THE RENAL CELL TUMORS- NEW CLASSIFICATION ACCORDING TO THE WORLD HEALTH ORGANISATION (2022)
Abstract
The fifth edition of the World Health Organization's classification of urogenital tumors, published in 2022, includes significant revisions regarding the classification of kidney cancer. In addition to the basic subsections for each type of kidney cancer, such as epidemiology, etiology, macroscopic and microscopic descriptions, and genetic research, a subsection called "Essential and Desired Diagnostic Criteria" has been included in the fifth edition of the WHO, which represents morphological diagnostic criteria combined with immunohistochemistry and relevant molecular tests. The global introduction of massive parallel sequencing will result in a diagnostic shift from morphology to molecular analysis. Therefore, a molecularly guided Classification of kidney tumors has been introduced, taking into account recent discoveries in renal tumor genomics.
Such newly molecularly defined epithelial kidney tumors include SMARCB1-deficient medullary renal cell carcinoma (RCC), TFEB-altered RCC, ALK-rearranged RCC, and ELOC-mutated RCC. Eosinophilic solid and cystic RCC is a new morphologically defined RCC entity primarily characterized by immunohistochemical positivity for CD20. Considering that kidney cancers are resistant to chemotherapy and radiation therapy, immunotherapy has been introduced for RCCs with detected mutations and has shown promising results and therapeutic response. For this reason, it is necessary to incorporate molecular testing into standard routine diagnostics in order to initiate immunotherapy for patients, thereby improving quality of life and extending overall survival.
References
1. Sung WW, Wang SC, Hsieh TY, Ho CJ, Huang CY, Kao YL, Chen WJ, Chen SL. Favorable mortality-to-incidence ratios of kidney Cancer are associated with advanced health care systems. BMC Cancer. 2018 Aug 6;18(1):792.
2. Kovacs G, Akhtar M, Beckwith BJ, et al. The Heidelberg classification of renal cell tumours. J Pathol 1997;183:131–3.
3. Eble J, Sauter G, Epstein J, Sesterhenn I. Tumours of the kidney. Tumours of the urinary system and male genital organs. WHO classification of tumours. IARC, Lyon. 2004.
4. Clark DJ, Dhanasekaran SM, Petralia F, et al. Integrated proteogenomic characterization of clear cell renal cell carcinoma. Cell 2019;179: 964–983.e31.
5. WHO. Classification of tumours of the urinary system and male genital organs. ed. 5. Lyon, France: International Agency for Research on Cancer; 2022.
6. Irmisch A, Bonilla X, Chevrier S, et al. The tumor profiler study: integrated, multi-omic, functional tumor profiling for clinical decision support. Cancer Cell 2021;39:288–93.
7. Argani P, Lae M, Hutchinson B, et al. Renal carcinomas with the t (6;11)(p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT- PCR, and DNA PCR. Am J Surg Pathol 2005;29:230–40.
8. Argani P, Reuter VE, Zhang L, et al. TFEB-amplified renal cell carcinomas: an aggressive molecular subset demonstrating variable melanocytic marker expression and morphologic heterogeneity. Am J Surg Pathol 2016;40:1484–95.
9. Sukov WR, Hodge JC, Lohse CM, et al. ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients. Mod Pathol 2012;25: 1516–25.
10. Shah RB, Stohr BA, Tu ZJ, et al. ‘‘Renal cell carcinoma with leiomyomatous stroma’’ harbor somatic mutations of TSC1, TSC2, MTOR, and/or ELOC (TCEB1): clinicopathologic and molecular characterization of 18 sporadic tumors supports a distinct entity. Am J Surg Pathol 2020;44:571–81.
11. Turajlic S, Xu H, Litchfield K, et al. Tracking cancer evolution reveals constrained routes to metastases: TRACERx renal. Cell 2018;173: 581–594.e12.
12. Choueiri TK, Cheville J, Palescandolo E, et al. BRAF mutations in metanephric adenoma of the kidney. Eur Urol 2012;62:917–22.
13. Dagher J, Kammerer-Jacquet SF, Brunot A, et al. Wild-type VHL clear cell renal cell carcinomas are a distinct clinical and histologic entity: a 10-year follow-up. Eur Urol Focus 2016;1:284–90.
14. Batavia AA, Schraml P, Moch H. Clear cell renal cell carcinoma with wild-type von Hippel-Lindau gene: a non-existent or new tumour entity? Histopathology 2019;74:60–7.
15. Palsgrove DN, Li Y, Pratilas CA, et al. Eosinophilic solid and cystic (ESC) renal cell carcinomas harbor TSC mutations: molecular analysis supports an expanding clinicopathologic spectrum. Am J Surg Pathol 2018;42:1166–81.
16. Trpkov K, Hes O, Bonert M, et al. Eosinophilic, solid, and cystic renal cell carcinoma: clinicopathologic study of 16 unique, sporadic neoplasms occurring in women. Am J Surg Pathol 2016;40:60–71.
17. Trpkov K, Abou-Ouf H, Hes O, et al. Eosinophilic solid and cystic renal cell carcinoma (ESC RCC): further morphologic and molecular characterization of ESC RCC as a distinct entity. Am J Surg Pathol 2017;41:1299–308.
18. Yunker A, Holder L, Nething J. Newly described eosinophilic, solid and cystic renal cell carcinoma: a case report and review of the literature. Arch Nephrol Urol 2020;3:38–45.
19. Hakimi AA, Tickoo SK, Jacobsen A, et al. TCEB1-mutated renal cell carcinoma: a distinct genomic and morphological subtype. Mod Pathol 2015;28:845–53.
