Abnormal MET activation in cancer triggers tumor growth, formation of new blood vessels (angiogenesis) and cancer spread to other organs. MET is deregulated in many types of human malignancies, including cancers of kidney, liver, stomach, breast, and brain. Normally, only stem cells and progenitor cells express MET, which allows these cells to grow invasively to generate new tissues in an embryo or regenerate damaged tissues in an adult. However, cancer stem cells are thought to acquire the ability of normal stem cells to express MET, thus causing persistence of cancer and leading to its spread to other sites in the body.30,31
HEREDITARY PAPILLARY RENAL CELL CARCINOMA WITH TYPE 2-LIKE MORPHOLOGY
Hereditary leiomyomatosis and renal cell cancer (HLRCC), is a rare autosomal cancer susceptibility syndrome characterized by the development of cutaneous and uterine leiomyomas and renal cancer. The lifetime risk of renal cancer is currently estimated to be 15%. These tumors tend to have an early age of onset with the mean age of 40 years at the time of diagnosis. Renal cancers associated with HLRCC have a characteristic pathologic appearance with large nuclei with inclusion like eosinophilic nucleoli surrounded by a clear halo. The pattern of renal cancer in HLRCC differs from other inherited renal cancer susceptibility syndromes in that the tumors tend to be solitary and unilateral and have a highly aggressive course of disease.32–38
The morphologic features of carcinomas associated with HLRCC frequently include papillary architecture with abundant eosinophilic cytoplasm, large nuclei, and very prominent nucleoli with perinucleolar clearing and thus resemble PRCC type 2. Papillary type 2 like component, however, is one of several morphologic features including collecting duct, solid, tubulocystic, cribriform, and cystic growth pattern.33–37 In the 2 recently published studies by Chen and colleagues and Trpkov and colleagues papillary pattern was predominant in 33% and 57% of the cases, respectively.36–37
These tumors, however, have now been recognized as a distinct entity in the recent WHO classification.4 Recognition of the clinical features of the HLRCC syndrome such as cutaneous and uterine leiomyomas may be helpful in establishing a definitive diagnosis. Immunohistochemical staining of the tumor may reveal lack of cytoplasmic staining for fumarate hydratase and overexpression of modified cysteine-s-(2-succino) cysteine, thus confirming the diagnosis.4 Cases in which history or stigmata of HLRCC are not present the tumors are called FH deficient RCC.35–37
The gene mutated in HLRCC corresponds to fumarate hydratase gene located at 1q42.3-q43. It encodes a protein called fumarate hydratase, which is an enzyme of the Krebs cycle that catalyzes the conversion of fumarate to malate. Biallelic inactivation is detected in almost all HLRCC tumors. Lack of FH activity results in intracellular accumulation of fumarate leading to a pseudo hypoxic drive characterized by stabilization of hypoxia inducible factor HIF-a. This results in generation of several downstream oncogenic signals for angiogenesis, cell proliferation, increased glucose uptake, and chemotaxis.33
SPORADIC PAPILLARY RENAL CELL CARCINOMA WITH TYPE II MORPHOLOGY
Albiges and colleagues investigated the MET gene status in a large well-annotated cohort of 220 patients with sporadic PRCC. Each sample was independently reviewed by 2 specialized pathologists, both blinded to the clinical outcome. This robust dataset expands our knowledge about MET gene status for both type I and II PRCC subtypes by reporting on different mechanisms of MET activation: gene expression, copy-number alterations (CNAs) and mutational status. MET expression was significantly higher in both type I and type II PRCC than in clear-cell histology. However, type I PRCC presented a higher expression of MET when compared with the type II subtype. CNAs of MET were identified in 46% of type II PRCC and in 81% of type I PRCC. The correlation of copy number abnormality and MET mRNA expression was significantly high, which may provide a biological basis for enhanced MET signaling. Of note, 11 somatic mutations of the MET gene, including four new mutations, were identified in 51 type I PRCC (21.5%). However mutational analysis of type II PRCC was not performed.39,40
COMPREHENSIVE MOLECULAR CHARACTERIZATION OF PAPILLARY RENAL CELL CARCINOMA USING NEXT-GENERATION SEQUENCING
Previously published next-generation sequencing studies have identified several mutated genes associated with PRCC including: MET, NF2, SETD2, and Nrf2 pathway genes. However, these mutations were found in only ~10% to 15% of PRCC tumors in these studies.41,42 The investigators of The Cancer Genome Atlas Research Network (TCGA) performed comprehensive molecular analysis, including whole-exome sequencing, identification of CNAs, micro RNA, and messenger RNA determination.43
On the basis of tumor histology, the authors identified 75 type 1 tumors, 60 type 2 tumors, and 26 tumors that could not be categorized as type 1 or type 2. Most of the type 1 tumors were localized (stage I), while the type 2 tumors were more frequently advanced or metastatic (stage III or IV). Analysis of chromosome alterations revealed 3 subgroups. One group, consisting mainly of type 1 and other low-grade tumors, showed chromosomal gains, particularly of chromosomes 7 and 17. The other 2 groups included predominantly type 2 tumors. One group revealed few genome copy number changes, while the other had multiple chromosome losses and was associated with poorer patient survival.43
The investigators sequenced the expressed regions of the genomes in 157 of the tumors to identify potential mutations. Significantly mutated genes included MET, SETD2, NF2, KDM6A, and SMARCB1, which were altered in 24% of tumors.
