Pathology Grading of Renal Cell Carcinoma 

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The grading schema of renal cell carcinoma (RCC) is based on the microscopic morphology of a neoplasm with hematoxylin and eosin (H&E) staining. The most popular and used widely system for grading renal cell carcinoma (RCC) is a nuclear grading system described in 1982 by Fuhrman et al. ^[1]

See Renal Cell Carcinoma: Recognition and Follow-up, a Critical Images slideshow, to help evaluate renal masses and determine when and what type of follow-up is necessary.

There are several significant clinical and pathologic prognostic factors in renal cell carcinoma (RCC), including primary tumor pathologic stage, lymph node involvement, nuclear grade, and histologic subtype. Of these, nuclear grade is one of the most important prognostic factors in patients with renal cell carcinoma (RCC). ^{[1, 2, 3, 4, 5, 6, 7]}

Currently, the Fuhrman grading system is most widely used by pathologists in Europe and the United States ^{[7, 8, 9, 10]} ; this system categorizes renal cell carcinoma (RCC) with grades 1, 2, 3, and 4 based on nuclear characteristics and represents one of the most significant prognostic variables in patients with all stages of renal cell carcinoma (RCC). ^[1] The conventional Fuhrman grading system is currently validated for grading clear cell renal cell carcinoma (CCRCC). ^[1]

Using the 10× objective, the nuclei of the tumor cells are small (< 10 µm), hyperchromatic, and round (resembling mature lymphocytes), with no visible nucleoli and little detail in the chromatin, as shown in the image below.

Using the 10× objective, the nuclei of the tumor cells are slightly larger (15 µm) with finely granular “open” chromatin but small, inconspicuous nucleoli (see the following image). The nucleoli are often present, and many appear as small chromocenters at 10× objective, with confirmation of their nature at higher power, but this does not count.

Using the 10× objective, the nuclei of the tumor cells are larger (20 µm in size) and may be oval in shape, with coarsely granular chromatin (see the image below). The nucleoli are easily unequivocally recognizable.

The nuclei are pleomorphic with open chromatin or hyperchromatic and single or multiple macronucleoli, as depicted in the following image.

Some researchers have tried to simplify the Fuhrman grading system in order to improve interobserver reproducibility. For example, Zisman et al introduced a 2-tiered grading system by grouping conventional Fuhrman grades 1 and 2 into grade 1 and grouping grades 3 and 4 into grade 2. ^[7] Ficarra et al suggested a simplified model that consisted of grouping grades 1 and 2 as grade 1 but with unchanged groupings of grades 3 and 4 into a 3-tiered grading system. ^[11]

Sun et al compared the simplified Fuhrman grading (ie, 2-tiered ^[7] and 3-tiered ^[11] ) grading systems with a 4-tiered grading system and confirmed that the 2-tiered and 3-tiered grading systems are equally as valuable as the conventional 4-tiered Furman grading system based on accuracy criteria in clear cell renal cell carcinoma (CCRCC). ^[12] Moreover, a large European study showed that a modified 2-tiered Fuhrman grading system has virtually equal accuracy relative to the conventional 4-tiered Fuhrman grading system in predicting cancer-specific mortality. ^[13]  Studies by Smith et al and Becker et al also found that the simplified 2-tiered or 3-tiered Fuhrman grading system performs similarly to the conventional system. ^{[14, 15]}

Mitotic activity is absent or rare in grade 1 and 2 tumors; mitoses are usually readily identified in grade 3 and 4 cases. Grade is assigned based on the highest grade present. Scattered cells may be discounted, but if several cells within a single high-power focus have high-grade characteristics, then the tumor should be graded accordingly. The majority of tumors are nuclear grades 2 and 3; grade 1 tumors are less common (< 5%), and grade 4 tumors account for 5-10% of cases. ^[4]

Nuclear grade has been shown to be independent of tumor type as a prognostic factor, but its value in specific histologic subtypes of renal cell carcinoma (RCC) is still in question. As the current World Health Organization (WHO) system referred, ^[16] there is no specific grading system for papillary renal cell carcinoma (RCC) and the Fuhrman system ^[1] is also accepted as applicable to it.

However, Sika-Paotonu et al showed that Furman grading was unrelated to cancer-specific mortality in patients with papillary renal cell carcinoma (RCC). ^[17] In recent years, studies have indicated that grading of papillary renal cell carcinoma (RCC) should not be based on nucleolar prominence alone. ^[18] Similarly, Delahunt et al ^{[18, 19]} pointed out that none of the proposed grading systems for renal cell carcinoma (RCC) — including the Fuhrman grading system — provides prognostic information for chromophobe renal cell carcinoma (RCC). Nonetheless, investigations that include large series of cases are still required to demonstrate whether or not nuclear grade is an independent prognostic factor in papillary and chromophobe renal cell carcinomas (RCCs).

Sarcomatoid change in renal cell carcinoma (RCC) is not very rare, and it is associated with aggressive tumor growth and the development of metastasis; therefore, this change is associated with a worse prognosis. Sarcomatoid change can be seen in clear cell renal cell carcinoma (CCRCC), papillary RCC, and chromophobe RCC and should be included in the pathologic report.

Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982 Oct. 6(7):655-63. [Medline].

Cheville JC, Blute ML, Zincke H, Lohse CM, Weaver AL. Stage pT1 conventional (clear cell) renal cell carcinmoa: pathological features associated with cancer specific survival. J Urol. 2001 Aug. 166(2):453-6. [Medline].

Ficarra V, Righetti R, Martignoni G, et al. Prognostic value of renal cell carcinoma nuclear grading: multivariate analysis of 333 cases. Urol Int. 2001. 67(2):130-4. [Medline].

Grignon DJ, Ayala AG, el-Naggar A, et al. Renal cell carcinoma. A clinicopathologic and DNA flow cytometric analysis of 103 cases. Cancer. 1989 Nov 15. 64(10):2133-40. [Medline].

Skinner DG, Colvin RB, Vermillion CD, Pfister RC, Leadbetter WF. Diagnosis and management of renal cell carcinoma. A clinical and pathologic study of 309 cases. Cancer. 1971 Nov. 28(5):1165-77. [Medline].

Srigley JR, Hutter RV, Gelb AB, et al. Current prognostic factors–renal cell carcinoma: Workgroup No. 4. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer. 1997 Sep 1. 80(5):994-6. [Medline].

Zisman A, Pantuck AJ, Dorey F, et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol. 2001 Mar 15. 19(6):1649-57. [Medline].

Zisman A, Pantuck AJ, Wieder J, et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol. 2002 Dec 1. 20(23):4559-66. [Medline].

Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J Urol. 2002 Dec. 168(6):2395-400. [Medline].

Karakiewicz PI, Briganti A, Chun FK, et al. Multi-institutional validation of a new renal cancer-specific survival nomogram. J Clin Oncol. 2007 Apr 10. 25(11):1316-22. [Medline].

Ficarra V, Martignoni G, Maffei N, et al. Original and reviewed nuclear grading according to the Fuhrman system: a multivariate analysis of 388 patients with conventional renal cell carcinoma. Cancer. 2005 Jan 1. 103(1):68-75. [Medline].

Sun M, Lughezzani G, Jeldres C, et al. A proposal for reclassification of the Fuhrman grading system in patients with clear cell renal cell carcinoma. Eur Urol. 2009 Nov. 56(5):775-81. [Medline].

Rioux-Leclercq N, Karakiewicz PI, Trinh QD, et al. Prognostic ability of simplified nuclear grading of renal cell carcinoma. Cancer. 2007 Mar 1. 109(5):868-74. [Medline].

Smith ZL, Pietzak EJ, Meise CK, et al. Simplification of the Fuhrman grading system for renal cell carcinoma. Can J Urol. 2015 Dec. 22(6):8069-73. [Medline].

Becker A, Hickmann D, Hansen J, et al. Critical analysis of a simplified Fuhrman grading scheme for prediction of cancer specific mortality in patients with clear cell renal cell carcinoma–Impact on prognosis. Eur J Surg Oncol. 2016 Mar. 42(3):419-25. [Medline].

Eble JN, Sauter G, Epstein JI, Sesterhenn IA, eds. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. World Health Organization Classification of Tumours. Lyon, France: IARC Press; 2004.

Sika-Paotonu D, Bethwaite PB, McCredie MR, William Jordan T, Delahunt B. Nucleolar grade but not Fuhrman grade is applicable to papillary renal cell carcinoma. Am J Surg Pathol. 2006 Sep. 30(9):1091-6. [Medline].

Delahunt B. Advances and controversies in grading and staging of renal cell carcinoma. Mod Pathol. 2009 Jun. 22 suppl 2:S24-36. [Medline].

Delahunt B, Sika-Paotonu D, Bethwaite PB, et al. Fuhrman grading is not appropriate for chromophobe renal cell carcinoma. Am J Surg Pathol. 2007 Jun. 31(6):957-60. [Medline].

YiFen Zhang, MD, PhD Vice-Chief Pathologist, Department of Pathology, Affiliated Drum Tower Hospital of Nanjing University Medical School, China

Disclosure: Nothing to disclose.

Chin-Lee Wu, MD, PhD Associate Professor of Pathology, Harvard Medical School; Associate Pathologist, Massachusetts General Hospital

Chin-Lee Wu, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Urological Association, Chinese American Medical Society, College of American Pathologists, United States and Canadian Academy of Pathology, International Society of Urological Pathology

Disclosure: Nothing to disclose.

Liang Cheng, MD Professor of Pathology and Urology, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine; Chief, Genitourinary Pathology Service, Indiana University Health

Liang Cheng, MD is a member of the following medical societies: American Association for Cancer Research, American Urological Association, College of American Pathologists, United States and Canadian Academy of Pathology, International Society of Urological Pathology, Arthur Purdy Stout Society

Disclosure: Nothing to disclose.

Pathology Grading of Renal Cell Carcinoma 

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