Increased establishment of lungworms after exposure to a combined infection of Ostertagia ostertagi and Cooperia oncophora

SPECIAL ARTICLE

Handling and Staging of Renal Cell Carcinoma The International Society of Urological Pathology Consensus (ISUP) Conference Recommendations Kiril Trpkov, MD, FRCPC,* David J. Grignon, MD, FRCPC,w Stephen M. Bonsib, MD,z Mahul B. Amin, MD,y Athanase Billis, MD,8 Antonio Lopez-Beltran, MD,z Hemamali Samaratunga, MD, FRCPA,# Pheroze Tamboli, MD,** Brett Delahunt, MD, FRCPA,ww Lars Egevad, MD, PhD,wwzz Rodolfo Montironi, MD, FRCPath,yy John R. Srigley, MD, FRCPC,88zz and the members of the ISUP Renal Tumor Panel

Abstract: The International Society of Urologic Pathology 2012 Consensus Conference on renal cancer, through working group 3, focused on the issues of staging and specimen handling of renal tumors. The conference was preceded by an online survey of the International Society of Urologic Pathology members, and the results of this were used to inform the focus of conference discussion. On formal voting a Z65% majority was considered a consensus agreement. For specimen handling it was agreed that with radical nephrectomy specimens the initial cut should be made along the long axis and that both radical and partial nephrectomy specimens should be inked. It was recommended that sampling of renal tumors should follow a general guideline of sampling 1 block/cm with a minimum of 3 blocks (subject to modification as needed in individual cases). When measuring a renal tumor, the length of a renal vein/caval

From the *Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB; 88Department of Laboratory Medicine, Credit Valley Hospital, Mississauga; zzDepartment of Pathology and Molecular Medicine, McMaster University, Toronto, ON, Canada; wDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN; zNephropath, Little Rock, AR; yDepartment of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA; **Department of Pathology, MD Anderson Cancer Center Houston, Houston, TX; 8School of Medical Sciences, State University of Campinas (Unicamp), Campinas, Brazil; zDepartment of Pathology and Surgery, University of Cordoba Medical School, Cordoba, Spain; #Aquesta Pathology, University of Queensland, Brisbane, Qld, Australia; wwDepartment of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand; zzDepartment of Oncology and Pathology, Karolinska University Hospital, Solna, Stockholm, Sweden; and yySection of Pathological Anatomy, Polytechnic University of Marche Region, United Hospitals Ancona, Ancona, Italy. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Kiril Trpkov, MD, FRCPC, Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, Canada T2V 1P9 (e-mail: [email protected]). Copyright r 2013 by Lippincott Williams & Wilkins

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thrombus should not be part of the measurement of the main tumor mass. In cases with multiple tumors, sampling should include at a minimum the 5 largest tumors. There was a consensus that perinephric fat invasion should be determined by examining multiple perpendicular sections of the tumor/perinephric fat interface and by sampling areas suspicious for invasion. Perinephric fat invasion was defined as either the tumor touching the fat or extending as irregular tongues into the perinephric tissue, with or without desmoplasia. It was agreed upon that renal sinus invasion is present when the tumor is in direct contact with the sinus fat or the loose connective tissue of the sinus, clearly beyond the renal parenchyma, or if there is involvement of any endothelium-lined spaces within the renal sinus, regardless of the size. When invasion of the renal sinus is uncertain, it was recommended that at least 3 blocks of the tumor-renal sinus interface should be submitted. If invasion is grossly evident, or obviously not present (small peripheral tumor), it was agreed that only 1 block was needed to confirm the gross impression. Other recommendations were that the renal vein margin be considered positive only when there is adherent tumor visible microscopically at the actual margin. When a specimen is submitted separately as “caval thrombus,” the recommended sampling strategy is to take 2 or more sections to look for the adherent caval wall tissue. It was also recommended that uninvolved renal parenchyma be sampled by including normal parenchyma with tumor and normal parenchyma distant from the tumor. There was consensus that radical nephrectomy specimens should be examined for the purpose of identifying lymph nodes by dissection/palpation of the fat in the hilar area only; however, it was acknowledged that lymph nodes are found in <10% of radical nephrectomy specimens. Key Words: pathology, kidney, renal cell carcinoma, specimen handling, stage, renal sinus, renal vein invasion, fat invasion, International Society of Urological Pathology, ISUP (Am J Surg Pathol 2013;37:1505–1517)

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taging of a malignant tumor utilizes various tumor characteristics to stratify patients into clinically meaningful and prognostically relevant categories. For www.ajsp.com |

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renal cell carcinoma (RCC), the stage is considered the single most important prognostic factor for determining patient outcome.1–5 A critical staging issue is determining whether the tumor is limited to the kidney or whether it has infiltrated into the perinephric tissue. Staging also relates to the size of the primary tumor, invasion of the adjacent structures, and vascular extension. Nephrectomy specimens should be handled appropriately to allow thorough gross examination, adequate sampling, and reporting of the stage and other important prognostic parameters. In view of this, it is important that the pathologist is familiar with the renal anatomy, is proficient in sampling of resected renal tumors, and is able to assess and accurately report the pathologic stage. During the last decade, several outcome-prediction models for RCC have been developed that have uniformly incorporated staging information for predicting survival, metastasis, and the pattern of disease recurrence.4,6–9 The seventh edition of the TNM staging system of the American Joint Commission on Cancer/International Union Against Cancer (AJCC/UICC) introduced several changes in the staging classification of RCC (Table 1).10,11 In this edition, the pT2 category was divided into 2 novel subcategories on the basis of the tumor size (pT2a: >7 cm and r10 cm; and pT2b: >10 cm). The new pT3a category included tumors with gross extension into the renal vein and its segmental (muscle-containing) branches, which was classified as pT3b in the sixth edition of the classification. Tumors with renal sinus involvement are also classified as pT3a, and this is now explicitly stated in the guidelines, being previously included only as a note. pT3b tumors are classified by invasion into the vena cava below the diaphragm, whereas the pT3c category includes not only tumors that grossly extend into the vena cava above the diaphragm but also tumors that invade the caval wall regardless of the level. A major change in the latest TNM revision was the upstaging of the tumors with contiguous extension into the ipsilateral adrenal gland from pT3a to pT4. Incorporating these changes, the current TNM system has been validated as a powerful prognostic parameter for RCC.12,13 To guide pathologists in the proper handling and accurate staging of renal tumors, several experts and expert groups have published recommendations on handling and dissection strategies and have produced protocols for the evaluation of RCC.5,14–20 These protocols have been widely used and have proved their utility in practice. In particular, some have included updated or alternative dissection strategies to accommodate various practice scenarios and to account for significant emerging data relating to important and novel prognostic parameters.5 For example, over the last decade, particularly through the work of Stephen Bonsib, renal sinus invasion has emerged as one of the most important RCC prognostic factors, prompting modification in grossing strategies to adequately sample and evaluate the renal sinus.21–28 Despite these advances, some previously published protocols reflect personal practice preferences or opinions of experts or expert groups. As such, they often

