Progression modellings in pancreas carcinoma and pancreatic intraepithelial neoplasia

Abstract

Pancreatic ductal adenocarcinomas (PDACs) make up more than 90%. Pancreatic carcinoma (PC) is the fourth most common cause of death in both genders. The most common PC types can be classified as PDAC. Rare types of ductal adenocarcinoma are; intraductal papillary-mucinous carcinomas, mucinous cystic neoplasia, medullary carcinoma, and other rare types. While 5-year survival rates of PDACs are less than 10% pancreatic precursor lesions, and carcinogenesis mechanisms are studied. It is accepted that PDACs develop by sequential tumor progression. Sequential preinvasive stages are well defined and morphologically different. Pancreatic intraepithelial neoplasia (PanIN) generally can’t be clinically identified, but still are the most common precursor of invasive ductal adenocarcinoma. For this reason, PanINs are of interest for PC diagnosis. In a simplified classification PanIN-1 A/B and PanIN-2 are low-grade, PanIN-3 is high-grade PanIN. The current progression model depending on the analysis of precursor lesions has two predictions: 1) PC develops according to specific alternations in genetic (KRAS> CDKN2A> TP53/SMAD4), and 2) as every alternation occurs independently PC development is stepwise. Intraductal papillary mucinous neoplasia (IPMN) is a separate entity of pancreatic cyst; an intraductal epithelial neoplasia secreting mucin, originating from the pancreatic duct, grossly visible (>5mm). Mucinous cystic neoplasia (MCN) is the rarest precancerous lesion of the pancreas. They are slow-growing cystic tumors and do not originate from the pancreatic ductal system. MCNs have dysplasia and focality. High-risk patients such as PanIN, MCN, and IPMN which would benefit from screenings made for premalignant disorders should be identified, though to date there is no acceptable screening test. the only curative treatment option available is radical surgical resection. Mechanism-based treatment options will be able in the future.

Keywords

• PanIN
• Pancreas cancer
• Progression models

Pankreas kanserlerinde progresyon modellemeleri ve pankreatik intraepitelyal neoplazi

Abstract

Pankreatik duktal adenokarsinomlar (PDAC) pankreas kanserlerinin %90’dan fazlasını oluşturur. Pankreas kanseri (PK) her iki cinsiyette de en sık dördüncü ölüm nedenidir. En sık PK türleri PDAC olarak sınıflanabilir. Duktal tip olup daha seyrek görülen duktal adenokarsinom varyantları; intraduktal papiller-musinöz kanserlerdir, müsinöz kistik neoplazi, medüller karsinom ve diğer nadir türler vardır. PDAC’lerin 5 yıllık sağ kalımının %10 un altında olması nedeni ile pankreatik prekürsör lezyonların çalışılması ile karsinogenesin mekanizmaları aydınlatılmaya çalışılmaktadır. Günümüzde PDAC’un basamaklı tümör progresyonu şeklinde geliştiği kabul edilmektedir. Ardışık preinvaziv evreler oldukça iyi tanımlanmıştır ve morfolojik olarak farklıdır. Pankreatik intraepitelyal neoplaziler (PanIN) genelde klinik olarak tanınamazlar, ancak yine de invaziv duktal adenokarsinomun en sık öncüleridir. Bu nedenle PanIN’ler pankreas kanseri tanısında ilgi kaynağı olmuştur. Sadeleştirilmiş bir sınıflamada PanIN-1A/B ve PanIN-2’yi low grade PanIN, PanIN-3 high grade olarak ayrılmıştır. Prekürsör lezyonların analizine dayanan mevcut progresyon modeli olan PanIN’in iki öngörüsü vardır: 1) PK genetik değişikliklerde özel bir sıralama ile oluştuğudur (KRAS> CDKN2A> TP53/SMAD4) ve 2) her bir değişim bağımsız olarak oluştuğundan PK gelişimi kademelidir. İntraduktal papiller müsinöz neoplazi (IPMN) pankreatik kistik hastalığın farklı bir antitesidir, gros olarak görülebilen (>5mm) pankreatik dukt hücrelerinden köken alan müsin salgılayan intraduktal epitelyal neoplazidir. İntestinal ve intestinal olmayan IPMN’lerin farklı biyolojik yolaklar izlediğine dair kanıtlar vardır. Tek bir IPMN birden fazla epitel tipi içerebilir. Müsinöz kistik neoplaziler (MCN) pankreasın en nadir kanser öncüsü lezyonlarıdır. Yavaş büyüyen kistik tümörlerdir, pankreasın duktal sisteminden köken almazlar. MCN’de displazi ve fokalite vardır. Premalign durumların tespiti için yapılacak taramalardan fayda görebilecek PanIN, MCN ve IPMN gibi yüksek riskli hastaların belirlenmesi gereklidir, ancak kabul edilebilir bir tarama testi henüz yoktur. Günümüzde tek küratif tedavi opsiyonu radikal yaklaşımlı cerrahi rezeksiyondur. Mekanizma bazlı tedavi seçenekleri gelecekte görülecektir.

