Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Dorin Novacescu
 -- 4856 2022-11-24 14:20:58 |
2 Format correction
Sirius Huang
 Meta information modification 4856 2022-11-29 08:39:33 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Novacescu, D.;  Feciche, B.O.;  Cumpanas, A.A.;  Bardan, R.;  Rusmir, A.V.;  Bitar, Y.A.;  Barbos, V.I.;  Cut, T.G.;  Raica, M.;  Latcu, S.C. Definitive Diagnosis in Renal Cell Carcinoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/36835 (accessed on 27 July 2024).
Novacescu D,  Feciche BO,  Cumpanas AA,  Bardan R,  Rusmir AV,  Bitar YA, et al. Definitive Diagnosis in Renal Cell Carcinoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/36835. Accessed July 27, 2024.
Novacescu, Dorin, Bogdan Ovidiu Feciche, Alin Adrian Cumpanas, Razvan Bardan, Andrei Valentin Rusmir, Yahya Almansour Bitar, Vlad Ilie Barbos, Talida Georgiana Cut, Marius Raica, Silviu Constantin Latcu. "Definitive Diagnosis in Renal Cell Carcinoma" Encyclopedia, https://encyclopedia.pub/entry/36835 (accessed July 27, 2024).
Novacescu, D.,  Feciche, B.O.,  Cumpanas, A.A.,  Bardan, R.,  Rusmir, A.V.,  Bitar, Y.A.,  Barbos, V.I.,  Cut, T.G.,  Raica, M., & Latcu, S.C. (2022, November 28). Definitive Diagnosis in Renal Cell Carcinoma. In Encyclopedia. https://encyclopedia.pub/entry/36835
Novacescu, Dorin, et al. "Definitive Diagnosis in Renal Cell Carcinoma." Encyclopedia. Web. 28 November, 2022.
Definitive Diagnosis in Renal Cell Carcinoma
Edit
This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10112926

Despite significant progress regarding clinical detection/imaging evaluation modalities and genetic/molecular characterization of pathogenesis, advanced renal cell carcinoma (RCC) remains an incurable disease and overall RCC mortality has been steadily rising for decades. Concomitantly, clinical definitions have been greatly nuanced and refined. RCCs are viewed as a heterogeneous series of cancers, with the same anatomical origin, but fundamentally different metabolisms and clinical behaviors. 

renal cell carcinoma (RCC) immunohistochemistry (IHC) molecular pathology differential diagnosis subtyping prognosis

1. Introduction

Over the past decades, major technological and scientific breakthroughs have allowed for the development of important clinical tools for better RCC detection, evaluation, and therapeutic decision-making, while also reshaping medical understanding of RCC pathogenesis and progression-driving molecularities. Even so, RCC remains, to this day, one of the deadliest urological malignancies, accounting for ~3% of the total cancer burden in the global adult population [1].
The widespread integration of ultrasonography (US) and computer tomography (CT) in routine clinical practice has significantly improved RCC detection yields, reflected in the long-standing and still ongoing stable increase in RCC incidence rates globally [2]. Concurrently, a significant drop in RCC initial stage at diagnosis has also occurred, with most RCCs being detected incidentally currently, as asymptomatic, localized, small renal masses. Within this subgroup of RCC cases, 5-year survival rates have been significantly improved as a consequence of earlier curative intervention, i.e., partial/radical nephrectomy [3]. Conversely, despite important recent progress in systemic RCC therapeutic management, advanced RCC patients remain incurable, with persistently poor clinical outcomes. Thus, overall, RCC-specific mortality rates have been steadily increasing since the 1990s (~1.1%/year) [3][4].
To address these pervasive clinical limitations, regarding systemic/recurrent RCC therapeutic management and outcomes, contemporary RCC clinical definitions have been greatly nuanced and refined to better serve in RCC subtyping, prognosis assessment, and therapeutic response prediction. Classically, RCCs were simply defined as malignant parenchymatous renal neoplasms, spawning from tubular epithelial cellularity. However, in light of recent extensive RCC genomic profiling efforts and comprehensive metabolic molecular analyses, RCCs are currently viewed as an extremely heterogenic group of distinctive tumor subtypes, which only share an anatomical origin, while having different cellular progenitors, within the renal parenchyma. In fact, individual RCC subtypes demonstrate relatively specific, yet widely pleomorphic, tumor-driving molecular pathologies and pathognomonic genomics. This emerging intricate molecular amalgamation of novel RCC metabolic profiles, is firmly corroborated by the similarly extensive and well-documented clinical variability in RCC malignant behavior and therapeutic response, both between different RCC cases and disease phenotypes comparatively, but also during the natural evolution of individual RCCs (disease progression, systemic dissemination, and/or metastatic recurrence) [5][6].
In lack of a definitive systemic treatment modality for advanced RCCs, integration of the amounting fundamental medical knowledge regarding RCC molecular pathology into RCC clinical management has been paramount to obtaining improved risk stratification and evidence-based therapeutic decision-making. As a result, definitive pathological diagnosis and RCC subtyping have become more nuanced and cumbersome, with the latest guidelines (i.e., the World Health Organization—WHO’s 4th edition of the Urological Tumors Classification, 2016) identifying almost twenty distinct subtypes of malignant renal cell tumors, alongside mesenchymal, neuroendocrine, nephroblastic, and cystic variants [5][7]. Even so, these classifications will only become more comprehensive further on, as additional RCC entities, with distinguishing clinical, morphological, immunohistochemical, and/or molecular traits, have already been identified and are still awaiting formal acknowledgement [8][9][10][11][12][13][14][15].
To further complicate the already elaborate and dynamic landscape of RCC clinical management, systemic RCC therapy has been greatly diversified recently, with the advent of personalized oncological therapy and RCC tumor microenvironment molecular/genomic characterization initiatives. Notably, focused evaluation of the biologic implications of various inflammatory pathways regarding RCC metabolomics and proliferation, mainly the Von Hippel–Lindau (VHL), mechanistic target of rapamycin (mTOR), tumor necrosis factor (TNF), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) [16] pathways, has proven fruitful, providing multiple clinically relevant RCC-associated-antigen targeted molecules. Moreover, immunotherapy, a novel and promising type of oncotherapy, aiming to reactivate the cytotoxic immune response against tumor cells, has found important applications in advanced/recurrent RCC therapeutic management. Despite clinical difficulties regarding adequate immunotherapy response prediction for RCCs and the extensive therapy-associated costs, immunotherapy represents the only type of oncotherapy which allows, even theoretically, for the elaboration of a definitive cure for disseminated RCCs/cancer in general, as it is the only oncotherapy capable of targeting and annihilating non-dividing, quiescent, stem-like dysplastic cells [7][17].
Currently, as clinical definitions have become greatly nuanced, a complete RCC diagnosis requires careful multimodal evaluation, in a well-coordinated and phased approach, involving, at times, very difficult differentials.

2. Conventional Staining and RCC Microscopic Morphological Evaluation

Notwithstanding the long-held, central role of RCC morphological evaluation, using standard microscopy and conventional hematoxylin–eosin (HE) staining, in RCC definitive pathological diagnosis, essential for further therapeutic decision-making and predicting prognosis/risk stratification, in light of recent insights into RCC molecular pathology, the method, although still important, has become insufficient for adequate RCC subtyping. Even within the classical triad of conventional morphologies, namely clear cell (ccRCC), papillary (pRCC), and chromophobe (chRCC), which demonstrate relatively distinctive architectures and cellular features, microscopic evaluation of morphology remains subjective and user-dependent. Additionally, more often than not, meticulous evaluation will encounter, at least focally, overlapping patterns and/or atypical architectures, hindering definitive RCC subtyping. High-grade cellularity and severely dedifferentiated renal tumors lose characteristic morphological traits completely and cannot be subtyped using solely conventional staining microscopy. Determining metastatic cell origin, in advanced RCCs, with the additional difficulty of non-renal origin differentials, will most certainly require ancillary studies [6].
In fact, as a general consensus among pathologists, no truly reliable, objective, and validated histologic/ultrastructural criteria exist for distinguishing between benign and malignant renal epithelial tumors [18], with the very meek exception of oncocytomas and small low-grade papillary adenomas (≤5 mm) [18]. Furthermore, the amounting, emergent RCC clinical entities, have shown, for the most part, unspecific and poorly defined architectures, with heavily disputed morphological growth characteristics. Even within conventional RCC morphologies, absolute homogeneity is extremely rare and non-specific arrangement patterns (solid, papillary, tubular/cystic, sarcomatoid/rhabdoid) and cellular features (cytoplasmic clearing, eosinophilia/basophilia) are routinely identified, particularly in high-grade and/or poorly preserved tumor areas. Clearly, meticulous sampling of gross RCC specimens, especially in those which prove to be difficult to classify, will prove to be much more useful and cost-effective than additional staining. Transitional areas, from well-differentiated/low-grade patterns to more unusual, pleomorphic patterns, should be sought after and evaluated preferentially, as they usually offer the most useful diagnostic information [6][19].
All in all, conventional microscopic evaluation of RCC morphology remains an important initial step in tumor pathological analysis. It allows for an essential primary classification into RCC predominant morphological trait subgroups, simplifying the differential diagnosis and guiding further targeted analysis, while greatly reducing financial costs. Even so, it has become insufficient for an accurate definitive RCC diagnosis and prognosis assessment.

3. Definitions and Comprehensive Profiles for RCC Subtyping

Definitive RCC pathological diagnosis, meaning irrefutable demonstration of tumor renal cell origin and accurate RCC subtype identification, as well as the subsequent prognosis assessment, requires careful integration of clinical, pathological, and molecular characteristics, to allow for objective carcinogenic metabolic profiling and characterization of progression-driving tumor biology. Thus, as our understanding of RCC molecular pathology has become more nuanced, ancillary studies, mainly immunohistochemistry (IHC), has become integrated in clinical practice, as essential tools for routine RCC pathological evaluation. Despite the plethora of seemingly promising diagnostic and predictive applications reported, for the dozens of novel tumor-associated molecules and their corresponding IHC targeted-antibodies, due to the lack of validation studies, these data constitute no more than level 2/3 evidence. Moreover, heterogeneity within existing data regarding specific IHC methodology and antibody clone used (monoclonal/polyclonal) further encumbers comparisons between existing results [20][21][22][23][24][25][26]. In fact, as an investigative method, IHC has multiple inherent conceptual limitations, as well as significant technical (clone selection, titration, validation, false positives/negatives etc.) and interpretative (subcellular localization and pattern) weaknesses [19]. Table 1 provides a comprehensive summary of evidence regarding morphological, IHC, and genetic profiles for all currently accepted RCC subtypes.