Evaluation of genes previously associated with cancer revealed 6 additional significantly mutated genes, FAT1, BAP1, PBRM1, STAG2, NFE2L2, and TP53, that increased the number of tumors with alterations to 36%.
Analysis of CNAs resulted in the identification of 3 patterns: predominantly type 1 tumors with frequent gain of chromosomes 7 and 17; type 2 tumors with few CNAs; and type 2 tumors with aneuploidy, including frequent loss of chromosome 9p. Most of type1 PRCC tumors (81%) had gains of chromosome 7 or altered MET status (mutation, gene fusion or splice variant of MET). While these findings support the hypothesis of MET as a driver mutation in type 1 PRCC, it cannot be concluded from this evidence alone. Further supporting this theory, however, is the finding that levels of MET mRNA expression were significantly higher in type 1 tumors than type 2 tumors.10
Whole-exome sequencing identified 11 significantly mutated genes, including previously identified genes such as MET, SETD2, NF2, and BAP1, among others. These mutations, many of which are part of known cancer-associated pathways, were present in a higher percentage of tumors than was reported by previous studies. CDKN2A alterations were found in 21 tumors (13%) and included 25% of type 2 tumors. These alterations included focal loss of 9p21, mutation, or promotor hypermethylation of CDKN2A. In addition, increased expression of miR-10b-5p was correlated with decreased expression of CDKN2A. CDKN2A altered tumors were found, on univariate analysis, to be associated with lower overall survival when compared to tumors without CDKN2A alterations.10
A novel CpG island methylator phenotype (CIMP) was identified in nine tumors, all of which also had hypermethylation of the CDKN2A promoter. Eight of 9 of these tumors were papillary type 2. CIMP-associated tumors were noted to have poor survival.
The CpG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5′→3′ direction.
Cytosines in CpG dinucleotides can be methylated to form 5-methylcytosine. In humans, about 70% of promoters located near the transcription start site of a gene (proximal promoters) contain a CpG island. Regulation of gene expression is a general key mechanism that is operative in normal tissues and has an important role in the preservation of genomic stability, embryonic development, and tissue differentiation. CpG islands are common in promoter sites rich in CpG dinucleotides. More than 50% of human genes have been found to be regulated in this way, by promoters including CpG islands. In cancer cells, CpG islands may also be aberrantly hypermethylated, causing inappropriate silencing of gene expression (Fig. 5). Aberrant genomic methylation is thought to result in tumorigenesis by deregulating gene expression of key (tumor suppressor) genes.43 This phenotype has been reported in several other tumor types, including gastric, lung, liver, ovarian, glioblastomas, endometrial, breast, leukemias, and colorectal carcinoma.
