Role of histopatological assessment of renal cancer specimen after radical and partial nephrectomy

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1 Role of histopatological assessment of renal cancer specimen after radical and partial nephrectomy Dr hab. n. med. Agnieszka Korolczuk Joanna Irla Natalia Pieszek Monika Orzeł Dr hab. n. med. Justyna Szumiło Department of Clinical Pathomorphology, Medical University, Lublin Lublin Jaczewskiego 8 Biomaxima SA, Lublin, Radical nephrectomy is the gold standard in the treatment of renal tumors. The surgical specimen handling is important since the pathologic features result in clinico-pathologic knowledge that determines prognosis, additional treatment and scientific studies. The correct handling of the specimen by urologists and pathologists becomes very basic in order to enable retrieval of a maximum of information. Among prognostic factors for renal cell carcinoma, Fuhrman s grading, based on nuclear atypia, plays an import role. Immunohistochemical expression for cytokeratin (CK), vimentin, CD 10, parvalbumin, TFE3 and TFEB helps to improve diagnosis of poorly differentiated cases, especially these with sarcomatoid differentiation or chromosome translocation. RCC is frequently associated with genes mutations. Among them, suppressor gene mutations for VHL (von Hippel- Lindau) syndrome is the most common. VHL mutations are associated with overexpression of tumor angiogenesis factors, such as VEGF, PDGF or erythropoietin. Histopatological diagnosis including expression of tumor angiogenesis factors correlated with genetic markers influences further postoperative chemotherapy. Key words: Renal cancer, histopathological assessment, nephrectomy Introduction Renal Cell Carcinoma (RCC) is the eight most common malignancy affecting adults, with approximately new cases a year [1]. It 1

2 accounts for 80-90% tumors in the kidney [2, 3]. The incidence of renal cell carcinoma has been rising steadily in Europe and the United States for the past 3 decades, with a particular rise in the proportion of small, asymptomatic tumors detected incidentally via abdominal imaging. Despite the increasing incidence of the disease in recent decades, survival has steadily improved, with a current overall 5-year survival of approximately 62%. The possible factors that have contributed to improved survival include advances in renal imaging and surgical techniques, stage migration to lowerstage disease as a result of earlier diagnosis in asymptomatic individuals and the introduction of immunotherapy for advanced disease [1]. The average age at diagnosis of RCC is years. However, 7% of sporadic RCC is diagnosed in patients younger than 40 years, and rare cases have been reported in patients aged years without evidence of familial disorders. Some tumors previously diagnosed as clear cell RCC in younger patients may in fact represent the Xp11 translocation tumor type, which has recently been analyzed [4, 5]. Renal Cell Carcinoma medical management A large proportion of patients diagnosed with renal cancer have small tumors discovered incidentally on imaging studies. A number of diagnostic modalities are used to evaluate and stage renal masses, including the following: excretory urography, CT scan, ultrasonography, arteriography, venography, MRI, PET [3]. The use of these techniques increased the number of T1-T2 tumors (table 1). The early detection of tumor improved the use of nephron-sparing surgery (NSS) which is now an established approach for patients with localized RCC [7, 8]. Such surgical management preserves renal function and limits the number of complications associated with radical nephrectomy [7, 8, 9]. Indications for NSS include also patients with only a solitary functioning kidney secondary to unilateral renal agenesis, prior removal of a kidney, or malfunction of a kidney due to design disease process such as calculous disease [9]. Radical nephrectomy is still the main standard curative operation for patients with RCC [9-13]. The surgical specimen handling is important since the pathologic features result in clinico-pathologic knowledge that determines prognosis, additional treatment and scientific studies. In 2004 Algaba et all [6] published the protocol in which authors determine the correct handling of the specimen by urologists and pathologists. The specimen must be sent 2