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TABLE 1. TNM Classification of RCC 2010 Primary Tumor (T) TX T0 T1

Primary tumor cannot be assessed No evidence of primary tumor Tumor r7 cm in greatest dimension, limited to the kidney T1a Tumor r4 cm in greatest dimension, limited to the kidney T1b Tumor >4 cm but r7 cm in greatest dimension, limited to the kidney T2 Tumor >7 cm in greatest dimension, limited to the kidney T2a Tumor >7 cm but r10 cm in greatest dimension, limited to the kidney T2b Tumor >10 cm, limited to the kidney T3 Tumor extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond the Gerota fascia T3a Tumor grossly extends into the renal vein or its segmental (muscle-containing) branches, or tumor invades perirenal and/or renal sinus fat but not beyond the Gerota fascia T3b Tumor grossly extends into the vena cava below the diaphragm T3c Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava T4 Tumor invades beyond the Gerota fascia (including contiguous extension into the ipsilateral adrenal gland) Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in regional lymph node(s) Distant metastasis (M) M0 No distant metastasis M1 Distant metastasis

do not provide sufficient rationale, justification, or comparison of different handling or sampling methods and have not been tested in a study setting. In fact, little or no published objective data exist regarding several handling and dissection issues despite their widespread implementation in clinical practice. The International Society of Urologic Pathology (ISUP) consensus conference,29–32 through working group 3, focused on issues of staging and specimen sampling by asking participating ISUP members specific questions regarding the handling and staging of renal tumors. During the initial discussion and construction of a questionnaire, a deliberate attempt was made to focus on high-yield topics, in an attempt to establish consensus regarding key issues. The premeeting survey questions, on which consensus were established by the participants (Z65% agreement), are summarized in Table 2. Questions on which near consensus (Z60% to <65% agreement) was achieved are presented in Table 3. On the basis of discussions among the working group members and the findings from the premeeting survey, we identified key issues that did not attain consensus agreement, as well as questions judged worthy of further discussion, for presentation and comment at the conference. The specific questions posed and voted on by r

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TABLE 2. ISUP Consensus Premeeting Survey: Consensus (Z65% Agreement) Achieved on the Following Handling and Staging Questions (% Agreement) Initial sectioning and inking of renal specimens In radical nephrectomy specimens the initial cut is made along the long axis (93.2%) Ink should be used in radical nephrectomies (87.2%) Ink should be used in partial nephrectomies (94.6%) Renal tumor measurement When measuring a renal tumor, the length of a renal vein/caval thrombus should not be part of the main tumor mass measurement (90.9%) Number of blocks for tumor sampling Sampling of renal tumors should follow a general guideline of sampling 1 block/cm with a minimum of 3 blocks (subject to modification as needed in individual cases) (96.5%) Sampling multiple tumors In cases with multiple tumors, sampling should include at a minimum the 5 largest tumors (89.9%) Assessment of perinephric fat invasion Perinephric fat invasion is determined by examining multiple perpendicular sections of the tumor/perinephric fat interface and, if present, by sampling the areas suspicious for invasion (79.2%) Perinephric fat invasion requires either tumor touching fat or extending as irregular tongues into the perinephric tissue (with or without desmoplasia) (70.9%) Assessment of renal sinus fat invasion Our prosectors (or I, if I do the dissection) are very familiar with the renal sinus anatomy (77.5%) When invasion of the renal sinus is uncertain at least 3 blocks of the tumor-renal sinus interface should be submitted. If invasion is grossly evident, or obviously not present (small peripheral tumor) only 1 block is needed to confirm the gross impression (97.5%) Renal sinus invasion is present when the tumor is in direct contact with the sinus fat (100%) Renal sinus invasion is present when the tumor is in direct contact with the loose connective tissue clearly beyond the renal parenchyma (74.7%) For staging purposes, renal sinus invasion (pT3a) is present when the sections show involvement of any endothelium-lined spaces within the renal sinus regardless of the size (90.3%) Renal vein margin positivity, vena cava invasion Renal vein margin is positive only when there is adherent tumor at the actual margin (confirmed microscopically) (74%) When a specimen is submitted separately as “caval thrombus,” the most appropriate sampling strategy is to perform Z2 sections to look for adherent caval wall tissue (84%) Sampling of uninvolved renal parenchyma Uninvolved renal parenchyma should be sampled by including normal parenchyma with tumor and normal parenchyma distant from the tumor (79.8%) Assessment of lymph nodes Radical nephrectomy specimens should be examined for the purpose of identifying lymph nodes by dissection/palpation of the fat in the hilar area only (93.9%) I estimate that I would find lymph nodes in <10% of radical nephrectomy specimens (80.3%)

the conference participants are presented in Table 4. In the following text the quoted percentages regarding specific issues are those derived from the survey; however, if the specific issue was voted on at the meeting then this result represents the overriding conclusion.

