Jurnal Reading

RENAL CELL CARCINOMA STAGING: PITFALLS,

CHALLENGES, AND UPDATES
PRESENTED BY:
MENTOR
INTRODUCTION

 Classic carcinoma might include features such as infiltrative growth, desmoplastic reaction, mitotic activity,
and necrosis.1
 Recognising higher-stage parameters in RCC not only for patient prognostication, but also for consideration of
enrolment in clinical trials for higher-risk renal cancers. 4-5
 This review discusses updates of the RCC staging system, including an emphasis on staging challenges and
approaches. The Union for Inter- national Cancer Control (UICC) counterpart of the TNM staging system
has also been recently released.8

1. Moch H, Bonsib SM, Delahunt B et al. Clear cell renal cell car- cinoma. In Moch H, Humphrey PA, Ulbright TM, Reuter VE eds. World Health Organization classification of tumours of the uri- nary system and
male genital organs. Lyon: IARC Press, 2016; 18–21.
4. Ravaud A, Motzer RJ, Pandha HS et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N. Engl. J. Med. 2016; 375; 2246–2254.
5. Haas NB, Manola J, Uzzo RG et al. Adjuvant sunitinib or sorafe- nib for high-risk, non-metastatic renal-cell carcinoma (ECOG- ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial.
Lancet 2016; 387; 2008–2016
8. Delahunt B, Egevad L, Samaratunga H et al. UICC drops the ball in the 8th edition TNM staging of urological cancers. Histopathology 2017; 71; 5–11.
 TUMOUR SIZE AND PT1/PT2 SUBCLASSIFICATION

 The determinant of the pT stage category

for pT1 and pT2 RCC is tumour size
(Figure 1).
 Some evidence, that tumour size decreases
slightly after formalin fixation.28

9. Hafez KS, Fergany AF, Novick AC. Nephron sparing surgery for localized renal cell carcinoma: impact of tumor size on patient survival, tumor recurrence and TNM staging. J. Urol. 1999; 162; 1930–1933.
28. Tran T, Sundaram CP, Bahler CD et al. Correcting the shrink- age effects of formalin fixation and tissue processing for renal tumors: toward standardization of pathological reporting of tumor size. J. Cancer
2015; 6; 759–766.
PT3 SUBCLASSIFICATION

 RENAL SINUS INVASION

 added to the AJCC TNM staging system as pT3a in the 2002 revision.
 Renal sinus is the central fatty compartment that houses prominent renal vasculature (Figure 2) and has no
discrete capsular barrier (in contrast to the renal capsule). 30-33
 Invasion of the renal sinus (particularly for clear cell tumours) increases with increasing tumour size. 33,34

30. 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.
31. 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.
32. 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.
33. Bonsib SM, Gibson D, Mhoon M, Greene GF. Renal sinus involvement in renal cell carcinomas. Am. J. Surg. Pathol. 2000; 24; 451–458.
34. Taneja K, Arora S, Rogers CG, Gupta NS, Williamson SR. Pathologic staging of renal cell carcinoma: a review of 300 consecutive cases with emphasis on retrograde venous inva- sion. Histopathology 2018;
73; 681–691.
PT3 SUBCLASSIFICATION
PT3 SUBCLASSIFICATION (CON’T)

 RENAL VEIN AND VEIN BRANCH INVASION

 RCC has a peculiar tendency to invade as large, finger-like structures into vein branches (Figure 3)
 As smaller venous nodules show a rounded contour (Figure 4)3
 RCC specimens is to regard any outpouching. Sometimes these outpouchings (Figure 5) are surrounded by a
cleft that can be exaggerated by placing slight flexion on the specimen.
 Although all forms of venous invasion are currently classified as pT3a. 38