A recurring issue is represented by the indiscriminate use of an inordinate number of antibodies, without a reasonable, structured, diagnostic approach, which only serves to generate additional confusion, while simultaneously wasting valuable resources. For this reason, in 2012, the International Society of Urological Pathology (ISUP) reviewed the use of IHC antibodies in adult renal tumors, in order to develop best practice recommendations regarding determining site of origin, typing, and prognosis, with the ultimate goal of establishing formal panels of biomarkers for specific diagnostic difficulties and, implicitly, establishing adequate guidelines for stewardship [6][19]. For a more systematic and practical approach to RCC subtyping, individual, differential diagnosis-driven IHC marker panels have been established (see Table 2), in order to differentiate among entities within the main RCC subgroups, manifesting specific morphological characteristics, namely predominantly clear cell (cc) population, significant papillary (p) component, extensive cytoplasmic eosinophilia, predominant sarcomatoid growth pattern, and architecture suggestive of distal nephron origin—collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC). Quantitative and qualitative assessments of the staining results are equally important and continuous refinement of antibody panels, taking into account the proven value of new IHC markers and new clones of established markers, as they enter the market, is mandatory [6].
Overall, Paired box (PAX) 8, a transcription factor (415 aminoacids/48 kDa), involved in kidney, thyroid, and paramesonephric duct-derived, organogenesis, and homeostasis, represents the most useful IHC marker for establishing the diagnosis of metastatic RCC(mRCC) [27], being expressed in all RCC subtypes, including sarcomatoid RCC, mucinous tubular and spindle cell carcinoma (MTSC), and microphtalmia (MiT)-family translocation RCC, with a sensitivity of approximately 95% [28]. In healthy kidney tissue, PAX8 normally manifests diffuse staining in the, preferentially distal, renal tubules, and patchy staining of urothelium in the renal pelvis. In accordance with this pattern of developmental expression, in addition to RCCs, PAX8 consistently stains Műllerian neoplasms and thyroid neoplasms, and, in smaller subsets (~20%), urothelial carcinomas of the renal pelvis, Wolffian duct lesions, and thymic neoplasms [6].
Out of the PAX gene family for tissue specific transcription factors [29], PAX8 is generally the more sensitive marker [30]. PAX2 stains similarly to PAX8 [31][32]; with the possibly useful difference of negative PAX2 staining in thyroid neoplasms, admittedly only reported in small series [33]. When using older, polyclonal preparations, endocrine neoplasms (pancreatic islet cell tumors and gastrointestinal tract carcinoids) are often positive for PAX8; however, cross-reactivity with PAX6 is clarifying [34]. Additionally, B-cell lymphomas stain positive on polyclonal PAX8 preparation, while also manifesting cross-reaction with PAX5.
Table 1. Summary of evidence regarding RCC histological, IHC, and genetic profiles [5][6][19][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116].
TYPE MYCROSCOPY IHC STAINING GENETICS
Clear cell (cc) RCC Hypercellularity: nests/sheets of cells, manifesting cytoplasmatic clearing and individualized membranes. Granular eosinophilic cytoplasm, seen in high-grade areas or near hemorrhage/necrosis. Rarely, intra/extracellular hyaline globules, basophilic cytoplasmic inclusions, abundant multinucleated giant cells.
Architecture: solid, alveolar/nested, acinar/tubular, microcystic/macrocystic, rarely pseudopapillary.
Stroma: ussually nonspecific, without desmoplasia or inflamatory modifications; may be fibromyxoid, with calcification/ossification.
Hypervascular tumor: ramified network of small calibre, thin-walled vessels.
High grade features: rhabdoid/sarcomatoid differentiation.		 POSITIVE: PAX8 (nuclear, ~100%); CAIX (diffuse membranous/box-like, 75–100%); proximal tubular antigens (also seen in normal cells): CD10 (membranous, 82–94%) and RCCm (cytoplasmic and membranous, 72–84%); epithelial markers (AE1/AE3, CAM 5.2, EMA); Vimentin (cytoplasmic and membranous).
NEGATIVE: CK7 (focally positive or patchy in high grade areas or cystic components); CK20; AMACR; 34βE12; CD117; HMB-45; TFE3/TFEB; Cathepsin-K; GATA3; MelanA; Inhibin.		 SPORADIC:
3p loss/deletions or biallelic alteration of VHL gene (3p25) by mutation or hypermethylation (80–98%).
ccRCC tumor suppressor genes harbored by 3p locus: KD-M6A (or UTX), KDM5C (or JARID1C), SETD2 and PBRM1.
Loss of chromosome 4p, 8p, 9p, 14q. Gain of chromosome 5q.
Mutations in BAP1 and PBRM1 genes.
FAMILIAL:
Von Hippel-Lindau disease;
constitutional chromosome 3 translocations.
Papillary (p) RCC Type 1 Hypovascular tumor.
Cellularity: small cuboidal cells; uniform, diminished, pale/basophilic cytoplasm; hyperchromatic nuclei, absent nucleoli, lower grade than type 2; foamy macrophages and psammoma bodies are usually encountered.
Architecture: single layer of of cells around fibrovascular cores (papillary), tubules and glomeruloid structures.		 POSITIVE: PAX8; CK7 (diffuse, but strong);
EMA (polarized expression); AMACR; AE1/AE3; CD10.
NEGATIVE: CAIX; GATA3; p63; 34βE12; TFE3/TFEB; Cathepsin-K.		 SPORADIC:
Activating mutations or amplifications of MET proto-oncogene in >80% of sporadic cases.
Gains in chromosomes 3, 7, and 17.
FAMILIAL:
Hereditary papillary renal carcinoma (HPRC).
pRCC Type 2 Cellularity: abundant eosinophilic cytoplasm; frequent nuclear atypia with clearly visible nucleoli (usually ISUP grade ≥3) and nuclear grooves; intracytoplasmic hemosiderin; possible areas of clear cytoplasm; less frequent foamy macrophages and psammoma bodies than type 1.
Architecture: papillary, with pseudostratified layers of large cells; variable necrosis.		 POSITIVE: PAX8; CD10; AMACR;
Topoisomerase II alpha.
NEGATIVE: CAIX; CK7 (or patchy positive); EMA (or focal positive); p63; HMB45; MelanA; Cathepsin-K; 34βE12; GATA3; TFE3/TFEB.		 SPORADIC:
Less consistent than type 1. Heterogeneous, losses or gains of chromosomes 1, 3, 4, 5, 6, 8, 9, 10, 11, 15, 18, and 22.
NRF-ARE2 pathway amplification. 8q gains and allelic imbalance of 9q13 (prognostic significance). In advanced stages, CDKN2A/B (18%), TERT (18%), NF2 (13%) and FH (13%) are commonly altered.
FAMILIAL:
FH gene (1q42–43) mutation in HLRCC.
Chromophobe (ch) RCC Cellularity: sharply defined, pale cells; “plant-like” cell borders (“vegetable cells”); wrinkled and angulated, irregular nuclei, with coarse chromatin (“raisinoid”); frequent bi/multinucleation and perinuclear halo (koilocytic atypia), with rare mitotic figures; Fuhrman/WHO nuclear grading has no prognostic value and is discouraged.
2 types of cellular morphologies:
Type 1—large, polygonal cells, hard cell borders, abundant cytoplasm with reticular pattern (classical variant);
Type 2—smaller cells with finely granular eosinophilic cytoplasm (predominant in eosinophilic variant).
Architecture: confluent, solid growth with nests, sheets or alveoli/trabeculae; minimal stroma, composed of incomplete fibro-vascular septae around solid sheets; minimal vasculature.		 POSITIVE: PAX8; Hale colloidal iron (histochemical stain; diffuse and strong, reticular); CK7 (diffuse and strong); CD117 (membranous); Ksp-cadherin (+/−); GATA3(+/−); E-cadherin; claudin7 (distal nephron marker); EMA (diffuse cytoplasmic); LMWCK (CK8/CK18); RCCm; CD10; Parvalbumin (calcium binding protein); Cytochrome c oxidase; DOG1; Progesteron Receptor (90% of cells); PDL1 22C3 (in a minority of cases).
NEGATIVE: Vimentin (or weak); CAIX; AMACR; N-cadherin; Cathepsin-K; HMB-45; low Ki67 labeling index; Cyclin D1.		 SPORADIC:
Multiple losses of whole chromosomes: 1, 2, 6, 10, 13, 17, 21 or Y.
DNA rearrangement breakpoints within the TERT promoter region.
Mutated TP53 and PTEN in 10–30% of cases (TCGA cohort) and NRAS, mTOR and TSC1/TSC2 in ~5%.
Mutations in mitochondrial DNA most commonly affect MT-ND5, with increased expression of genes encoding Krebs cycle enzymes.
FAMILIAL:
Birt-Hogg-Dube (BHD) syndrome—FLCN gene mutation (17p11.2)
Clear Cell Papillary (ccp) RCC Cellularity: clear cytoplasm; characteristic linear arrangement of nuclei away from the basal aspect of cells; low nuclear grade (Fuhrman grade 1–2).
Architecture: variable mixture of cystic, branched tubular, solid and papillary components; papillae often tightly packed into anastomosing clear cell ribbons or projecting into cystic spaces; fibrous capsule and variable amounts of hyalinized or sclerotic stroma that may separate the tumor into nodules; never encountered: foamy macrophages, vascular invasion, oxalate crystals, necrosis.		 POSITIVE: PAX8; CK7 (strong and diffuse); CAIX (diffuse membranous or characteristic “cup shaped” distribution—lack of staining along luminal aspect); AE1/AE3; CAM 5.2; Vimentin; EMA; GATA3 (+/−); 34βE12.
NEGATIVE: AMACR; CD10; RCCm; TFE3/TFEB; low PCNA; CD117; Cathepsin-K; HMB-45.		 No specific genomic imbalances.
Lacks genetic modifications of classic pRCC (no +7/+17 or -Y) and/or classic ccRCC (no -3/-3p).
Activation of hypoxia inducible factor (HIF) pathway, with underexpressed VHL transcripts, but without typical VHL mechanism (no VHL gene mutations/promoter hypermethylation).
May appear in VHL disease.
Collecting duct carcinoma (CDC) Cellularity: irregular channels, lined with high-grade cuboidal to hobnail cells, with eosinophilic cytoplasm; pleomorphic kariomegaly, with visible nucleoli and coarse chromatin; abundant mitosis.
