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Received: October 22^nd 2014

Accepted: March 6^th 2015

Renal cell carcinoma: pathological prognostic factors, staging and histopathological classification of 355 cases

Elsa Acosta-Jiménez,^a Debbie Jerónimo-Guerrero,^a María de los Ángeles Macías Clavijo,^a Deia Rivera-Diez,^a Liliana Hernández-Briseño,^a Edgar Beltrán-Suárez,^b Jocabed Martínez-Olivares,^a Ulises Ángeles-Garay^c

^aServicio de Anatomía Patológica

^bServicio de Urología

^cServicio de Epidemiologia

Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Distrito Federal, México

Communication with: Elsa Acosta-Jiménez

Telephone: (55) 5724 5900, extension: 23052

Email: elsa_acosta25@hotmail.com

Background: New morphologic entities for Renal Cell Carcinoma (RCC) that influence the prognosis have been described. Clinical staging has also undergone several modifications, the last one published in 2010 7th edition of the American Joint Committee on Cancer. The aim of this article is to determine the prevalence of histological subtypes, Fuhrman grading and clinical staging of renal cell carcinomas.

Methods: This is a retrospective, descriptive and comparative study, from January 2008 to June 2013. 355 cases of RCC were reclassified according to nuclear grading and new histopathological diagnostics and staging according to the TNM. A Kappa index was used for the diagnostic concordance and nuclear grading.

Results: Conventional renal cell carcinoma corresponded to 84.51 %, followed by chromophobe carcinoma and papillary. Less common subtypes were: multilocular cystic carcinoma, papillary clear cell carcinoma and others. Nuclear grading was directly related to the tumoral size and clinical staging (p < 0.001). The predominant stage was pT1b N0 M0, followed by pT3a N0 M0.

Conclusions: The most frequent tumor was clear cell RCC, followed by chromophobe carcinoma and papillary carcinoma. Nuclear grading, necrosis, eosinophilic cells areas with areas of sarcomatoid and rhabdoid differentiation are prognostic factors associated with an increased aggression and risk of metastases.

Keywords: Renal cell carcinoma; Kidney neoplasms; Urologic neoplasms

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Renal cell carcinoma (RCC) represents 3% of all neoplasia. In our country it is 1.5% of all cancers, and is the third most common malignant neoplasia of the genitourinary tract. In the United States approximately 30 000 new cases of the disease occur each year with 12 000 deaths.^1-3 In 1999 it caused death in 2.2% of men and 1% of women in our country, according to the Histopathological Registry of Malignant Neoplasms in Mexico. The classification of renal tumors was proposed in 2004 by WHO; this classification summarized the contributions of previous classifications, including Mainz and Heldelberg.^4,5 The latest update of this classification (4th edition) was proposed by the Pathological Clinical Study of Kidney Tumors in Tokyo, Japan (2010), although this describes features based on genetic and pathological analysis, and with recent developments new subtypes have been proposed.^4-7 The International Society of Urological Pathology (ISUP) has categorized these injuries (Vancouver classification) and proposed some as new epithelial neoplasms: tubular-cystic RCC, RCC associated with acquired cystic disease, clear cell papillary renal cell carcinoma, RCC with translocation of MiT family genes, RCC associated with leiomyomatosis hereditary syndrome (Reed syndrome) and other such provisional entities.⁸ This study aims to provide information on subtypes, including new entities, as well as the secondary characteristics related to prognosis, nuclear classification, and clinical stage.

Methods

The study was conducted in the Departamento de Anatomía Patológica at the Hospital de Especialidades del Centro Médico Nacional La Raza. It was a retrospective, open, observational, descriptive and comparative study, within the period from January 2008 to June 2013.

