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Current Urology Reports
Erschienen in: Current Urology Reports 1/2018

01.01.2018 | Kidney Diseases (G Ciancio, Section Editor)

Pathological Bases and Clinical Impact of Intratumor Heterogeneity in Clear Cell Renal Cell Carcinoma

verfasst von: José I. López, Javier C. Angulo

Erschienen in: Current Urology Reports | Ausgabe 1/2018

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Abstract

Purpose of Review

Intratumor heterogeneity is an inherent event in tumor development that is receiving much attention in the last years since it is responsible for most failures of current targeted therapies. The purpose of this review is to offer clinicians an updated insight of the multiple manifestations of a complex event that impacts significantly patient’s life.

Recent Findings

Clear cell renal cell carcinoma is the most common renal tumor and a paradigmatic example of a heterogeneous neoplasm. Next-generation sequencing has demonstrated that intratumor heterogeneity encompasses genetic, epigenetic, and microenvironmental variability. Currently accepted protocols of tumor sampling seem insufficient in unveiling intratumor heterogeneity with reliability and need to be updated. This variability challenges the precise morphological diagnosis, its molecular characterization, and the selection of optimal personalized therapies in clear cell renal cell carcinoma, a neoplasm traditionally considered chemo- and radio-resistant.

Summary

We review the state of the art of the different approaches to intratumor heterogeneity in clear cell renal cell carcinomas, from the simple morphology to the most sophisticated massive sequencing tools.
Literatur
1.
2.
3.
Palsdottir HB, Hardarson S, Petursdottir V, et al. Incidental detection of renal cell carcinoma is an independent prognostic marker: results of a long-term, whole population study. J Urol. 2012;187:48–53.CrossRefPubMed
4.
Hiley C, de Bruin EC, McGranahan N, Swanton C. Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine. Genome Biol. 2014;15:453.CrossRefPubMedPubMedCentral
5.
Renovanz M, Kim EL. Intratumoral heterogeneity, its contribution to therapy resistance and methodological caveats to assessment. Front Oncol. 2014;4:142.CrossRefPubMedPubMedCentral
6.
•• Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883–92. Seminal paper describing intratumor heterogeneity in clear cell renal cell carcinomas unveiled by multiregion sequencing.
7.
Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 2013;501:338–45.CrossRefPubMed
8.
Morris LGT, Riaz N, Desrichard A, et al. Pan-cancer analysis of intratumor heterogeneity as a prognostic determinant of survival. Oncotarget. 2016;7:10051–63.PubMedPubMedCentral
9.
Tsuzuki T, Sassa N, Shimoyama Y, et al. Tyrosine kinase inhibitor-induced vasculopathy in clear cell renal cell carcinoma: an unrecognized antitumour mechanism. Histopathology. 2014;64:484–93.CrossRefPubMed
10.
11.
• Diesboeck TS, Couzin ID. Collective behavior in cancer cell populations. BioEssays. 2009;31:190–7. Review paper describing swarming patterns in cancers paralleling with what happens in animal collectivities.
12.
Merlo LMF, Pepper JW, Reid BJ, Maley CC. Cancer as an evolutionary and ecological process. Nat Rev Cancer. 2006;6:924–35.CrossRefPubMed
13.
• Nawaz S, Yuan Y. Computational pathology: exploring the spatial dimension of tumor ecology. Cancer Lett. 2016;380:296–303. Modeling approach to the spatial organization of neoplasms regarded as collectivities with ecological behaviors.
14.
15.
Futakuchi M, Fukamachi K, Suzui M. Heterogeneity of tumor cells in the bone microenvironment: mechanisms and therapeutic targets for bone metastasis of prostate or breast cancer. Adv Drug Deliv Rev. 2016;99:206–11.CrossRefPubMed
16.
Graham TA, Sottoriva A. Measuring cancer evolution from the genome. J Pathol. 2017;241:183–91.CrossRefPubMed
17.
18.
Turajlic S, McGranahan N, Swanton C. Inferring mutational timing and reconstructing tumour evolutionary histories. Biochim Biophys Acta. 1855;2015:264–75.
19.
Caiado F, Silva-Santos B, Norell H. Intra-tumour heterogeneity—going beyond genetics. FEBS J. 2016;283:2245–58.CrossRefPubMed
20.
•• Davis A, Gao R, Navin N. Tumor evolution: Linear, branching, neutral or punctuated? Biochim Biophys Acta. 2017;1867:151–61. This is a review paper describing four different patterns of temporal tumor evolution with practical application.
21.
22.
23.
24.
Bozic I, Antal T, Ohtsuki H, et al. Accumulation of driver and passenger mutations during tumor progression. Proc Natl Acad Sci U S A. 2010;107:18545–50.CrossRefPubMedPubMedCentral
25.
Horswell S, Matthews N, Swanton C. Cancer heterogeneity and “the struggle for existence”: diagnostic and analytical challenges. Cancer Lett. 2013;340:220–6.CrossRefPubMed
26.
Kon R. Dynamics of competitive systems with a single common limiting factor. Math Biosci Eng. 2015;12:71–81.CrossRefPubMed
27.
Gatenby RA, Vincent TL. Application of quantitative models from population biology and evolutionary game theory to tumor therapeutic strategies. Mol Cancer Ther. 2003;2:919–27.PubMed
28.
Nagy JD. Competition and natural selection in a mathematical model of cancer. Bull Math Biol. 2004;66:663–87.CrossRefPubMed
29.
30.
Pongor L, Harami-Papp H, Méhes E, Czirók A, Gyorffy B. Cell dispersal influences tumor heterogeneity and introduces a bias in NGS data interpretation. Sci Rep. 2017;7:7358.CrossRefPubMedPubMedCentral
31.
Venkatesan S, Birkbak NJ, Swanton C. Constraints in cancer evolution. Biochem Soc Trans. 2017;45:1–13.CrossRefPubMed
32.
Alves JM, Prieto T, Posada D. Multiregional tumor trees are not phylogenies. Trend Cancer. 2017;3:546–50.CrossRef
33.
Collins J, Epstein JI. Prognostic significance of extensive necrosis in renal cell carcinoma. Hum Pathol. 2017;66:108–14.CrossRefPubMed
34.
de Peralta-Venturina M, Moch H, Amin M, et al. Sarcomatoid differentiation in renal cell carcinoma: a study of 101 cases. Am J Surg Pathol. 2001;25:275–84.CrossRefPubMed
35.
Thompson RH, Blute ML, Krambeck AE, et al. Patients with pT1 renal cell carcinoma who die from disease after nephrectomy may have unrecognized renal sinus fat invasion. Am J Surg Pathol. 2007;31:1089–93.CrossRefPubMed
36.
Soultati A, Stares M, Swanton C, et al. How should clinicians address intratumor heterogeneity in clear cell renal cell carcinoma? Curr Opin Urol. 2015;25:358–66.CrossRefPubMed
37.
Williamson SR, Kum JB, Goheen MP, Cheng L, Grignon DJ, Idrees MT. Clear cell renal cell carcinoma with a syncytial-type multinucleated giant tumor cell component: implications for differential diagnosis. Hum Pathol. 2014;45:735–44.CrossRefPubMed
38.
39.
López JI, Guarch R, Larrinaga G, et al. Cell heterogeneity in clear cell renal cell carcinoma. APMIS. 2013;121:1187–91.CrossRefPubMed
40.
Zaldumbide L, Erramuzpe A, Guarch R, et al. Large (>3.8 cm) clear cell renal cell carcinomas are morphologically and immunohistochemically heterogeneous. Virchows Arch. 2015;466:61–6.CrossRefPubMed
41.
Romero Q, Bendahl PO, Klintman M, et al. Ki67 proliferation in core biopsies versus surgical samples. A model for neo-adjuvant breast cancer studies. BMC Cancer. 2011;11:341.CrossRefPubMedPubMedCentral
42.
Fukuoka J, Hofer MD, Hori T, et al. Spiral array. A new high-throughput technology covers tissue heterogeneity. Arch Pathol Lab Med. 2012;136:1377–84.CrossRefPubMed
43.
• López JI, Cortés JM. A divide-and-conquer strategy in tumor sampling enhances detection of intratumor heterogeneity in pathology routine: a modeling approach in clear cell renal cell carcinoma (version 2; referees: 4 approved). F1000 Res. 2016;5:385. https://​doi.​org/​10.​12688/​f1000research.​8196.​2. First paper proposing an alternative efficient and affordable sampling method based on an in silico computational modeling.
44.
López JI, Cortés JM. Multi-site tumor sampling (MSTS): a new tumor selection method to enhance intratumor heterogeneity detection. Hum Pathol. 2017;64:1–6.CrossRefPubMed
45.
Kim TM, Jung SH, Baek IP, et al. Regional biases in mutation screening due to intratumoural heterogeneity of prostate cancer. J Pathol. 2014;233:425–35.CrossRefPubMed
46.
Ledgerwood LG, Kumar D, Eterovic AK, et al. The degree of intratumor mutational heterogeneity varies by primary tumor sub-site. Oncotarget. 2016;7:27185–98.CrossRefPubMedPubMedCentral
47.
Lopez-Knowles E, Gao Q, Cheang MCU, et al. Heterogeneity in global gene expression profiles between biopsy specimens taken peri-surgically from primary ER-positive breast carcinomas. Breast Cancer Res. 2016;18:39.CrossRefPubMedPubMedCentral
48.
Pearce DA, Arthur LM, Turnbull AK, et al. Tumour sampling method can significantly influence gene expression profiles derived from neoadjuvant window studies. Sci Rep. 2016;6:29434.CrossRefPubMedPubMedCentral
49.
Algaba F, Delahunt B, Berney DM, et al. Handling and reporting of nephrectomy specimens for adult renal tumours: a survey by the European Network of Uropathology. J Clin Pathol. 2012;65:106–13.CrossRefPubMed
50.
Trpkov K, Grignon DJ, Bonsib SM, et al. Handling and staging of renal cell carcinoma: The International Society of Urological Pathology Consensus (ISUP) conference recommendations. Am J Surg Pathol. 2013;37:1505–17.CrossRefPubMed
51.
Blumenfeld AJ, Guru K, Fuchs GJ, Kim HL. Percutaneous biopsy of renal cell carcinoma underestimates nuclear grade. Urology. 2010;76:610–3.CrossRefPubMed
52.
• Jason Abel E, Carrasco A, Culp SH, et al. Limitations of preoperative biopsy in patients with metastatic renal cell carcinoma: comparison to surgical pathology in 405 cases. BJU Int. 2012;110:1742–6. In this paper, the authors describe the usefulness and limitations of small biopsies in renal cell carcinomas. The representativeness of the obtained tissue is compared with the analysis of the surgical specimen in a large series of cases.
53.
Bettoni F, Masotti C, Habr-Gama A, et al. Intratumoral genetic heterogeneity in rectal cancer. Are single biopsies representative of the entirety of the tumor? Ann Surg. 2017;265:e4–6.CrossRefPubMed
54.
Ellsworth RE, Blackburn HL, Shriver CD, Soon-Shiong P, Ellsworth DL. Molecular heterogeneity in breast cancer: state of the science and implications for patient care. Semin Cell Dev Biol. 2017;64:65–72.CrossRefPubMed
55.
Beltrame L, Di Marino M, Fruscio R, et al. Profiling cancer gene mutations in longitudinal epithelial ovarian cancer biopsies by targeted next-generation sequencing: a retrospective study. Ann Oncol. 2015;26:1363–71.CrossRefPubMed
56.
Hsieh JJ, Manley BJ, Khan N, Gao J, Carlo MI, Cheng EH. Overcome tumor heterogeneity-imposed therapeutic barriers through convergent genomic biomarker discovery: a braided cancer river model of kidney cancer. Semin Cell Dev Biol. 2017;64:98–106.CrossRefPubMed
57.
Serrano MF, Katz M, Yan Y, Kibel AS, Humphrey PA. Percentage of high-grade carcinoma as a prognostic indicator in patients with renal cell carcinoma. Cancer. 2008;113:477–83.CrossRefPubMed
58.
• López JI. Intratumor heterogeneity in clear cell renal cell carcinoma. An approach for the practicing pathologist. APMIS. 2016;124:153–9. Review paper of intratumor heterogeneity in clear cell renal cell carcinoma with practical issues for pathologists.
59.
Zaldumbide L, Erramuzpe A, Guarch R, Pulido R, Cortés JM, López JI. Snail heterogeneity in clear cell renal cell carcinoma. BMC Cancer. 2016;16:194.CrossRefPubMedPubMedCentral
60.
Sankin A, Hakimi AA, Mikkilineni N, et al. The impact of genetic heterogeneity on biomarker development in kidney cancer assessed by multiregional sampling. Cancer Med. 2014;3:1485–92.CrossRefPubMedPubMedCentral
61.
Serie DJ, Joseph RW, Cheville JC, et al. Clear cell type A and B molecular subtypes in metastatic clear cell renal cell carcinoma: tumor heterogeneity and aggressiveness. Eur Urol. 2017;71:979–85.CrossRefPubMed
62.
Beksac AT, Paulucci DJ, Blum KA, Yadav SS, Sfakianos JP, Badani KK. Heterogeneity in renal cell carcinoma. Urol Oncol. 2017;35:507–15.CrossRefPubMed
63.
Errarte P, Guarch R, Pulido R, et al. The expression of fibroblast activation protein in clear cell renal cell carcinomas is associated with synchronous lymph node metastases. PLoS One. 2016;11:e0169105.CrossRefPubMedPubMedCentral
64.
Kwon T, Lee JL, You D, et al. Impact of surgery on the prognosis of metastatic renal cell carcinoma with IVC thrombus received TKI therapy. J Surg Oncol. 2014;110:145–50.CrossRefPubMed
65.
•• Tomaszewski JJ, Uzzo RG, Smaldone MC. Heterogeneity and renal mass biopsy: a review of its role and reliability. Cancer Biol Med. 2014;11:162–72. The authors describe in this paper the usefulness and limitations of small biopsies in renal cell carcinomas. The supposed representativeness of the obtained tissue by this method is criticized.
66.
Yuang Q, Kapur P, Zhang Y, et al. Intratumor heterogeneity of perfusion and diffusion in clear-cell renal cell carcinoma: correlation with tumor cellularity. Clin Genitourin Cancer. 2016;14:e585–94.CrossRef
67.
Zhang Y, Kapur P, Yuan Q, et al. Tumor vascularity in renal masses: correlation of arterial spin-labeled and dynamic contrast-enhanced magnetic resonance imaging assessments. Clin Genitourin Cancer. 2016;14:e25–36.CrossRefPubMed
68.
Brooks SA, Khandani AH, Fielding JR, et al. Alternate metabolic programs define regional variation of relevant biological features in renal cell carcinoma progression. Clin Cancer Res. 2016;22:2950–9.CrossRefPubMedPubMedCentral
69.
Goh V, Ganeshan B, Nathan P. Assessment of response to tyrosine kinase inhibitors in metastatic renal cell cancer: CT texture as a predictive biomarker. Radiology. 2011;261:165–71.CrossRefPubMed
70.
Polcari AJ, Gorbonos A, Milner JE, et al. The role of cytoreductive nephrectomy in the era of molecular targeted therapy. Int J Urol. 2009;16:227–33.CrossRefPubMed
71.
Bedke J, Gauler T, Grünwald V, et al. Systemic therapy in metastatic renal cell carcinoma. World J Urol. 2017;35:179–88.CrossRefPubMed
72.
Santoni M, Santini D, Massari F, et al. Heterogeneous drug target expression as possible basis for different clinical and radiological response to the treatment of primary and metastatic renal cell carcinoma: suggestions from bench to bedside. Cancer Metastasis Rev. 2014;33:321–31.CrossRefPubMed
Metadaten
Titel
Pathological Bases and Clinical Impact of Intratumor Heterogeneity in Clear Cell Renal Cell Carcinoma
verfasst von
José I. López
Javier C. Angulo
Publikationsdatum
01.01.2018
Verlag
Springer US
Erschienen in
Current Urology Reports / Ausgabe 1/2018
Print ISSN: 1527-2737
Elektronische ISSN: 1534-6285
DOI
https://doi.org/10.1007/s11934-018-0754-7

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