INITIAL SECTIONING AND INKING OF RENAL SPECIMENS The goal of specimen dissection is to achieve proper fixation before or after sampling and to allow gross evaluation of extrarenal invasion into the perinephric fat, renal sinus, renal vein, and adrenal gland.5 The survey established that the preferred method was to make an initial section into radical nephrectomy specimens along the long axis (93%) (Fig. 1). The alternatives to this approach include taking a section along the midpoint from either the lateral or the medial aspect of the specimen (46%), followed by a method using probes placed in the collecting system (35%) or in the largest hilar veins (12%). Sectioning through the collecting system provides the advantage of a full cross-sectional view of the collecting system and optimizes the exposure of the tumorrenal sinus interface.5 This approach, however, does miss the plane anterior to the renal pelvis where the major sinus veins are located, and, therefore, opening the r

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specimen through the venous system has been proposed, to ensure that this plane is examined. Alternatively, if additional cuts are made parallel to the initial cut through the collecting system, with at least 1 placed anterior to the pelvis, this important region of the kidney can be evaluated. Another possible approach is to bivalve the kidney through the midpoint of the tumor, angling toward the renal hilum, with Z1 parallel cuts, including 1 anterior to the renal pelvis.5 These approaches can be adapted in accordance with personal choice, as currently there is no TABLE 3. ISUP Consensus Premeeting Survey: Near Consensus (Z60% to < 65% Agreement) Achieved on the Following Handling and Staging Questions Initial sectioning and inking of renal specimens In partial nephrectomies, selectively ink the grossly visible renal parenchymal margin in all cases (61.9%) Renal tumor measurement In cases with >1 tumor, measure all tumors up to some designated maximum (eg, 5) (61.6%) Assessment of renal sinus fat invasion I am certain that I can recognize grossly renal sinus involvement by tumor in the majority of cases (62.9%) Sampling of renal vein Renal vein is sampled by submitting the margin plus additional section(s) in which the tumor is adherent to the vein away from the margin (if suspected grossly) (63.5%)

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TABLE 4. Results of Questions Discussed at the ISUP Consensus Meeting When invasion of the renal sinus is uncertain, at least 3 blocks of the tumor-renal sinus interface should be submitted. If invasion is grossly evident, or obviously not present (small peripheral tumors), only 1 block is needed to confirm the gross impression Agree 98% Disagree 2% For staging purposes, do you consider renal sinus invasion (pT3a) to be present when sections show involvement of any endothelium-lined spaces within the renal sinus, regardless of size? Yes 90% No 10% When measuring a renal tumor, should the length of a renal vein/caval thrombus be part of the main tumor mass measurement? Yes 9% No 91% Sampling of renal tumors should follow a general guideline of sampling 1 block/cm with a minimum of 3 blocks (subject to modification as needed in individual cases) Agree 97% Disagree 3% In cases with multiple tumors, sampling should include at a minimum the 5 largest tumors Agree 90% Disagree 10% When a specimen is submitted separately as “caval thrombus,” the most appropriate sampling strategy is 1 section to confirm it is tumor 16% Z2 sections to look for adherent caval wall and possible caval 84% wall invasion How should radical nephrectomy specimens be examined for the purpose of identifying lymph nodes? Dissection/palpation of all the fat including perinephric fat 6% Dissection/palpation of the fat in the hilar area only 94%

evidence to suggest the superiority of any single sectioning method. Radical or partial nephrectomies are the standard surgical procedures for localized RCC. There was agreement in the survey (87%) that ink should be used for margin assessment in radical nephrectomies following

FIGURE 1. The preferred method to make the initial section in radical nephrectomy specimens is along the long axis. Kidney opened through the collecting system is illustrated.

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1 of 2 approaches, reflecting practice preferences. Localized use of ink, restricted only to the areas suspicious for the presence of tumor, was preferred by a slight majority (45%), followed by inking of the entire external surface of the specimen (42%). Both methods are acceptable in practice as no data exist to indicate the superiority of any single method. The great majority of participants (95%) also used ink for partial nephrectomies, with a significant majority in favor of selective (62%) rather than entire specimen (33%) inking. In the absence of supporting data or specific studies on this issue, both methods are acceptable in practice. The preference for selective inking of partial nephrectomies primarily relates to inking of the renal parenchymal margins, as margin status is especially important in these specimens. These specimens are typically sectioned perpendicular to the inked marginal surface; if the specimen contains a portion of perinephric fat, this margin should also be assessed.18,19

RENAL TUMOR MEASUREMENT Accurate determination of the tumor size is important for AJCC/UICC TNM staging. This represents a key determinant for the pT categorization of tumors confined to the kidney and has been repeatedly demonstrated to have prognostic significance.33–40 Increased tumor size also correlates with an increased likelihood of perinephric extension and renal sinus invasion, and tumor size is routinely included in postoperative predictive nomograms and models.6–9 No objective data exist in the literature as to how tumor size should be measured. Specifically, there are no data on whether renal vein thrombus should be measured as part of the main tumor mass. Tumor size should be estimated after meticulous sectioning of the entire renal tumor, and the greatest tumor dimension should be recorded. Special attention should be given to size determination in and around cutoff points of 4, 7, and 10 cm, which are important for accurate staging. Typically, when the kidney is bivalved, the greatest size is based on the 2-dimensional assessment of the tumor. Sometimes after bivalving the kidney, it may be necessary to perform additional perpendicular or parallel cuts to evaluate the greatest tumor dimension. Regarding the approach to tumor size measurement, a consensus was achieved in the survey that the main tumor should be measured with the inclusion, when present, of any tumor invading beyond the kidney into the peripheral extracapsular tissue (92%) and the renal sinus (88%) (Fig. 2A). The great majority (91%) also agreed that renal vein/caval thrombus should not be measured and reported as part of the main tumor mass (Fig. 2B). When multiple tumors are encountered, there are no data to indicate how these specimens should be approached. Is it important to document the size and histologic features of each discrete nodule, the largest mass only, the mass that grossly appears most advanced with invasion beyond the kidney, or to use some other r

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FIGURE 2. A, The main tumor should be measured with the inclusion, when present, of the tumor invading beyond the kidney into the peripheral extracapsular tissue and the renal sinus. B, Renal vein (or caval) thrombus should not be measured and reported as part of the main tumor mass.

measurement strategy? In the survey, there was a near consensus (62%) on reporting the tumor dimensions for all tumors up to some designated maximum such as 5, with lesser support in favor of measuring the largest 2 tumors as well as providing a range for all remaining ones (27%). It was generally accepted that smaller satellite nodules should not be included in the estimation of the size of a dominant tumor mass. After discussion at the conference, consensus (90%) was achieved that sampling of multiple tumors should include at least 5 largest ones. It was also noted that this approach could be followed for the measurement of tumor size.