A cluster-of-clusters analysis was performed using the various data types to identify PRCC subgroups. Four subgroups were identified (C1, C2a, C2b, and C2c) and were associated with progressively worse overall survival. C1 included primarily papillary type 1 tumors, while C2a and C2b included primarily papillary type 2. Subgroup C2c included only type 2 PRCC with CIMP-associated tumors, which had the lowest overall survival. This analysis, which elucidated the complexity of PRCC and the heterogeneity of type 2 PRCC specifically, has significant implications for the design of future clinical trials and the development of targeted therapies for PRCC.10
Examination of these changes according to PRCC subtypes, revealed several alterations that were specific to each. For example, most of MET mutations were identified in type 1 tumors. In contrast, alterations in CDKN2A, due to loss of chromosome 9p21, as well as mutations in SETD2, BAP1, and PBRM1 were associated with type 2 tumors.
One distinguishing feature of type 2 tumors that emerged from the combined analysis was increased expression of the Nrf2-antioxidant response element pathway, that is exemplified by the expression of the well-known NRF2-ARE gene NQO1.10 Nrf2 antioxidant response element signaling is a major mechanism in the cellular defense against oxidative stress (Fig. 6). Activation of this pathway controls the expression of genes whose protein products are involved in the detoxication and elimination of reactive oxidants through conjugative reactions and by enhancing cellular antioxidant capacity. NQO1 expression was lowest in cluster C1 tumors, intermediate in cluster C2a and C2b tumors, and highest in cluster C2c tumors.44,45 Interestingly, increased NQO1expression was associated with decreased survival.10
Taken together, the findings from this comprehensive study revealed that type 1 and type 2 PRCC are 2 distinct diseases and that type 2 can be further stratified into 3 subgroups. This improved classification of PRCC may lead to the development of more specific, targeted therapies as well as improved disease management and design of clinical trials.10
In a more recent study Pal and colleagues performed molecular characterization of advanced PRCC via targeted sequencing of 315 genes in tumors from 169 patients, of whom 60% had stage IV disease. Most of their findings are in line with TCGA highlights, but the study has also shed light on pivotal issues that characterize metastatic disease.11 MET is yet again a central oncogenic alteration in type 1 PRCCs, with mutations in 20% and amplifications in 13% of cases. The frequency of MET alterations in this study is onethird of >80% with MET alterations in the TCGA dataset. Indeed, this is because Pal and colleagues chose to consider CNAs with only high-level MET amplifications (>6). This study also revealed that the ontogeny of type 2 PRCC might share similarities with type 1 PRCC. Indeed, both subtypes exhibit alterations in cell cycle genes CDKN2A/B, TERT, RAS/RAF signaling, the DNA damage pathway, and the mTOR pathway with comparable frequency. Above all, we still must understand whether type 2 PRCCs encompass similar entities or multiple diseases. The answers might come from dedicated studies of specific type 2 PRCC alterations, including FH mutations, NF2 mutations, and SWI/SNF chromatin remodeling complex alterations that might induce genome-wide reprogramming.
NEW PROPOSED SUBCLASSIFICATION OF PAPILLARY RENAL CELL CARCINOMA
In a recent study Saleeb et al12 have proposed a new classification system of PRCC integrating morphologic, immunophenotypical, and molecular analysis. In a study of cohort of 108 cases of PRCC it was shown that these cases may be divided into 3 categories, each with its characteristic immunohistochemical staining profile (Table 1). A panel of 3 potentially distinguishing markers (CA9, ABCC2, and GATA3) was assessed by immunohistochemistry. The panel exhibited distinct staining patterns between the 2 classic PRCC subtypes (PRCC1&2), sub classified 30% of the histologically unclassified group into either PRCC1 or PRCC2; and additionally, recognized another group of tumors (PRCC3) that accounted for 35% of the total cohort. Molecular testing using miRNA expression and copy number variation analysis confirmed the presence of 3 distinct molecular signatures corresponding to the 3 subtypes. Disease-free survival was significantly enhanced in PRCC1 versus 2 and 3 (P=0.047) on univariate analysis. The newly described PRCC3 has overlapping morphologic features between PRCC1 and pRCC2 and would therefore be difficult to classify on histologic appearance alone but can be diagnosed by using the immunohistochemical panel (Table 1). Molecularly PRCC3 has a distinct signature although clinically it behaves like PRCC2. Thus, it seems that the new classification stratifies PRCC patients into subgroups, which may have significant implications on the management of PRCC.12
The markers also further characterized the oncocytic PRCC (PRCC4) as a distinct subtype.12 PRCCs with eosinophilic (oncocytic) cytoplasm and oncocytoma-like low-grade nuclei have been called oncocytic PRCCs (Fig. 7). Because tumors with this morphology have not yet been fully characterized, they are not considered a distinct WHO entity. The Vancouver consensus conference has recommended diagnosing such tumors as type 2 PRCC for the time being.3
Most reported cases are clinically indolent and showed no disease progression. Despite having an immunophenotype more comparable with PRCC2 (strong diffuse positivity for ABCC2), the authors suggest that PRCC4 may be closer to PRCC1 molecularly and clinically based on similar gains of chromosomes 7 and 17 and a good prognosis.12
UNCOMMON HISTOLOGIC VARIANTS OF PAPILLARY RENAL CELL CARCINOMA
Several categories of apparent PRCCs with unusual morphology features have been reported in the literature.
