (Cowden syndrome) have a risk of tumors in the breast, thyroid, endometrium, and kidney [30].

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Fig. 2.3. c-MET pathway. Mutation of c-MET overactivate protein products of the MET gene, potentially driving uncontrolled growth

FLCN pathway in renal cell carcinoma

FLCN forms a complex with folliculin-interacting proteins (FNIP1 and FNIP2). These components bind to AMP-activated protein kinase (AMPK). AMPK acts to sense cellular energy and assists in the regulation of the mTOR activity level. In tumors that are noted to have FLCN alterations in both alleles, mTOR activation (mTORC1 and mTORC2) and also increased TFE3 transcriptional activity has been observed [31] (Fig. 2.4).

TFE3 is a member of the MiT family of transcription factors (TFE3, TFEB, MITF, and TFEC), which are overexpressed in RCC for translocations in chromosomes 1 and X, t(X:1)(p11.2;p34), and chromosomes 6 and 11, t(6;11)(p21;q13). These translocations create active fusion proteins with MiT transcription factor activity but without their normal regulation [32], conditioning mTOR pathway activation and increase in HIF-1α [33].

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Fig. 2.4. FLCN pathway. Folliculin gene mutations deregulate mTOR activity and increased TFE3 transcriptional activity

Renal cell carcinoma pathology according to molecular pathway

Pseudo-hypoxic pathway

Association with VHL gene changes and TSC1/TSC2 Loss

Like the majority of patients with TSC1/TSC2 loss, the familial and sporadic cases with VHL gene changes can develop ccRCC [34]. This neoplasm consists of clear cytoplasm (empty) cells (Fig. 2.5). Cells of high nuclear grade can acquire an eosinophilic aspect due to the higher mitochondrial content. The most frequent arrangement is a solid pattern, though tubular and occasionally cystic patterns can also be present. Papillary areas are very rarely observed. Sarcomatoid transformation is observed in 5 % of cases [35]. A prominent vascular stroma is typical. Expression of CAIX and CD10 occurs in the majority of cases [36].

In multilocular ccRCC, 3p deletion is present in 74 % of cases and VHL gene mutation in 25 % [37]; for this reason it can be considered a variant of classical ccRCC of low aggressivity.

In addition to the VHL gene, other parts of chromosome 3 can be lost, such as 3p12, 3p14, and 3p21, which contain the PBRM1 gene, with truncating mutations in 41 % of cases of ccRCC [38]. Other chromosomes affected are 5q, 9p, and 14q.

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Fig. 2.5. Clear cell RCC. The cells have an empty cytoplasm for lipids and glycogen dissolution during the technical handing of the tumor

Around 10 % of cases of sporadic ccRCC do not have the VHL gene mutation, and some of them have somatic NF2 gene (22q12.2) mutations [39].

Association with Krebs cycle mutations

These carcinomas ful?ll the Warburg model of cancer because they depend on anaerobic glycolysis instead of oxidative phosphorylation [40].

HLRCC patients (with FH gene mutation) and 42 % of those with sporadic papillary RCC have a similar histological subtype to type 2 pRCC, with eosinophilic cells of high nuclear grade and pseudostrati?ed nucleus in papillary cores [41] (Fig. 2.6).

Lack of expression of cytokeratin 7 and positive alpha-methylacyl-CoA racemase (AMACR) are typical. The sporadic type 2 pRCC has a higher frequency of allelic imbalance on 9p21 and a lower frequency of trisomy 17q, which is typical for the other pRCCs [42]. Other changes are in 1p, 3p, and 5q. At present there are doubts over whether HLRCC and sporadic type 2 pRCC are in fact the same entity or not and whether they follow the same pathway as the familial forms. The International Society of Urogenital Pathology (ISUP) has considered HLRCC to be a separate entity from the other histological subtypes, and the majority of authors regard sporadic type 2 pRCC as a heterogeneous variant [43].

