Pathology Grading of Renal Cell Carcinoma

Tumor stage is the key prognostic parameter in renal cell carcinoma (RCC). ^[1] 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) has been a nuclear grading system described in 1982 by Fuhrman et al, ^[2]  which concurrently evaluates nuclear size and shape, and nucleolar prominence. ^[3] However, discordance and grading imprecision may occur among these three parameters, rendering the Fuhrman grading inapplicable. ^[3]

In 2012, the International Society of Urologic Pathologists (ISUP) proposed a novel, validated grading system for clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) that has been implemented by the World Health Organization (WHO). ^{[3, 4]} This system is based primarily on the nucleoli assessment of the tumors, as follows ^[4] :

• Grade 1: Inconspicuous nucleoli at ×400 magnification and basophilic
• Grade 2: Clearly visible nucleoli at ×400 magnification and eosinophilic
• Grade 3: Clearly visible nucleoli at ×100 magnification
• Grade 4: Extreme pleomorphism or rhabdoid and/or sarcomatoid morphology

The ISUP/WHO grading system has been shown to provide superior prognostic information in cases of ccRCC compared with the Fuhrman grading system. ^[5]  A study of 681 cases of ccRCC found that 144 tumors (21.1%) could not be assigned a Fuhrman grade owing to ambiguous grading features. ^[5]

Studies suggest that adding the presence of tumor-associated necrosis into the ISUP/WHO grading system improves outcome predictions as it is an independent prognostic factor for ccRCC. ^{[3, 6]}

Although the ISUP/WHO grading system is not validated as a prognostic parameter for other tumor subtypes, it has utility for descriptive purposes. ^{[3, 4]} This grading system and the Fuhrman grading system are not recommended for grading chromophobe renal cell carcinomas (RCCs), ^{[3, 4]} as validation studies did not demonstrate a correlation between grade and outcome with both grading systems. ^[3]

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). ^{[2, 7, 8, 9, 10, 11, 12]}

As noted earlier, the Fuhrman grading system has been extensively used by pathologists in Europe and the United States ^{[12, 13, 14, 15]} ; this system categorizes renal cell carcinoma (RCC) with grades 1, 2, 3, and 4 based on nuclear characteristics and has represented one of the most significant prognostic variables in patients with all stages of renal cell carcinoma (RCC). ^[2] The conventional Fuhrman grading system is validated for grading clear cell renal cell carcinoma (ccRCC), ^[2]  but the International Society of Urologic Pathologists (ISUP)/World Health Organization grading system has been shown to be superior to the Fuhrman grading system for this subtype of renal cell carcinoma (RCC).

Fuhrman system grade 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.

Fuhrman system grade 2

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.

Fuhrman system grade 3

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.

Fuhrman system grade 4

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 two-tiered grading system by grouping conventional Fuhrman grades 1 and 2 into grade 1 and grouping grades 3 and 4 into grade 2. ^[12] 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 three-tiered grading system. ^[16]

Sun et al compared the simplified Fuhrman grading (ie, two-tiered ^[12] and three-tiered ^[16] ) grading systems with a four-tiered grading system and confirmed that the two-tiered and three-tiered grading systems are equally as valuable as the conventional four-tiered Furman grading system based on accuracy criteria in ccRCC. ^[17] Moreover, a large European study showed that a modified two-tiered Fuhrman grading system has virtually equal accuracy relative to the conventional four-tiered Fuhrman grading system in predicting cancer-specific mortality. ^[18]  Studies by Smith et al and Becker et al also found that the simplified two-tiered or three-tiered Fuhrman grading system performs similarly to the conventional system. ^{[19, 20]}

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. ^[9]

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) remains in question.

The ISUP/WHO grading system is validated for papilllary renal cell carcinoma (pRCC), ^{[3, 4]} whereas Furman grading has been shown to be unrelated to cancer-specific mortality in patients with pRCC. ^[21]  Studies have indicated that grading of pRCC should not be based on nucleolar prominence alone. ^[22] Similarly, Delahunt et al ^{[22, 23]} 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 ccRCC, pRCC, and chromophobe RCC and should be included in the pathologic report.