Architecture: the tumor is complex, infiltrative, and poorly circumscribed, composed of cords, tubules, tubulopapillary or tubulocystic structures, within an inflammatory-desmoplastic stroma; intracytoplasmic/intraluminal mucin, microcystic changes from dilation of the tubular structures and sarcomatoid transformation may be present. Tumor-adjacent tubular epithelium, lining collecting ducts, may appear dysplastic.		 POSITIVE: PAX8/PAX2; HMWCK (34βE12); LMWCK (CK7, CK8/18, CK19); Ulex europaeus lectins (Ulex-1); peanut lectin agglutinin (PNA); Mucin (strong); Vimentin; EMA; S100A1; INI-1/BAF47 retained.
NEGATIVE: p63; Uroplakin II; CD10; AMACR; E-cadherin; CAIX; OCT3/4; CD117; GATA3.		 Lacking loss of 3p or trisomies 7 and 17. HER2/neu amplifications in 45% of cases. Genomic alterations in NF2 (29%), SETD2 (24%), SMARCB1 (18%) and CDKN2A (12%). Recurrent somatic single nucleotide variants in ATM, CREBBP, PRDM1, CBFB, FBXW7, IKZF1, KDR, KRAS, NACA, NF2, NUP98, SS18, TP53 and ZNF521. SLC7A11 (cisplatin resistance associated gene), overexpressed in 80% of cases.
Renal medullary carcinoma (RMC) Cellularity: cohesive groups of pleomorphic tumor cells, with vacuolated eosinophilic cytoplasm, that often displaces or indents the hyperchromatic, enlarged nuclei; nuclear membranes are often irregular, with coarse or vesicular chromatin and prominent nucleoli; rhabdoid traits are frequent; abundant intratumoral neutrophils and lymphocytes at tumor rim; abundant sickled erythrocytes (drepanocytes) may be pathognomonic.
Architecture: multiple distinct morphologic patterns—reticular; microcystic and adenoid cystic-like; tubular, glandular, tubulopapillary and solid (overlapping with CDC patterns); hemorrhagic and geographic necrosis; angiolymphatic invasion, desmoplastic stroma and infiltrative borders.		 POSITIVE: CAM 5.2; AE1/AE3; CK7/CK20 (may be variable); Vimentin; EMA and CEA; p53; PAX8; OCT3/4; Ulex-1 (focally positive in a minority of cases); vascular endothelial growth factor (VEGF) and hypoxia inducible factor (HIF) may be strongly positive.
NEGATIVE: Loss of INI-1/BAF47 expression; colloidal iron; PAS; desmin; 34βE12; GATA3		 Prevalent loss of SMARCB1/INI1, a major driving feature, identifiable by IHC. Hypoxia inducible factor and VHL abnormalities.
ALK rearrangement with vinculin (VCN) fusion. DNA topoisomerase II amplification.
Rarely, vinculin—ALK fusion (young patients, less aggressive).
Associated with sickle cell trait (monosomy 11—beta globin gene is at end of 11p).
Succinate dehydrogenase deficient renal (SDHD) RCC Cellularity: flocculent, pale, eosinophilic, cytoplasmic vacuolation, with a wispy/bubbly appearance and low grade nuclei, with smooth nuclear contours and fine chromatin, with no nucleoli, represents a characteristic finding and must be present at least focally.
Architecture: well circumscribed tumor or with a “pushing” border, commonly entrapping tubules; solid, nested or tubular growth pattern with scattered cysts containing eosinophilic material; necrosis, sarcomatoid change and areas with higher grade nuclei may also be present; variant morphologies have been rarely reported.
Shares features with chRCC, oncocytoma, ccRCC and pRCC type 2.		 POSITIVE: PAX8; focal pancytokeratin and
CAM 5.2; EMA.
NEGATIVE: Loss of SDHB IHC staining (indicates disruption of the mitochondrial complex 2 for any reason, not just SDHB gene mutation and caution regarding overinterpretation of negativity in tumors with very clear cytoplasm is essential); CK7; CK20; AE1/AE3; CAIX; RCCm; CD117 (mast cells only); Vimentin; S100A1; TFE3/TFEB; neuroendocrine markers;
minimal AMACR staining.		 Wild-type VHL, PIK3CA, AKT, mTOR, MET or TP53 genes.
Genes for succinate dehydrogenase subunits (SDH-A, -B, -C, -D), encode protein components of mitochondrial complex II, linking the Krebs cycle with the electron transport chain, being involved in most cases of SDHD RCC. Germline mutations of SDH-A, SDH-B (1p36.13), SDH-C (1q23.3), SDH-D(11q23.1), SHDAF2, determining double hit inactivation, leads to dysfunction of mitochondrial complex II, increased oxidative stress, genomic injury and HIF1α stabilization.
Microphtalmia family translocation (MiT) RCC—Xp11/t(6;11) Cellularity: voluminous cytoplasm and high-grade nuclei, with frequent psammoma bodies and occasional melanin pigment, similar to a pigmented perivascular epithelioid tumor—(PEC)coma.
t(6:11) rearranged carcinomas are characteristically biphasic, with small cells clustered around basement membrane material (reminiscent of Call-Exner bodies in adult granulosa cell tumor) and larger epithelioid cells.
Architecture: usually papillary and solid alveolar growth pattern, composed of clear to eosinophilic, discohesive pseudostratified cells.		 POSITIVE: TFE3/TFEB (strong nuclear staining, but difficult to standardize on automated platforms; FISH assays are more reliable)—weak TFE3 staining in adults may not be specific; PAX8; Cathepsin-K (~50%, cytoplasmic); CD10; AMACR; Vimentin; E-cadherin; melanocytic markers (HMB45 and MelanA), are common for t(6:11) carcinomas, but always focal, and infrequent for Xp11, which usually manifest variable CD117.
NEGATIVE: Variable cytokeratin (only 30–50% positive, less than other RCC types) and EMA (50%, frequently only focal); CAIX usually negative except areas of necrosis; CK7; 34βE12; CD45; calretinin; smooth muscle actin.		 Fluorescence in situ hybridization (FISH) with a TFE3/TFEB breakapart probe is highly sensitive and specific, offering the final diagnosis when morphology and IHC are inconclusive.
The TFE3 gene (on Xp11) has been reported to have multiple translocation gene partners, most commonly, ASPL (17q25) and PRCC (1q21), and less commonly NONO (Xq12), PSF/SFPQ (1p34), CLTC (17q23).
t(6;11)(p21;q12), a translocation between TFEB and MALAT1 genes, results in overexpression of TFEB.
t(X;17)(p11.2;q25), with balanced translocation of TFE3 gene at Xp11.2 and ASPL gene at 17q25, is present in renal neoplasms, whereas in alveolar soft part sarcoma, this translocation is unbalanced, der(17)t(X;17)(p11.2;q25).
Melanotic Xp11 RCC and PSF/SFPQ-TFE3 (PEComa), may share the same genetic abnormalities.
Acquired cystic disease-associated (ACDA) RCC Cellularity: moderately cellular, papillary clusters of polygonal to columnar cells with abundant eosinophilic granular cytoplasm, round and central nuclei, finely granular chromatin, prominent, central, grade 3 nucleoli; sometimes with prominent clear cell cytology.
Architecture: cribriform, microcystic or sieve-like layout; intratumoral calcium oxalate crystals are very common, but not mandatory for diagnosis; nodules arising from cyst walls or masses separated from cysts may be encountered.		 POSITIVE: No specific IHC profile is required for diagnosis. CD10; AE1/AE3; AMACR;
NEGATIVE: EMA; CK7 (but may be focally positive).		 Comparative genomic microarray and FISH studies reveal gains and losses of multiple chromosomes.
Gains of sex chromosomes and gains of 3, 7, 16, 17, with a high prevalence of gains of Y, 3 and 16, distinguishing ACDA RCC from pRCC, which also has gains in chromosomes 7 and 17.
VHL gene alterations. Chromosome 3p deletion.
Multilocular cystic clear cell renal neoplasm of low malignant potential (MCLMP) RCC Cellularity: single layer of clear cells lining thin fibrous septae or in small clusters; low grade nuclei without nucleoli (ISUP grade 1–2); bland clear cells in septa may be mistaken for lymphocytes (vascularity is important).
Architecture: cyst lining may be denuded and, in rare cases, cyst lining may be multilayered, with granular cytoplasm cells and small intracystic papillations; septa may contain calcification or ossification; no expansile growth of clear tumor cells/solid nodules; no necrosis, vascular invasion or sarcomatoid change.		 POSITIVE: PAX8/PAX2; CA IX; EMA; variable CK7.
NEGATIVE: AMACR (negative in 80% of cases).		 Genetically related to ccRCC, with 74% of cases demonstrating 3p loss and VHL mutations identified in 25%.
Tubulocystic
(TC) RCC		 Cellularity: tubules/cysts are lined by a single layer of flattened, cuboidal or columnar cells; hobnailing may be present, with modest to abundant amounts of eosinophilic cytoplasm, resembling oncocytoma cell; uniform, round nuclei, with distinct nucleoli (ISUP grade 3); minimal mitotic activity and atypia; very rare necrosis.
Architecture: mixture of closely packed tubules and variably sized cysts, with overall low-grade morphology; cysts are separated by fibrous septa; no desmoplasia or cellular stroma; frequently associated with papillary cell neoplasms.		 POSITIVE: CK7; AMACR; Vimentin; EMA; PAX8; fumarate hydratase (FH); Mucin; keratins (AE1/AE3, Cam 5.2, CK8/18, CK19); variable 34βE12; CD10.
NEGATIVE: 2 succino-cysteine, CA IX and CD117.		 Distinct molecular signature from other RCCs.
Frequently, gains of chromosomes 7 and 17, and loss of Y, similar to pRCC.
Mutations in 14 different genes have been documented by targeted, next generation sequencing, most frequently (60% of cases) in ABL1 and PDFGRA genes.
Mucinous tubular and spindle cell (MTSC) RCC Cellularity: relatively uniform, bland, low-grade cuboidal cells, with round to oval nuclei and focally vacuolated, eosinophilic cytoplasm, within strands of metachromatic stromal tissue, which transition into anastomosing spindle cells; may present clear cells and focal clusters of foamy macrophages; rare high-grade nuclei may be present.
Architecture: well circumscribed epithelial tumor, partially surrounded by a rim of compressed fibrous tissue; long tubular/cord-like growth pattern; myxoid and bubbly stroma, with abundant extracellular mucin, highlighted by Alcian blue (although some cases may be mucin poor); may manifest well-formed papillae, necrosis, rarely neuroendocrine differentiation or sarcomatoid change; usually, infiltrative growth, desmoplasia, inflammation, hobnail epithelium, and/or cysts are not encountered.		 POSTIVE: PAX2/PAX8; EMA (95%); AMACR (93%); AE1/AE3; E-cadherin; LMWCK: CK7 (81%); CK 8/18; CK19; Neuron Specific Enolase (NSE) and either Chromogranin or Synaptophysin.