Solid Variant of Papillary Renal Cell Carcinoma
Argani et al46 described 5 cases of PRCC with low-grade spindle cell component, which they characterized as solid variant of PRCC. All patients were male, and ranged in age from 17 to 68 years. All tumors were predominantly solid, featuring compact areas of low-grade spindle cells lining thin, angulated tubules. Mucinous stroma was not appreciated in any case. All cases were diffusely immunoreactive for cytokeratin 7, and focally CD10 positive. All 5 cases showed trisomy of chromosome 7, and 3 of 5 showed trisomy of chromosome 17 by fluorescence in situ hybridization (FISH), supporting classification as PRCC. Zhang et al47 documented 2 additional cases of solid variant of PRCC by light microscopy, special staining, immunohistochemical staining and FISH and compared their findings with 2 cases of mucinous tubular spindle cell tumors. They found that morphologic and immunophenotyping features showed more overlap between these 2 types of tumor. In addition, gains of chromosomes 7 and 17 and loss of Y, which are characteristic of PRCC, were observed in 2 cases of solid PRCC and one case of mucinous tubular spindle cell tumor. Ren et al48 compared the genome-wide CNAs in tumors displaying classic histologic features of MTSCC in comparison to the solid variant of type 1 PRCC and indeterminate cases with overlapping histologic features. The study included 11 histologically typical MTSCC, 9 tumors with overlapping features between MTSCC and PRCC, and 6 cases of solid variant of type PRCC. DNA samples extracted from macrodissected or microdissected tumor areas were analyzed for genome-wide CNAs using an SNP array platform suitable for clinical archival material. All cases in the MTSCC group exhibited multiple chromosomal losses, most frequently involving chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22, while lacking trisomy 7 or 17. In contrast, cases with overlapping morphologic features of MTSCC and PRCC predominantly showed multiple chromosomal gains, most frequently involving chromosomes 7, 16, 17, and 20, similar to the chromosomal alteration pattern that was seen in the solid variant of type 1 PRCC cases. Morphologic comparison of these molecularly characterized tumors identified histologic features that help to distinguish MTSCC from PRCC, but immunohistochemical profiles of these tumors remained overlapping. The study concluded that characteristic patterns of genome-wide CNAs strongly support mucinous tubular spindle cell carcinoma and solid variant of PRCC as distinct entities despite their immunohistochemical and certain morphologic overlap.