3. Williamson SR, Rao P, Hes O et al. Challenges in pathologic staging of renal cell carcinoma: a study of interobserver vari- ability among urologic pathologists. Am. J. Surg. Pathol. 2018; 42; 1253–1261.
38. Ball MW, Gorin MA, Harris KT et al. Extent of renal vein inva- sion influences prognosis in patients with renal cell carcinoma. BJU Int. 2016; 118; 112–117.
PT3 SUBCLASSIFICATION (CON’T)
PT3 SUBCLASSIFICATION (CON’T)

 VEIN INVASION CHANGES TO THE 2016 AJCC TNM STAGING SYSTEM

 Vein invasion has been clarified in the 2016 AJCC TNM staging (Table 1). 7
 Plugging of entire small veins by tumour might theoretically attenuate this muscle even further or be
interpreted as tumour pseudocapsule rather than vein wall (Figure 6).

7. Rini BI, McKiernan JM, Chang SS et al. Kidney. In Amin MB, Edge SB, Greene FL, Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, Compton CC, Hess KR, Sulli- van DC, Jessup
JM, Brierley Gaspar LE, Schilsky RL, Balch CM, Winchester DP, Asare EA, Madera M, Gress DM, Meyer LR eds. AJCC cancer staging manual. Berlin, Germany: Springer, 2017; 739–755.
PT3 SUBCLASSIFICATION (CON’T)
PT3 SUBCLASSIFICATION (CON’T)
PT3 SUBCLASSIFICATION (CON’T)

 RENAL VEIN MARGIN EVALUATION

 Interpret the margin as positive only if the tumour is
histologically adherent to or invading the vein wall at the
margin (Figure 7)3
 Two options for sampling the vein margin include:
 amputating the distal-most vein wall crosssection, including
the tumour.
 trimming the vein wall separately from the tumour with
scissors (if the wall is freely mobile).

3. Williamson SR, Rao P, Hes O et al. Challenges in pathologic staging of renal cell carcinoma: a study of interobserver vari-
ability among urologic pathologists. Am. J. Surg. Pathol. 2018; 42; 1253–1261.
6. Trpkov K, Grignon DJ, Bonsib SM et al. Handling and staging of renal cell carcinoma: the International Society of
Urological Pathology Consensus (ISUP) Conference Recommendations. Am. J. Surg. Pathol. 2013; 37; 1505–1517.
PT3 SUBCLASSIFICATION (CON’T)

 RETROGRADE VENOUS INVASION

 RCCs can also spread backwards within vein branches.
 a phenomenon that appears to be exclusively associated with occlusion of the main renal vein by tumour, and
that is found in approximately 5–8% of RCCs.34,35
 This can then result in multiple ‘satellite’ tumour nodules (Figure 8).

34. Taneja K, Arora S, Rogers CG, Gupta NS, Williamson SR. Pathologic staging of renal cell carcinoma: a review of 300 consecutive cases with emphasis on retrograde venous inva- sion. Histopathology 2018; 73;
681–691.
35. Bonsib SM, Bhalodia A. Retrograde venous invasion in renal cell carcinoma: a complication of sinus vein and main renal vein invasion. Mod. Pathol. 2011; 24; 1578–1585.
PT3 SUBCLASSIFICATION (CON’T)
PT3 SUBCLASSIFICATION (CON’T)

 VENA CAVA INVOLVEMENT

 Involvement of the vena cava defines the higher pT3 stage categories pT3b and pT3c. 6
 For assessment of vena cava wall invasion, any additional specimen of ‘tumour thrombus’ be sampled
histologically (at least two or three tissue blocks). 6

6. Trpkov K, Grignon DJ, Bonsib SM et al. Handling and staging of renal cell carcinoma: the International Society of Urological Pathology Consensus (ISUP) Conference Recommendations. Am. J. Surg. Pathol.
2013; 37; 1505–1517.
PT3 SUBCLASSIFICATION (CON’T)

 PERINEPHRIC FAT INVASION

 Perinephric fat invasion (Figure 9A–C) is considered under the same category (pT3a) as renal sinus and renal
vein invasion.34
 The criteria for perinephric invasion; as exophytic renal masses can markedly distort the shape of the kidney
and bulge well beyond the normal plane of the renal capsule.