Histochemical stains: Periodic Acid-Schiff (PAS) (basal lamina around tubules), Alcian blue (mucin).
Occasionally, HMWCK: 34βE12 (15%); vimentin; Ulex or CD10 (15%).
NEGATIVE: CA IX (positive next to necrosis or focal cytoplasmatic in high-grade areas); GATA3; p63; RCCm (positive in 7%); Villin;
Ki67 (<1%).		 Seemingly lacking the characteristic genetic modifications of classic pRCC
(trisomies of chromosomes 7/17 or loss of chromosomes Y).
Usually hypodiploid, with multiple chromosomal losses
(-1, -4, -6, -8, -9, -13, -14, -15, -22), even hypertriploid in some cases, but with no identifiable pattern.
Hybrid oncocytic-chromophobe (HOCh) RCC Cellularity: usually, dual population of eosinophilic cells—oncocytic (medium sized, round cell, with granular eosinophilic cytoplasm and concentric round nucleus, low nuclear:cytoplasmic ratios, prominent nucleolus) and chromophobe (large, polygonal, “plant-like” cell, with a distinct cell membrane, containing flaky eosinophilic cytoplasm, often with a perinuclear halo and an irregular “raisinoid” wrinkled nucleus), with a third cell subtype, manifesting overlapping cytonuclear features of both oncocytic and chromophobe morphology, being sometimes encountered; mitotic rate is very low.
Architecture: well circumscribed, non-infiltrative, intrarenal tumor, with a solid alveolar and cystic architecture; may manifest vascular invasion and, rarely, necrosis.		 POSITIVE: CK7 (may be focal); AE1/AE3;
Parvalbumin; Antimitochondrial Antigen; EMA; E-cadherin (most); CD117; S100A1; CD82; Vimentin (few cases); Hale colloidal iron (stains apical/luminal oncocytic cells and, often, intracytoplasmic in chromophobe cells.
NEGATIVE: AMACR; CK20; CD10 and CA IX.		 SPORADIC:
May present numerous molecular anomalies (both mono- and polysomies) of chromosomes 1, 2, 6, 9, 10, 13, 17, 21, and 22. Lack of mutations in the VHL, c-kit, PDGFRA, and FLCN genes.
FAMILIAL:
May be associated with BHD, autosomal dominant syndrome, characterized by a genetic abnormality on chromosome 17p11.2, leading to a mutation in the FLCN gene.
Table 2. Differential diagnosis-driven IHC panels and profiles for morphological RCC traits [6][19].
Predominant
Morphological Trait		 Specific Panel Entities Entering Differential Diagnosis with
Corresponding IHC Profiles
Clear cell
Population		 CAIX
CK7
CD117
Cathepsin-K
HMB-45		 ccRCC: CAIX(+, diffuse membranous), CK7(−), CD117(−), Cathepsin-K(−), HMB-45(−)
ccPRCC: CAIX(+, cup-like pattern), CK7(+), CD117(−), Cathepsin-K(−), HMB-45(−)
classic chRCC: CAIX(−), CK7(+, cytoplasmic), CD117(+, membranous), Cathepsin-K(−), HMB-45(−)
eAML: CAIX(−), CK7(−), CD117(−), Cathepsin-K(+, cytoplasmic), HMB-45(+, cytoplasmic)
MiT-TFE RCC:
- Xp11/TFE3: CAIX(+/−, focal), CK7(−), CD117(+/−), Cathepsin-K (+, 50%, cytoplasmic), HMB-45(−)
- t[6;11]/TFEB: CAIX(+/−, focal), CK7(−), CD117(−), Cathepsin-K(+, cytoplasmic), HMB-45(+, focal)
Papillary
Component		 CAIX
CK7
AMACR
Cathepsin-K
34βE12
TFE3/TFEB		 ccRCC with papillary growth: CAIX(+, membranous), CK7(−), AMACR(−), Cathepsin-K(−), 34βE12(−), TFE3/TFEB(−)
pRCC “type I”: CAIX(−), CK7(+), AMACR(+), Cathepsin-K(−), 34βE12(−), TFE3/TFEB(−)
pRCC “type II”: CAIX(−), CK7(+/variable), AMACR(+), Cathepsin-K(−), 34βE12(−), TFE3/TFEB(−)
ccPRCC: CAIX(+, cup-like pattern), CK7(+, diffuse), AMACR(−), Cathepsin-K(−), 34βE12(−), TFE3/TFEB(−)
MiT-TFE RCC: CAIX(variable, focal), CK7(−), AMACR(+), Cathepsin-K(+, 50%), 34βE12(−), TFE3/TFEB(+, but difficult to standardize on automated platforms, requires FISH assays)
Solid growth pattern CK7
AMACR
WT-1
CD57		 Solid pRCC “type I”: CK7(+), AMACR(+), WT-1(−), CD57(−)
Metanephric adenoma: CK7(−)/isolated cells, AMACR(−), WT-1(+, nuclear), CD57(+)
Wilms’ Tumor: CK7(−)/isolated cells, AMACR(−), WT-1(+, nuclear), CD57(−)
Cytoplasmic
Eosinophilia		 CD117
CK7
Ksp-cadherin
HMB-45
Cathepsin-K		 Oncocytoma: CD117(+, membranous), CK7(−), Ksp-cadherin(+), HMB-45(−), Cathepsin-K(−)
Eosinophilic chRCC: CD117(+, membranous), CK7(+, but variable), Ksp-cadherin (+, mostly), HMB-45(−), Cathepsin-K(−)
Oncocytic PRCC: CD117(−), CK7(+, focal), Ksp-cadherin (unknown), HMB-45(−), Cathepsin-K (unknown)
Oncocytic AML: CD117(−), CK7(−), Ksp-cadherin(−), HMB-45(+, focal), Cathepsin-K(−)
Sarcomatoid
growth pattern		 Vimentin
CAIX
PAX8
CK7
34βE12
GATA3
p63		 ccRCC: Vimentin(+), CAIX(+) membranous, PAX8(+), CK7(−), 34βE12(−), GATA3(−), p63(−)
pRCC: Vimentin(+), CAIX(−), PAX8(+), CK7(focal/-), 34βE12(−), GATA3(−), p63(−)
chRCC: Vimentin(+), CAIX(−), PAX8(+), CK7(+), 34βE12(−), GATA3(−), p63(−)
MTSC: Vimentin(+), CAIX(−), PAX8(+), CK7(+), 34βE12(variable), GATA3(−), p63(−)
Urothelial: Vimentin(+), CAIX variable/mostly(−), PAX8 mostly(−), CK7(+), 34βE12(+), GATA3(+), p63(+)
Sarcoma: Vimentin(+), CAIX(−), PAX8(−), CK7(−), 34βE12(−), GATA3(−), p63(−)
Distal nephron origin INI-1/BAF47
OCT4
GATA3
PAX8		 CDC: INI-1/BAF47 (+, and—in 15%), OCT4(−), GATA3(−), PAX8(+)
RMC: INI-1/BAF47 (−), OCT4(+), GATA3(−), PAX8(+)
Urothelial: INI-1/BAF47 (+), OCT4(−), GATA3(+), PAX8(−, but + in 20%)
Novel PAX8 antibodies (PAX8R1), to address the specificity issues of polyclonal PAX8 preparations, have been developed. They bind to the C-terminal of PAX8, targeting amino acids 318–426, which are highly divergent among PAX proteins, thus abolishing cross-reactivity with other PAX species [117].
Further nuancing of IHC differential diagnosis in mRCC involves markers almost always negative in RCC, such as pulmonary marker TTF-1, the intestinal marker homeobox protein CDX2, p63, prostate-specific antigen, and estrogen receptor, which will be useful in excluding other carcinomas that may manifest cross-positivity for PAX8. Positive staining with any of the aforementioned markers represents a strong argument against the diagnosis of mRCC [6]. Another useful distinction, between urothelial and renal epithelial origins, can be made using GATA3, a transcription factor involved in cell differentiation and proliferation in a variety of tissues and cell types, which will be expressed in most urothelial tumors, but not in RCCs [118][119].
Other supportive IHC markers of mRCC, currently in common practice—cluster of differentiation (CD)10, RCC marker antigen (RCCm), Kidney-Specific Cadherin (Ksp-cadherin)—manifest inadequate specificity and are not usually indicated or useful, outside of very specific, punctual, diagnostic subtleties.
RCCm stains a proximal tubular antigen and demonstrates focal labeling in approximately 80% of RCC [120][121], yet with notoriously poor specificity, seeing as it also labels many other carcinomas (breast, lung, colon, and of adrenal origin). It is useful in differentiating clear cell RCC (ccRCC) from ovarian clear cell carcinoma, as PAX8 would be positive in both tumors, whereas RCCm would be positive only in the renal neoplasm. Moreover, PAX8 is negative in adrenal cortical neoplasms, which preferentially stain for steroid factor-1 [122].
Another proximal tubular marker, CD10, also manifests high sensitivity, but again very low specificity for RCC, as lung, bladder, colon, and ovarian carcinomas all label for CD10 [123]. However, CD10 fairly consistently labels ccRCC, thus CD10 negative metastatic lesions represent an argument against this diagnosis for the primary tumor.
Lastly, Ksp-cadherin, a distal tubular marker, manifests high sensitivity for chromophobe RCC (chRCC), although it is not so useful in the metastatic diagnosis context, as the chromophobe variant rarely disseminates systemically [124]. Even so, at least focal staining can also be seen in other renal tumor variants, including high-grade ccRCC.

References

  1. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer Statistics, 2020. CA Cancer J. Clin. 2020, 70, 7–30.
  2. Decastro, G.J.; McKiernan, J.M. Epidemiology, Clinical Staging, and Presentation of Renal Cell Carcinoma. Urol. Clin. N. Am. 2008, 35, 581–592.
  3. Kane, C.J.; Mallin, K.; Ritchey, J.; Cooperberg, M.R.; Carroll, P.R. Renal Cell Cancer Stage Migration: Analysis of the National Cancer Data Base. Cancer 2008, 113, 78–83.
  4. Mancini, M.; Righetto, M.; Baggio, G. Gender-Related Approach to Kidney Cancer Management: Moving Forward. Int. J. Mol. Sci. 2020, 21, 3378.
  5. Moch, H.; Cubilla, A.L.; Humphrey, P.A.; Reuter, V.E.; Ulbright, T.M. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. Eur. Urol. 2016, 70, 93–105.
  6. Reuter, V.E.; Argani, P.; Zhou, M.; Delahunt, B.; Members of the ISUP Immunohistochemistry in Diagnostic Urologic Pathology Group. Best Practices Recommendations in the Application of Immunohistochemistry in the Kidney Tumors: Report from the International Society of Urologic Pathology Consensus Conference. Am. J. Surg. Pathol. 2014, 38, e35–e49.
