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Molecular Cytology Applications in Metastases

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Molecular Applications in Cytology

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Abstract

Metastatic disease is the main cause of death by cancer. Metastases are frequently diagnosed using cytology specimens, either using fine-needle aspiration (FNA) or effusion specimens. Over the last couple of decades, several molecular techniques have been successfully applied to cytological specimens. In situ hybridization and sequencing can nowadays be routinely performed in cytological specimens, and the application of these techniques in the metastatic cancer setting has the potential to change the landscape of patient care with advanced cancer. Additionally, as concepts like tumor clonal evolution are being translated to clinical trials and clinical care, the role and potential applications of molecular cytology are exponentially growing. Cytology, coupled with molecular techniques, has the potential to be the main source of specimens for longitudinal tracking of tumor metastasis and therefore have a central role in upcoming biomarker evaluation. In this chapter, we will review some the contemporary challenges that metastatic disease presents and how molecular cytology can help overcoming many of these, to ultimately improve patient diagnosis and care.

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References

  1. American Cancer Society. Cancer facts & figures 2016. Atlanta: American Cancer Society; 2016.

    Google Scholar 

  2. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49(6):1374–403. https://doi.org/10.1016/j.ejca.2012.12.027.

    Article  PubMed  CAS  Google Scholar 

  3. Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer. 2009;9(4):302–12. https://doi.org/10.1038/nrc2627.

    Article  PubMed  CAS  Google Scholar 

  4. Collins VP, Loeffler RK, Tivey H. Observations on growth rates of human tumors. Am J Roentgenol Radium Therapy, Nucl Med. 1956;76(5):988–1000. https://doi.org/10.1016/j.ijthermalsci.2004.09.006.

    Article  CAS  Google Scholar 

  5. Steel GG, Lamerton LF. The growth rate of human tumours. Br J Cancer. 1966;20(1):74–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Friberg S, Mattson S. On the growth rates of human malignant tumors: implications for medical decision making. J Surg Oncol. 1997;65(4):284–97. https://doi.org/10.1002/(SICI)1096-9098(199708)65:4<284::AID-JSO11>3.0.CO;2-2[pii].

    Article  PubMed  CAS  Google Scholar 

  7. Huyge V, Garcia C, Alexiou J, et al. Heterogeneity of metabolic response to systemic therapy in metastatic breast cancer patients. Clin Oncol. 2010;22(10):818–27. https://doi.org/10.1016/j.clon.2010.05.021.

    Article  CAS  Google Scholar 

  8. Baldus SE, Schaefer KL, Engers R, Hartleb D, Stoecklein NH, Gabbert HE. Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res. 2010;16(3):790–9. https://doi.org/10.1158/1078-0432.CCR-09-2446.

    Article  PubMed  CAS  Google Scholar 

  9. Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010;11(1):38–47. https://doi.org/10.1016/S1470-2045(09)70330-4.

    Article  PubMed  CAS  Google Scholar 

  10. Aparicio S, Caldas C. The implications of clonal genome evolution for cancer medicine. N Engl J Med. 2013;368(9):842–51. https://doi.org/10.1056/NEJMra1204892.

    Article  PubMed  CAS  Google Scholar 

  11. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26. https://doi.org/10.1126/scitranslmed.3002003.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Navin N, Krasnitz A, Rodgers L, et al. Inferring tumor progression from genomic heterogeneity. Genome Res. 2010;20(1):68–80. https://doi.org/10.1101/gr.099622.109.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Navin N, Kendall J, Troge J, et al. Tumour evolution inferred by single-cell sequencing. Nature. 2011;472(7341):90–4. https://doi.org/10.1038/nature09807.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Maley CC, Galipeau PC, Finley JC, et al. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat Genet. 2006;38(4):468–73. https://doi.org/10.1038/ng1768.