 RENAL PELVIS INVASION

 Invasion of the renal pelvis by RCC was not addressed prior to the 2016 AJCC classification, but this has been
added as an additional route to pT3a in the current scheme (Figure 9D). 7

7. Rini BI, McKiernan JM, Chang SS et al. Kidney. In Amin MB, Edge SB, Greene FL, Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, Compton CC, Hess KR, Sulli- van DC, Jessup
JM, Brierley Gaspar LE, Schilsky RL, Balch CM, Winchester DP, Asare EA, Madera M, Gress DM, Meyer LR eds. AJCC cancer staging manual. Berlin, Germany: Springer, 2017; 739–755.
34. Taneja K, Arora S, Rogers CG, Gupta NS, Williamson SR. Pathologic staging of renal cell carcinoma: a review of 300 consecutive cases with emphasis on retrograde venous inva- sion. Histopathology 2018; 73;
681–691.
PT3 SUBCLASSIFICATION (CON’T)
 LYMPHOVASCULAR INVASION

 Lymphovascular invasion is not currently a direct staging parameter

in the AJCC TNM system7
 Microscopic lymphovascular invasion as a small tumour plug within
a lymphovascular space, usually at the tumour leading edge
(Figure 10).

7. Rini BI, McKiernan JM, Chang SS et al. Kidney. In Amin MB, Edge SB, Greene FL, Amin MB, Edge SB,
Greene FL, Byrd DR, Brookland RK, Washington MK, Compton CC, Hess KR, Sulli- van DC, Jessup JM,
Brierley Gaspar LE, Schilsky RL, Balch CM, Winchester DP, Asare EA, Madera M, Gress DM, Meyer LR
eds. AJCC cancer staging manual. Berlin, Germany: Springer, 2017; 739–755.
PT4

 The pT4 category includes direct invasion of the ipsilateral adrenal gland 52,53 and invasion of the Gerota fascia.
 A morphological clue to this distinction is that adrenal cortical tissue and nodules usually have extensively
vacuolated morphology rather than entirely clear cytoplasm. 54
 immunohistochemistry may be used.
 Gerota fascia involvement is rare in renal cancer specimens, and the pathological criteria for assigning pT4 on this
basis are not well defined.
 Invasion of the liver also fit in the pT4 category.

52. Han KR, Bui MH, Pantuck AJ et al. TNM T3a renal cell carci- noma: adrenal gland involvement is not the same as renal fat invasion. J. Urol. 2003; 169; 899–903; discussion 903–904.
53. Thompson RH, Leibovich BC, Cheville JC et al. Should direct ipsilateral adrenal invasion from renal cell carcinoma be classi- fied as pT3a? J. Urol. 2005; 173; 918–921.
54. Li H, Hes O, MacLennan GT, Eastwood DC, Iczkowski KA. Immunohistochemical distinction of metastases of renal cell carcinoma to the adrenal from primary adrenal nodules, including oncocytic tumor.
Virchows Arch. 2015; 466; 581– 588.
LYMPH NODES

 Lymph nodes are not routinely dissected by urologists in all RCC cases, 56,57
 The ISUP handling guidelines recommend that palpation and dissection of the hilar area be performed (as this is
the area most likely to contain lymph nodes).6
 found metastases only in grossly identifiable lymph nodes
 Microscopic assessment of hilar fat for microscopic lymph nodes may be unnecessary.
 the current AJCC system, only pN1 for involvement of one or more regional lymph nodes. 7