  7. Novacescu, D.; Cut, T.G.; Cumpanas, A.A.; Latcu, S.C.; Bardan, R.; Ferician, O.; Secasan, C.-C.; Rusmir, A.; Raica, M. Evaluating Established Roles, Future Perspectives and Methodological Heterogeneity for Wilms’ Tumor 1 (WT1) Antigen Detection in Adult Renal Cell Carcinoma, Using a Novel N-Terminus Targeted Antibody (Clone WT49). Biomedicines 2022, 10, 912.
  8. Peckova, K.; Martinek, P.; Ohe, C.; Kuroda, N.; Bulimbasic, S.; Condom Mundo, E.; Perez Montiel, D.; Lopez, J.I.; Daum, O.; Rotterova, P.; et al. Chromophobe Renal Cell Carcinoma with Neuroendocrine and Neuroendocrine-like Features. Morphologic, Immunohistochemical, Ultrastructural, and Array Comparative Genomic Hybridization Analysis of 18 Cases and Review of the Literature. Ann. Diagn. Pathol. 2015, 19, 261–268.
  9. Hes, O.; Condom Mundo, E.; Peckova, K.; Lopez, J.I.; Martinek, P.; Vanecek, T.; Falconieri, G.; Agaimy, A.; Davidson, W.; Petersson, F.; et al. Biphasic Squamoid Alveolar Renal Cell Carcinoma: A Distinctive Subtype of Papillary Renal Cell Carcinoma? Am. J. Surg. Pathol. 2016, 40, 664–675.
  10. Trpkov, K.; Hes, O.; Bonert, M.; Lopez, J.I.; Bonsib, S.M.; Nesi, G.; Comperat, E.; Sibony, M.; Berney, D.M.; Martinek, P.; et al. Eosinophilic, Solid, and Cystic Renal Cell Carcinoma: Clinicopathologic Study of 16 Unique, Sporadic Neoplasms Occurring in Women. Am. J. Surg. Pathol. 2016, 40, 60–71.
  11. Falzarano, S.M.; McKenney, J.K.; Montironi, R.; Eble, J.N.; Osunkoya, A.O.; Guo, J.; Zhou, S.; Xiao, H.; Dhanasekaran, S.M.; Shukla, S.; et al. Renal Cell Carcinoma Occurring in Patients With Prior Neuroblastoma: A Heterogenous Group of Neoplasms. Am. J. Surg. Pathol. 2016, 40, 989–997.
  12. Kusano, H.; Togashi, Y.; Akiba, J.; Moriya, F.; Baba, K.; Matsuzaki, N.; Yuba, Y.; Shiraishi, Y.; Kanamaru, H.; Kuroda, N.; et al. Two Cases of Renal Cell Carcinoma Harboring a Novel STRN-ALK Fusion Gene. Am. J. Surg. Pathol. 2016, 40, 761–769.
  13. Hes, O.; Compérat, E.M.; Rioux-Leclercq, N. Clear Cell Papillary Renal Cell Carcinoma, Renal Angiomyoadenomatous Tumor, and Renal Cell Carcinoma with Leiomyomatous Stroma Relationship of 3 Types of Renal Tumors: A Review. Ann. Diagn. Pathol. 2016, 21, 59–64.
  14. Hakimi, A.A.; Tickoo, S.K.; Jacobsen, A.; Sarungbam, J.; Sfakianos, J.P.; Sato, Y.; Morikawa, T.; Kume, H.; Fukayama, M.; Homma, Y.; et al. TCEB1-Mutated Renal Cell Carcinoma: A Distinct Genomic and Morphological Subtype. Mod. Pathol. 2015, 28, 845–853.
  15. Dawane, R.; Grindstaff, A.; Parwani, A.V.; Brock, T.; White, W.M.; Nodit, L. Thyroid-like Follicular Carcinoma of the Kidney: One Case Report and Review of the Literature. Am. J. Clin. Pathol. 2015, 144, 796–804.
  16. Shi, J.; Wang, K.; Xiong, Z.; Yuan, C.; Wang, C.; Cao, Q.; Yu, H.; Meng, X.; Xie, K.; Cheng, Z.; et al. Impact of Inflammation and Immunotherapy in Renal Cell Carcinoma. Oncol. Lett. 2020, 20, 272.
  17. Iiyama, T.; Udaka, K.; Takeda, S.; Takeuchi, T.; Adachi, Y.C.; Ohtsuki, Y.; Tsuboi, A.; Nakatsuka, S.; Elisseeva, O.A.; Oji, Y.; et al. WT1 (Wilms’ Tumor 1) Peptide Immunotherapy for Renal Cell Carcinoma. Microbiol. Immunol. 2007, 51, 519–530.
  18. Partin, A.W.; Wein, A.J.; Kavoussi, L.R.; Peters, C.A.; Dmochowski, R.R. Neoplasms of the Upper Urinary Tract. In Campbell-Walsh-Wein Urology, 12th ed.; Elsevier Health Sciences; Elsevier: Amsterdam, The Netherlands, 2020; Volume 2, pp. 1438–1439, 2148.
  19. Amin, M.B.; Epstein, J.I.; Ulbright, T.M.; Humphrey, P.A.; Egevad, L.; Montironi, R.; Grignon, D.; Trpkov, K.; Lopez-Beltran, A.; Zhou, M.; et al. Best Practices Recommendations in the Application of Immunohistochemistry in Urologic Pathology: Report From the International Society of Urological Pathology Consensus Conference. Am. J. Surg. Pathol. 2014, 38, 1017–1022.
  20. Zhou, M.; Roma, A.; Magi-Galluzzi, C. The Usefulness of Immunohistochemical Markers in the Differential Diagnosis of Renal Neoplasms. Clin. Lab. Med. 2005, 25, 247–257.
  21. Skinnider, B.F.; Amin, M.B. An Immunohistochemical Approach to the Differential Diagnosis of Renal Tumors. Semin. Diagn. Pathol. 2005, 22, 51–68.
  22. Reuter, V.E.; Tickoo, S.K. Differential Diagnosis of Renal Tumours with Clear Cell Histology. Pathology 2010, 42, 374–383.
  23. Tickoo, S.K.; Reuter, V.E. Differential Diagnosis of Renal Tumors with Papillary Architecture. Adv. Anat. Pathol. 2011, 18, 120–132.
  24. Truong, L.D.; Shen, S.S. Immunohistochemical Diagnosis of Renal Neoplasms. Arch. Pathol. Lab. Med. 2011, 135, 92–109.
  25. Shen, S.S.; Truong, L.D.; Scarpelli, M.; Lopez-Beltran, A. Role of Immunohistochemistry in Diagnosing Renal Neoplasms: When Is It Really Useful? Arch. Pathol. Lab. Med. 2012, 136, 410–417.
  26. Tan, P.H.; Cheng, L.; Rioux-Leclercq, N.; Merino, M.J.; Netto, G.; Reuter, V.E.; Shen, S.S.; Grignon, D.J.; Montironi, R.; Egevad, L.; et al. Renal Tumors: Diagnostic and Prognostic Biomarkers. Am. J. Surg. Pathol. 2013, 37, 1518–1531.
  27. Ordóñez, N.G. Value of PAX 8 Immunostaining in Tumor Diagnosis: A Review and Update. Adv. Anat. Pathol. 2012, 19, 140–151.
  28. Sangoi, A.R.; Karamchandani, J.; Kim, J.; Pai, R.K.; McKenney, J.K. The Use of Immunohistochemistry in the Diagnosis of Metastatic Clear Cell Renal Cell Carcinoma: A Review of PAX-8, PAX-2, HKIM-1, RCCma, and CD10. Adv. Anat. Pathol. 2010, 17, 377–393.
  29. Chi, N.; Epstein, J.A. Getting Your Pax Straight: Pax Proteins in Development and Disease. Trends Genet. 2002, 18, 41–47.
  30. Sangoi, A.R.; Fujiwara, M.; West, R.B.; Montgomery, K.D.; Bonventre, J.V.; Higgins, J.P.; Rouse, R.V.; Gokden, N.; McKenney, J.K. Immunohistochemical Distinction of Primary Adrenal Cortical Lesions from Metastatic Clear Cell Renal Cell Carcinoma: A Study of 248 Cases. Am. J. Surg. Pathol. 2011, 35, 678–686.
  31. Ozcan, A.; Zhai, J.; Hamilton, C.; Shen, S.S.; Ro, J.Y.; Krishnan, B.; Truong, L.D. PAX-2 in the Diagnosis of Primary Renal Tumors: Immunohistochemical Comparison With Renal Cell Carcinoma Marker Antigen and Kidney-Specific Cadherin. Am. J. Clin. Pathol. 2009, 131, 393–404.
  32. Sharma, S.G.; Gokden, M.; McKenney, J.K.; Phan, D.C.; Cox, R.M.; Kelly, T.; Gokden, N. The Utility of PAX-2 and Renal Cell Carcinoma Marker Immunohistochemistry in Distinguishing Papillary Renal Cell Carcinoma from Nonrenal Cell Neoplasms with Papillary Features. Appl. Immunohistochem. Mol. Morphol. 2010, 18, 494–498.
  33. Zhai, Q.J.; Ozcan, A.; Hamilton, C.; Shen, S.S.; Coffey, D.; Krishnan, B.; Truong, L.D. PAX-2 Expression in Non-Neoplastic, Primary Neoplastic, and Metastatic Neoplastic Tissue: A Comprehensive Immunohistochemical Study. Appl. Immunohistochem. Mol. Morphol. 2010, 18, 323–332.
  34. Lorenzo, P.I.; Moreno, C.; Delgado, I.; Cobo-Vuilleumier, N.; Meier, R.; Gomez-Izquierdo, L.; Berney, T.; Garcia-Carbonero, R.; Rojas, A.; Gauthier, B. Immunohistochemical Assessment of Pax8 Expression during Pancreatic Islet Development and in Human Neuroendocrine Tumors. Histochem. Cell Biol. 2011, 136, 595–607.
  35. Paner, G.P.; Srigley, J.R.; Radhakrishnan, A.; Cohen, C.; Skinnider, B.F.; Tickoo, S.K.; Young, A.N.; Amin, M.B. Immunohistochemical Analysis of Mucinous Tubular and Spindle Cell Carcinoma and Papillary Renal Cell Carcinoma of the Kidney: Significant Immunophenotypic Overlap Warrants Diagnostic Caution. Am. J. Surg. Pathol. 2006, 30, 13–19.
  36. The Cancer Genome Atlas Research Network. Comprehensive Molecular Characterization of Clear Cell Renal Cell Carcinoma. Nature 2013, 499, 43–49.