    Article  PubMed  CAS  Google Scholar 

  15. Almendro V, Cheng YK, Randles A, et al. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity. Cell Rep. 2014;6(3):514–27. https://doi.org/10.1016/j.celrep.2013.12.041.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C. Emerging landscape of oncogenic signatures across human cancers. Nat Genet. 2013;45(10):1127–33. https://doi.org/10.1038/ng.2762.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Schmitt FC, Longatto-Filho A, Valent A, Vielh P. Molecular techniques in cytopathology practice. J Clin Pathol. 2008;61(3):258–67. https://doi.org/10.1136/jcp.2006.044347.

    Article  PubMed  CAS  Google Scholar 

  18. Schmitt F, Barroca H. Role of ancillary studies in fine-needle aspiration from selected tumors. Cancer Cytopathol. 2012;120(3):145–60. https://doi.org/10.1002/cncy.20197.

    Article  PubMed  CAS  Google Scholar 

  19. Di Lorito A, Schmitt FC. (Cyto)pathology and sequencing: next (or last) generation? Diagn Cytopathol. 2012;40(5):459–61. https://doi.org/10.1002/dc.21691.

    Article  PubMed  Google Scholar 

  20. Schmitt FC, Soares R, Cirnes L, Seruca R. PCR amplification of DNA obtained from archived hematoxylin-eosin-and giemsa-stained breast cancer aspirates. Diagn Cytopathol. 1998;19(5):395–7. https://doi.org/10.1002/(SICI)1097-0339(199811)19:5<395::AID-DC19>3.0.CO;2-4.

    Article  PubMed  CAS  Google Scholar 

  21. Nagel H, Schulten HJ, Gunawan B, Brinck U, Füzesi L. The potential value of comparative genomic hybridization analysis in effusion-and fine needle aspiration cytology. Mod Pathol. 2002;15(8):818–25. https://doi.org/10.1097/01.MP.0000024521.67720.0F.

    Article  PubMed  Google Scholar 

  22. Gailey MP, Stence AA, Jensen CS, Ma D. Multiplatform comparison of molecular oncology tests performed on cytology specimens and formalin-fixed, paraffin-embedded tissue. Cancer Cytopathol. 2015;123(1):30–9. https://doi.org/10.1002/cncy.21476.

    Article  PubMed  CAS  Google Scholar 

  23. Kanagal-Shamanna R, Portier BP, Singh RR, et al. Next-generation sequencing-based multi-gene mutation profiling of solid tumors using fine needle aspiration samples: promises and challenges for routine clinical diagnostics. Mod Pathol. 2014;27(2):314–27. https://doi.org/10.1038/modpathol.2013.122.

    Article  PubMed  CAS  Google Scholar 

  24. Karnes HE, Duncavage EJ, Bernadt CT. Targeted next-generation sequencing using fine-needle aspirates from adenocarcinomas of the lung. Cancer Cytopathol. 2014;122(2):104–13. https://doi.org/10.1002/cncy.21361.

    Article  PubMed  CAS  Google Scholar 

  25. Shah RH, Scott SN, Brannon AR, Levine DA, Lin O, Berger MF. Comprehensive mutation profiling by next-generation sequencing of effusion fluids from patients with high-grade serous ovarian carcinoma. Cancer Cytopathol. 2015;123(5):289–97. https://doi.org/10.1002/cncy.21522.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Zheng G, Lin M-T, Lokhandwala PM, et al. Clinical mutational profiling of bone metastases of lung and colon carcinoma and malignant melanoma using next-generation sequencing. Cancer Cytopathol. 2016;124(10):744–53. https://doi.org/10.1002/cncy.21743.

    Article  PubMed  CAS  Google Scholar 

  27. Piqueret-Stephan L, Marcaillou C, Reyes C, et al. Massively parallel DNA sequencing from routinely processed cytological smears. Cancer Cytopathol. 2016;124(4):241–53. https://doi.org/10.1002/cncy.21639.

    Article  PubMed  CAS  Google Scholar 

  28. Beca F, Schmitt F. MicroRNA signatures in cytopathology: are they ready for prime time? Cancer Cytopathol. 2016;124(9):613–5. https://doi.org/10.1002/cncy.21728.