NUMBER OF BLOCKS FOR TUMOR SAMPLING The optimal sampling strategy for a renal tumor should allow for determination of histologic type (or subtype), tumor stage, evaluation of the surgical margin, and assessment of grade and other relevant findings, such as tumor multifocality or underlying incidental renal pathology. Any sampling strategy that would address these key questions should primarily focus on the tumor r

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interface with adjacent structures, such as perirenal fat, renal sinus, renal vein, and adjacent normal parenchyma, as well as areas of tumor showing differing gross appearances.5 In partial nephrectomies, it is also important to adequately sample the tumor-margin interface. A section of the adrenal gland, if present, should also be included, as should sections of the vascular and ureteric margins. To date, however, no study has specifically examined the appropriate number of sections needed to adequately evaluate a renal tumor. There was almost unanimous agreement (97%) in the survey that when sampling renal tumors, a general guideline of sampling 1 block/cm of tumor should be followed, with a minimum of 3 blocks (subject to modification as needed in individual cases). Sampling at least 1 section/cm of the greatest dimension of the tumor was previously suggested in published recommendations for both pediatric41,42 and adult renal tumors.16,17 During the survey, it was initially proposed that submission of the entire tumor would be preferred for tumors <3 cm, whereas 1 section/cm would be the appropriate sampling strategy for tumors >3 cm. This approach, however, may potentially result in more blocks being submitted for a smaller tumor; for example, many more blocks would be generated for a 3 cm tumor if routine sections are taken at 3 to 4 mm than for a 4 cm tumor if sampled at 1 section/cm. Modifications of the sampling approach should be tailored to ensure the sampling of areas showing differing gross appearances or consistencies, such as necrosis, as well as for appropriate assessment of possible invasion into the renal sinus, perinephric fat, adrenal gland or renal pelvis.

SAMPLING MULTIPLE TUMORS Multiple tumors are most frequently encountered in the setting of hereditary RCC, such as von Hippel-Lindau disease, hereditary papillary RCC, Birt-Hogg-Dube´ syndrome, hereditary leiomyomatosis and RCC syndrome, and tuberous sclerosis.43–45 Multifocality also occurs in acquired cystic kidney disease46 and renal oncocytosis.47,48 Sporadic multifocal renal cell tumors are seen much less often, with a reported frequency from 4.3% to 25%. It would seem that reported frequencies of multifocal tumors are distorted by the inclusion of papillary adenoma as part of the definition of multifocality. Larger series, containing >1000 patients, demonstrated a prevalence of 4.3% to 5.4%.49–51 In 1 study, multivariate analysis showed tumor multifocality to be associated with bilateral involvement, papillary subtype, advanced tumor stage, and lymph node metastasis.49 The incidence of multifocal papillary RCC is reported to be higher when compared with clear cell RCC (10.9% vs. 2%50 and 16% vs. 3.9%49). The majority of secondary or satellite tumors demonstrate a type identical to the index tumor. In these and other studies discordant tumor morphology was documented in 17% to 26% of cases (typically clear cell with papillary); however, this had no bearing on outcome.49–51 Patients with bilateral and multifocal RCC www.ajsp.com |

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would appear to be potentially at risk for focally recurrent disease after nephron-sparing surgery. Despite this, studies comparing outcomes for multifocal versus unifocal RCC, showed no additional risk for adverse outcome after radical nephrectomy.49–51 Before the ISUP meeting, no specific sampling strategies for multifocal tumors had been evaluated or recommended in the literature. In cases with multiple tumors, the great majority (90%) of the conference participants agreed that sampling should include at a minimum the 5 largest tumors. In cases when >5 tumors are present, one may assess only the 5 largest tumors, particularly if the remaining, smaller tumors show similar gross appearances. This recommendation does not place restrictions on sampling but rather aims to provide a pragmatic approach. If there is concern regarding the histologic typing of tumors or possible adverse findings in the remaining nonsampled tumors, additional sampling should be performed.

ASSESSMENT OF PERINEPHRIC FAT INVASION Perinephric fat is located outside of the renal capsule and within the confines of the Gerota fascia. The quantity of perinephric fat varies in nephrectomy specimens, and the adrenal gland is typically located within the fat at the inner aspect of the upper pole of the kidney. Many RCCs grow and distort the renal contour by pushing into the perinephric fat. The presence of a circumscribed pushing border, even if extending well beyond the normal outline of the renal cortex, is not diagnostic of perinephric fat invasion (Fig. 3A). Penetration of the renal capsule and infiltration into the perinephric fat can sometimes be established on gross examination when the tumor loses its rounded and smooth interface with the capsule and the perinephric fat or when visible as nodules or irregular tumor masses protruding within the perinephric fat (Fig. 3B).5,18 The consensus opinion (79%) of the participants in the survey was that perinephric fat invasion is best determined by gross examination of multiple perpendicular sections of the tumor/perinephric fat interface. If present, these areas should be sampled for confirmation of invasion. By consensus (71%), it was proposed that to establish perinephric fat invasion the tumor has to either touch the fat (Fig. 4A) or extend as irregular tongues into the perinephric tissue (with or without desmoplasia) (Fig. 4B). Renal capsule evaluation, either by maintaining the perinephric fat intact or by carefully stripping off the perinephric fat, was not specifically addressed and discussed, but both alternatives have been documented in the literature and would appear acceptable.5,20

ASSESSMENT OF RENAL SINUS INVASION Renal sinus fat is the central perinephric fat compartment that is located between the pelvicalyceal system and the renal parenchyma and contains the main lymphovascular supply of the kidney (Fig. 5).5 The importance of renal sinus fat invasion was initially

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FIGURE 3. A, Presence of a circumscribed, pushing tumor border, even if extending well beyond the normal outline of the renal cortex, is not diagnostic of perinephric fat invasion. B, Penetration of the renal capsule and infiltration into the perinephric fat can sometimes be established grossly when the tumor loses its rounded and smooth interface with the capsule and the perinephric fat or when visible as nodules or irregular tumor masses protruding within the perinephric fat.

