Case 2 -
Kidney and Adrenal, Left Radical Nephrectomy
Stephen M. Bonsib
Louisiana State University Health Sciences Center
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A.B is 54-year old female who presented to University Hospital with dyspnea and chest pain. A
pulmonary work up revealed a 2 cm lung mass. A wedge excision contained a clear cell carcinoma
consistent with a metastasis. A urology consult was obtained and an 11 cm left renal mass was identified
leading to left radical nephrectomy.
The nephrectomy specimen was opened through the renal venous system. It demonstrated a 10.5 cm
multinodular, focally cystic, yellow mass with a central region of sclerosis and a separate zone of
necrosis. Extension beyond the peripheral renal capsule and extension into the central sinus fat was not
identified. The main renal vein was not involved. However, a 2 mm nodule of yellow tumor was noted
within a large vein in the renal sinus, 1 cm from the main tumor. A second 0.6 cm yellow cortical nodule
was noted several cms from the dominant mass.
Microscopic evaluation revealed a clear cell renal cell carcinoma, Fuhrman nuclear grade 3. No
extension into peripheral perinephric fat or central sinus fat was identified. However, the small
intravenous nodule noted 1 cm from the main tumor and the separate 0.6 cortical nodule were both clear
cell renal cell carcinoma.
Case 2 - Slide 1
Renal cell carcinoma (RCC) is has a reputation for unpredictable behavior with unusual sites of
metastases, spontaneous regression of metastases, long term survival with metastases and long interval
between nephrectomy and subsequent metastases. Despite biologic eccentricities the anatomic extent of
disease, tumor stage, remains the single most important prognostic feature in renal cell carcinoma.
Stage is also important with bilateral tumors where the prognosis is determined by the stage of each
Although surgical therapy is the mainstay of treatment for renal cell carcinomas, molecular targeted
therapies are beginning to show promise. Thus, identification of patients at risk for progression has
assumed great importance. Since pathologic stage is clearly the most powerful prognostic indicator,
pathologists must be familiar with the nuances of staging systems so that dissection protocols and
histologic sampling strategies can be designed to achieve an accurate pathologic stage. For most
oncology programs this means the American Joint Commission on Cancer/Union Internationale Contra le
Cancer (AJCC/UICC) TNM staging system.
The first staging system for RCC was formulated by Flocks and Kadesky in 1958. This was followed by
the Robson staging system introduced in the 1960s. The Robson system remained in vogue until the 1980s.
Both successful in correlating tumor stage with outcomes, although there has been substantial variability
in survival rates in reported series as note below.
Five-year Survival Rate for Renal Cell Carcinoma by Robson Stage
|1st Author ||Year ||# Patients ||Stage 1 ||Stage 2 ||Stage 3 ||Stage 4|
|Robson ||1969 ||88 ||66% ||51% ||33% ||13%|
|McNichols ||1981 ||499 ||67% ||64% ||42% ||11%|
|Selli ||1983 ||115 ||93% ||63% ||80% ||13%|
|Golimbu ||1986 ||326 ||88% ||67% ||40% ||2%|
|Mederios ||1988 ||121 ||85% ||48% ||42% ||0%|
|Dinney ||1992 ||314 ||73% ||68% ||51% ||20%|
The most widely used staging system today is the TNM system. Although the TNM staging system has been
in widespread use in North America since the 1980s, it was first formulated decades earlier. It is a
dynamic formulation, undergoing periodic revisions. Although, its capacity to evolve in parallel with
advances in understanding tumor biology is a strength, this creates difficulties in evaluating the
literature and compare studies whose patients have been staged using different TNM versions. The table
below illustrates the major T-stage differences between the 1978, 1987, and 1997 formulations.
Comparison of Three TNM Formulation
|T stage ||1978 TNM ||1987 TNM ||1997 TNM|
|pT1 ||"small tumor" ||< 2.5 cm ||< 7.0 cm|
|pT2 ||"large tumor" ||> 2.5 cm ||< 7.0 cm|
|pT3 ||perinephric spread ||-- ||--|
|pT3a ||-- ||perinephric or adrenal extension ||perinephric or adrenal extension|
|pT3b ||-- ||renal vein involved ||renal vein or VC below diaphragm|
|pT3c ||-- ||VC below diaphragm ||VC above diaphragm|
|pT4 ||adjacent organ or abdominal wall ||-- ||Extension beyond Gerota's fascia|
|pT4a ||-- ||extension beyond Gerota's fascia ||--|
|pT4b ||-- ||VC above diaphragm ||--|
All three staging systems, Flocks and Kadesky, Robson and TNM have in common a renal-limited category,
a category for local spread and a category for distant spread. The TNM classification differs from its
predecessors by having 2 categories for renal-limited disease, pT1 and pT2. All 3 classifications have
been shown in multiple large series to correlate with patient outcome. In the table below survival data
from the National Cancer Data Base is shown using the 1987 formulation.
Collated Survival Data - AJCC/UICC 1987 version
|Stage ||Diagnosis ||Year 1 ||Year 2 ||Year 3 ||Year 4 ||Year 5|
|I ||100% ||94.5% ||91.4% ||89.5% ||87.2% ||84.7%|
|II ||100% ||94.3% ||87.4% ||87.4% ||85.0% ||82.9%|
|III ||100% ||83.1% ||73.4% ||68.0% ||63.1% ||59.8%|
|IV ||100% ||36.6% ||22.6% ||16.7% ||13% ||11.1%|
Unfortunately, with all staging systems at least 15-20% of patients presenting with "putatively"
renal-limited disease at diagnosis (pT1 and pT2 in the TNM system), succumb to metastatic disease. In
the 1980s the National Wilms Tumor Study, following the seminal observations of Bruce Beckwith,
identified the importance of the renal sinus, particularly renal sinus veins, in tumor dissemination. In
an effort to determine if similar biologic behavior occurs with renal cell carcinomas of adults, the
author initiated a prospective analysis of renal cortical neoplasms in 1998. To date over 300 renal
cortical neoplasms have been examined by the author focusing on renal sinus involvement. The major
findings of these studies can be briefly summarized as follows:
Observations applicable to clear cell renal cell carcinoma, but not necessarily to other types of renal cell carcinoma.
- Renal sinus involvement is the primary (initial site and most common site) of tumor extension outside of the kidney for all RCCs.
Relationship between renal sinus invasion and tumor size: 120 clear cell renal
- Sinus venous involvement represents the initial site of extrarenal extension for clear cell RCC; it first gains access to large tumor draining vein(s) while still renal-limited and then extends along these venous channels into the renal sinus.
- Clear cell RCC extends into the sinus fat most often from sites of initial intravenous involvement by invading through the vein wall into sinus fat.
- When large sinus veins +/- the main renal vein are occluded by tumor, retrograde venous spread occurs into the non neoplastic cortex.
- When a clear cell RCC is 4-5 cm size range or larger, renal sinus involvement is extremely common.
- In keeping with #5 above, pT2 clear cell RCC is rare (1-5% of cases) if careful examination of the renal sinus is performed as shown in the graph below.
In 2002 the TNM formulation was last modified. Two major revisions of the 1997 version were
Justification for pT1 subdivision was based upon outcome data. A number of studies (but not all)
published before the 2002 TNM formulation, and subsequent, found that the recurrence rate and patient
outcome appears to have a breakpoint for tumors above versus below a 4-5 cm cutoff (see Table). The 4-5
cm size range is also the point at which renal sinus involvement becomes very common, pathologic
variables that I believe are related.
- pT1 was subdivided into two categories:
- pT1a - tumor 4 cm or less
- pT1b - tumor greater than 4 cm to 7 cm.