Another type of solid variant of PRCC has also been recognized where distinct papillary structures are not easily discernable. Renshaw et al49 identified 6 tumors composed of solid sheets of cells without true papillae but that otherwise resembled PRCCs. Four of 4 tumors tested showed trisomies for chromosome 7, chromosome 17, or both by either cytogenetic analysis or FISH. Four cases were composed of solid sheets of cells containing distinct micronodules that in some cases resembled abortive papillae. The cells composing the micronodules had abundant eosinophilic cytoplasm, open chromatin, and in some cases prominent nucleoli. The intervening cells had similar nuclei, but the amount of cytoplasm was variable. This tumor may have strong morphologic resemblance to metanephric adenoma. Mantoan Padhilla et al50 studied the immunohistochemical profile of a series of solid variant of PRCC and metanephric adenoma and found overlapping immunoreactivity for S100, CD57, and CK7. Metanephric adenomas however were positive for WT1 and negative for epithelial membrane antigen (EMA) and alphamethylacyl-CoA racemase (AMACR). By contrast the tumor cells in solid variant of PRCC were positive for EMA and AMACR and negative for WT1. Ulamec and colleagues studied the immunohistochemical profile of 10 cases of solid variant of PRCC. All 10 cases were strongly and diffusely positive for CK7 and negative for WT-1.51
Biphasic Squamoid Alveolar Renal Cell Carcinoma
Biphasic squamoid alveolar renal cell carcinoma is another rare morphologic variant of PRCC that has been recently described as a distinct neoplasm. The largest series consists of 21 cases from 12 institutions that were analyzed using routine histology, immunohistochemistry, array comparative genomic hybridization and FISH. The size of tumors ranged from 1.5 to 16 cm. Follow-up information was available for 14 patients (range, 1 to 96 mo), and metastatic spread was found in 5 cases. All tumors comprised 2 cell populations arranged in organoid structures: small, low-grade neoplastic cells with scant cytoplasm usually lining the inside of alveolar structures, and larger squamoid cells with more prominent cytoplasm and larger vesicular nuclei arranged in compact nests. In 9 of 21 tumors there was a visible transition from such solid and alveolar areas into papillary components. Areas composed of large squamoid cells comprised 10% to 80% of total tumor volume. Emperipolesis was present in all (21/21) tumors. Immunohistochemically, all cases were positive for cytokeratin 7, EMA, vimentin, and cyclin D1. The authors concluded that tumors show a morphologic spectrum ranging from RCC with papillary architecture and large squamoid cells to fully developed BSARCC. Emperipolesis in squamoid cells was a constant finding. All carcinomas expressed CK7, EMA, vimentin, and cyclin D1. Multiple chromosomal aberrations were identified in all analyzable cases including gains of chromosomes 7 and 17, indicating that they are akin to PRCC. Thus, available microscopic, immunohistochemical, and molecular genetic data strongly support the view that biphasic squamoid renal cell carcinoma is a distinctive and peculiar morphologic variant of PRCC.52
PRCC With Oncocytic Morphology
Cases of PRCC with distinct eosinophilic cytoplasm named oncocytic PRCC have been described by several authors. However, owing to the rarity of oncocytic PRCC, the clinicopathologic and genetic features of the tumor have still not been well elucidated and whether it should be regarded as an independent subtype of PRCC remains controversial. Microscopically, typical oncocytic PRCC possessed fine papillary structures with delicate fibrovascular cores, lined with a single layer cell with large, deeply eosinophilic granular cytoplasm and round or polygonal-shaped nucleus exhibiting low nuclear grade. Furthermore, solid oncocytoma-like pattern as well as cases with sarcomatoid differentiation have also been recognized.
Immunohistochemically, the majority of tumors presented high expression rates of AMACR, CD10 and vimentin, similar to type 2 PRCC. Genetically, FISH analysis reveals trisomy of chromosome 7 in 7 OPRCCs and trisomy of chromosome 17. Among male patients, loss of chromosome Y may also be seen. Prognosis is generally favorable, although occasional tumors may behave aggressively.53 As mentioned earlier, since tumors with this morphology have not yet been fully characterized, they are not considered a distinct WHO entity. The Vancouver consensus conference has recommended diagnosing such tumors as type 2 PRCC for the time being.3
Warthin-like Papillary Renal Cell Carcinoma
Warthin-like PRCC is morphologically very close to oncocytic PRCC, from which it differs by the presence of dense lymphoid stroma. In a recent study Skenderi and colleagues analyzed clinicopathologic, morphologic, immunohistochemical, and molecular-genetic characteristics of 11 oncocytic PRCCs with prominent tumor lymphocytic infiltrate, morphologically resembling Warthin’s tumor. Papillary growth pattern was predominant, comprising >60% of tumor volume. Tubular and solid components were present in 5 and 3 cases, respectively. Uniform immunohistochemical positivity was found for AMACR, PAX-8, MIA, vimentin, and OSCAR. Tumors were mostly negative for carboanhydrase 9, CD117, CK20, and TTF-1. Tumor infiltrating lymphocytes consisted of both B and T cells. Chromosomal copy number variation analysis showed great variability in 5 cases, ranging from a loss of one single chromosome to complex genome rearrangements. Only one case showed gains of chromosomes 7 and 17, among other aberrations. In 6 patients no lethal progression was noted, while 3 died of disease indicating that Warthin-like PRCC is a potentially aggressive tumor.54
MISCELLNEOUS RENAL CARCINOMAS WITH VARIABLE PAPILLARY COMPONENT
Minor papillary carcinoma components have been seen in a variety of renal carcinomas. These include tubulocystic carcinoma, mucinous tubular spindle cell carcinoma, clear cell PRCC, collecting duct carcinoma, medullary carcinoma, MiT family translocation renal cell carcinoma, HLRCC and other fumarate hydratase deficient tumors.1–4 Whether the presence of papillary component in these tumors indicates a histogenetic relationship with PRCC is a matter of debate.
