Papillary Renal Cell Carcinoma in Lynch/Muir-Torre Syndrome with Germline Pathogenic Variant in MSH6 and Molecular Analysis Report of a Case and Review of the Literature

Main Article Content

Yu Yang
Shweta Dhar
Jennifer Taylor
Bhuvaneswari Krishnan

Keywords

Colon adenocarcinoma; Lynch syndrome; MSH6 mutation; Muir-Torre syndrome; Papillary renal cell carcinoma

Abstract

Lynch syndrome (LS) is an autosomal dominant inherited disorder due to pathogenic variations in the mismatch repair genes, which predisposes to malignancies, most commonly colon and endometrial carcinoma. Muir-Torre syndrome is a subset of LS with cutaneous sebaceous adenoma and keratoacanthoma in addition to the malignancies. Renal cell carcinoma (RCC) in patients with LS is extremely rare. Only 26 cases have been reported and among them, only two cases of papillary RCC. We report a case of synchronous papillary RCC and colonic adenocarcinoma in an 85-year-old male with Lynch/Muir-Torre syndrome. The LS was diagnosed when he presented with multiple sebaceous adenomas and genetic testing showed a pathogenic variant in MSH6 mismatch repair gene. A colonoscopy at that time showed multiple tubular adenomas with high-grade dysplasia. He was lost to follow-up and presented with gastrointestinal bleeding after 20 years. A right colonic mass, and a solid mass in the lower pole of the right kidney, was detected by imaging. Right Colectomy showed a T3N0 mucin-producing adenocarcinoma. Right nephrectomy showed a T3a papillary RCC which was microsatellite stable with MSH6, and KRAS mutation. The 36-month follow-up exams showed additional sebaceous neoplasms, and an absence of metastatic carcinoma. Analysis of the reported cases of RCC in LS show clear cell RCC as the most common type. These tumors showed MLH1 mutation most commonly, unlike the urothelial malignancies in LS which involve MSH2. Among the 4 cases of RCC with MSH6 mutation, three were in females, indicating some gender differences.