From pathological anatomy files, all those specimens (total renal biopsies, partial or radical nephrectomy) with histologically confirmed renal cell carcinoma (malignant epithelial tumors) were selected; the study included patients over 16 years of age, of both sexes, with medical records, paraffin blocks and viable tumor slides. Patient demographics were pulled from the clinical files; macroscopic examination data were pulled from histopathology reports, such as: laterality, location (upper pole, middle or bottom) focality (unifocal, multifocal), size, margins, adrenal gland involvement, venous and lymphatic invasion, as well as areas of necrosis and hemorrhage. The presence of metastases and regional lymph nodes were taken from imaging studies, pathological stage was established according to the tumor-node-metastasis system (TNM) published in the renal cell carcinoma staging guidelines of the American Joint Committee on Cancer (AJCC) in its seventh edition, published in 2010. With the help of the Leica light microscope with objectives 4x, 10x and 40x, according to the architectural plans, which occupied more than 10% of neoplasia (Table I), a reclassification of histopathological diagnoses with routine staining (hematoxylin and eosin) was performed, only immunohistochemical studies were used to confirm some lesions with diagnostic difficulty.

The nuclear grade was also reclassified, the gradation is performed according to the area of ​​greatest nuclear degree, regardless of size. The measurements were performed with photomicrographs obtained with a Moticam 2300 digital camera serial number SO11263M (Motic Images Plus 2.0 ML) and Leica Microsystems Wetzler Gim6V light microscope type: 020-518.500DM / LS with amplifications at 100X and 400X, using measurements in µm, taking the Fuhrman classification as reference:

• Grade 1: small nucleus, round, 10 µm, hyperchromatic reminiscent of mature lymphocytes, the nucleolus is not visible and the chromatin is fine (magnified 400').
• Grade 2: slightly irregular nucleus of 15 µm, has an "open" fine granular chromatin with inconspicuous nucleoli at 400' magnification.
• Grade 3: Irregular nucleus of approximately 20 µm with a nucleolus prominent at 100' magnification.
• Grade 4: Similar to grade 3 but with more pleomorphism, multilobed nuclei with clumped chromatin.

A database was designed to codify the variables in the computer program Microsoft Access, from which quantitative variables were obtained (mean ± standard deviation). Categorical variables were presented as simple frequencies and proportions. Kappa index was performed to determine the diagnostic agreement and nuclear grading; the association of qualitative variables were compared using the chi square test.

Results

A total of 428 cases were included in the study, of which 73 patients were excluded for not having slides, paraffin blocks or imaging studies that would yield the clinical stage of their disease. A total of 355 cases were analyzed, the number of slides varying from 10 to 25 per case. The most frequently performed procedure was radical nephrectomy, in these cases only 24.23% had an adrenal gland. These general characteristics and demographics of renal epithelial tumors are summarized in Table II.

The percentage of the initial histopathological diagnoses were obtained: Clear cell renal cell carcinoma (CCRCC) accounted for 330 cases (92.96%), followed by chromophobe renal cell carcinoma (chromophobe RCC) with 16 cases (4.51%) and only 5 patients with papillary renal cell carcinoma (papillary RCC) (1.41%); other tumor variants occurred less frequently.

All histological preparations were reviewed again to reclassify lesions and record other histomorphological features. The distribution was as follows: conventional clear cell renal cell carcinoma was predominant in 84.51% which corresponded to 300 patients; followed by chromophobe carcinoma in 9.30%, corresponding to 33 patients; third, papillary carcinoma in 2.2%, ie in 8 patients; less often multilocular cystic carcinoma, clear cell papillary carcinoma, two cases of collecting duct carcinoma, and two hybrid tumors: CRCCC with type 2 papillary renal carcinoma, and chromophobe carcinoma with oncocytoma; in one case the lesion was impossible to classify (in Figure 1 the histological appearance of some of these entities is exemplified). The diagnostic equivalence of the malignant epithelial tumors was obtained, from the initial to the final histopathologic diagnoses, in order to estimate the diagnostic concordance with a Kappa index of 0.51 with p <0.01, finding six more cases of papillary carcinoma and 15 more of chromophobe carcinoma (Table III).

Another important histomorphological feature studied was the nuclear grade, initial nuclear grade and final nuclear grade were obtained, in which measurements were made besides nuclear histomorphological characteristics. In both evaluations nuclear grade 2 predominated, and in the final classification the least frequent grade was grade 3 (Figure 2). The agreement was weak to moderate (Table IV). The nuclear grade was associated with the size (tumor stage), finding that at higher nuclear grade, tumor size was larger and tumor stage was higher (p <0.001) (Figures 3 and 4).