    Article  PubMed  Google Scholar 

  29. Nishino M. Molecular cytopathology for thyroid nodules: a review of methodology and test performance. Cancer Cytopathol. 2015;124(1):14–27. https://doi.org/10.1002/cncy.21612.

    Article  PubMed  Google Scholar 

  30. Tayari M, Winkle M, Kortman G, et al. Long noncoding RNA expression profiling in normal B-cell subsets and Hodgkin lymphoma reveals hodgkin and reed-sternberg cell–specific long noncoding RNAs. Am J Pathol. 2016;186(9):2462–72. https://doi.org/10.1016/j.ajpath.2016.05.011.

    Article  PubMed  CAS  Google Scholar 

  31. Su X, Malouf GG, Chen Y, et al. Comprehensive analysis of long non-coding RNAs in human breast cancer clinical subtypes. Oncotarget. 2014;5(20):9864–76. https://doi.org/10.18632/oncotarget.2454.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Pauli C, Puca L, Mosquera JM, et al. An emerging role for cytopathology in precision oncology. Cancer Cytopathol. 2015;124(3):167–73. https://doi.org/10.1002/cncy.21647.

    Article  PubMed  Google Scholar 

  33. DeRose YS, Wang G, Lin Y-C, et al. Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med. 2011;17(11):1514–20. https://doi.org/10.1038/nm.2454.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Zhao X, Liu Z, Yu L, et al. Global gene expression profiling confirms the molecular fidelity of primary tumor-based orthotopic xenograft mouse models of medulloblastoma. Neuro-Oncology. 2012;14(5):574–83. https://doi.org/10.1093/neuonc/nos061.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Reyal F, Guyader C, Decraene C, et al. Molecular profiling of patient-derived breast cancer xenografts. Breast Cancer Res. 2012;14(1):R11. https://doi.org/10.1186/bcr3095.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Beca F, Schmitt F. Growing indication for FNA to study and analyze tumor heterogeneity at metastatic sites. Cancer Cytopathol. 2014;122(7):504–11.

    Article  PubMed  Google Scholar 

  37. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70. https://doi.org/10.1038/nature11412.

    Article  CAS  Google Scholar 

  38. Amir E, Miller N, Geddie W, et al. Prospective study evaluating the impact of tissue confirmation of metastatic disease in patients with breast cancer. J Clin Oncol. 2012;30(6):587–92. https://doi.org/10.1200/JCO.2010.33.5232.

    Article  PubMed  Google Scholar 

  39. Wilking U, Karlsson E, Skoog L, et al. HER2 status in a population-derived breast cancer cohort: discordances during tumor progression. Breast Cancer Res Treat. 2011;125(2):553–61. https://doi.org/10.1007/s10549-010-1029-2.

    Article  PubMed  CAS  Google Scholar 

  40. Simmons C, Miller N, Geddie W, et al. Does confirmatory tumor biopsy alter the management of breast cancer patients with distant metastases? Ann Oncol. 2009;20(9):1499–504. https://doi.org/10.1093/annonc/mdp028.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Martins D, Beca F, Schmitt F. Metastatic breast cancer: mechanisms and opportunities for cytology. Cytopathology. 2014;25(4):225–30. https://doi.org/10.1111/cyt.12158.

    Article  PubMed  CAS  Google Scholar 

  42. Beca F, Polyak K. Intratumor heterogeneity in breast cancer. In: Stearns V, editor. Novel biomarkers in the continuum of breast cancer. Cham: Springer; 2016. p. 169–89. https://doi.org/10.1007/978-3-319-22909-6_7.

    Chapter  Google Scholar 

  43. Zhou M, Yu P, Hou K, et al. Effect of RAS status on anti-EGFR monoclonal antibodies+5-FU infusion-based chemotherapy in first-line treatment of metastatic colorectal cancer: a meta-analysis. Meta Gene. 2016;9:110–9. https://doi.org/10.1016/j.mgene.2016.05.001.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Tabernero J, Van Cutsem E, Diaz-Rubio E, et al. Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2007;25(33):5225–32. https://doi.org/10.1200/JCO.2007.13.2183.