  37. Srigley, J.R.; Delahunt, B.; Eble, J.N.; Egevad, L.; Epstein, J.I.; Grignon, D.; Hes, O.; Moch, H.; Montironi, R.; Tickoo, S.K.; et al. The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia. Am. J. Surg. Pathol. 2013, 37, 1469–1489.
  38. Cheville, J.C.; Lohse, C.M.; Zincke, H.; Weaver, A.L.; Leibovich, B.C.; Frank, I.; Blute, M.L. Sarcomatoid Renal Cell Carcinoma: An Examination of Underlying Histologic Subtype and an Analysis of Associations with Patient Outcome. Am. J. Surg. Pathol. 2004, 28, 435–441.
  39. Mantilla, J.G.; Antic, T.; Tretiakova, M. GATA3 as a Valuable Marker to Distinguish Clear Cell Papillary Renal Cell Carcinomas from Morphologic Mimics. Hum. Pathol. 2017, 66, 152–158.
  40. Chevarie-Davis, M.; Riazalhosseini, Y.; Arseneault, M.; Aprikian, A.; Kassouf, W.; Tanguay, S.; Latour, M.; Brimo, F. The Morphologic and Immunohistochemical Spectrum of Papillary Renal Cell Carcinoma: Study Including 132 Cases with Pure Type 1 and Type 2 Morphology as Well as Tumors with Overlapping Features. Am. J. Surg. Pathol. 2014, 38, 887–894.
  41. Perret, A.G.; Clemencon, A.; Li, G.; Tostain, J.; Peoc’h, M. Differential Expression of Prognostic Markers in Histological Subtypes of Papillary Renal Cell Carcinoma. BJU Int. 2008, 102, 183–187.
  42. Pal, S.K.; Ali, S.M.; Yakirevich, E.; Geynisman, D.M.; Karam, J.A.; Elvin, J.A.; Frampton, G.M.; Huang, X.; Lin, D.I.; Rosenzweig, M.; et al. Characterization of Clinical Cases of Advanced Papillary Renal Cell Carcinoma via Comprehensive Genomic Profiling. Eur. Urol. 2018, 73, 71–78.
  43. Cancer Genome Atlas Research Network; Linehan, W.M.; Spellman, P.T.; Ricketts, C.J.; Creighton, C.J.; Fei, S.S.; Davis, C.; Wheeler, D.A.; Murray, B.A.; Schmidt, L.; et al. Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. N. Engl. J. Med. 2016, 374, 135–145.
  44. Saleeb, R.M.; Brimo, F.; Farag, M.; Rompré-Brodeur, A.; Rotondo, F.; Beharry, V.; Wala, S.; Plant, P.; Downes, M.R.; Pace, K.; et al. Toward Biological Subtyping of Papillary Renal Cell Carcinoma With Clinical Implications Through Histologic, Immunohistochemical, and Molecular Analysis. Am. J. Surg. Pathol. 2017, 41, 1618–1629.
  45. Yang, X.J.; Tan, M.-H.; Kim, H.L.; Ditlev, J.A.; Betten, M.W.; Png, C.E.; Kort, E.J.; Futami, K.; Furge, K.A.; Takahashi, M.; et al. A Molecular Classification of Papillary Renal Cell Carcinoma. Cancer Res. 2005, 65, 5628–5637.
  46. Antonelli, A.; Tardanico, R.; Balzarini, P.; Arrighi, N.; Perucchini, L.; Zanotelli, T.; Cozzoli, A.; Zani, D.; Cunico, S.C.; Simeone, C. Cytogenetic Features, Clinical Significance and Prognostic Impact of Type 1 and Type 2 Papillary Renal Cell Carcinoma. Cancer Genet. Cytogenet. 2010, 199, 128–133.
  47. Klatte, T.; Rao, P.N.; de Martino, M.; LaRochelle, J.; Shuch, B.; Zomorodian, N.; Said, J.; Kabbinavar, F.F.; Belldegrun, A.S.; Pantuck, A.J. Cytogenetic Profile Predicts Prognosis of Patients with Clear Cell Renal Cell Carcinoma. J. Clin. Oncol. 2009, 27, 746–753.
  48. Sanders, M.E.; Mick, R.; Tomaszewski, J.E.; Barr, F.G. Unique Patterns of Allelic Imbalance Distinguish Type 1 from Type 2 Sporadic Papillary Renal Cell Carcinoma. Am. J. Pathol. 2002, 161, 997–1005.
  49. Schraml, P.; Müller, D.; Bednar, R.; Gasser, T.; Sauter, G.; Mihatsch, M.J.; Moch, H. Allelic Loss at the D9S171 Locus on Chromosome 9p13 Is Associated with Progression of Papillary Renal Cell Carcinoma. J. Pathol. 2000, 190, 457–461.
  50. Delahunt, B.; Eble, J.N.; Egevad, L.; Samaratunga, H. Grading of Renal Cell Carcinoma. Histopathology 2019, 74, 4–17.
  51. Zhao, W.; Tian, B.; Wu, C.; Peng, Y.; Wang, H.; Gu, W.-L.; Gao, F.-H. DOG1, Cyclin D1, CK7, CD117 and Vimentin Are Useful Immunohistochemical Markers in Distinguishing Chromophobe Renal Cell Carcinoma from Clear Cell Renal Cell Carcinoma and Renal Oncocytoma. Pathol. Res. Pract. 2015, 211, 303–307.
  52. Memeo, L.; Jhang, J.; Assaad, A.M.; McKiernan, J.M.; Murty, V.V.V.S.; Hibshoosh, H.; Tong, G.-X.; Mansukhani, M.M. Immunohistochemical Analysis for Cytokeratin 7, KIT, and PAX2: Value in the Differential Diagnosis of Chromophobe Cell Carcinoma. Am. J. Clin. Pathol. 2007, 127, 225–229.
  53. Huo, L.; Sugimura, J.; Tretiakova, M.S.; Patton, K.T.; Gupta, R.; Popov, B.; Laskin, W.B.; Yeldandi, A.; Teh, B.T.; Yang, X.J. C-Kit Expression in Renal Oncocytomas and Chromophobe Renal Cell Carcinomas. Hum. Pathol. 2005, 36, 262–268.
  54. Hornsby, C.D.; Cohen, C.; Amin, M.B.; Picken, M.M.; Lawson, D.; Yin-Goen, Q.; Young, A.N. Claudin-7 Immunohistochemistry in Renal Tumors: A Candidate Marker for Chromophobe Renal Cell Carcinoma Identified by Gene Expression Profiling. Arch. Pathol. Lab. Med. 2007, 131, 1541–1546.
  55. Osunkoya, A.O.; Cohen, C.; Lawson, D.; Picken, M.M.; Amin, M.B.; Young, A.N. Claudin-7 and Claudin-8: Immunohistochemical Markers for the Differential Diagnosis of Chromophobe Renal Cell Carcinoma and Renal Oncocytoma. Hum. Pathol. 2009, 40, 206–210.
  56. Adley, B.P.; Gupta, A.; Lin, F.; Luan, C.; Teh, B.T.; Yang, X.J. Expression of Kidney-Specific Cadherin in Chromophobe Renal Cell Carcinoma and Renal Oncocytoma. Am. J. Clin. Pathol. 2006, 126, 79–85.
  57. Shen, S.S.; Krishna, B.; Chirala, R.; Amato, R.J.; Truong, L.D. Kidney-Specific Cadherin, a Specific Marker for the Distal Portion of the Nephron and Related Renal Neoplasms. Mod. Pathol. 2005, 18, 933–940.
  58. Langner, C.; Ratschek, M.; Rehak, P.; Schips, L.; Zigeuner, R. Expression of MUC1 (EMA) and E-Cadherin in Renal Cell Carcinoma: A Systematic Immunohistochemical Analysis of 188 Cases. Mod. Pathol. 2004, 17, 180–188.
  59. Martignoni, G.; Pea, M.; Brunelli, M.; Chilosi, M.; Zamó, A.; Bertaso, M.; Cossu-Rocca, P.; Eble, J.N.; Mikuz, G.; Puppa, G.; et al. CD10 Is Expressed in a Subset of Chromophobe Renal Cell Carcinomas. Mod. Pathol. 2004, 17, 1455–1463.
  60. Martignoni, G.; Pea, M.; Chilosi, M.; Brunelli, M.; Scarpa, A.; Colato, C.; Tardanico, R.; Zamboni, G.; Bonetti, F. Parvalbumin Is Constantly Expressed in Chromophobe Renal Carcinoma. Mod. Pathol. 2001, 14, 760–767.
  61. Adam, A.C.; Scriba, A.; Ortmann, M.; Huss, S.; Kahl, P.; Steiner, S.; Störkel, S.; Büttner, R. Immunohistochemical Analysis of Cytochrome C Oxidase Facilitates Differentiation between Oncocytoma and Chromophobe Renal Cell Carcinoma. Appl. Immunohistochem. Mol. Morphol. 2015, 23, 54–59.
  62. Iczkowski, K.A.; Czaja, R.C. Eosinophilic Kidney Tumors: Old and New. Arch. Pathol. Lab. Med. 2019, 143, 1455–1463.
  63. Erlmeier, F.; Hartmann, A.; Autenrieth, M.; Wiedemann, M.; Ivanyi, P.; Steffens, S.; Weichert, W. PD-1/PD-L1 Expression in Chromophobe Renal Cell Carcinoma: An Immunological Exception? Med. Oncol. 2016, 33, 120.
  64. Michalova, K.; Tretiakova, M.; Pivovarcikova, K.; Alaghehbandan, R.; Perez Montiel, D.; Ulamec, M.; Osunkoya, A.; Trpkov, K.; Yuan, G.; Grossmann, P.; et al. Expanding the Morphologic Spectrum of Chromophobe Renal Cell Carcinoma: A Study of 8 Cases with Papillary Architecture. Ann. Diagn. Pathol. 2020, 44, 151448.
  65. Ng, K.L.; Ellis, R.J.; Samaratunga, H.; Morais, C.; Gobe, G.C.; Wood, S.T. Utility of Cytokeratin 7, S100A1 and Caveolin-1 as Immunohistochemical Biomarkers to Differentiate Chromophobe Renal Cell Carcinoma from Renal Oncocytoma. Transl. Urol. 2019, 8 (Suppl. 2), S123–S137.
  66. Liu, Y.J.; Ussakli, C.; Antic, T.; Liu, Y.; Wu, Y.; True, L.; Tretiakova, M.S. Sporadic Oncocytic Tumors with Features Intermediate between Oncocytoma and Chromophobe Renal Cell Carcinoma: Comprehensive Clinicopathological and Genomic Profiling. Hum. Pathol. 2020, 104, 18–29.