Secondary histomorphological characteristics were studied such as: eosinophilic cell changes, sarcomatoid differentiation, rhabdoid, and all those lesions accompanying carcinomas, 229; no other feature were found. The rest were divided into two groups: those with secondary histomorphologic characteristics related to increased aggressiveness of the tumor (Figure 5), and those secondary histomorphological features that do not change the prognosis (Table V).

Another feature analyzed was necrosis, which was considered positive from a microscopic focus at low magnification, which in 135 cases (38.03%) was positive. All cases of necrosis were associated with the presence of metastases and it was found that of the 28 cases with metastases, 71.34% had necrosis; while of the 325 cases that had not metastasized, only 35% had necrosis (p = 0.001).

The predominant pathological stage was pT1b N0 M0 at 29.58%; Table VI shows the combinations that our patients presented, and Figure 6 shows some macroscopic examples of them. The percentages of tumor stage and histological subtypes diagnosed are summarized in Table VII.

Discussion

The incorporation of immunohistochemistry and molecular biology techniques as diagnostic aids in everyday practice has resulted in an evolution in the classification of epithelial tumors in recent years. The most common variants occupy 85 to 90%; only 10% are less common or are related to familiar carcinomas. Chromophobe renal cell carcinoma is the second most common tumor in our population, unlike those reported in international literature, probably because in everyday practice immunohistochemistry is lacking as an auxiliary tool to differentiate it from renal clear cell carcinoma with eosinophilic areas, plus in some tumors there is a mixture of cells with morphological features of oncocytoma and chromophobe renal cell carcinoma, so one should not try to categorize these tumors as one or other entity but they should be seen as "hybrid" which is recognized as a subcategory of chromophobe renal cell carcinoma, although some prefer the term uncertain oncocytic neoplasm with malignant potential.8 In our study we found a chromophobe carcinoma combined with an oncocytoma (hybrid tumor / probable Birt-Hogg-Dubé syndrome). In the literature, papillary renal cell carcinoma is ranked as the second most frequent, but it ranks third in our population, reversed with respect to the chromophobe. The presence of papillae in various epithelial tumors poses difficulties in daily practice,⁹ from a conventional renal clear cell carcinoma, to renal papillary carcinoma and rarely the presence of hybrid tumors, whose clinical significance is still unknown, however, the presence of these allows us to ask questions about the histogenesis of these tumors. In addition to the above, consider the new epithelial neoplasms proposed in the Vancouver classification, which posed a differential diagnosis with papillary renal cell carcinoma, as being of tubular-cystic renal carcinoma (CCR-TQ), papillary clear cell renal cell carcinoma (ACOR-CC / tubular-papillary), renal cell carcinoma with Xp11 translocation, and others less common, such as: as mucinous carcinoma of renal tubular cells and spindle cells, 4-8 all those likely categorized before as papillary renal cell carcinoma, which may explain the results obtained in our study, those carcinomas of papillary renal cell, with oncocytic features that should not be identified as a specific subtype, 8 other entities we found to a lesser extent were multilocular cystic renal cell carcinoma, which in the 2004 classification was defined as a tumor composed entirely of numerous cysts with septa containing large groups of clear cells indistinguishable from clear cell carcinoma grade 1. Multiple publications with over 5 years of follow-up have reported no recurrence or metastasis, based on the excellent prognosis. ISUP redefined these as multilocular cystic neoplasms of kidney cells with low malignant potential.8 Another change was applied to collecting duct carcinoma, it was established that the tumor must show the following characteristics: a part of the lesion must involve the renal medulla, predominant tubule formation, it must present stromal desmoplastic reaction, high-grade cytologic features, infiltrative growth pattern, and absence of other typical subtypes of renal cell carcinoma or urothelial carcinoma. Emphasizing this last point, it is considered that upon its presentation, focal urothelial carcinoma must be diagnosed as urothelial carcinoma with prominent glandular differentiation.⁸