20. Sugawara E, Togashi Y, Kuroda N, et al. Identification of anaplastic lymphoma kinase fusions in renal cancer: large-scale immunohistochemical screening by the intercalated antibody- enhanced polymer method. Cancer 2012;118:4427–36.
21. Debelenko LV, Raimondi SC, Daw N, et al. Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum. Mod Pathol 2011;24:430–42.
22. Tao JJ, Wei G, Patel R. ALK fusions in renal cell carcinoma: response to entrectinib. JCO Precis Oncol 2018;2:1–8.
23. Calderaro J, Moroch J, Pierron G, et al. SMARCB1/INI1 inactivation in renal medullary carcinoma. Histopathology 2012;61:428–35.
24. Calderaro J, Masliah-Planchon J, Richer W, et al. Balanced
translocations disrupting SMARCB1 are hallmark recurrent genetic alterations in renal medullary carcinomas. Eur Urol 2016;69:1055–61.
25. Jia L, Carlo MI, Khan H, et al. Distinctive mechanisms underlie the loss of SMARCB1 protein expression in renal medullary carcinoma: morphologic and molecular analysis of 20 cases. Mod Pathol 2019;32:1329–43.
26. Colombo P, Smith SC, Massa S, et al. Unclassified renal cell carcinoma with medullary phenotype versus renal medullary carcinoma: lessons from diagnosis in an Italian man found to harbor sickle cell trait. Urol Case Rep 2015;3:215–8.
27. Yu L, Li J, Xu S, Navia Miranda M, Wang G, Duan Y. An Xp11.2 translocation renal cell carcinoma with SMARCB1 (INI1) inactivation in adult end-stage renal disease: a case report. Diagn Pathol 2016;11:98.
28. Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO classification of tumours of the urinary system and male genital organs—part A: renal, penile, and testicular tumours. Eur Urol 2016;70:93–105.
29. Smith SC, Trpkov K, Chen YB, et al. Tubulocystic carcinoma of the kidney with poorly differentiated foci: a frequent morphologic pattern of fumarate hydratase-deficient renal cell carcinoma. Am J Surg Pathol 2016;40:1457–72.
30. Trpkov K, Hes O, Agaimy A, et al. Fumarate hydratase-deficient renal cell carcinoma is strongly correlated with fumarate hydratase mutation and hereditary leiomyomatosis and renal cell carcinoma syndrome. Am J Surg Pathol 2016;40:865–75.
31. Smith SC, Sirohi D, Ohe C, et al. A distinctive, low-grade oncocytic fumarate hydratase-deficient renal cell carcinoma, morphologically reminiscent of succinate dehydrogenase-deficient renal cell carcinoma. Histopathology 2017;71:42–52.
32. Wyvekens N, Valtcheva N, Mischo A, et al. Novel morphological and genetic features of fumarate hydratase deficient renal cell carcinoma in HLRCC syndrome patients with a tailored therapeutic approach. Genes Chromosomes Cancer 2020; 59:611–9.
33. Srinivasan R, Su D, Stamatakis L, et al. 5 Mechanism based targeted therapy for hereditary leiomyomatosis and renal cell cancer (HLRCC) and sporadic papillary renal cell carcinoma: interim results from a phase 2 study of bevacizumab and erlotinib. Eur J Cancer 2014;50:8.
34. Delahunt B, Eble JN. Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol 1997;10:537–44.
35. Jiang F, Richter J, Schraml P, et al. Chromosomal imbalances in papillary renal cell carcinoma: genetic differences between histological subtypes. Am J Pathol 1998;153:1467–73.
36. Cancer Genome Atlas Research Network, Linehan WM, Spellman PT, et al. Comprehensive molecular characterization of papillary renal- cell carcinoma. N Engl J Med 2016;374:135–45.
37. Al-Obaidy KI, Eble JN, Cheng L, et al. Papillary renal neoplasm with reverse polarity: a morphologic, immunohistochemical, and molecular study. Am J Surg Pathol 2019;43:1099–111.
38. Argani P, Reuter VE, Eble JN, et al. Biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC): a distinctive neoplasm associated with somatic NF2 mutations. Am J Surg Pathol 2020;44:901–16.
39. Hes O, Condom Mundo E, Peckova K, et al. Biphasic squamoid alveolar renal cell carcinoma: a distinctive subtype of papillary renal cell carcinoma? Am J Surg Pathol 2016;40:664–75.
40. Angell SK, Pruthi R, Freiha FS. Primary thyroid-like carcinoma of the kidney. Urology 1996;48:632–5.
41. Jung SJ, Chung JI, Park SH, Ayala AG, Ro JY. Thyroid follicular carcinoma-like tumor of kidney: a case report with morphologic, immunohistochemical, and genetic analysis. Am J Surg Pathol 2006;30:411–5.
42. Amin MB, Gupta R, Ondrej H, et al. Primary thyroid-like follicular carcinoma of the kidney: report of 6 cases of a histologically distinctive adult renal epithelial neoplasm. Am J Surg Pathol 2009;33:393–400.
43. Gill AJ, Pachter NS, Chou A, et al. Renal tumors associated with germline SDHB mutation show distinctive morphology. Am J Surg Pathol 2011;35:1578–85.
44. Delahunt B, Eble JN, Egevad L, Yaxley J, Thunders M, Samaratunga H. Emerging entities of renal cell neoplasia. Surg Exp Pathol 2019;2:1–7.
45. Siadat F, Trpkov K. ESC, ALK, HOT and LOT: three letter acronyms of emerging renal entities knocking on the door of the WHO classification. Cancers (Basel) 2020;12:168
46. Guo J, Tretiakova MS, Troxell ML, et al. Tuberous sclerosis-associated renal cell carcinoma: a clinicopathologic study of 57 separate carcinomas in 18 patients. Am J Surg Pathol 2014;38:1457–67.