Malignant Melanoma – from Classical Histology towards Molecular Genetic Testing

Česká verze

Authors: A. Ryška ¹; O. Horký ²; J. Berkovcová ²; I. Tichá ³; M. Kalinová ⁴; M. Matějčková ⁵; Á. Bóday ⁶; J. Drábek ⁷; P. Martínek ⁸; J. Šimová ⁹; K. Sieglová ¹; H. Vošmiková ¹
Authors place of work: Fingerlandův ústav patologie, LF UK a FN Hradec Králové ¹; Oddělení onkologické patologie, Masarykův onkologický ústav, Brno ²; Ústav patologie, 1. LF UK a VFN v Praze ³; Ústav patologie a molekulární medicíny, 2. LF UK a FN Motol, Praha ⁴; Oddělení patologie a molekulární medicíny, Thomayerova nemocnice, Praha ⁵; Oddělení lékařské genetiky, Laboratoře AGEL, Nový Jičín ⁶; Laboratoř experimentální medicíny, FN Olomouc ⁷; Bioptická laboratoř, s. r. o., Plzeň ⁸; CGB laboratoř, a. s., Ostrava ⁹
Published in the journal: Klin Onkol 2017; 30(3): 182-189
Category: Přehled
doi: https://doi.org/10.14735/amko2017182

Summary

Background:
Malignant melanoma is – in comparison with other skin tumors – a relatively rare malignant neoplasm with highly aggressive biologic behavior and variable prognosis. Recent data in pathology and molecular diagnostics indicate that malignant melanoma is in fact not a single entity but a group of different neoplasms with variable etiopathogenesis, biologic behavior and prognosis. New therapeutic options using targeted treatment blocking MAPK signaling pathway require testing of BRAF gene mutation status. This helps to select patients with highest probability of benefit from this treatment.

Aim:
This article summarizes information on the correlation of morphological findings with genetic changes, discusses the representation of individual genetic types in various morphological subgroups and deals with the newly proposed genetic classification of melanoma and the current possibilities, pitfalls and challenges in BRAF testing of malignant melanoma. It also describes the current testing situation in the Czech Republic – the methods used, the representation of BRAF mutations in the tested population and the future of testing. It also shows the limitations of the BRAF and MEK targeted treatment concept resulting from the heterogeneity of the tumor population. Mechanisms of acquired resistance to MAPK pathway inhibitors, possibilities of their detection, and issues of combination of targeted therapy and immunotherapy are discussed.

Key words:
malignant melanoma – BRAF – mutation – molecular targeted therapy – tumor microenvironment – tumor heterogeneity

This work was supported by projects PROGRES Q40/11, BBMRICZ LM2015089, SVV 260398 and GACR 17-10331S.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted:
28. 3. 2017

Accepted:
16. 5. 2017

Zdroje

1. Dusek L, Muzik J, Maluskova D et al. Cancer incidence and mortality in the Czech Republic. Klin Onkol 2014; 27 (6): 406–423. doi: 10.14735/amko2014406.

2. Pavlik T, Majek O, Buchler T et al. Trends in stage-specific population-based survival of cancer patients in the Czech Republic in the period 2000–2008. Cancer Epidemiol 2014; 38 (1): 28–34. doi: 10.1016/j.canep.2013.11.002.

3. Kelly JW, Rivers JK, MacLennan R et al. Sunlight: a major factor associated with the development of melanocytic nevi in Australian schoolchildren. J Am Acad Dermatol 1994; 30 (1): 40–48.

4. MacKie RM, Aitchison T. Severe sunburn and subsequent risk of primary cutaneous malignant melanoma in scotland. Br J Cancer 1982; 46 (6): 955–960.

5. Noonan FP, Recio JA, Takayama H et al. Neonatal sunburn and melanoma in mice. Nature 2001; 413 (6853): 271–272.

6. Whiteman DC, Watt P, Purdie DM et al. Melanocytic nevi, solar keratoses, and divergent pathways to cutaneous melanoma. J Natl Cancer Inst 2003; 95 (11): 806–812.

7. Beral V, Robinson N. The relationship of malignant melanoma, basal and squamous skin cancers to indoor and outdoor work. Br J Cancer 1981; 44 (6): 886–891.