recognized in the staging of nephroblastoma,52,53 and during the past decade, its significance has also been established in adult RCC.16,21–24,26,27 These studies have demonstrated that renal sinus invasion is the principal route for extrarenal extension of the tumor, particularly for clear cell RCC, but also for papillary and chromophobe RCCs. In an important study, Bonsib23 found that >90% of clear cell RCCs Z7 cm invaded the renal sinus. In a further study, Thompson et al28 reexamined wet tissue from 33 patients with pT1 clear cell RCC who had died of their disease. Additional sections from the renal sinus identified renal sinus invasion in 14 (42%) of these cases, in contrast to a matched set of 33 patients not dying of RCC, wherein additional sections of the sinus showed invasion in only 2 (6%) cases. There are also data indicating that renal sinus invasion has a worse prognosis than perinephric fat invasion.24 During the past decade, the recognition of renal sinus invasion has prompted r

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FIGURE 4. The most significant histologic findings required to establish perinephric fat invasion are the tumor either touching the fat (A) or extending as irregular tongues into the perinephric tissue (with or without desmoplasia) (B).

FIGURE 5. A, Renal sinus fat is the centrally located perinephric fat compartment that is located between the pelvicalyceal system and the renal parenchyma and contains the main lymphovascular supply of the kidney. Diagram showing renal sinus fat (S) and its rich venous system that envelops the collecting system. The renal capsule terminates (arrow) just inside the vestibule of the hilus. B, An RCC is constrained by the renal capsule (arrow), yet no fibrous capsule impedes its growth into the vascular tissue of the renal sinus (curved arrows). From Bonsib et al,21 reproduced with permission from Wolters Kluver Health.

practice changes, resulting in targeted sampling of the renal sinus area in nephrectomy specimens. When questioned on their familiarity with renal sinus anatomy, 78% of respondents to the survey stated that they (or their prosectors) were very familiar with this, thus confirming the growing recognition of the clinical significance of sinus invasion. Similarly, 63% of survey respondents felt certain that they could recognize renal sinus involvement by tumor on gross examination in the majority of cases. Previous studies have presented somewhat varied strategies and recommendations for renal sinus sampling and evaluation.15,22,26,28 In the original studies of Bonsib,22,26 the initial series of 50 cases had the entire tumorrenal sinus embedded; when present, renal sinus invasion was demonstrated in the first few blocks of tissue sampled, and the study protocol was revised to recommend that a “minimum of 5 blocks” be sampled from the interface. In the study by Thompson et al,28 in which additional tissue from previously reported pT1 tumors was

reexamined, an additional 10 sections were submitted from the renal sinus. Subsequently, other authors have proposed alternate strategies relating to sampling a specific number of blocks of the tumor-sinus interface ranging from 1 block/cm tumor-renal sinus interface15 to 2 to 3 blocks.5,18 At the consensus meeting, there was almost unanimous agreement (98%) that when there was uncertainty as to the presence of renal sinus invasion at least 3 blocks of the tumor-renal sinus interface should be submitted. If sinus invasion is grossly evident, or obviously not present, in a small peripheral tumor, for example, only 1 block would be needed to confirm the gross impression that renal sinus invasion is present or absent. There was unanimous consensus that renal sinus invasion can be established by histologic examination when the tumor is in direct contact with the sinus fat (100%) (Fig. 6A) or in the loose connective tissue clearly beyond the renal parenchyma (75%) (Fig. 6B); the study by Thompson et al28 included both of these observations in their report. In addition, a substantial majority (90%)

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FIGURE 6. Renal sinus invasion can be established when the tumor is in direct contact with the sinus fat (A) or in the loose connective tissue clearly beyond the renal parenchyma (B). C, In addition, it was agreed upon that involvement of any endothelium-lined spaces within the renal sinus, regardless of the size, should also be considered renal sinus invasion (pT3a).

of participants agreed that involvement of any endothelium-lined spaces within the renal sinus, regardless of the size, should also be considered renal sinus invasion (pT3a) (Fig. 6C). In summary, renal sinus involvement can be diagnosed by tumor involvement of any of the structures of the renal sinus, including the sinus fat, the loose connective tissue, or any sinus-based endothelium-lined space. A separate scenario includes direct tumor invasion into the renal pelvis, with or without renal sinus involvement. This issue was not specifically addressed at the ISUP consensus conference and is currently not part of the TNM staging system but remains a question that warrants further study (Fig. 7).

SAMPLING OF RENAL VEIN, RENAL VEIN MARGIN POSITIVITY, VENA CAVA INVASION The AJCC/TNM staging system defines renal vein invasion (pT3a) as a tumor that “grossly extends into the renal vein or its segmental (muscle-containing) branches”

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FIGURE 7. Tumor shows direct invasion into the renal pelvis, which can be present with or without renal sinus involvement. This issue warrants further study and was not specifically addressed at the ISUP consensus conference and is currently not part of the TNM staging system. r

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FIGURE 8. A, Renal vein invasion (pT3a) is when the tumor grossly extends into the renal vein or its segmental (musclecontaining) branches. B, In sections taken from the renal sinus, it is not uncommon to identify the tumor within musclecontaining branches of the renal vein that was not documented on gross examination.