    Article  PubMed  CAS  Google Scholar 

  45. André T, Blons H, Mabro M, et al. Panitumumab combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational molecular study. Ann Oncol. 2013;24(2):412–9. https://doi.org/10.1093/annonc/mds465.

    Article  PubMed  Google Scholar 

  46. Lièvre A, Bachet J-B, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26(3):374–9. https://doi.org/10.1200/JCO.2007.12.5906.

    Article  PubMed  CAS  Google Scholar 

  47. Lièvre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66(8):3992–5. https://doi.org/10.1158/0008-5472.CAN-06-0191.

    Article  PubMed  Google Scholar 

  48. Oliveira C, Velho S, Moutinho C, et al. KRAS and BRAF oncogenic mutations in MSS colorectal carcinoma progression. Oncogene. 2007;26(1):158–63. https://doi.org/10.1038/sj.onc.1209758.

    Article  PubMed  CAS  Google Scholar 

  49. Stoffel EM, Erichsen R, Frøslev T, et al. Clinical and molecular characteristics of post-colonoscopy colorectal cancer: a population-based study. Gastroenterology. 2016;151(5):870–878.e3.

    Article  CAS  PubMed  Google Scholar 

  50. Pang NKB, Nga ME, Chin SY, et al. KRAS and BRAF mutation analysis can be reliably performed on aspirated cytological specimens of metastatic colorectal carcinoma. Cytopathology. 2011;22(6):358–64. https://doi.org/10.1111/j.1365-2303.2010.00812.x.

    Article  PubMed  CAS  Google Scholar 

  51. Cai G, Wong R, Chhieng D, et al. Identification of EGFR mutation, KRAS mutation, and ALK gene rearrangement in cytological specimens of primary and metastatic lung adenocarcinoma. Cancer Cytopathol. 2013;121(9):500–7. https://doi.org/10.1002/cncy.21288.

    Article  PubMed  CAS  Google Scholar 

  52. Pelliccioni S, Lupi C, Sensi E. Anaplastic lymphoma kinase gene rearrangements in cytological samples of non-small cell lung cancer comparison with histological assessment. Cancer Cytopathol. 2014;122:445–53. https://doi.org/10.1002/cncy.21418.

    Article  PubMed  CAS  Google Scholar 

  53. Smouse JH, Cibas ES, Jänne PA, Joshi VA, Zou KH, Lindeman NI. EGFR mutations are detected comparably in cytologic and surgical pathology specimens of nonsmall cell lung cancer. Cancer Cytopathol. 2009;117(1):67–72. https://doi.org/10.1002/cncy.20011.

    Article  Google Scholar 

  54. Khode R, Larsen DA, Culbreath BC, et al. Comparative study of epidermal growth factor receptor mutation analysis on cytology smears and surgical pathology specimens from primary and metastatic lung carcinomas. Cancer Cytopathol. 2013;121(7):361–9. https://doi.org/10.1002/cncy.21273.

    Article  PubMed  CAS  Google Scholar 

  55. Billah S, Stewart J, Staerkel G, Chen S, Gong Y, Guo M. EGFR and KRAS mutations in lung carcinoma: molecular testing by using cytology specimens. Cancer Cytopathol. 2011;119(2):111–7. https://doi.org/10.1002/cncy.20151.

    Article  PubMed  CAS  Google Scholar 

  56. Ulivi P, Romagnoli M, Chiadini E, et al. Assessment of EGFR and K-ras mutations in fixed and fresh specimens from transesophageal ultrasound-guided fine needle aspiration in non-small cell lung cancer patients. Int J Oncol. 2012;41(1):147–52. https://doi.org/10.3892/ijo.2012.1432.