THE WAY FORWARD
Efforts aimed at the development of effective forms of therapy for PRCC have been hindered over the past decades by a lack of understanding of the molecular basis of sporadic PRCC. For many years, what was known about PRCC was based on the insight gained from hereditary forms of the disease. However, recent genomic profiling studies, have refined our understanding of the heterogeneity within PRCC. These efforts identified a multitude of key dysregulated pathways beyond the MET pathway that may prove to be promising targets for development of new therapeutic agents.
Clinical trials targeting MET in type 1 PRCC with MET alterations are ongoing. However, given the wide range of genomic alterations reported in type 2 PRCC, the integration of molecular profiling into clinical routine is of utmost importance. Clear understanding of the molecular basis of the various subtypes of type 2 papillary renal carcinoma as well as separately recognized entities with PRCC2-like morphologic features will go a long way toward finding appropriate therapies for these cancers. As multiple oncogenic mutations might co-occur in the same tumor, advanced models are needed to identify the most important oncogenic drivers. This it is hoped will avoid the disappointments encountered in the earlier trials using targeted therapies such as MTOR inhibition in PRCC.55,56 It will also be necessary to closely study tumor heterogeneity especially in relation to the various categories of type 2 PRCC encompassing indolent local tumor to aggressive phenotype. Indeed, new integrative models for histologic and molecular analysis of PRCCs will be needed to define distinct phenotypic and molecular portraits of PRCC subgroups for potential targeted therapies.57
1. Cohen HT, McGovern FJ. Renal-cell carcinoma. New Eng J Med. 2005;353:2477–2490.
2. Cairns P. Renal cell carcinoma. Cancer Biomark. 2011;9:461–473.
3. Moch H, Antonio L, Cubilla AL, et al. 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.
4. Moch H, Humphery PA, Ulbright TM, Reuter V, eds. WHO Classification of the Tumours of the Urinary System and Male Genital Organs (Chapter 1). Geneva, Switzerland: WHO Press, World Health Organization; 2016:23–25.
5. Amin MB, Corless CL, Renshaw AA, et al. Papillary
(chromophil) renal cell carcinoma: histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 62 cases. Am J Surg Pathol. 1997;21:621–635.
6. Kuroda N, Toi M, Hiroi M, et al. Review of papillary
renal cell carcinoma with focus on clinical and pathobiological aspects. Histol Histopathol. 2003;18:487–494.
7. Mancilla-Jimenez R, Stanley RJ, Blath RA. Papillary
renal cell carcinoma: a clinical, radiologic, and pathologic study of 34 cases. Cancer. 1976;38:2469–2480.
8. Delahunt B, Eble JN. History of the development of the classification of renal cell neoplasia. Clin Lab Med. 2005;25:231–246.
9. Yang XJ, Tan MH, Kim HL, et al. A molecular classification of papillary
renal cell carcinoma. Cancer Res. 2005;65:5628–5637.
10. Lee BH. Commentary on: “Comprehensive molecular characterization of papillary
renal-cell carcinoma”. Cancer Genome Atlas Research Network. N Engl J Med. 2016;374:135–145.
11. Pal SK, Ali SM, Yakirevich E, et al. Characterization of clinical cases of advanced papillary
renal cell carcinoma via comprehensive genomic profiling. Eur Urol. 2018;73:71–78.
12. Saleeb RM, Brimo F, Farag M, 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.
13. Kovacs G, Akhtar M, Beckwith BJ, et al. The Heidelberg classification of renal cell tumours. J Pathol. 1997;183:131–133.