(Fig. 8A). Although careful gross examination of the renal vein and its major branches is an important part of the dissection of radical nephrectomy specimens, it is unlikely that dissection will expose all “muscle-containing” branches. In sections taken from the renal sinus, it is not uncommon to identify the tumor within musclecontaining branches of the renal vein that was not documented on gross examination (Fig. 8B). Many authorities have argued that this finding should be considered sufficient to assign stage pT3a if it is judged that the tumor would have been grossly evident, had the dissection of the vessel in question been performed with sufficient rigor. Vascular tumor invasion can be established when the tumor is attached to the vessel wall or when the tumor fills and distends the vessel lumen.52 This can be present in the main renal vein and its major branches. In many scenarios, however, vascular invasion cannot be fully ascertained, and widespread sampling of the vessels is required. Another question that arises is when should the renal vein margin be considered positive, particularly because of the tendency of the vessel wall to retract beyond the bulging thrombus after surgical resection and fixation (Fig. 9). Survey participants achieved a near consensus on the question as to how the renal vein should be sampled; 64% of the respondents reported that they would submit the actual margin plus additional sections of the tumor thrombus, if it is grossly suspected to be adherent to the wall of the vein. It is noteworthy that 35% of respondents would submit the margin in all cases even if there is no identifiable thrombus. A consensus opinion (74%) was achieved on the definition of the renal vein margin positivity. The margin was considered positive only if there is an adherent tumor at the actual margin (Fig. 10A), which had been confirmed microscopically (Fig. 10B). r

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Vena cava wall invasion represents staging category pT3c in the seventh edition of the AJCC/UICC TNM classification, and it is defined as a tumor that “grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava” (Fig. 11).10,11 This is important, because for those tumors in which caval thrombus is present below the diaphragm, identification of invasion of the caval wall alters the stage from pT3b to pT3c, with its adverse prognostic impact. As a consequence, when a specimen is submitted separately as “caval thrombus,” the pathologist’s role is to confirm that the thrombus contains tumor and to establish whether there is adherent caval wall tissue, in order to examine the caval wall for invasion by the tumor (Fig. 12). The most appropriate sampling strategy in this setting would be to

FIGURE 9. The assessment of the renal vein margin can also be problematic, particularly because the vessel wall tends to retract beyond the bulging thrombus after surgical resection and fixation (arrow). www.ajsp.com |

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FIGURE 10. The renal vein margin is considered positive only if there is a grossly adherent tumor at the actual margin (A), which is confirmed microscopically (B).

include Z2 sections to search for adherent caval wall tissue and possible caval vein invasion, being supported by 84% of survey participants. Zini et al54 pointed out that invasion of the renal vein ostium or inferior vena cava (IVC) wall by a renal tumor thrombus is often overlooked, because pathologists tend to receive such surgical specimens with no indication as to the site of origin. They determined IVC wall invasion to be present when tumor cells infiltrate into the intima of the IVC.54 Sometimes, however, this can be difficult or impossible to achieve because the thrombus is received piece-meal, which highlights the primary surgical goal of removing all visible disease in the IVC.

SAMPLING OF UNINVOLVED RENAL PARENCHYMA The surveyed participants agreed (80%) that, in addition to sampling of the tumor, the uninvolved renal parenchyma should also be routinely evaluated by including both normal parenchyma with (or adjacent to) the tumor and renal parenchyma distant from the tumor. This would allow for routine assessment of the

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FIGURE 11. Renal tumor thrombus extends from the tumor in the left kidney into the vena cava above the diaphragm. Courtesy Dr Amy Bromley, University of Calgary and Calgary Laboratory Services.

non-neoplastic renal parenchyma, which may contain concurrent glomerular, tubulointerstital, and vascular kidney disease.19

ADRENAL GLAND INVOLVEMENT The latest AJCC/TNM staging system considers direct invasion of the adrenal gland to be pT4 disease (Fig. 13A). This is a significant change from the 2002 staging system in which this was included in the pT3a category. The change was made on the basis of published data showing that invasion of the adrenal gland is associated with a significantly worse prognosis than perinephric fat invasion and more closely matches that of pT4 tumors.56,57 When the adrenal gland is involved, gross examination is critical in determining whether this represents contiguous spread (pT4) or a metastasis (pM1), which itself is of prognostic significance (Fig. 13B). The gross description and submitted sections should specifically reflect the prosector’s impression in this regard. r

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FIGURE 12. When a specimen is submitted separately as “caval thrombus,” the pathologist’s role is to confirm that the thrombus consists of tumor and to establish whether there is adherent caval wall tissue, in order to examine the caval wall invasion.

ASSESSMENT OF LYMPH NODES With respect to the question of how radical nephrectomy specimens should be examined for the purpose of identifying lymph nodes, the great majority of the conference participants (94%) reported that they would restrict their evaluation to the palpation and dissection to the renal hilar area fat, rather than all the fat in the nephrectomy specimen. It is apparent that any search for lymph nodes in radical nephrectomy specimens produces a relatively low yield, with 80% of respondents estimating that they would find nodes in <10% of the cases.

Handling and Staging of Renal Cell Carcinoma

Previous sampling recommendations have dwelt on the issue of the extent of lymph node search in a radical nephrectomy specimen (sample all fat15 vs. hilar fat only17), generally acknowledging that nodes are rarely identifiable unless specifically dissected by the surgeon.15 Although gross examination of hilar tissue is routinely performed to assess nodal status, it is not known whether this approach is adequate. A recent study by Mehta and colleagues, which included appraisal of 861 adult nephrectomies with microscopic examination of the hilar fat, demonstrated that grossly visible hilar lymph nodes were positive in 80% of the cases. They further showed that microscopic hilar nodes were found in only 25% of cases and, as these were all benign,58 concluded that searching for occult lymph nodes is not practical. They recommended that regional lymphadenectomy and its associated morbidity could be avoided in patients who are not at high risk for nodal metastases and do not have grossly visible lymph nodes at the time of surgery. Sometimes lymph nodes are submitted as separate specimens resected during regional lymphadenectomy, although this is not generally performed during a radical nephrectomy, primarily because of the low prevalence of nodal metastases.19,59,60 Lymph node sampling does allow for more accurate stage assignment but has no value in changing outcome.61 Once the specimen is received and properly fixed in 10% buffered formalin, it becomes the responsibility of the pathologist to retrieve and examine all lymph nodes from the submitted tissue, which is important for accurate nodal staging. Although the number of nodes that should be dissected for assessment purposes was not established by consensus, the reported evidence suggests that 12 to 13 nodes are currently accepted as a minimum for accurate pN staging.60,62–64

FIGURE 13. A, The latest AJCC/TNM staging system considers direct invasion of the adrenal gland to be pT4 disease. B, When the adrenal gland is involved, the gross examination is critical in determining whether this represents contiguous spread (pT4) or a metastasis (pM1). Figure B from Srigley JR et al.55 Reproduced with permission. r