Keywords

• Pankreas kanseri
• Progresyon modellemeleri
• PanIN

References

1. 1. Buchholz M, Gress TM. Molecular changes in pancreatic cancer. Expert Rev Anticancer Ther. 2009;9(10):1487-97.
2. 2. Lüttges J, Hahn S, Klöppel G. Where and when does pancreatic carcinoma start? Med Klin (Munich). 2004;99(4):191-5.
3. 3. Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res. 2000;6(8):2969-72.
4. 4. McGuigan A, Kelly P, Turkington RC, Jones C, Coleman HG, McCain RS. Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol. 2018;24(43):4846-61.
5. 5. Ottenhof NA, Milne AN, Morsink FH, et al. Pancreatic intraepithelial neoplasia and pancreatic tumorigenesis: of mice and men. Arch Pathol Lab Med. 2009;133(3):375-81.
6. 6. Toruner M, Fernandez-Zapico ME, Pin CL. New aspects of the epigenetics of pancreatic carcinogenesis. Epigenomes. 2020;4(3): 18.
7. 7. Krempley BD, Yu KH. Preclinical models of pancreatic ductal adenocarcinoma. Chin Clin Oncol. 2017;6(3):25.
8. 8. Nasca V, Chiaravalli M, Piro G, et al. Intraductal pancreatic mucinous neoplasms: A tumor-biology based approach for risk stratification. Int J Mol Sci. 2020;21(17): 6386.

9. 9. Wiest NE, Moktan VP, Oman SP, Chirilă RM. Screening for pancreatic cancer: A review for general clinicians. Rom J Intern Med. 2020;58(3):119-28.
10. 10. Sommers SC, Murphy SA, Warren S. Pancreatic duct hyperplasia and cancer. Gastroenterology. 1954;27(5):629-40.
11. 11. Maitra A, Adsay NV, Argani P, et al. Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Mod Pathol. 2003;16(9):902-12.
12. 12. Haugk B. Pancreatic intraepithelial neoplasia-can we detect early pancreatic cancer? Histopathology. 2010;57(4):503-14.
13. 13. Notta F, Chan-Seng-Yue M, Lemire M, et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature. 2016;538(7625):378-82.
14. 14. Cornish TC, Hruban RH. Pancreatic intraepithelial neoplasia. Surg Pathol Clin. 2011;4(2):523-35.
15. 15. Distler M, Aust D, Weitz J, Pilarsky C, Grützmann R. Precursor lesions for sporadic pancreatic cancer: PanIN, IPMN, and MCN. Biomed Res Int. 2014;2014:474905.
16. 16. Hata T, Suenaga M, Marchionni L, et al. Genome-wide somatic copy number alterations and mutations in high-grade pancreatic intraepithelial neoplasia. Am J Pathol. 2018;188(7):1723-33.
17. 17. Zhang L, Sanderson SO, Lloyd RV, Smyrk TC. Pancreatic intraepithelial neoplasia in heterotopic pancreas: evidence for the progression model of pancreatic ductal adenocarcinoma. Am J Surg Pathol. 2007;31(8):1191-5.
18. 18. Hruban RH, Takaori K, Canto M, et al. Clinical importance of precursor lesions in the pancreas. J Hepatobiliary Pancreat Surg. 2007;14(3):255-63.
19. 19. Maitra A, Kern SE, Hruban RH. Molecular pathogenesis of pancreatic cancer. Best Pract Res Clin Gastroenterol. 2006;20(2):211-26.
20. 20. Ansari D, Gustafsson A, Andersson R. Update on the management of pancreatic cancer: Surgery is not enough. World J Gastroenterol. 2015;21(11):3157-65.
21. 21. Abreu FB, Liu X, Tsongalis GJ. miRNA analysis in pancreatic cancer: The Dartmouth experience. Clin Chem Lab Med. 2017;55(5):755-62.
22. 22. Goggins M, Hruban RH, Kern SE. BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia: Evidence and implications. Am J Pathol. 2000;156(5):1767-71.
23. 23. Xue Y, Abou Tayoun AN, Abo KM, et al. MicroRNAs as diagnostic markers for pancreatic ductal adenocarcinoma and its precursor, pancreatic intraepithelial neoplasm. Cancer Genet. 2013;206(6):217-21.
24. 24. Kern S, Hruban R, Hollingsworth MA, et al. A white paper: The product of a pancreas cancer think tank. Cancer Res. 2001;61(12):4923-32.
25. 25. Misiura M, Zińczuk J, Zaręba K, Kamińska D, Guzińska-Ustymowicz K, Pryczynicz A. Actin-bundling proteins (actinin-4 and fascin-1) are involved in the development of pancreatic intraepithelial neoplasia (PanIN). Am J Med Sci. 2020;359(3):147-55.
26. 26. Kanda M, Matthaei H, Wu J, et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology. 2012;142(4):730-3.e9.
27. 27. Singhi AD, Wood LD, Parks E, et al. Recurrent rearrangements in PRKACA and PRKACB in intraductal oncocytic papillary neoplasms of the pancreas and bile duct. Gastroenterology. 2020;158(3):573-82.e2.
28. 28. Basturk O, Tan M, Bhanot U, et al. The oncocytic subtype is genetically distinct from other pancreatic intraductal papillary mucinous neoplasm subtypes. Mod Pathol. 2016;29(9):1058-69.
29. 29. Omori Y, Ono Y, Tanino M, et al. Pathways of progression from intraductal papillary mucinous neoplasm to pancreatic ductal adenocarcinoma based on molecular features. Gastroenterology. 2019;156(3):647-61.e2.
30. 30. Fischer CG, Beleva Guthrie V, Braxton AM, et al. Intraductal papillary mucinous neoplasms arise from multiple independent clones, each with distinct mutations. Gastroenterology. 2019;157(4):1123-37.e22.
31. 31. Canto MI, Almario JA, Schulick RD, et al. Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. Gastroenterology. 2018;155(3):740-51.e2.