8. Bastian BC, Olshen AB, LeBoit PE et al. Classifying melanocytic tumors based on DNA copy number changes. Am J Pathol 2003; 163 (5): 1765–1770.

9. Curtin JA, Fridlyand J, Kageshita T et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005; 353 (20): 2135–2147.

10. Viros A, Fridlyand J, Bauer J et al. Improving melanoma classification by integrating genetic and morphologic features. PLoS Med 2008; 5 (6): e120. doi: 10.1371/journal.pmed.0050120.

11. Yazdi AS, Palmedo G, Flaig MJ et al. Mutations of the BRAF gene in benign and malignant melanocytic lesions. J Invest Dermatol 2003; 121 (5): 1160–1162.

12. Maldonado JL, Fridlyand J, Patel H et al. Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst 2003; 95 (24): 1878–1890.

13. Sauter ER, Yeo UC, von Stemm A et al. Cyclin D1 is a candidate oncogene in cutaneous melanoma. Cancer Res 2002; 62 (11): 3200–3206.

14. Shinozaki M, Fujimoto A, Morton DL et al. Incidence of BRAF oncogene mutation and clinical relevance for primary cutaneous melanomas. Clin Cancer Res 2004; 10 (5): 1753–1757.

15. DeLuca AM, Srinivas A, Alani RM. BRAF kinase in melanoma development and progression. Expert Rev Mol Med 2008; 10: e6. doi: 10.1017/S1462399408000604.

16. Omholt K, Platz A, Kanter L et al. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res 2003; 9 (17): 6483–6488.

17. Pollock PM, Harper UL, Hansen KS et al. High frequency of BRAF mutations in nevi. Nat Genet 2003; 33 (1): 19–20.

18. Platz A, Egyhazi S, Ringborg U et al. Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site. Mol Oncol 2008; 1 (4): 395–405. doi: 10.1016/j.molonc.2007.12.003.

19. Bastian BC, Kashani-Sabet M, Hamm H et al. Gene amplifications characterize acral melanoma and permit the detection of occult tumor cells in the surrounding skin. Cancer Res 2000; 60 (7): 1968–1973.

20. Wong CW, Fan YS, Chan TL et al. BRAF and NRAS mutations are uncommon in melanomas arising in diverse internal organs. J Clin Pathol 2005; 58 (6): 640–644.

21. Cancer Genome Atlas Network. Genomic Classification of Cutaneous Melanoma. Cell 2015; 161 (7): 1681–1696. doi: 10.1016/j.cell.2015.05.044.

22. Goydos JS, Mann B, Kim HJ et al. Detection of B-RAF and N-RAS mutations in human melanoma. J Am Coll Surg 2005; 200 (3): 362–370.

23. Kumar R, Angelini S, Hemminki K. Activating BRAF and N-Ras mutations in sporadic primary melanomas: an inverse association with allelic loss on chromosome 9. Oncogene 2003; 22 (58): 9217–9224.

24. Lee JH, Choi JW, Kim YS. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol 2011; 164 (4): 776–784. doi: 10.1111/j.13652133.2010.10185.x.

25. Curtin JA, Busam K, Pinkel D et al. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006; 24 (26): 4340–4346.

26. Libra M, Malaponte G, Navolanic PM et al. Analysis of BRAF mutation in primary and metastatic melanoma. Cell Cycle 2005; 4 (10): 1382–1384.

27. Melis C, Rogiers A, Bechter O et al. Molecular genetic and immunotherapeutic targets in metastatic melanoma. Virchows Arch. In press 2017. doi: 10.1007/s00428-017-2113-3.

28. Davies H, Bignell GR, Cox C et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417 (6892): 949–954.

29. Hauschild A, Grob JJ, Demidov LV et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380 (9839): 358–365. doi: 10.1016/S0140-6736 (12) 60868-X.

30. Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364 (26): 2507–2516. doi: 10.1056/NEJMoa1103782.

31. Thomas NE, Edmiston SN, Alexander A et al. Number of nevi and early-life ambient UV exposure are associated with BRAF-mutant melanoma. Cancer Epidemiol Biomarkers Prev 2007; 16 (5): 991–997.

32. Menzies AM, Lum T, Wilmott JS et al. Intrapatient homogeneity of BRAFV600E expression in melanoma. Am J Surg Pathol 2014; 38 (3): 377–382. doi: 10.1097/PAS.0000000000000136.