- pT3 criteria was expanded to include renal sinus involvement:
- pT3a - tumor invades renal sinus fat
- pT3b - tumor invades segmental (muscle-containing) branches (of renal sinus veins)
Breakpoint in Patient Outcome versus Tumor Size
|1st Author ||Year ||# Cases ||Tumor Type ||Breakpoint|
|Ficarrio ||2004 ||813 ||RCCa ||5.5 cm|
|Elmore ||2003 ||351 ||RCCa ||5.0 cm|
|Frank ||2002 ||1801 ||RCCa ||5.0 cm|
|Lau ||2002 ||682 ||Clear Cell ||4.5 - 5.0 cm|
|Delehunt ||2001 ||130 ||Clear Cell ||Continuous variable|
|Zisman ||2001 ||661 ||RCCa ||4.5 cm|
|Igarashi ||2001 ||333 ||RCCa (96%CC) ||4 cm|
|Cheville ||2001 ||277 ||RCCa ||5 cm|
|Moch ||2000 ||487 ||Clear cell ||No cutoff in 4 - 8 cm|
|Hafez ||1999 ||485 ||RCCa ||4 cm|
Frank et. al. in 2005 validated the pT1a and pT1b separation as shown in the figure below. [J Urol
When cases carefully examined for renal sinus involvement are staged by both the 1997 and 2002
formulation, many cases staged pT1 and pT2 by 1997 TNM, shift into pT3 by 2002 TNM criteria. If renal
sinus involvement conveys prognostic importance, then one could postulate that many cases stage pT1 and
pT2 by 1997 TNM that metastasized (the 15-20% alluded to above) did so because they were under staged
extrarenal pT3 tumors by 2002 TNM. This postulate was tested by the Mayo Clinic group who had access the
original specimens from patients with pT1 and pT2 tumors staged by 1997 TNM formulation. They found that
over 50% of tumor specimens when re-examined were found to have sinus extension, and were extrarenal pT3
tumors by 2002 criteria.
The most critical staging issue for RCC is identification of renal-limited disease versus extension
beyond the kidney. The latter may entail involvement of veins of the complex renal venous system or
extension into either of the two perinephric fat compartments, peripheral and renal sinus. Pathologists
must employ a specimen evaluation strategy to include renal sinus evaluation which likely differs from
that learned during training and applied for years in practice. Although, there are a number of
nephrectomy dissection protocols in reference texts and journal articles, most were published prior to
the 2002 TNM iteration and are obsolete since they do not address renal sinus examination. Three
articles published after 2002 contain useful recommendations for specimen dissection that include the
renal sinus are referenced in the bibliography.
The author's preferred dissection approach is to open through the collecting system and mid point of
the tumor, followed by careful perinephric fat removal. A series of parallel slices through the specimen
is then performed. This allows excellent display of the tumor-renal sinus interface. Opening through
the venous system also has merit as shown by the case presented, in which sinus vein involvement could
well have been missed with other dissection strategies. This small quantity of tumor adherent to and
invading the wall of a large sinus vein is all that is required to merit pT3b designation. Finally,
since renal sinus invasion is almost invariable for clear cell tumors larger than 7 cm, we should be wary
of diagnosing pT2 clear cell RCC without thorough sinus evaluation.
Academicians reporting outcome data relative to tumor stage must recognize the limitations of archival
material collected prior to 2002 that was not likely evaluated for renal sinus involvement. Thus, some
cases must be under staged by 2002 TNM criteria which reduces the validity of retrospective analysis of
old cases. In future outcome analyses, urologic pathologists should consider including only cases
accessioned after their laboratory implemented a sampling protocol that addresses the 2002 staging
parameters. If this is done, future outcome studies may reveal significantly improved survival curves
for truly renal-limited pT1 and pT2 tumors, from the historic 15-20% death
rate, using 1997 or older TNM staging.
Kidney and adrenal, left radical nephrectomy:
- Clear cell renal cell carcinomas, two separate tumors, 10.5 cm and 0.6 cm.
- Fuhrman nuclear grade 3.
- Renal sinus vein invasion identified.
- Final Stage: pT3b, Nx, M1
The discontinuous focus of carcinoma with the sinus vein may be the residua of an intravenous tumor
extension, most of which metastasized to the lung leading to the initial cancer diagnosis.
Staging and prognostic factors:
- Flocks RH, Kadesky MC. Malignant neoplasms of the kidney: an analysis of 353 patients followed for 5
years or more. J Urol 79:196, 1958.
- Robson CJ, Churchill BM, Anderson W. The results of radical nephrectomy for renal cell carcinoma. J
Urol 101:297-301, 1969.
- Sobin LH, Wittekind Ch. TNM Classification of Malignant Tumours,
5th ed. New York, NY: Wiley-Liss, 1997
- Green FL, Page D, Marrow M, Fritz AG, Balch CM, Haller DG, Marrow M. AJCC Cancer
Staging Manual, 6th ed. New York, NY: Springer, 2002.