  67. Brunelli, M.; Eble, J.N.; Zhang, S.; Martignoni, G.; Delahunt, B.; Cheng, L. Eosinophilic and Classic Chromophobe Renal Cell Carcinomas Have Similar Frequent Losses of Multiple Chromosomes from among Chromosomes 1, 2, 6, 10, and 17, and This Pattern of Genetic Abnormality Is Not Present in Renal Oncocytoma. Mod. Pathol. 2005, 18, 161–169.
  68. Davis, C.; Ricketts, C.J.; Wang, M.; Yang, L.; Cherniack, A.; Shen, H.; Buhay, C.; Kang, H.; Kim, S.; Fahey, C.; et al. The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma. Cancer Cell 2014, 26, 319–330.
  69. Casuscelli, J.; Weinhold, N.; Gundem, G.; Wang, L.; Zabor, E.C.; Drill, E.; Wang, P.I.; Nanjangud, G.J.; Redzematovic, A.; Nargund, A.M.; et al. Genomic Landscape and Evolution of Metastatic Chromophobe Renal Cell Carcinoma. JCI Insight 2017, 2, 92688.
  70. Adam, J.; Couturier, J.; Molinié, V.; Vieillefond, A.; Sibony, M. Clear-Cell Papillary Renal Cell Carcinoma: 24 Cases of a Distinct Low-Grade Renal Tumour and a Comparative Genomic Hybridization Array Study of Seven Cases. Histopathology 2011, 58, 1064–1071.
  71. Rohan, S.M.; Xiao, Y.; Liang, Y.; Dudas, M.E.; Al-Ahmadie, H.A.; Fine, S.W.; Gopalan, A.; Reuter, V.E.; Rosenblum, M.K.; Russo, P.; et al. Clear-Cell Papillary Renal Cell Carcinoma: Molecular and Immunohistochemical Analysis with Emphasis on the von Hippel-Lindau Gene and Hypoxia-Inducible Factor Pathway-Related Proteins. Mod. Pathol. 2011, 24, 1207–1220.
  72. Albadine, R.; Schultz, L.; Illei, P.; Ertoy, D.; Hicks, J.; Sharma, R.; Epstein, J.I.; Netto, G.J. PAX8(+)/P63(−) Immunostaining Pattern in Renal Collecting Duct Carcinoma (CDC): A Useful Immunoprofile in the Differential Diagnosis of CDC versus Urothelial Carcinoma of Upper Urinary Tract. Am. J. Surg. Pathol. 2010, 34, 965–969.
  73. Pal, S.K.; Choueiri, T.K.; Wang, K.; Khaira, D.; Karam, J.A.; Van Allen, E.; Palma, N.A.; Stein, M.N.; Johnson, A.; Squillace, R.; et al. Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling. Eur. Urol. 2016, 70, 516–521.
  74. Wang, J.; Papanicolau-Sengos, A.; Chintala, S.; Wei, L.; Liu, B.; Hu, Q.; Miles, K.M.; Conroy, J.M.; Glenn, S.T.; Costantini, M.; et al. Collecting Duct Carcinoma of the Kidney Is Associated with CDKN2A Deletion and SLC Family Gene Up-Regulation. Oncotarget 2016, 7, 29901–29915.
  75. Assad, L.; Resetkova, E.; Oliveira, V.L.; Sun, W.; Stewart, J.M.; Katz, R.L.; Caraway, N.P. Cytologic Features of Renal Medullary Carcinoma. Cancer 2005, 105, 28–34.
  76. Swartz, M.A.; Karth, J.; Schneider, D.T.; Rodriguez, R.; Beckwith, J.B.; Perlman, E.J. Renal Medullary Carcinoma: Clinical, Pathologic, Immunohistochemical, and Genetic Analysis with Pathogenetic Implications. Urology 2002, 60, 1083–1089.
  77. Rao, P.; Tannir, N.M.; Tamboli, P. Expression of OCT3/4 in Renal Medullary Carcinoma Represents a Potential Diagnostic Pitfall. Am. J. Surg. Pathol. 2012, 36, 583–588.
  78. Beckermann, K.E.; Sharma, D.; Chaturvedi, S.; Msaouel, P.; Abboud, M.R.; Allory, Y.; Bourdeaut, F.; Calderaro, J.; De Cubas, A.A.; Derebail, V.K.; et al. Renal Medullary Carcinoma: Establishing Standards in Practice. J. Oncol. Pract. 2017, 13, 414–421.
  79. Liu, Q.; Galli, S.; Srinivasan, R.; Linehan, W.M.; Tsokos, M.; Merino, M.J. Renal Medullary Carcinoma: Molecular, Immunohistochemistry, and Morphologic Correlation. Am. J. Surg. Pathol. 2013, 37, 368–374.
  80. Gatalica, Z.; Lilleberg, S.L.; Monzon, F.A.; Koul, M.S.; Bridge, J.A.; Knezetic, J.; Legendre, B.; Sharma, P.; McCue, P.A. Renal Medullary Carcinomas: Histopathologic Phenotype Associated with Diverse Genotypes. Hum. Pathol. 2011, 42, 1979–1988.
  81. Mariño-Enríquez, A.; Ou, W.-B.; Weldon, C.B.; Fletcher, J.A.; Pérez-Atayde, A.R. ALK Rearrangement in Sickle Cell Trait-Associated Renal Medullary Carcinoma. Genes Chromosom. Cancer 2011, 50, 146–153.
  82. Schaeffer, E.M.; Guzzo, T.J.; Furge, K.A.; Netto, G.; Westphal, M.; Dykema, K.; Yang, X.; Zhou, M.; Teh, B.T.; Pavlovich, C.P. Renal Medullary Carcinoma: Molecular, Pathological and Clinical Evidence for Treatment with Topoisomerase-Inhibiting Therapy. BJU Int. 2010, 106, 62–65.
  83. Smith, N.E.; Deyrup, A.T.; Mariño-Enriquez, A.; Fletcher, J.A.; Bridge, J.A.; Illei, P.B.; Netto, G.J.; Argani, P. VCL-ALK Renal Cell Carcinoma in Children with Sickle-Cell Trait: The Eighth Sickle-Cell Nephropathy? Am. J. Surg. Pathol. 2014, 38, 858–863.
  84. Williamson, S.R.; Eble, J.N.; Amin, M.B.; Gupta, N.S.; Smith, S.C.; Sholl, L.M.; Montironi, R.; Hirsch, M.S.; Hornick, J.L. Succinate Dehydrogenase-Deficient Renal Cell Carcinoma: Detailed Characterization of 11 Tumors Defining a Unique Subtype of Renal Cell Carcinoma. Mod. Pathol. 2015, 28, 80–94.
  85. Gill, A.J.; Hes, O.; Papathomas, T.; Šedivcová, M.; Tan, P.H.; Agaimy, A.; Andresen, P.A.; Kedziora, A.; Clarkson, A.; Toon, C.W.; et al. Succinate Dehydrogenase (SDH)-Deficient Renal Carcinoma: A Morphologically Distinct Entity: A Clinicopathologic Series of 36 Tumors from 27 Patients. Am. J. Surg. Pathol. 2014, 38, 1588–1602.
  86. Gill, A.J.; Pachter, N.S.; Clarkson, A.; Tucker, K.M.; Winship, I.M.; Benn, D.E.; Robinson, B.G.; Clifton-Bligh, R.J. Renal Tumors and Hereditary Pheochromocytoma-Paraganglioma Syndrome Type 4. N. Engl. J. Med. 2011, 364, 885–886.
  87. Cardaci, S.; Ciriolo, M.R. TCA Cycle Defects and Cancer: When Metabolism Tunes Redox State. Int. J. Cell Biol. 2012, 2012, e161837.
  88. Argani, P. MiT Family Translocation Renal Cell Carcinoma. Semin. Diagn. Pathol. 2015, 32, 103–113.
  89. Zhong, M.; De Angelo, P.; Osborne, L.; Paniz-Mondolfi, A.E.; Geller, M.; Yang, Y.; Linehan, W.M.; Merino, M.J.; Cordon-Cardo, C.; Cai, D. Translocation Renal Cell Carcinomas in Adults: A Single-Institution Experience. Am. J. Surg. Pathol. 2012, 36, 654–662.
  90. Argani, P.; Olgac, S.; Tickoo, S.K.; Goldfischer, M.; Moch, H.; Chan, D.Y.; Eble, J.N.; Bonsib, S.M.; Jimeno, M.; Lloreta, J.; et al. Xp11 Translocation Renal Cell Carcinoma in Adults: Expanded Clinical, Pathologic, and Genetic Spectrum. Am. J. Surg. Pathol. 2007, 31, 1149–1160.
  91. Cheng, L.; Williamson, S.R.; Zhang, S.; Maclennan, G.T.; Montironi, R.; Lopez-Beltran, A. Understanding the Molecular Genetics of Renal Cell Neoplasia: Implications for Diagnosis, Prognosis and Therapy. Expert. Rev. Anticancer 2010, 10, 843–864.
  92. Rao, Q.; Shen, Q.; Xia, Q.Y.; Wang, Z.Y.; Liu, B.; Shi, S.S.; Shi, Q.L.; Yin, H.L.; Wu, B.; Ye, S.B.; et al. PSF/SFPQ Is a Very Common Gene Fusion Partner in TFE3 Rearrangement-Associated Perivascular Epithelioid Cell Tumors (PEComas) and Melanotic Xp11 Translocation Renal Cancers: Clinicopathologic, Immunohistochemical, and Molecular Characteristics Suggesting Classification as a Distinct Entity. Am. J. Surg. Pathol. 2015, 39, 1181–1196.
  93. Rivera, M.; Tickoo, S.K.; Saqi, A.; Lin, O. Cytologic Findings of Acquired Cystic Disease-Associated Renal Cell Carcinoma: A Report of Two Cases. Diagn. Cytopathol. 2008, 36, 344–347.
  94. Sule, N.; Yakupoglu, U.; Shen, S.S.; Krishnan, B.; Yang, G.; Lerner, S.; Sheikh-Hamad, D.; Truong, L.D. Calcium Oxalate Deposition in Renal Cell Carcinoma Associated with Acquired Cystic Kidney Disease: A Comprehensive Study. Am. J. Surg. Pathol. 2005, 29, 443–451.
  95. Cossu-Rocca, P.; Eble, J.N.; Zhang, S.; Martignoni, G.; Brunelli, M.; Cheng, L. Acquired Cystic Disease-Associated Renal Tumors: An Immunohistochemical and Fluorescence in Situ Hybridization Study. Mod. Pathol. 2006, 19, 780–787.