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REFERENCES 1. Ficarra V, Schips L, Guille F, et al. Multiinstitutional European validation of the 2002 TNM staging system in conventional and papillary localized renal cell carcinoma. Cancer. 2005;104:968–974. 2. Association of Directors of Anatomic and Surgical Pathology. Recommendations for the reporting of resected neoplasms of the kidney. Hum Pathol. 1996;27:1005–1007. 3. 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;89:604–614. 4. Leibovich BC, Blute ML, Cheville JC, et al. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer. 2003;97:1663–1671. 5. Bonsib SM. Macroscopic assessment, dissection protocols and histologic sampling strategy for renal cell carcinomas. Diagn Pathol. 2008;14:151–156. 6. 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;20: 4559–4566. 7. Kattan MW, Reuter V, Motzer RJ, et al. A postoperative prognostic nomogram for renal cell carcinoma. J Urol. 2001;166:63–67. 8. Sorbellini M, Kattan MW, Snyder ME, et al. A postoperative prognostic nomogram predicting recurrence for patients with conventional clear cell renal cell carcinoma. J Urol. 2005;173:48–51. 9. Karakiewicz PI, Briganti A, Chun FK, et al. Multi-institutional validation of a new renal cancer-specific survival nomogram. J Clin Oncol. 2007;25:1316–1322. 10. Sobin LH, Compton CC. TNM seventh edition: What’s new, what’s changed: communication from the International Union Against Cancer and the American Joint Committee on Cancer. Cancer. 2010;116:5336–5339. 11. Edge SB, Byrd DR, Carducci M, et al. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2009. 12. Novara G, Ficarra V, Antonelli A, et al. Validation of the 2009 TNM version in a large multi-institutional cohort of patients treated for renal cell carcinoma: are further improvements needed? Eur Urol. 2010;58:588–595. 13. Kim SP, Alt AL, Weight CJ, et al. Independent validation of the 2010 American Joint Committee on Cancer TNM classification for renal cell carcinoma: results from a large, single institution cohort. J Urol. 2011;185:2035–2039. 14. Griffiths DF, Nind N, O’Brien CJ, et al. Evaluation of a protocol for examining nephrectomy specimens with renal cell carcinoma. J Clin Pathol. 2003;56:374–377. 15. Fleming S, Griffiths DF. Best Practice No 180. Nephrectomy for renal tumour; dissection guide and dataset. J Clin Pathol. 2005;58:7–14. 16. Che M, Grignon DJ. Handling and reporting of tumor-containing kidney specimens. Clin Lab Med. 2005;25:417–432. 17. Algaba F, Trias I, Scarpelli M, et al. Handling and pathology reporting of renal tumor specimens. Eur Urol. 2004;45:437–443. 18. Higgins JP, McKenney JK, Brooks JD, et al. Recommendations for the reporting of surgically resected specimens of renal cell carcinoma: the Association of Directors of Anatomic and Surgical Pathology. Hum Pathol. 2009;40:456–463. 19. Srigley JR, Amin MB, Delahunt B, et al. Protocol for the examination of specimens from patients with invasive carcinoma of renal tubular origin. Arch Pathol Lab Med. 2010;134:e25–e30. 20. Eble JN. Recommendations for examining and reporting tumorbearing kidney specimens from adults. Semin Diagn Pathol. 1998;15:77–82. 21. Bonsib SM, Gibson D, Mhoon M, et al. Renal sinus involvement in renal cell carcinomas. Am J Surg Pathol. 2000;24:451–458. 22. Bonsib SM. The renal sinus is the principal invasive pathway: a prospective study of 100 renal cell carcinomas. Am J Surg Pathol. 2004;28:1594–1600. 23. Bonsib SM. T2 clear cell renal cell carcinoma is a rare entity: a study of 120 clear cell renal cell carcinomas. J Urol. 2005;174:1199–1202; discussion 1202.

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24. Thompson RH, Leibovich BC, Cheville JC, et al. Is renal sinus fat invasion the same as perinephric fat invasion for pT3a renal cell carcinoma? J Urol. 2005;174:1218–1221. 25. Grignon D, Paner GP. Renal cell carcinoma and the renal sinus. Adv Anat Pathol. 2007;14:63–68. 26. Bonsib SM. Renal lymphatics, and lymphatic involvement in sinus vein invasive (pT3b) clear cell renal cell carcinoma: a study of 40 cases. Mod Pathol. 2006;19:746–753. 27. Bonsib SM. Renal veins and venous extension in clear cell renal cell carcinoma. Mod Pathol. 2007;20:44–53. 28. Thompson RH, Blute ML, Krambeck AE, et al. Patients with pT1 renal cell carcinoma who die from disease after nephrectomy may have unrecognized renal sinus fat invasion. Am J Surg Pathol. 2007;31:1089–1093. 29. Delahunt B, Egevad L, Montironi R, et al. The International Society of Urological Pathology (ISUP) consensus conference on renal neoplasia: rationale and organization. Am J Surg Pathol. 2013. 30. Srigley JR, Delahunt B, Eble JN, et al. The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia. Am J Surg Pathol. 2013. 31. Delahunt B, Cheville JC, Martignoni R, et al. The International Society of Urological Pathology (ISUP) grading classification for renal cell carcinoma and other prognostic parameters. Am J Surg Pathol. 2013. 32. Tan PH, Cheng L, Rioux-Leclercq N, et al. Renal tumors: diagnostic and prognostic biomarkers. Am J Surg Pathol. 2013. 33. Frank I, Blute ML, Cheville JC, et al. Solid renal tumors: an analysis of pathological features related to tumor size. J Urol. 2003;170:2217–2220. 34. Elmore JM, Kadesky KT, Koeneman KS, et al. Reassessment of the 1997 TNM classification system for renal cell carcinoma. Cancer. 2003;98:2329–2334. 35. Siddiqui SA, Frank I, Leibovich BC, et al. Impact of tumor size on the predictive ability of the pT3a primary tumor classification for renal cell carcinoma. J Urol. 2007;177:59–62. 36. Delahunt B, Kittelson JM, McCredie MR, et al. Prognostic importance of tumor size for localized conventional (clear cell) renal cell carcinoma: assessment of TNM T1 and T2 tumor categories and comparison with other prognostic parameters. Cancer. 2002;94:658–664. 37. Zisman A, Pantuck AJ, Chao D, et al. Reevaluation of the 1997 TNM classification for renal cell carcinoma: T1 and T2 cutoff point at 4.5 rather than 7 cm. better correlates with clinical outcome. J Urol. 2001;166:54–58. 38. Ficarra V, Prayer-Galetti T, Novara G, et al. Tumor-size breakpoint for prognostic stratification of localized renal cell carcinoma. Urology. 2004;63:235–239. 39. Igarashi T, Tobe T, Nakatsu HO, et al. The impact of a 4 cm cutoff point for stratification of T1N0M0 renal cell carcinoma after radical nephrectomy. J Urol. 2001;165:1103–1106. 40. Yaycioglu O, Rutman MP, Balasubramaniam M, et al. Clinical and pathologic tumor size in renal cell carcinoma: difference, correlation, and analysis of the influencing factors. Urology. 2002;60:33–38. 41. Zuppan CW. Handling and evaluation of pediatric renal tumors. Am J Clin Pathol. 1998;109(suppl 1):S31–S37. 42. Qualman SJ, Bowen J, Amin MB, et al. Protocol for the examination of specimens from patients with Wilms tumor (nephroblastoma) or other renal tumors of childhood. Arch Pathol Lab Med. 2003;127:1280–1289. 43. Axwijk PH, Kluijt I, de Jong D, et al. Hereditary causes of kidney tumours. Eur J Clin Invest. 2010;40:433–439. 44. Verine J, Pluvinage A, Bousquet G, et al. Hereditary renal cancer syndromes: an update of a systematic review. Eur Urol. 2010;58:701–710. 45. Shuch B, Singer EA, Bratslavsky G. The surgical approach to multifocal renal cancers: hereditary syndromes, ipsilateral multifocality, and bilateral tumors. Urol Clin North Am. 2012;39:133–148. 46. Tickoo SK, dePeralta-Venturina MN, Harik LR, et al. Spectrum of epithelial neoplasms in end-stage renal disease: an experience from 66 tumorbearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia. Am J Surg Pathol. 2006;30:141–153. 47. Gobbo S, Eble JN, Delahunt B, et al. Renal cell neoplasms of oncocytosis have distinct morphologic, immunohistochemical, and cytogenetic profiles. Am J Surg Pathol. 2010;34:620–626. r