- Eble J N, Sauter G, Epstein J I, et al. World Health Organization Classification
of Tumours: Tumours of the Urinary System and Male Genital Organs. Lyon, France: IARC Press,
- Shuch B, La Rochelle JC, Pantuck AJ, Belldegrun AS.
The staging of renal cell carcinoma. Curr Opin Urol 18:455-461, 2008.
- Frank I, Blute ML, Leibovich BC, et. al. Independent validation of the 2002 AJC on cancer primary
tumor classification for renal cell carcinoma using a large single institution cohort. J Urol
- Ficarra VF, Schips L, Guillè F, et al. Multi-institutional European validation of the 2002 TNM
staging system in conventional and papillary localized renal cell carcinoma. Cancer 104:968-974, 2005.
- Cheville J C, Lohse C M, Zincke H, Weaver A L, Blute M L. Comparisons of outcome and prognostic
features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol 2003; 27:612-624.
- Moch H, Gasser T, Amin M B, Torhorst J, Sauter G, Mihatsch M J. 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.
- Leibovich BC, Blute ML, Cheville JC, et al. Prediction of progression after radical nephrectomy for
patients with clear cell renal cell carcinoma. Cancer 2003, 97:1663-1671.
- Kane CJ, Mallin K, Ritchey J, Cooperberg MR, Carroll PR. Renal cell cancer stage migration Cancer
- Lam JS, Shvarts O, Leppert JT, Figlin RA, Belldegrun AS. Renal cell carcinoma 2005: new frontiers in
staging, prognostication and targeted molecular therapies. J Urol 173:1853-1862, 2005.
- Ficarra V, Novara G, Galfano A, Artibani W. Neoplasm staging and organ'confined renal cell carcinoma:
a systematic review. Eur Urol 46: 559-564, 2004.
- Bonsib SM. Risk and Prognostic Factors: The Pathologist's Perspective. Urologic Clinics of
North America 1999; 26:3,643-660. Editor David G. Bostwick, W. B.
- Delahunt B. Histopathologic prognostic indicators for renal cell carcinoma. Semin Diag Pathol 1998;
- Guinan P, Sobin LH, Algaba F, et al. TNM staging of renal cell carcinoma: Workgroup No. 3. Union
International Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer
- Weeks DA, Beckwith JB, Luckey DW. Relapse-associated variables in stage 1 favorable histology Wilms'
tumor. A report form the National Wilms' Tumor Study. Cancer 60:1204-1212, 1987.
- Bonsib SM, Gibson D, Mhoon M, Greene GF. Renal sinus involvement in renal cell carcinomas. Am J Surg
Pathol, 24: 451, 2000.
- Bonsib SM. The renal sinus is the principal invasive pathway: a prospective study of 100 renal cell
carcinomas. Am J Surg Pathol, 28: 1594, 2004.
- Bonsib SM. T2 clear cell renal cell carcinoma is a rare tumor: a study of 120 clear cell renal cell
carcinomas. J Urol 174:1-4, 2005.
- Bonsib, SM. Renal veins and venous extension in clear cell renal cell carcinoma. Mod Pathol 20:
- Grignon D, Paner GP. Renal cell carcinoma and the renal sinus. Adv Anat Pathol 14:63-68, 2007.
- Thompson RH, Leibovich BC, Cheville JC, Webster WS, Lohse CM, Kwon ED, Frank I, Kinnkcke H, Blute ML.
Is renal sinus fat invasion the same as perinephric fat invasion for pT3a renal cell carcinoma? J Urol
- Thompson RH, Blute ML, Krambeck ML, Lohse CM, Magera JS, Leibovich BC, et. al. Patients with pT1
renal cell carcinoma who die form disease after nephrectomy may have unrecognized renal sinus fat
invasion. Am J Surg Pathol 31: 1089, 2007.
Renal neoplasm dissection protocols
- Che M, Grignon DJ. Handling and reporting of tumor-containing kidney specimens. Clin Lab Med
- Fleming S, Griffiths DFR. Best Practice No 180. Nephrectomy for renal tumour; dissection guide and
dataset. J Clin Pathol 58:7-14, 200
- Bonsib SM. Macroscopic assessment, dissection protocols, and histologic sampling strategy for renal
cell carcinomas. Diag Histopathol 14: 151-156, 2008.