33. Saroufim M, Habib RH, Gerges R et al. Comparing BRAF mutation status in matched primary and metastatic cutaneous melanomas: implications on optimized targeted therapy. Exp Mol Pathol 2014; 97 (3): 315–320. doi: 10.1016/j.yexmp.2014.09.008.

34. Yancovitz M, Litterman A, Yoon J et al. Intra-and inter-tumor heterogeneity of BRAF (V600E)) mutations in primary and metastatic melanoma. PLoS One 2012; 7 (1): e29336. doi: 10.1371/journal.pone.0029336.

35. Dadzie OE, Yang S, Emley A et al. RAS and RAF muta-tions in banal melanocytic aggregates contiguous with primary cutaneous melanoma: clues to melanomagenesis. Br J Dermatol 2009; 160 (2): 368–375. doi: 10.1111/j.1365-2133.2008.08887.x.

36. Busam KJ, Hedvat C, Pulitzer M et al. Immunohistochemical analysis of BRAF (V600E) expression of primary and metastatic melanoma and comparison with mutation status and melanocyte differentiation antigens of metastatic lesions. Am J Surg Pathol 2013; 37 (3): 413–420. doi: 10.1097/PAS.0b013e318271249e.

37. Johnson DB, Menzies AM, Zimmer L et al. Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms. Eur J Cancer 2015; 51 (18): 2792–2799. doi: 10.1016/j.ejca.2015.08.022.

38. Manzano JL, Layos L, Buges C et al. Resistant mechanisms to BRAF inhibitors in melanoma. Ann Transl Med 2016; 4 (12): 237. doi: 10.21037/atm.2016.06.07.

39. Fisher KE, Cohen C, Siddiqui MT et al. Accurate detection of BRAF p.V600E mutations in challenging melanoma specimens requires stringent immunohistochemistry scoring criteria or sensitive molecular assays. Hum Pathol 2014; 45 (11): 2281–2293. doi: 10.1016/j.humpath.2014.07.014.

40. Mai R, Zhou S, Zhong W et al. Therapeutic efficacy of combined BRAF and MEK inhibition in metastatic melanoma: a comprehensive network meta-analysis of randomized controlled trials. Oncotarget 2015; 6 (29): 28502–28512. doi: 10.18632/oncotarget.4375.

41. Queirolo P, Spagnolo F. BRAF plus MEK-targeted drugs: a new standard of treatment for BRAF-mutant advanced melanoma. Cancer Metastasis Rev 2017; 36 (1): 35–42. doi: 10.1007/s10555-017-9660-6.

42. Simeone E, Grimaldi AM, Festino L et al. Combination Treatment of Patients with BRAF-Mutant Melanoma: A New Standard of Care. BioDrugs 2017; 31 (1): 51–61. doi: 10.1007/s40259-016-0208-z.

43. Deken MA, Gadiot J, Jordanova ES et al. Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma. Oncoimmunology 2016; 5 (12): e1238557. doi: 10.1080/2162402X.2016.1238557.

44. Hermel DJ, Ott PA. Combining forces: the promise and peril of synergistic immune checkpoint blockade and targeted therapy in metastatic melanoma. Cancer Metastasis Rev 2017; 36 (1): 43–50. doi: 10.1007/s10555-017-9656-2.

45. Hu-Lieskovan S, Mok S, Homet Moreno B et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF (V600E) melanoma. Sci Transl Med 2015; 7 (279): 279ra241. doi: 10.1126/scitranslmed.aaa4691.

46. Kim T, Amaria RN, Spencer C et al. Combining targeted therapy and immune checkpoint inhibitors in the treatment of metastatic melanoma. Cancer Biol Med 2014; 11 (4): 237–246. doi: 10.7497/j.issn.2095-3941.2014.04.002.

47. Pasquali S, Chiarion-Sileni V, Rossi CR et al. Immune checkpoint inhibitors and targeted therapies for metastatic melanoma: A network meta-analysis. Cancer Treat Rev 2017; 54: 34–42. doi: 10.1016/j.ctrv.2017.01.006.

48. Prieto PA, Reuben A, Cooper ZA et al. Targeted Therapies Combined With Immune Checkpoint Therapy. Cancer J 2016; 22 (2): 138–146. doi: 10.1097/PPO.0000000000000182.