3 complete, without any cut, and with anatomical continuity with the surrounding tissues, fixed In 10% buffered formalin if needed for transport. Personal and demographic data should be included as well as results of additional examinations such as ultrasound, X-ray or CT scan. It is advisable that the urologist informs the pathologist if adrenal or lymph nodes are included. The specimen is than examined by pathologist to define the histological type of RCC, tumor grading and staging [13, 14]. Molecular genetic research can be performed to determine chromosomal aberrations [14]. Mutations of the VHL (von Hippel-Lindau) suppressor gene are present in the majority of clear cell RCC, the most common histological type. Certain genetic conditions are associated with an increased incidence of RCC, including VHL disease, hereditary papillary renal cancer, and possibly tuberous sclerosis [1]. RCC occurs in VHL disease in 35-40% of patients, occurs at a younger age, and is frequently bilateral (75%) or multifocal (87%) [1]. Chromosomal aberrations lead to increased expression of tumor growth factors and factors of angiogenesis, such as VEGF (ang. Vascular Endothelial Growth Factor) or EGFR (ang. Endothelial Growth Factor). Understanding of the molecular pathways involved in renal carcinogenesis has provided a rationale for novel therapeutics that specifically target molecules of aberrantly activated pathways [14]. Both histological examination and cytogenetic research depend on handling of the surgical specimen [4-6, 14]. Renal cell carcinoma histopatological assessment The main role of histopatological assessment of surgical specimen coming from radical or partial nephrectomy is to establish the histological type of tumors according to WHO classification of kidney tumors. The pathologist should follow the generally accepted standards of surgical specimen handling [6, 13]. Gross description of the kidney specimen must include: side, size, weight of the specimen and anatomical structures included, side, size and location of the tumor, features of the lesion including percentage of necrosis. It should also include the description of normal renal parenchyma and structures of renal sinus, as well as description of adrenal, if it is included [6]. Microscopic report must include: histological type of the tumor (according to WHO classification, 2004), grading according to Fuhrman scale, staging (TNM-table 1) involvement of renal vein or infiltration of perirenal fat. Gettman et all [10] reviewed histopatological reports of 1547 patients treated surgically in years for RCC. Authors correlated the tumor staging established at the time of diagnosis with patient s survival. This analysis showed that tumor size (T1-T2), infiltration of fat of the 3

4 kidney capsule (T3a) and invasion of renal vein (T3b,c) are the most significant predictive factors for patients with RCC. Lymph node status was not a predictor for specific survival [10]. Moch et all [15] published similar results based on their analysis of 588 patients with RCC. Soilleux et all [13] showed that renal sinus vein invasion is associated with poor prognosis. In the analysis of 192 patients with RCC, the assessment of renal sinus vein invasion increased number of tumors staged as T3b in 29/77 (37,7%) cases, what significantly correlated with patient s survival. Our unpublished data show differences in staging of RCC before the operation and in the pathologist s report. In 11 of 55 RCC (20%) examined in our Department in 2010, pathologic staging (ptnm) was higher comparing to one based on images (TNM). Nephron sparing surgery (NSS) provides therapy in patients with a solitary sporadic renal tumor 4cm or less and a normal contralateral kidney. The minimal surgical margin of normal renal parenchyma should be no less than 2mm. The histopatological assessment of NSS material should follow guidelines provided for radical nephrectomy specimens and the final report should contain all previously discussed information. Surgical margins must be carefully examined and described with the information about the most narrow margin. The handling of NSS specimen by the urologist is similar to radical nephrectomy specimen [6-9]. Table 1 TNM Staging System for RCC T Tumor: Tx Primary tumor cannot be assessed T0 No evidence of primary tumor T1 7 cm or smaller limited to the kidney T1a 4 cm or less in maximal diameter T1b greater than 4 cm but not greater than 7 cm T2 greater than 7 cm T2a greater than 7 cm, no greater than 10 cm in maximal diameter T2b greater than 10 cm, limited to the kidney T3 tumor / tumor thrombus extension into adrenal or renal vein or perinephric tissues (but contained by Gerota's fascia) T3a spread to perinephric fat, renal vein T3b spread to renal vein and intra diaphragmatic IVC (inferior vena cava) T3c spread to supra diaphragmatic IVC T4 beyond Gerota's fascia. N Nodes Nx lymph nodes cannot be assessed 4