Abstract 98 | PDF Downloads 42 XML Downloads 30 HTML Downloads 4

References

1. Moreira L, Balaguer F, Lindor N, Chapelle ADL, Hampel H, Aaltonen LA, et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA. 2012;308(15):1555–65. http://dx.doi.org/10.1001/jama.2012.13088
2. Lancaster JM, Powell CB, Chen L, Richardson DL. Society of gynecologic oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol. 2015;136(1):3–7. http://dx.doi.org/10.1016/j.ygyno.2014.09.009
3. Mahalingam M. MSH6, past and present and Muir-Torre syndrome-connecting the dots. Am J Dermpathol. 2017;39(4):239– 49. http://dx.doi.org/10.1097/DAD.0000000000000633
4. Metcalfe MJ, Petros FG, Rao P, Mork ME, Xiao L, Broaddus RR, et al. Universal point of care testing for Lynch syndrome in patients with upper tract urothelial carcinoma. J Urol. 2018;199(1):60–5. http://dx.doi.org/10.1016/j.juro.2017.08.002
5. Joost P, Therkildsen C, Dominguez-Valentin M, Jonsson M, Nilbert M. Urinary tract cancer in Lynch syndrome; increased risk in carriers of MSH2 mutations. Urology. 2015;86(6):1212– 17. http://dx.doi.org/10.1016/j.urology.2015.08.018
6. Harper HL, McKenney JK, Heald B, Stephenson A, Campbell SC, Plesec T, et al. Upper tract urothelial carcinomas: Frequency of association with mismatch repair protein loss and Lynch syndrome. Mod Pathol. 2017;30(1):146–56. http://dx.doi. org/10.1038/modpathol.2016.171
7. Aarnio M, Saily M, Juhola M, Gylling A, Peltomaki P, Jarvinen HJ, et al. Uroepithelial and kidney carcinoma in Lynch syndrome. Fam Cancer. 2012;11(3):395–401. http://dx.doi. org/10.1007/s10689-012-9526-6
8. Stratton KL, Alanee S, Glogowski EA, Schrader KA, Rau-Murthy R, Klein R, et al. Outcome of genetic evaluation of patients with kidney cancer referred for suspected hereditary cancer syndromes. Urol Oncol. 2016;34(5):238.e1–e7. http://dx. doi.org/10.1016/j.urolonc.2015.11.021
9. Mendez LE, Atlass J. Triple synchronous primary malignancies of the colon of the colon, endometrium and kidney in a patient with Lynch syndrome treated vis minimally invasive techniques. Gynecol Oncol Rep. 2016;17:29–32. http://dx.doi.org/10.1016/j. gore.2016.05.007
10. Therkildsen C, Joost P, Lindberg LJ, Ladelund S, Smith-Hansen  L, Nilbert M. Renal cell cancer linked to Lynch syndrome: Increased incidence and loss of mismatch repair protein expression. Int J Urol. 2016;23(6):528–29. http://dx.doi. org/10.1111/iju.13094
11. Mongiat-Artus P, Miquel C, Flejou JF, Coulet F, Verine J, Buhard O, et al. Spectrum of molecular alterations in colorectal, upper urinary tract, endocervical and renal carcinomas arising in a patient with hereditary non-polyposis colorectal cancer. Virchows Arch. 2006;449(2):238–43. http://dx.doi.org/10.1007/ s00428-006-0182-9
12. Boland PM, Yurgelun MB, Boland R. Recent progress in Lynch syndrome and other familial colorectal cancer syndromes. CA: Cancer J Clin. 2018;68(3):217–31. http://dx.doi.org/10.3322/ caac.21448
13. Sinicrope FA. Lynch syndrome-associated colorectal cancer. N Eng J Med. 2018;379(8):764–73. http://dx.doi.org/10.1056/ NEJMcp1714533
14. Baglietto L, Lindor NM, Dowty JG, White DM, Wagner A, Gomez Garcia EB, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102(3):193– 201. http://dx.doi.org/10.1093/jnci/djp473
15. Tavakkol Z, Keller JJ, Furmanczyk PS, Bennett RL, Chien AJ. Germline mutation is MSH6 associated with multiple malignant neoplasms in a patient with Muir-Torre syndrome. J Clin Oncol. 2012;30(22):e195–8. http://dx.doi.org/10.1200/JCO.2011.41.5562
16. Allory Y, Ouazana D, Boucher E, Thiounn N, Vieillefond  A. Papillary renal cell carcinoma. Prognostic value of morphological subtypes in a clinicopathologic study of 43 cases. Virchows Arch. 2003;442(4):336–42. http://dx.doi.org/10.1007/ s00428-003-0787-1
17. Lefavre M, Couturier J, Sibony M, Bazille C, Boyer K, Callard P, et al. Adult papillary renal tumor with oncocytic cells: Clinicopathologic, immunohistochemical and cytogenetic features of 10 cases. Am J Surg Pathol. 2005;29(12):1576–81. http:// dx.doi.org/10.1097/01.pas.0000184821.09871.ec