14. Kovacs G. Papillary
renal cell carcinoma. A morphologic and cytogenetic study of 11 cases. Am J Pathol. 1989;134:27–34.
15. Kovacs G, Fuzesi L, Emanuel A, et al. Cytogenetics of papillary
renal cell tumors. Genes Chromosomes Cancer. 1991;3:249–255.
16. Kovacs G. Molecular cytogenetics of renal cell tumors. Adv Cancer Res. 1993;62:89–124.
17. Delahunt B, Eble JN. Papillary
renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol. 1997;10:537–544.
18. Delahunt B, Eble JN, McCredie MR, et al. Morphologic typing of papillary
renal cell carcinoma: comparison of growth kinetics and patient survival in 66 cases. Hum Pathol. 2001;32:590–595.
19. Leroy X, Zini L, Leteurtre E, et al. Morphologic subtyping of papillary
renal cell carcinoma: correlation with prognosis and differential expression of MUC1 between the two subtypes. Mod Pathol. 2002;15:1126–1130.
20. Zbar B, Tory K, Merino M, et al. Hereditary papillary
renal cell carcinoma. J Urol. 1994;151:561–566.
21. Schmidt L, Duh FM, Chen F, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary
renal carcinomas. Nat Genet. 1997;16:68–73.
22. Dharmawardana PG, Giubellino A, Bottaro DP. Hereditary papillary renal carcinoma
type I. Curr Mol Med. 2004;4:855–868.
23. Schmidt LS, Nickerson ML, Angeloni D, et al. Early onset hereditary papillary renal carcinoma
: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene. J Urol. 2004;172:1256–1261.
24. Bernues M, Casadevall C, Miro R, et al. Cytogenetic characterization of a familial papillary
renal cell carcinoma. Cancer Genet Cytogenet. 1995;84:123–127.
25. Zhuang Z, Park WS, Pack S, et al. Trisomy 7-harbouring non random duplication of the mutant MET allele in hereditary papillary
renal carcinomas. Nat Genet. 1998;20:66–69.
26. Fischer J, Palmedo G, Rolf von Knobloch RV, et al. Duplication and overexpression of the mutant allele of the MET proto oncogene in multiple hereditary papillary
renal cell tumours. Oncogene. 1998;17:733–739.
27. Yin X, Zhang T, Su X, et al. Relationships between Chromosome 7 Gain, MET Gene copy number Increase and MET protein overexpression in Chinese papillary
renal Cell carcinoma patients. PLoS One. 2015;10:e0143468.
28. Lubensky IA, Schmidt L, Zhuang Z, et al. Hereditary and sporadic papillary
renal carcinomas with c-met
mutations share a distinct morphological phenotype. Am J Pathol. 1999;155:517–526.
29. Schmidt L, Junker K, Nakaigawa N, et al. Novel mutations of the MET proto-oncogene in papillary
renal carcinomas. Oncogene. 1999;18:2343–2350.
30. Tovar EA, Graveel CR. MET in human cancer: germline and somatic mutations. Ann Transl Med. 2017;5:205.
31. Organ SL, Tsao M-S. An overview of the c-MET
signaling pathway. Ther Adv Med Oncol. 2011;3(suppl):S7–S19.
32. Patel VM, Handler MZ, Schwartz RA, et al. Hereditary leiomyomatosis and renal cell cancer syndrome: an update and review. J Am Acad Dermatol. 2017;77:14329–158.
33. Linehan WM, Rouault TA. Molecular pathways: fumarate hydratase deficient kidney cancer: targeting the Warburg effect in cancer. Clin Cancer Res. 2013;19:3345–3352.
34. Merino MJ, Torres-Cabala C, Pinto P, et al. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol. 2007;31:1578–1585.
35. Smith SC, Trpkov K, Chen YB, et al. Tubulocystic carcinoma of the kidney with poorly differentiated foci: a frequent morphologic pattern of fumarate hydratase deficient renal cell carcinoma. Am J Surg Pathol. 2016;40:1457–1472.
36. Chen YB, Brannon AR, Toubaji A, et al. Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. Am J Surg Pathol. 2014;38:627–637.