5 N0 no nodal involvement N1 single regional lymph node involved N2 beyond N1 (NB laterality does NOT affect nodal staging) M Metastases Mx metastases cannot be assessed M0 no distant metastases M1 distant metastases WHO classification of RCC WHO (World Health Organization) classification for RCC is based on microscopic, molecular and immunohistochemical features of this group of tumors [16, 17]. In 2004 the recent classification was published (presented in table 2) that includes molecular and immunohistochemical features of all RCC subtypes [18]. The most common histological subtypes of RCC are clear cell, papillary, chromophobe and collecting duct carcinoma. These subtypes account for 85-90% all RCC. Most of the rest tumors were previously reported as unclassified RCC. Molecular and immunohistochemical studies improved the assessment of kidney cancer an many of these tumors have similar phenotype but different genotype and express certain spectrum of antigens that can be detected immunohistologically [18, 19]. Based on the genetic background, there are some chromosomal markers associated with prognosis; loss of chromosome 9p, 10q and 14q in clear cell RCC results in poor prognosis. Understanding of the molecular pathways in renal carcinogenesis has provided a rationale for novel therapeutics that specifically target molecules of aberrantly activated pathways. Immunohistochemical markers improve the diagnosis of poorly differentiated tumors: typical for clear cell RCC: cytokeratins (CK), CD10, vimentin, or in rare tumors: parvalbumin, TFE3 and TFEB, positive for RCC with chromosomal translocations. Translocation carcinoma, included in WHO classification in 2004, involves the transcription factor E3 (TFE3) located on chromosome Xp11.2 (90% of cases). Translocation carcinomas are generally found in children and young adults and the average age is 24,7 [20, 21]. These tumors share histological features with clear cell and papillary RCC. A confirmation of the diagnosis of translocation carcinoma requires immunohistochemical identification of the nuclear trasnscription factor (TFE3, TFEB) and/or cytogenetic or molecular genetic identification of translocation. From a clinical outcome perspective, TFE3 translocation carcinomas seem to have a relatively indolent course, despite 5

6 their advanced stage at presentation. Mucinous and spindle cell carcinoma is an uncommon and recently described variant of RCC, which is recognized as distinct entity in the 2004 WHO tumor classification [18]. This tumor has female predominance [22, 23]. Previously this tumor had been referred to under a variety of terms including low-grade collecting duct carcinoma, myxoid renal epithelial neoplasm or spindle and cuboidal renal cell carcinoma. Several genetic studies have identified multiple chromosome losses in this subtype of RCC. Tubulocystic Carcinoma is next rare RCC that was recently descrided [23] and is not listed in the 2004 WHO classification. Some of these tumors had been previously reported as collecting duct carcinoma as these both subtypes share symilar microscopic features. Immunohistochemical studies showed that tubulocystic RCC does not express High Molecular Cytokeratin (HM CK), which is positive for collecting duct carcinoma. Tubulocystic RCC is associated with more indolent outcome than collecting duct subtype [23, 24]. Some of RCC cases present as cystic tumors [11, 26, 27]. The cystic form can be misdiagnosed on images as benign renal cyst. Benign lesions don t need radical surgical treatment and the laparoscopy is, in most cases, the treatment of choice [26]. Due to the fact that these cystic lesions can contain malignant cells, careful handling is strongly recommended with further detailed sampling and microscopic assessment of several samples. Table 2 WHO (2004) classification of renal cell carcinoma RCC Clear cell RCC Multifocal (cystic) clear cell RCC Papillary RCC Chromophobe RCC Collecting duct RCC Renal medullary carcinoma Translocation Xp11 carcinoma Mucinous tubular and spindle-cell carcinoma RCC in neuroblastoma survivors Unclassified RCC Summary The incidence of renal cell carcinoma has been rising for the past 3 decades, new cases are reported each year in children and young adults [28]. Radical or partial nephrectomy is the standard treatment for RCC. Partial nephrectomy is not only employed in tumors limited to the kidney, but in cystic tumors and in more advanced tumors in younger patients [7-9, 11, 12]. 6

7 Staging (TNM) remains still one of the most important prognostic factors for patients with RCC. Precise TNM assessment is possible when surgical specimen is examined by the pathologist. Other important factors that improve the choice of postoperative chemotherapy are immunochistochemical expression of certain factors such as factors of angiogenesis, or results of molecular and genetic studies [14]. Many laboratories can perform microscopic, immunohistochemical and molecular studies at the same time. Postoperative handling of the specimen plays crucial role for the proper assessment by the pathologist. Pathologist should follow all the established criteria for gross and microscopic assessment including, staging, grading and current WHO classification of tumors. He should also perform the most important immunochistochemical markers as well as molecular studies (if possible), in all cases of uncertain microscopic appearance. Summarizing, the correct handling of the specimen by urologist and pathologist becomes very basic in order to enable retrieval of a maximum of information to improve prognosis for patients with renal cell carcinoma. References 1. Ng CS, Wood CG, Silverman PM. et al. Renal cell carcinoma: diagnosis, staging, and surveillance. AJR 2008; 191, s Jemal A, Siegel R, Ward E. et al. Cancer statistics CA Cancer J Clin 2007; 57, s Escudier B., Kataja V. Renal cell carcinoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Annals of Oncology 2009: 20 (Suppl 4) s Bruder E, Passera O, Harms D. et al. Morphologic and molecular characterization of renal cell carcinoma in children and young adults. Am J Surg Pathol 2004; 28(9), s Argani P, Olgac S, Tickoo SK. et al. Xp11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum. Am J Surg Pathol 2007;31(8), s Algaba F., Trias., Scarpelli M. et al. Handling and pathology reporting of renal tumor specimens. European Urology 2004: 45, s Matin FS., Gill IS., Worley S. et al. Outcome of laparoscopic radical and open partial nephrectomy for the sporadic 4 cm. or less renal tumor with a normal contralateral kidney. J Urol 2002; 168, s Novick AC. Laparoscopic and partial nephrectomy. Clin Cancer Res 2004; 10, s