Another mutation in the Krebs cycle is at the level of SDHB genes. This mutation is associated with the risk of development of succinate dehydrogenase germline mutation-associated carcinoma (SDHB RCC), a variant also characterized by eosinophilic cells with vacuoles and entrapped normal tubules in the periphery [21] (Fig. 2.7).

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Fig. 2.6. Papillary type 2 RCC. Eosinophilic cells with nucleolus with a pseudostrati?ed papillary arrangements

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Fig. 2.7. Succinate dehydrogenase (SDHB) germline mutation-associated RCC. The cells have an eosinophilic cytoplasm with occasional vacuolization and bland nucleus (courtesy Dr. K. Trpkov—Calgary)

c-MET pathway

HPRC and the sporadic cases are characterized by a type 1 pRCC defined by a monolayer of basophilic-cuboidal cells with scant cytoplasm, regular nuclei, and small nucleoli around capillary cores in 50–70 % of the entire tumor (Fig. 2.8). Expression of AMACR is also present [44]. Approximately 75 % of the sporadic forms have trisomy 7q31, which contains genes for c-MET and ligand HGF, but an activating MET mutation is seen in only 13 % of these sporadic cases [45]. In addition, gains in chromosome 17q (full trisomy, isochromosome 17q, or duplication of 17q21-qter) are typical.

Mucinous tubular and spindle-cell RCC is composed of small basophilic-cuboidal cells with round and elongated tubules and spindle cells with mucinous stroma (Fig. 2.9). It has some similarities with type 1 pRCC, with gains in 12q, 16q, 17, and 20q and losses in 1, 4, 6, 8, 9, 13, 14, 15, and 22, but no gains in 7 or 17 [46].

The RCC with PTEN mutation in Cowden syndrome is, in the majority of cases, similar to type 1 pRCC [47].

Tubulocystic RCC is composed of packed tubules and cysts lined by cuboidal or hobnail cells with eosinophilic cytoplasm and large nuclei showing prominent nucleoli (Fig. 2.10). The expression of AMACR and the gains in chromosomes 7 and 17 [48] are considered by some authors to suggest that it is closely related to type 1 pRCC [49].

FLCN pathway

Mutation or loss of the wild-type allele of the FLCN gene has been identified in 70 % of BHD families, with associated risk of development of various RCC subtypes, especially chRCC, oncocytomas, and hybrid oncocytoma–chromophobe renal cell carcinoma. However, this mutation is present in only 10.9 % of the sporadic cases [50].

The cells of chRCC are larger than those of ccRCC. They display polyhedral outlines with good delimitation of the cellular membrane (giving them a vegetal cell appearance) and abundant pale reticular cytoplasm. Numerous, sometimes invaginated vesicles of 150–300 nm in diameter are present, resembling those of type B intercalated cells in the cortical collecting duct. The cytoplasm can be clear or eosinophilic according to the quantity of mitochondria [51] (Fig. 2.11). The architecture is solid, in sheets, and with a trabecular distribution. Losses in chromosomes Y, 1, 2, 6, 10, 3, 17, and 21 are typical of this RCC. The massive chromosomal losses lead to a hypodiploid DNA index. In spite of losses in chromosomes 10 and 17, there are no alterations in PTEN [52], and mutation of the TP53 tumor suppressor gene is present in only 27 % of cases.

Overexpression of c-kit mRNA is found in not only chRCC but also oncocytomas, and differential expression of c-kit in renal tumors makes it an excellent immunohistochemical marker for diagnosis [53].

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Fig. 2.8. Papillary type 1 RCC. Cuboidal cells with small nucleus and no evident nucleoli with scant cytoplasm (basophilic cells) arranged in a papillary way

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Fig. 2.9. Mucinous tubular and spindle-cell RCC. A neoplasm with bland nucleus cuboidal aspect (basophilic cells) arranged in a tubular way and with areas of spindle appearance for compression and mucinous stroma

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Fig. 2.10. Tubulocystic RCC. Neoplasm with cystic arrangement lined by cuboidal or hobnail cells with scant eosinophilic cytoplasm and occasionally large nuclei with evident nucleoli

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Fig. 2.11. Chromophobe RCC. Large cells with evident cellular outline with granular (clear-like) cytoplasm

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Fig. 2.12. MiT germline mutation RCC. Large cells with clear and eosinophilic cytoplasm, large nucleus, and solid or tubular arrangement

In folliculin-deficient RCC, increased TFE3 transcriptional activity has been found, and this represents a connection with the MiT germline mutation RCC [31]. RCCs with TFE3 accumulation display an increase in pS6, activation of the mTOR pathway, and HIF-1α expression [33], but transactivation of the MET promoter by ASPL-TFE3 fusion protein has also been reported [54]. TFEB-associated RCCs express HMB45 and melanocytic markers. The morphology of the MiT germline mutation RCC is characterized by large and bizarre clear and eosinophilic cells, some papillary areas, calci?cations, and a biphasic pattern in some cases [43] (Fig. 2.12).

Undefined pathway

Collecting duct (Bellini) RCC (cdRCC) and medullary RCC (mRCC) are infrequent neoplasms characterized by very atypical cells and an overlapping appearance. Eosinophilic cells are present in a solid, papillary, or cribriform arrangement with desmoplasia in cdRCC (Fig. 2.13) while marked inflammatory cells are observed in the stroma in mRCC [43] (Fig. 2.14).

The molecular genetic abnormalities in these tumors are heterogeneous, and there have been few studies on the topic. Recently immunohistochemical loss of INI1 was found in 15 % of cdRCC [55], and many alterations suggestive of mRCC have been observed in the INI1 gene (hSNF5/BAF47), a remodeling gene of cell differentiation [43].

Some of these tumors have high expression of c-MET and HIF-1α, and for this reason, some authors also relate them to the pseudo-hypoxic pathway [54].

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Fig. 2.13. Collecting duct RCC. High-grade carcinoma with tubular pattern in a desmoplastic stroma

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Fig. 2.14. Medullary RCC. Undifferentiated high-grade carcinoma in a solid pattern with some inflammatory cells. Notice sickle-cell erythrocytes

Other pathological renal cell carcinomas entities

Other morphological subtypes of RCC with different chromosomal and molecular features have been reported, but the series of these other types are few in number and small; accordingly, conclusive data have not yet been obtained. The entities most frequently cited in the literature are discussed below:

Acquired Renal Cystic Disease-Associated Carcinoma: Patients with end-stage renal disease can have different RCC subtypes [56], but in those with acquired cystic disease of the kidney, the typical composition is large eosinophilic cells with a rounded nucleus and large nucleoli arranged in variety of architectural patterns; in addition, calcium oxalate crystals are observed within the tumors [57] (Fig. 2.15). These carcinomas express AMACR. At the molecular genetic level, gains in chromosomes 1, 2, 6, and 10 and monosomies 3, 9, and 16 are reported, suggesting a distinction from the other RCCs [58].

Clear Cell Tubulopapillary Renal Cell Carcinoma: This tumor was initially described in end-stage kidneys but has recently also been detected in nonterminal kidney disease. In 50 % of cases, a pronounced cystic component is observed; solid, tubular, and microcystic areas are also present. The tumor cells show a clear cytoplasm and low-grade nuclear atypia, with the nucleus situated toward the surface of the papillary tufts [59] (Fig. 2.16). They show neither deletion of 3p nor trisomies of chromosomes 7 and 17 [59].

Thyroid-Like Follicular Renal Cell Carcinoma: Very few cases of this entity have been reported. It has a follicular architecture resembling that of follicular carcinoma of the thyroid and is composed of cells showing low-grade pleomorphism with amphophilic to eosinophilic cytoplasm. Gene expression pro?ling has revealed widespread underexpression or overexpression involving chromosomes 1, 2, 3, 5, 6, 10, 11, 16, and 17 [60].