37. Trpkov K, Hes O, Agaimy A, et al. Fumarate hydratase deficient renal cell carcinoma is strongly correlated with fumarate hydratase mutation and hereditary leiomyomatosis and renal cell carcinoma syndrome. Am J Surg Pathol. 2016;40:865–875.
38. Ohe C, Smith SC, Sirohi D, et al. Reappraisal of morphologic differences between renal medullary carcinoma, collecting duct carcinoma, and fumarate hydratase-deficient renal cell carcinoma. Am J Surg Pathol. 2018;42:279–292.
39. Lehtonen HJ. Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics. Fam Cancer. 2011;10:397–411.
40. Albiges L, Justine Guegan J, Formal AL. MET is a potential target across all papillary
renal cell carcinomas: result from a large molecular study of pRCC with CGHa and matching Gene Expression array. Clin Cancer Res. 2014;20:3411–3421.
41. Fay AP, Signoretti S, Choueiri TK. CMET as a target in papillary
renal cell carcinoma. Clin Cancer Res. 2014;20:3361–3363.
42. Durinck S, Stawiski EW, Pavía-Jiménez A, et al. Spectrum of diverse genomic alterations define non-clear cell renal carcinoma
subtypes. Nat Genet. 2015;47:13–21.
43. Kovac M, Navas C, Horswell S, et al. Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary
renal cancer evolution. Nat Commun. 2015;6:6336.
44. Miller BF, Sánchez-Vega F, Elnitski L. The emergence of pan-Cancer CIMP and its elusive interpretation. Biomolecules. 2016;6:1–14.
45. Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and Its activation by oxidative stress. J Biol Chem. 2009;284:13291–13295.
46. Argani P, Netto GJ, Parwani AV. Papillary
renal cell carcinoma with low-grade spindle cell foci: a mimic of mucinous tubular and spindle cell carcinoma. Am J Surg Pathol. 2008;32:1353–1359.
47. Zhang Y, Yong X, Wu Q, et al. Mucinous tubular and spindle cell carcinoma and solid variant papillary
renal cell carcinoma: a clinicopathologic comparative analysis of four cases with similar molecular genetics datum. Diagn Pathol. 2014;9:194.
48. Ren Q, Wang L, Al-Ahmadie HA, et al. Distinct genomic copy number alterations distinguish mucinous tubular and spindle cell carcinoma of the kidney from papillary
renal cell carcinoma with overlapping histologic features. Am J Surg Pathol. 2018;42:767777.
49. Renshaw AA, Zhang H, Corless CL, et al. Solid variants of papillary
(chromophil) renal cell carcinoma: clinicopathologic and genetic features. Am J Surg Pathol. 1997;21:1203–1209.
50. Mantoan Padilha M, Billis A, Allende D, et al. Metanephric adenoma and solid variant of papillary
renal cell carcinoma: common and distinctive features. Histopathology. 2013;62:941–953.
51. Ulamec M, Skenderi F, Trpkovet K, et al. Solid papillary
renal cell carcinoma: clinicopathologic, morphologic, and immunohistochemical analysis of 10 cases and review of literature. Ann Diagn Pathol. 2016;23:51–57.
52. Hes O, Condom Mundo E, Peckova K, et al. Biphasic squamoid alveolar renal cell carcinoma: a distinctive subtype of papillary
renal cell carcinoma? Am J Surg Pathol. 2016;40:664–675.
53. Han G, Yu W, Chu J, et al. Oncocytic papillary
renal cell carcinoma: a clinicopathological and genetic analysis and indolent clinical course in 14 cases. Pathol Res Pract. 2017;213:1–6.
54. Skenderi F, Ulamec M, Vanecek T, et al. Warthin-like papillary
renal cell carcinoma: morphologic, immunohistochemical and molecular genetic analysis of 11 cases. Ann Diagn Pathol. 2017;27:48–56.
55. Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open label, randomized phase 2 trial. Lancet Oncol. 2016;17:378–388.
56. Tannir NM, Jonasch E, Albiges L, et al. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016;69:866–874.
57. Flippot R, Compérat E, Nizar M, et al. Papillary
renal cell carcinoma: a family portrait. Eur Urol. 2018;73:79–80.
Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
renal carcinoma; papillary; familial; sporadic; c-Met; next generation sequencing; type 1; type 2