8 9. Tsui K-F.,van Ophoven A., Shvarts O. et al. Nephron-sparing surgery for renal cell carcinoma. Rev Urol 1999; 1, s Gettman MT., Blute ML., Spotts B. et al. Pathologic staging of renal cell carcinoma. Cancer 2001; 91, s DiMarco DS., Lohse CM., Zincke H. et al. Long-term survival of patients with unilateral sporadic multifocal renal cell carcinoma according to histologic subtype compared with patients with solitary tumors after radical nephrectomy. Urology 2004; 64,s Krejci KG., Blute ML., Cheville JC. et al. Nephron-sparing surgery for renal cell carcinoma: clinicopathologic features predictive of patient outcome. Urology2003; 62, s Soilleux EJ., Roberts ISD. Assessment of the Cardiff nephrectomy cutup protocol with total blocking of the renal sinus: effect on tumor staging and practical issues. J Clin Pathol 2006; 59, s Storkel S., Kristiansen G., Moch H. The importance of pathology and genetics for the diagnosis and therapy of renal cell carcinoma. Eur Urol Suppl., 2007; 6, s Moch H, Gasser T, Amin MB. et al. Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma: a Swiss experience with 588 tumors. Cancer 2000; 89, s Renshaw AA. Subclassification of renal cell neoplasms: an update for the practicing pathologist. Histopathology 2002; 41, s Eble JN, Sauter G, Epstein JI. et al. Pathology and genetics of tumors of the urinary system and male genital organs. Lyon, France: IARC Press; Srigley JR., Delahunt B. Uncommon and recently described renal carcinomas. Modern Pathology 2009; 22, s Kobayashi N, Matsuzaki O, Shirai S. et al. Colecting duct carcinoma of the kidneys: an immunohistochemical evaluation of the use of antibodies for differential diagnosis. Hum Pathol 2008; 39, s Bruder E, Passera O, Harms D. et al. Morphologic and molecular characterization of renal cell carcinoma in children and young adults. Am J Surg Pathol 2004; 28, s Camparo P, Vasiliu V, Molinie V. et al. Renal translocation carcinomas-clinicopathologic, immunohistochemical and gene expression 8

9 profiling analysis of 31 cases with a review of the literature. Am J Surg Pathol 2008; 35, s Ferlicot S, Allory Y, Compe E. et al. Mucinous tubular and spindle cell carcinoma: a report of 15 cases and a review of the literature. Virchows Arch 2005; 47, s MacLennan GT, Bostwick DG. Tubulocystic carcinoma, mucinous tubular and spindle cell carcinoma, and other recently described rare renal tumors. Clin Lab Med 2005; 25, s Azoulay S, Vieillefond A, Paraf F. et al. Tubulocystic carcinoma of the kidney: a new entity among renal tumors. Virchows Arch 2007; 451, s Yang XJ, Zhou M, Ondrej H. et al. Tubulocystic carcinoma of the kidney. Clinicopathologic and molecular characterization. Am J Surg Pathol 2008; 32, s Aubert S., Zini L., Delomez J. et al. Cystic renal cell carcinomas in adults. is preoperative recognition of multilocular cystic renal cell carcinoma. possible? J Urol 2005; 174, s Nassir A., Jollimore J., Gupta R. et al. Multilocular cystic renal cell carcinoma: a series of 12 cases and review of the literature. Urology 2002; 60, s Latif F., Mubarak M., Kazi JI. Histopathological characteristics of adult renal tumors: a preliminary report. JPMA 2011; 61, s Dall'Oglio MF, Antunes AA, Pompeo AC. et al. Prognostic relevance of the histological subtype of renal cell carcinoma. Int Braz J Urol 2008; 34, s Jain P, Surdas R, Aga P. et al. Renal cell carcinoma: impact of mode of detection on its pathological characteristics. Indian J Urol 2009; 25, s

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