Fig. 2.15. Acquired cystic disease-associated RCC. Eosinophilic cells with calcium oxalate crystals


Fig. 2.16. Clear cell tubulo(papillary) RCC. Cuboidal clear cells with tubular arrangement (in some areas can be papillary) with apical nucleus localization

Leiomyomatous Renal Cell Carcinoma: This entity is composed of tubular aggregates of neoplastic clear cells intermixed in a prominent leiomyomatous proliferation. There is controversy over the chromosome 3 status [61].

Anaplastic Lymphoma Kinase (ALK) Translocation-Associated Renal Cell Carcinoma: This entity displays structural karyotypic abnormalities involving the ALK locus on chromosomal band 2p23 [62]; two cases of VCL (vinculin)-ALK fusion have been detected, and two each of TPM3-ALK and EML4-ALK fusions.

Biphasic Alveolosquamoid Renal Cell Carcinoma: There is a dual cell population, and the larger tumor cells with squamous features are arranged in well-demarcated islands, with the smaller cells surrounding them. Partial or complete losses of chromosomes 2, 5, 6, 9, 12, 15, 16, 17, 18, and 22 and partial gains of chromosomes 1, 5, 11, 12, and 13 have been reported [63].

Unclassified renal cell carcinoma

This diagnostic category is for renal cell carcinomas that are impossible to classify as any of the other histological subtypes. It includes pure sarcomatoid RCCs without any evidence of the cellular origin, oncocytic RCCs without sufficient features for a precise diagnosis, any mixture of histological subtypes except oncocytoma–chromophobe varieties, and all RCCs with an unidentifiable morphology.

This diagnostic category can include different biologic entities, and for this reason in each individual case, the prognosis correlates only with the stage and grade [64].


After the identification of the chromosomal and molecular bases of the RCC familial syndromes and the discovery that these correspond with concrete morphological variants, it appeared that these same molecular alterations were present in the sporadic forms, with similar alterations being found in 90 % of sporadic ccRCCs and between 5 and 15 % of the other variants. In recent years, investigations have centered on the development of new therapies based on the consequences of HIF accumulation, the c-MET and FLCN mutations, and the pseudo-hypoxic status that they induce. On this basis it has been possible to reclassify RCCs according to the molecular pathway (Table 2.3) in order to help in therapeutic decision making.

However, not all the sporadic RCCs follow these pathways, and research continues. Recently some deletions in histone-modifying genes immediately next to the VHL gene have been detected in ccRCC. This observation has shifted biological interest away from hypoxia-induced epigenetic regulation and specifically toward the methylation of histone 3 and chromatin structure [65], opening potential avenues for new therapeutic approaches [66].

Table 2.3. Proposed renal cell carcinoma classification according to molecular pathway

  • Pseudo-hypoxic pathway
    • VHL pathway—clear (empty) cells
      • Clear cell renal cell carcinoma
      • Multilocular clear cell renal cell carcinoma
    • Krebs cycle mutations—granular (eosinophilic) cells
      • Papillary type 2 renal cell carcinoma
      • SDHB germline mutation-associated carcinoma
    • C-MET pathway—basophilic-cuboidal cells
      • Papillary type 1 renal cell carcinoma
      • Mucinous tubular and spindle renal cell carcinoma
      • Tubulocystic carcinoma
    • FLCN pathway—large cells
      • Chromophobe renal cell carcinoma
      • Hybrid oncocytoma–chromophobe renal cell carcinoma
      • MiT family renal cell carcinomas
    • Undefined pathway
      • Collecting duct renal cell carcinoma
      • Medullary renal cell carcinoma
      • Tubulopapillary clear cell renal cell carcinoma
    • Unclassified renal cell carcinomas
      • Pure sarcomatoid renal cell carcinoma
      • Mixed cellular types no chromophobe and oncocytoma
      • Oncocytic tumors without characteristics of typical subtype


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