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48. Tickoo SK, Reuter VE, Amin MB, et al. Renal oncocytosis: a morphologic study of fourteen cases. Am J Surg Pathol. 1999;23:1094–1101. 49. Richstone L, Scherr DS, Reuter VR, et al. Multifocal renal cortical tumors: frequency, associated clinicopathological features and impact on survival. J Urol. 2004;171:615–620. 50. 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;64:462–467. 51. Crispen PL, Lohse CM, Blute ML. Multifocal renal cell carcinoma: clinicopathologic features and outcomes for tumors
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Handling and Staging of Renal Cell Carcinoma

APPENDIX The members of the ISUP Renal Tumor Panel are: Anila Abraham, Adebowale Adeniran, Khalid Ahmed, Hikmat Al Ahmadie, Ferran Algaba, Robert Allan, Mahul Amin, Pedram Argani, Ulrika Axcrona, Marc Barry, Dilek Baydar, Louis Be´gin, Dan Berney, Peter Bethwaite, Athanase Billis, Ruth Birbe, Stephen Bonsib, David Bostwick, Fadi Brimo, Helen Cathro, Ying-Bei Chen, Liang Cheng, John Cheville, Yong Mee Cho, Ai-Ying Chuang, Cynthia Cohen, Henry Crist, Brett Delahunt, Warick Delprado, Fang-Ming Deng, Lars Egevad, Jonathan Epstein, Andrew Evans, Oluwole Fadare, Daniel Fajardo, Sara Falzarano, Samson Fine, Stewart Fleming, Eddie Fridman, Bungo Furusato, Masoud Ganji, Masoumeh Ghayouri, Giovanna Giannico, Neriman Gokden, David Griffiths, David Grignon, Nilesh Gupta, Omar Hameed, Ondrej Hes, Michelle Hirsch, Jiaoti Huang, Wei Huang, Christina Hulsbergen-van de Kaa, Peter Humphrey, Sundus Hussein, Kenneth Iczkowski, Rafael Jimenez, Edward Jones, Laura Irene Jufe, James Kench, Masatoshi Kida, Glen Kristiansen, Lakshmi Priya Kunju, Zhaoli Lane, Mathieu Latour, Claudio Lewin, Kathrine Lie, Josep Lloreta, Barbara Loftus, Antonio Lopez-Beltran, Fiona Maclean, Cristina Magi-Galluzzi, Guido Martignoni, Teresa McHale, Jesse McKenney, Maria Merino, Rose Miller, Hiroshi Miyamoto, Holger Moch, Rodolfo Montironi, Hedwig Murphy, John Nacey, Tipu Nazeer, Gabriella Nesi, George Netto, Peter Nichols, Marie O’Donnell, Semra Olgac, Roberto Orozco, Adeboye Osunkoya, Aysim Ozagari, Chin-Chen Pan, Anil Parwani, Joanna Perry-Keene, Constantina Petraki, Maria Picken, Maria PydaKarwicka, Victor Reuter, Katayoon Rezaei, Nathalie Rioux-Leclercq, Brian Robinson, Stephen Rohan, Ruben Ronchetti, Laurie Russell, Hemamali Samaratunga, Marina Scarpelli, Ahmed Shabaik, Rajal Shah, Jonathan Shanks, Steven Shen, Maria Shevchuk, Mathilde Sibony, John Srigley, Bhuvana Srinivasan, Martin Susani, Sueli Suzigan, Joan Sweet, Hiroyuki Takahashi, Pheroze Tamboli, Puay Hoon Tan, Satish Tickoo, Isabel Trias, Kiril Trpkov, Larry True, Toyonori Tsuzuki, Funda Vakar-Lopez, Theo Van der Kwast, Cheng Wang, Anne Warren, Jorge Yao, Asli Yilmaz, Jin Zhao, Ming Zhou, Debra Zynger.

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