6. Trpkov K, Grignon DJ, Bonsib SM et al. Handling and staging of renal cell carcinoma: the International Society of Urological Pathology Consensus (ISUP) Conference Recommendations. Am. J. Surg. Pathol. 2013; 37;
1505–1517.
7. Rini BI, McKiernan JM, Chang SS et al. Kidney. In Amin MB, Edge SB, Greene FL, Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, Compton CC, Hess KR, Sulli- van DC, Jessup JM,
Brierley JD, Gaspar LE, Schilsky RL, Balch CM, Winchester DP, Asare EA, Madera M, Gress DM, Meyer LR eds. AJCC cancer staging manual. Berlin, Germany: Springer, 2017; 739–755.
56. Gershman B, Takahashi N, Moreira DM et al. Radiographic size of retroperitoneal lymph nodes predicts pathological nodal involvement for patients with renal cell carcinoma: develop- ment of a risk prediction model.
BJU Int. 2016; 118; 742– 749.
57. Capitanio U, Leibovich BC. The rationale and the role of lymph node dissection in renal cell carcinoma. World J. Urol. 2017; 35; 497–506.
DISTANT METASTASES

 RCC is known to show some usual behaviour, including metastasis to surprising sites, such as the gallbladder,
even years to decades after diagnosis.61
 An interesting site that appears to be enriched for RCC metastases is the pancreas. 62,63
 As few pancreatic tumours are metastases, and as RCC may mimic primary tumours of the pancreas, especially as
pancreatic masses are often diagnosed by biopsy or fine needle aspiration.
 PAX8 is probably a helpful immunohistochemical marker in the distinction of RCC from neuroendocrine
tumours.64-66

2. Thompson RH, Blute ML, Krambeck AE et al. Patients with pT1 renal cell carcinoma who die from disease after nephrec- tomy may have unrecognized renal sinus fat invasion. Am. J. Surg. Pathol. 2007; 31; 1089–1093.
61. Chung PH, Srinivasan R, Linehan WM, Pinto PA, Bratslavsky G. Renal cell carcinoma with metastases to the gallbladder: four cases from the National Cancer Institute (NCI) and review of the literature. Urol. Oncol. 2012; 30; 476–481.
62. Cheng SK, Chuah KL. Metastatic renal cell carcinoma to the pancreas: a review. Arch. Pathol. Lab. Med. 2016; 140; 598– 602.
63. Tosoian JJ, Cameron JL, Allaf ME et al. Resection of isolated renal cell carcinoma metastases of the pancreas: outcomes from the Johns Hopkins Hospital. J. Gastrointest. Surg. 2014; 18; 542–548.
64. Liau JY, Tsai JH, Jeng YM et al. The diagnostic utility of PAX8 for neuroendocrine tumors: an immunohistochemical reap- praisal. Appl. Immunohistochem. Mol. Morphol. 2016; 24; 57–63.
65. Tacha D, Qi W, Zhou D, Bremer R, Cheng L. PAX8 mouse monoclonal antibody [BC12] recognizes a restricted epitope and is highly sensitive in renal cell and ovarian cancers but does not cross-react with B cells and tumors of pancreatic ori- gin. Appl.
Immunohistochem. Mol. Morphol. 2013; 21; 59–63.
66. Sangoi AR, Ohgami RS, Pai RK, Beck AH, McKenney JK, Pai RK. PAX8 expression reliably distinguishes pancreatic well-dif- ferentiated neuroendocrine tumors from ileal and pulmonary well-differentiated neuroendocrine tumors and pancreatic aci- nar cell
carcinoma. Mod. Pathol. 2011; 24; 412–424.
SUMMARY

 RCC includes a heterogeneous group of tumours with some unusual clinical and pathological characteristics that
contrast with those of other cancers.
 Key points for the pathologist are to regard larger tumours and those with any deviation from a spherical shape
(especially finger-like protrusions) with extreme suspicion for vascular or renal sinus invasion, which results in a
pT3a stage category.
 Sampling of the renal sinus interface routinely (up to submission of the entire interface for larger tumours),
sectioning to illustrate any finger-like tumour outpouching (Figure 11), and representative sampling of the tumour
to perinephric fat (two sections or more with adherent fat or mushroom-shaped outpouching into the fat).
 Renal pelvis invasion is added to the AJCC TNM system as an additional route to pT3a.
SUMMARY
THANK YOU