    Article  PubMed  CAS  Google Scholar 

  57. Treece AL, Montgomery ND, Patel NM, et al. FNA smears as a potential source of DNA for targeted next-generation sequencing of lung adenocarcinomas. Cancer Cytopathol. 2016;124(6):406–14. https://doi.org/10.1002/cncy.21699.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Centeno BA, Enkemann SA, Coppola D, Huntsman S, Bloom G, Yeatman TJ. Classification of human tumors using gene expression profiles obtained after microarray analysis of fine-needle aspiration biopsy samples. Cancer. 2005;105(2):101–9. https://doi.org/10.1002/cncr.20737.

    Article  PubMed  Google Scholar 

  59. Wei S, Lieberman D, Morrissette JJD, Baloch ZW, Roth DB, McGrath C. Using “residual” FNA rinse and body fluid specimens for next-generation sequencing: an institutional experience. Cancer Cytopathol. 2016;124(5):324–9. https://doi.org/10.1002/cncy.21666.

    Article  PubMed  CAS  Google Scholar 

  60. Jayson GC, Kohn EC, Kitchener HC, Ledermann JA. Ovarian cancer. Lancet. 2014;384(9951):1376–88. https://doi.org/10.1016/S0140-6736(13)62146-7.

    Article  PubMed  Google Scholar 

  61. Marchetti C, Palaia I, De Felice F, et al. Tyrosine-kinases inhibitors in recurrent platinum-resistant ovarian cancer patients. Cancer Treat Rev. 2016;42:41–6. https://doi.org/10.1016/j.ctrv.2015.10.011.

    Article  PubMed  Google Scholar 

  62. Jang S, Atkins MB. Which drug, and when, for patients with BRAF-mutant melanoma? Lancet Oncol. 2013;14(2):e60–9. https://doi.org/10.1016/S1470-2045(12)70539-9.

    Article  PubMed  CAS  Google Scholar 

  63. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54. https://doi.org/10.1038/nature00766.

    Article  PubMed  CAS  Google Scholar 

  64. Grob JJ, Amonkar MM, Karaszewska B, et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-l. Lancet Oncol. 2015;16(13):1389–98. https://doi.org/10.1016/S1470-2045(15)00087-X.

    Article  PubMed  CAS  Google Scholar 

  65. Mandala M, Merelli B, Massi D. Nras in melanoma: targeting the undruggable target. Crit Rev Oncol Hematol. 2014;92(2):107–22. https://doi.org/10.1016/j.critrevonc.2014.05.005.

    Article  PubMed  Google Scholar 

  66. Murali R, Thompson JF, Uren RF, Scolyer RA. Fine-needle biopsy of metastatic melanoma: clinical use and new applications. Lancet Oncol. 2010;11(4):391–400. https://doi.org/10.1016/S1470-2045(09)70332-8.

    Article  PubMed  Google Scholar 

  67. Hookim K, Roh MH, Willman J, et al. Application of immunocytochemistry and BRAF mutational analysis to direct smears of metastatic melanoma. Cancer Cytopathol. 2012;120(1):52–61. https://doi.org/10.1002/cncy.20180.

    Article  PubMed  CAS  Google Scholar 

  68. Bernacki KD, Betz BL, Weigelin HC, et al. Molecular diagnostics of melanoma fine-needle aspirates: a cytology-histology correlation study. Am J Clin Pathol. 2012;138(5):670–7. https://doi.org/10.1309/AJCPEQJW3PLOOZTC.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA

    Francisco Beca

  2. Department of Pathology, Medical Faculty of Porto University, Porto, Portugal

    Fernando C. Schmitt

  3. I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

    Fernando C. Schmitt

  4. IPATIMUP, Institute of Molecular Pathology and Immunology of Porto University, Porto, Portugal

    Fernando C. Schmitt

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  1. Francisco Beca
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  1. Medical Faculty of Porto University, Porto, Portugal

    Fernando C. Schmitt

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Beca, F., Schmitt, F.C. (2018). Molecular Cytology Applications in Metastases. In: Schmitt, F. (eds) Molecular Applications in Cytology. Springer, Cham. https://doi.org/10.1007/978-3-319-74942-6_13

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