18. Kunju LP, Wojno K, Wolf S, Cheng L, Shah RB. Papillary renal cell carcinoma with oncocytic cells and nonoverlapping low grade nuclei: Expanding the morphologic spectrum with emphasis on clinicopathologic, immunohistochemical and molec-ular features. Hum Pathol. 2008;39(1):96–101. http://dx.doi. org/10.1016/j.humpath.2007.05.016
19. Park BH, Ro JY, Park WS, Jee KJ, Gong G, Cho YM. Oncocytic papillary renal cell carcinoma with inverted nuclear pattern: Distinct subtype with an indolent clinical course. Pathol Int. 2009;59(3):137–46. http://dx.doi. org/10.1111/j.1440-1827.2009.02341.x
20. Cheverie-Davis M, Riazalhosseini Y, Arsenault M, Aprikian A, Kassouf W, Tanguay S, et al. Morphologic and immunohistochemical spectrum of papillary renal cell carcinoma: Study including 132 case with pure type 1 and type 2 mor-phology as well as tumors with overlapping features. Am J Surg Pathol. 2014;38(7):887–94. http://dx.doi.org/10.1097/ PAS.0000000000000247
21. Saleeb RM, Brimo F, Farag M, Rompre-Brodeur A, Rotondo F, Beharry V, 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(12):1618–29. http://dx.doi.org/10.1097/ PAS.0000000000000962
22. Al-Obaidy K, Eble JN, Cheng L, Williamson SR, Sakr WA, Gupta N, et al. Papillary renal neoplasm with reverse polarity a morphologic, immunohistochemical and molecular study. AM J Surg Pathol. 2019;43(8):1099–111. http://dx.doi.org/10.1097/ PAS.0000000000001288
23. Al-Obaidy KI, Eble JN, Nassiri M, Cheng L, Eldomery  MK, Williamson SR, et al. Recurrent KRAS mutations in papillary renal neoplasm with reverse polarity. Mod Pathol. 2020;33(6):1157–64. http://dx.doi.org/10.1038/s41379-019-0362-1
24. Lee HJ, Shin DH, Park JY, Kim SY, Hwang CS, Lee JH, et al. Unilateral synchronous papillary renal neoplasm with reverse polarity and clear cell renal cell carcinoma: A case report with KRAS and PIK3CA mutations. Diag Pathol. 2020;15:123. http://dx.doi.org/10.1186/s13000-020-01042-7
25. Kim SS, Cho YM, Kim GH, Kee KH, Kim H, Kim KM, et al. Recurrent KRAS mutations identified in papillary renal neoplasm with reverse polarity – A comparative study with papillary renal cell carcinoma. Mod Pathol. 2020;33(4):690–9. http:// dx.doi.org/10.1038/s41379-019-0420-8
26. Tong K, Zhu W, Fu H, Cao F, Wand S, Zhou W, et al. Frequent KRAS mutations in oncocytic papillary renal neoplasm with inverted nuclei. Histopathology. 2020;76(7):1070–83. http://dx. doi.org/10.1111/his.14084
27. Bayrak O, Sen H, Bulut E, Cengiz B, Karakok M, Erturhan S, et al. Evaluation of EGFR, KRAS and BRAF gene mutations in renal cell carcinoma. J Kidney Cancer VHL. 2014;1(4):40–5. http://dx.doi.org/10.15586/jkcvhl.2014.10
28. Roth RM, Haraldsdottir S, Hampel H, Arnold CA, Frankel W. Discordant mismatch repair protein immunoreactivity in Lynch syndrome-associated neoplasms: A recommendation for screening synchronous/metachronous neoplasms. Am J Clin Pathol. 2016;146(1):50–6. http://dx.doi.org/10.1093/ajcp/aqw067
29. Steinhagen E, Moore HG, Lee-Kong SA, Shia J, Eaton  A, Markowitz AJ, et al. Patients with colorectal and renal cell carcinoma diagnosis appear to be at risk for additional malignancies. Clin Colorectal Cancer. 2013;12(1):23–7. http://dx.doi. org/10.1016/j.clcc.2012.07.004
30. Karamurzin Y, Zeng Z, Stadler ZK, Zhang L, Ouansafi I, Al-Ahmadie H, et al. Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: A report of new cases and review of the literature. Hum Pathol. 2012;43(10):1677–87. http://dx.doi. org/10.1016/j.humpath.2011.12.012
31. Shih AR, Kradin RL. Malignant mesothelioma in Lynch syndrome: A report of two cases and review of the literature. Am J Ind Med. 2019;62(5):448–52. http://dx.doi.org/10.1002/ ajim.22968
32. Makiuchi S, Yoshida H, Ishikawa M, Kojima N, Kanai Y, Kato T. Primary peritoneal low grade serous carcinoma in a patient with Lynch syndrome: A case report. Int J Gynecol Pathol. 2020;39(4):327–32. http://dx.doi.org/10.1097/PGP. 0000000000000622
33. Gylling AHS, Nieminen TT, Abdel-Rahman WM, Nuorva K, Juhola M, Joensuu EI, et al. Differential cancer predisposition in Lynch syndrome: Insights from molecular analysis of brain and urinary tract tumors. Carcinogenesis. 2008;29(7):1351–9. http://dx.doi.org/10.1093/carcin/bgn133