In the Fuhrman system, the criteria are subject to interobserver errors, in particular for degree 2-3.¹⁰ In our study we conducted micrometer measurements, which are not routinely performed for lack of this tool, and we found a weak to moderate agreement with the initial nuclear degree for which this tool was used, with Kappa 0.25 (p <0.001). Since the original report of the Fuhrman classification, based on nuclear grade in various studies, the usefulness of this as a prognostic factor has been reported; Zantana et al.¹¹ found a relationship between nuclear grade 3 and 4 with more aggressive behavior. Recent research has specifically assessed the validity of the Fuhrman classification with histological types, specifically for renal papillary carcinoma and chromophobe cell carcinoma, for the first the use of nucleolar prominence was tried; however the Fuhrman ranking has been found of greater utility, so it is suggested to continue using this.^12,13 For chromophobe cell carcinoma, no relationship was found between Fuhrman nuclear grade and prognosis, so Paner et al.¹⁴ have proposed another nuclear classification, however there is still no international consensus on its application, so we associate nuclear grade with the size and tumor stage: we find the higher nuclear grade, the larger tumor size and higher tumor stage (p <0.001), regardless of histological subtype, which reaffirms the importance of this as a prognostic factor.¹⁵ In this study, clinical restaging was also done; during the last decades pathological stage (TNM system) has undergone several changes as an attempt to improve the predictive prognostic value,¹⁶ the most recent was published in 2010 by the American Joint Committee on Cancer (AJCC) in its seventh edition,¹⁷ with significant changes: T2 is divided into T2a for tumors between 7 and 10 cm in size, and T2b for tumors larger than 10 cm confined to the kidney. Infiltration of the ipsilateral adrenal gland is reclassified as T4 if contiguous and as M1 and if not contiguous. The involvement of the renal vein is reclassified as T3a and involvement of lymph is simplified to N0 and N1 when positive, regardless of the number. There is evidence of size dependence with the infiltration of the renal sinus, both with prognostic significance. In our study no difference between histological type and clinical stage were found, but in other studies no relationship has been found between histological type and patient survival, as in Patard et al.^18,19

Additionally, other morphological features associated with poor prognosis were found, such as the presence of areas of eosinophilic, rhabdoid and sarcomatoid cells, which presented more risk of metastases, mainly clear cell carcinoma with eosinophilic areas (p <0.001). It should be remembered that sarcomatoid features are a dedifferentiation from renal clear cell carcinoma and not an independent entity.¹⁰

Necrosis was found as a predictor of survival, Lam et al.²⁰ reported that the survival drops from 75% of those without necrosis, to 36% in patients with necrosis. We have also found a relationship with metastasis, lymph node involvement and tumor size.^20,21 In our study an association between necrosis and the presence of metastasis was found.

The review of our study was mainly morphological with hematoxylin and eosin staining, the immunohistochemical studies were only trying to classify some lesions as chromophobe carcinomas and papillary renal cell carcinomas, still it would be necessary to broaden the immunohistochemistry diagnostic tests to try describe other new entities in our population.

Conclusions

Clear cell renal cell carcinoma corresponds to 84.51%, followed by chromophobe cell carcinoma (9.30%), and the third most common tumor was papillary renal cell carcinoma (2.2%), reversed with respect to chromophobe, unlike those reported with literature.

Others less frequently found were: multilocular cystic renal cell carcinoma and collecting duct carcinoma "chromophobe carcinoma with oncocytoma". In an ongoing study of this work immunohistochemistry and molecular biology are proposed to detect renal carcinomas associated with translocations.

Macroscopic examination is essential for the pathological stage, adequate sampling will identify eosinophilic areas, rhabdoid and sarcomatoid differentiation, which sometimes accompany areas of necrosis. All of them should be shown in the histopathological reports routinely as they are useful prognostics.22

The concordance of the initial nuclear grade with respect to the final in which micrometer measurement was not done, was weak to moderate with a kappa of 0.25 (p <0.001), so we suggest the micrometer measurement in addition to the evaluation of nuclear grade, if not routinely possible, then in those cases where nuclear grading is difficult, especially in grades 2 and 3, since some with low nuclear grade are overdiagnosed and with high nuclear grade are underdiagnosed.

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