  96. Williamson, S.R.; Halat, S.; Eble, J.N.; Grignon, D.J.; Lopez-Beltran, A.; Montironi, R.; Tan, P.-H.; Wang, M.; Zhang, S.; Maclennan, G.T.; et al. Multilocular Cystic Renal Cell Carcinoma: Similarities and Differences in Immunoprofile Compared with Clear Cell Renal Cell Carcinoma. Am. J. Surg. Pathol. 2012, 36, 1425–1433.
  97. von Teichman, A.; Compérat, E.; Behnke, S.; Storz, M.; Moch, H.; Schraml, P. VHL Mutations and Dysregulation of PVHL- and PTEN-Controlled Pathways in Multilocular Cystic Renal Cell Carcinoma. Mod. Pathol. 2011, 24, 571–578.
  98. Halat, S.; Eble, J.N.; Grignon, D.J.; Lopez-Beltran, A.; Montironi, R.; Tan, P.-H.; Wang, M.; Zhang, S.; MacLennan, G.T.; Cheng, L. Multilocular Cystic Renal Cell Carcinoma Is a Subtype of Clear Cell Renal Cell Carcinoma. Mod. Pathol. 2010, 23, 931–936.
  99. Lawrie, C.H.; Armesto, M.; Fernandez-Mercado, M.; Arestín, M.; Manterola, L.; Goicoechea, I.; Larrea, E.; Caffarel, M.M.; Araujo, A.M.; Sole, C.; et al. Noncoding RNA Expression and Targeted Next-Generation Sequencing Distinguish Tubulocystic Renal Cell Carcinoma (TC-RCC) from Other Renal Neoplasms. J. Mol. Diagn. 2018, 20, 34–45.
  100. Fine, S.W.; Argani, P.; DeMarzo, A.M.; Delahunt, B.; Sebo, T.J.; Reuter, V.E.; Epstein, J.I. Expanding the Histologic Spectrum of Mucinous Tubular and Spindle Cell Carcinoma of the Kidney. Am. J. Surg. Pathol. 2006, 30, 1554–1560.
  101. Shen, S.S.; Ro, J.Y.; Tamboli, P.; Truong, L.D.; Zhai, Q.; Jung, S.-J.; Tibbs, R.G.; Ordonez, N.G.; Ayala, A.G. Mucinous Tubular and Spindle Cell Carcinoma of Kidney Is Probably a Variant of Papillary Renal Cell Carcinoma with Spindle Cell Features. Ann. Diagn. Pathol. 2007, 11, 13–21.
  102. Jung, S.J.; Yoon, H.K.; Chung, J.I.; Ayala, A.G.; Ro, J.Y. Mucinous Tubular and Spindle Cell Carcinoma of the Kidney With Neuroendocrine Differentiation: Report of Two Cases. Am. J. Clin. Pathol. 2006, 125, 99–104.
  103. Owens, C.L.; Argani, P.; Ali, S.Z. Mucinous Tubular and Spindle Cell Carcinoma of the Kidney: Cytopathologic Findings. Diagn. Cytopathol. 2007, 35, 593–596.
  104. Marks-Jones, D.A.; Zynger, D.L.; Parwani, A.V.; Cai, G. Fine Needle Aspiration Biopsy of Renal Mucinous Tubular and Spindle Cell Carcinoma: Report of Two Cases. Diagn. Cytopathol. 2010, 38, 51–55.
  105. Molinié, V.; Balaton, A.; Rotman, S.; Mansouri, D.; De Pinieux, I.; Homsi, T.; Guillou, L. Alpha-Methyl CoA Racemase Expression in Renal Cell Carcinomas. Hum. Pathol. 2006, 37, 698–703.
  106. Zhao, M.; He, X.-L.; Teng, X.-D. Mucinous Tubular and Spindle Cell Renal Cell Carcinoma: A Review of Clinicopathologic Aspects. Diagn. Pathol. 2015, 10, 168.
  107. Kuroda, N.; Hes, O.; Miyazaki, E.; Shuin, T.; Enzan, H. Frequent Expression of Neuroendocrine Markers in Mucinous Tubular and Spindle Cell Carcinoma of the Kidney. Histol. Histopathol. 2006, 21, 7–10.
  108. Brandal, P.; Lie, A.K.; Bassarova, A.; Svindland, A.; Risberg, B.; Danielsen, H.; Heim, S. Genomic Aberrations in Mucinous Tubular and Spindle Cell Renal Cell Carcinomas. Mod. Pathol. 2006, 19, 186–194.
  109. Petersson, F.; Gatalica, Z.; Grossmann, P.; Perez Montiel, M.D.; Alvarado Cabrero, I.; Bulimbasic, S.; Swatek, A.; Straka, L.; Tichy, T.; Hora, M.; et al. Sporadic Hybrid Oncocytic/Chromophobe Tumor of the Kidney: A Clinicopathologic, Histomorphologic, Immunohistochemical, Ultrastructural, and Molecular Cytogenetic Study of 14 Cases. Virchows Arch. 2010, 456, 355–365.
  110. Poté, N.; Vieillefond, A.; Couturier, J.; Arrufat, S.; Metzger, I.; Delongchamps, N.B.; Camparo, P.; Mège-Lechevallier, F.; Molinié, V.; Sibony, M. Hybrid Oncocytic/Chromophobe Renal Cell Tumours Do Not Display Genomic Features of Chromophobe Renal Cell Carcinomas. Virchows Arch. 2013, 462, 633–638.
  111. Adley, B.P.; Schafernak, K.T.; Yeldandi, A.V.; Yang, X.J.; Nayar, R. Cytologic and Histologic Findings in Multiple Renal Hybrid Oncocytic Tumors in a Patient with Birt-Hogg-Dubé Syndrome: A Case Report. Acta Cytol. 2006, 50, 584–588.
  112. Hes, O.; Petersson, F.; Kuroda, N.; Hora, M.; Michal, M. Renal Hybrid Oncocytic/Chromophobe Tumors—A Review. Histol. Histopathol. 2013, 28, 1257–1264.
  113. Iribe, Y.; Kuroda, N.; Nagashima, Y.; Yao, M.; Tanaka, R.; Gotoda, H.; Kawakami, F.; Imamura, Y.; Nakamura, Y.; Ando, M.; et al. Immunohistochemical Characterization of Renal Tumors in Patients with Birt-Hogg-Dubé Syndrome. Pathol. Int. 2015, 65, 126–132.
  114. Caliò, A.; Segala, D.; Munari, E.; Brunelli, M.; Martignoni, G. MiT Family Translocation Renal Cell Carcinoma: From the Early Descriptions to the Current Knowledge. Cancers 2019, 11, 1110.
  115. Athanazio, D.A.; Amorim, L.S.; da Cunha, I.W.; Leite, K.R.; da Paz, A.R.; de Paula Xavier Gomes, R.; Tavora, F.R.; Faraj, S.F.; Cavalcanti, M.S.; Bezerra, S.M. Classification of Renal Cell Tumors—Current Concepts and Use of Ancillary Tests: Recommendations of the Brazilian Society of Pathology. Surg. Exp. Pathol. 2021, 4, 4.
  116. Available online: https://www.pathologyoutlines.com/kidneytumor.html (accessed on 18 September 2022).
  117. Moretti, L.; Medeiros, L.J.; Kunkalla, K.; Williams, M.D.; Singh, R.R.; Vega, F. N-Terminal PAX8 Polyclonal Antibody Shows Cross-Reactivity with N-Terminal Region of PAX5 and Is Responsible for Reports of PAX8 Positivity in Malignant Lymphomas. Mod. Pathol. 2012, 25, 231–236.
  118. Miettinen, M.; McCue, P.A.; Sarlomo-Rikala, M.; Rys, J.; Czapiewski, P.; Wazny, K.; Langfort, R.; Waloszczyk, P.; Biernat, W.; Lasota, J.; et al. GATA3: A Multispecific but Potentially Useful Marker in Surgical Pathology: A Systematic Analysis of 2500 Epithelial and Nonepithelial Tumors. Am. J. Surg. Pathol. 2014, 38, 13–22.
  119. Gonzalez-Roibon, N.; Faraj, S.F.; Munari, E.; Bezerra, S.M.; Albadine, R.; Sharma, R.; Argani, P.; Allaf, M.E.; Netto, G.J. Comprehensive Profile of GATA Binding Protein 3 Immunohistochemical Expression in Primary and Metastatic Renal Neoplasms. Hum. Pathol. 2014, 45, 244–248.
  120. Bakshi, N.; Kunju, L.P.; Giordano, T.; Shah, R.B. Expression of Renal Cell Carcinoma Antigen (RCC) in Renal Epithelial and Nonrenal Tumors: Diagnostic Implications. Appl. Immunohistochem. Mol. Morphol. 2007, 15, 310–315.
  121. McGregor, D.K.; Khurana, K.K.; Cao, C.; Tsao, C.C.; Ayala, G.; Krishnan, B.; Ro, J.Y.; Lechago, J.; Truong, L.D. Diagnosing Primary and Metastatic Renal Cell Carcinoma: The Use of the Monoclonal Antibody “Renal Cell Carcinoma Marker”. Am. J. Surg. Pathol. 2001, 25, 1485–1492.
  122. Clayton, E.F.; Ziober, A.; Yao, Y.; Bing, Z. Malignant Tumors with Clear Cell Morphology: A Comparative Immunohistochemical Study with Renal Cell Carcinoma Antibody, Pax8, Steroidogenic Factor 1, and Brachyury. Ann. Diagn. Pathol. 2013, 17, 192–197.
  123. Chu, P.; Arber, D.A. Paraffin-Section Detection of CD10 in 505 Nonhematopoietic Neoplasms. Frequent Expression in Renal Cell Carcinoma and Endometrial Stromal Sarcoma. Am. J. Clin. Pathol. 2000, 113, 374–382.
  124. Kuehn, A.; Paner, G.P.; Skinnider, B.F.; Cohen, C.; Datta, M.W.; Young, A.N.; Srigley, J.R.; Amin, M.B. Expression Analysis of Kidney-Specific Cadherin in a Wide Spectrum of Traditional and Newly Recognized Renal Epithelial Neoplasms: Diagnostic and Histogenetic Implications. Am. J. Surg. Pathol. 2007, 31, 1528–1533.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Urology & Nephrology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Dorin Novacescu
,
Bogdan Ovidiu Feciche
,
Alin Adrian Cumpanas
,
Razvan Bardan
,
Andrei Valentin Rusmir
,
Yahya Almansour Bitar
,
Vlad Ilie Barbos
,
Talida Georgiana Cut
,
Marius Raica
,
Silviu Constantin Latcu
View Times: 570
Revisions: 2 times (View History)
Update Date: 29 Nov 2022
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback