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Homepage – Forum Forums Non-Muscle Invasive Bladder Cancer Updates on Grading System on Histopathology and Cytopathology

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    In recent years, there have been efforts made in both histology and cytology fields to further refine the guidelines for its grading system.


    Histo (tissue) pathology is to analyze tissue obtained commonly at the time of TURBT.    Non Muscle Invasive Bladder Cancer (NMIBC) is defined as a tumour(s) which has not progressed to muscle tissue of the bladder wall.  There are papillary (bumpy looking) tumours and carcinoma in-situ or CIS (flat) tumours.  Here, the grading system for papillary tumours is described.

    At present in Canada, papillary tumours of NMIBC are graded according to the grading system recommended by WHO in 2004/2016, which consists of  papillary urothelial neoplasm of low malignant potential (PUNLMP). low-grade papillary urothelial carcinoma (LG) and high-grade papillary urothelial carcinoma (HG).   Prior to WHO 2004 grading system, papillary tumours were divided to Grade 1 (G1), Grade 2 (G2) and Grade 3(G3) which was recommended by WHO in 1973 (WHO 1973 grading system).    Out side of Canada and the US, especially in several countries in Europe, WHO 1973 grading system is continued to be used.     In 2020, European Association of Urology (EAU) published their review of WHO 1973 and WHO 2004  grading classifications with 3401 patients and their prognosis, resulting in the classification into  LG, Intermediate Grade, HG, and very HG.   It look like  WHO 1973 and WHO 2004 combined such that  G1 becomes LG,  G2 is slit into Intermediate  and HG,  G3 becomes HG.    PUNLMP which was incorporated in WHO 2004  is now included in LG.   PUNLMP which occurs in younger patients was incorporated in WHO 2004 not to use the word carcinoma to avoid younger patients to be labeled as cancer patients.   But, clinically, the treatment for PUNLMP is the same as for LG  so they decided to include it in LG.   The reason why HG is split to HG and Very HG is because it is important to distinguish usual HG from HG with high probability of becoming muscle invasive, which will help deciding bladder preservation vs cystectomy.  From the multivariable analyses of 3,500 patients, tumor stage, WHO 1973/ 2004–2016 grade, concomitant carcinoma in situ, number of tumors, tumor size, and age were used to form four risk groups for which the probability of progression at 5 yr varied from <1% to >40%.

    Subsequently, in 2023,  International Opinions on Grading of Urothelial Carcinoma: A Survey Among European Association of Urology and International Society of Urological Pathology Members was published.  The submitted answers from 214 ISUP members, 191 EAU members, and 13 experts were analyzed.  One of 13 experts was Dr. Peter Black, Prof of UBC, who is on BCC medical advisory board.

    a) WHO 1973:   G1, G2, G3   b) WHO2004/2016:   PUNLMP, LG, HG   c)  Hybrid 3 tier:    LG, HG-G2, HG-G3      d)  Hybrid 4 tier:   e)  LG-G1,  LG-G2,  HG-G2, HG-G3

    According to the survey,  Hybrid 3 tier classification received most favorable votes  receiving 44% from urologists, 35% from pathologists and experts.   It is noted that only 20% favored to continue to use the current WHO 2004 LG, HG classification, and majority is willing to go back to WHO 1973 G1,2,3 classification if more details are defined.   The 2023 report does not state if and when the new classifications will be implemented.

    Reference on the survey



    Cytopathology – Cytology

    The new reporting system for urinary analysis is called The Paris System (TPS) as it was presented in 2013 international cytopathologist congress held in Paris in 2013.  The 1st edition of TPS was published in 2016 and the 2nd edition was published in 2022, which you can download by paying us $20, which I did.

    Prior to TPS,  urine analysis was on the brink of losing clinical relevance at least in the US because the rate of “Apypia or Atypical” was raging and credibility with urologists was dwindling.  Atypical category was a wastebasket.  It lacked accuracy in reporting LG urothelial carcinoma.    So, TPS focused on reducing reporting of Atypical and improving over all accuracy in reporting.   TPS  decided to make a significant paradigm shift in reporting such that the role of cytology is detection high risk tumours only, e.g. HG and CIS can be life threatening if not detected early and not treated whereas low risk tumours, i.e. are considered not life threatening as they rarely progress to high risk tumors.  TPS employed quantification such as the size of nucleus where DNA are stored vs cytoplasm within cell membrane, and number of abnormal cells, in addition to qualitative morphological appearance of cells. TPS 2.0 (2022) further refined TPS 1.0 based upon clinical experience with TPS 1.0 since 2016.   Consequently, TPS 2.0 has following classifications in its reporting as follows.

    a) Negative for High Grade Urothelial Carcinoma (NHGUC); b) Atypical Urothelial Carcinoma (AUC);  c)Suspicious for High Grade Urothelial Carcinoma (SHGUC); d) High Grade Urothelial Carcinoma (HGUC)

    Notice that there are no classifications for LG, except that papillary urothelial neoplasm of low malignant potential (PUNLMP) is now reported supplementary as text under NHGUC .   The number of cases reported  Atypical (AUC) has been reduced to about 8% in TPS compared to the old reporting system which reported 20-30% as Atypical.   TPS 2.0 recommends additional urine test for Atypical, such as UroVysion.  It seems that different urine analysis such as UroVysion is prescribed in the US and in the UK, but Urovysion is not available.  I think Health Canada should allow Canadian patients to access alternative urine analysis  for those patients who are diagnosed as Atypical in cytology.    One of goal of TPS is to reduce disparities in reporting between different cytology labs and among cytopathologists.   Still those discrepancies exist and the accuracy for each classification is reflected by it.   The probability of having high risk (HG or CIS) tumours for each classification is listed below.  The range of probability reflect disparities among different cytology labs.

    a) Negative for High Grade Urothelial Carcinoma (NHGUC)     0 – 10%  probability of being diagnosed as high risk (HG, CIS) if biopsy from TURBT is examined.

    b) Atypical Urothelial Carcinoma (AUC)     8-35%

    c) Suspicious for High Grade Urothelial Carcinoma (SHGUC)     50-90%

    d) High Grade Urothelial Carcinoma (HGUC)  > 90%

    A summary of TPS including TPS 2.0 is available in Youtube





    Joe, thanks this wonderful and most detailed update. I read it a few times but (and I am sure I speak for many others), find it confusing in parts. If at all possible, a summary would be wonderful.

    Also, is there a link to the multivariable analysis of of 3,500 patients in the WHO 1973/ 2004–2016 grade.


    Thanks and thanks.




    Cohort study of 13 054 patients aged 66 to 90 years with a diagnosis of low-grade papillary Ta NMIBC


    Hi Gopal,

    The link to EAU study is here.


    To get actual data, you may need access to the publication, which often requires subscription membership or belongs to an institution, eg. university or healthcare who subscribes the publication.

    Summary for EAU review of risk stratification for NMIBC.

    It is beneficial to  add “very high risk” to the existing risk stratification which consists of “low risk”, “intermediate risk” and “high risk”.    Though the risk of progression is about 15% for “high risk”, it increases to 50% when it is classified as “very high risk”.   Adding “very high risk” category will help making more appropriate decision for treatment, e.g.  in some cases. early cystectomy can be better choice than going though bladder preservation treatment if it is diagnosed as “very high risk” NMIBC.  The  new stratification of progression was made for both WHO1973 grading (G1,G2,G3) classification and WHO2004 grading (LG,HG) classification. Note that  if I read it right,  EAU study included patients who had no or intravesical chemotherapy after TURBT, and did not include patients who received BCG.   As the data has shown that the risk of progression who received BCG is lower than those who did not receive BCG,  the result (risk for progression)  from EAU review may over estimate compared to risk of those with BCG treatment.

    Recommended treatments for NMIBC are described in Guidelines, e.g. Canadian Urological Association (CUA).   Recommended treatment options are based upon risk for recurrence and progression, i.e. Low, Intermediate, High.   The risk stratification came from early large scale studies involving patients in Europe.  One of such studies was conducted by the European Organization for Research and Treatment of Cancer (EORTC) and EPRTC came up with scoring model for risk stratification.  The scoring system is based upon the 6 most significant clinical and pathological factors in patients mainly treated by intravesical chemotherapy.   Note that CUA guidelines for NMIBC states that “It is important to note that the EORTC risk calculator likely overestimates the risk of tumour recurrence and disease progression, as very few of the patients in these prospective trials received Intravesical BCG”.   Anyway, EORTC scoring model is based upon age,  number of tumours, tumour diameter, prior recurrence rate, stage Ta, T1, concurrent CIS, WHO 1973 tumour grades.

    CUA guidelines states on risk stratification as follows

    In general, patients with NMIBC can be stratified into low risk (solitary and low grade Ta [TaLG] lesion and < 3cm, intermediate-risk (>3cm, multiple, or multiple-recurrent low-intermediate grade tumors), and high-risk (high-grade Ta, T1 tumours or CIS) disease.  Patients with low-grade non-invasive disease are also classified and treated as high-risk NMIBC if they possess all of the following: Large (> 3cm), and multifocal and multi-recurrent low-grade Ta lesions.  It is important to note that the EORTC risk calculator likely overestimates the risk of tumour recurrence and disease progression, as very few of the patients in these prospective trials received Intravesical BCG

    Roughly speaking,  LG consists of G1 plus a lower half of G2, and HG consists of upper half of G2 and G3.    I think this is why EAU has decided to review how relevant EORTC risk stratification model which was based upon WHO 1973 G1,G2, G3 grading classification is when WHO 2004 LG, HG grading classification.   The review also includes various studies conducted since the original 2006 EORTC risk stratification model was published.    The review also included statistical analysis of initial diagnosis and subsequent incidents of recurrence and progression of 3401 patients treatment with TURBT with or without intravesical chemotherapy.   The analyses were based upon age, number of tumours, tumour diameter, stage Ta, T1, and contaminant CIS, and WHO/1973-2004-2016 grade, which are almost the same parameters used for 2006 EORTC risk stratification model except they added WHO2004  LG, HG grading classification in addition to WHO1973 G1,G2,G3 grading classification.

    It seems the review was more focused on risk of progression rather than recurrence.

    The review stratified  four different risks of progression by adding very high risk to low risk, intermediate risk, high risk  which most guidelines including CUA guidelines are currently using.   The addition of higher risk classification, which shows over 50% progression rate at 10 years, should help making suitable treatment decision.   The satirical analysis showed risk of progression at 10 years as follows.  Note that  numbers are very approximate.

    The current EORTC risk stratification model (  low risk, intermediate risk and high risk), which is based upon G1,G2,G3

    Low Risk  0.5%      Intermediate Risk  10%     High Risk   15%

    New risk stratification model (low risk,  intermediate,  high risk and very high risk) based upon WHO1973 G1,G2,G3 grading classification

    Low Risk  0.8%    Intermediate Risk 12%      High Risk  15%       very high risk  50%

    New risk stratification model (low risk,  intermediate,  high risk and very high risk) based upon WHO2004 LG, HG grading classification

    Almost the same as the data based upon WHO1973 grading classification


    How they classified  very high risk.

    Risk factors   1.  Age > 70,  2.   Multiple tumours, 3.  Diameter of tumour > 3 cm.

    a.  Ta HG/G3 and CIS with all 3 risk factors

    b.  T1 G2 and CIS with at least 2 risk factors

    c.   T1 HG/G3 and  CIS with at least 1 risk factor

    d.   T1 HG/G3  no CIS with all 3 risk factors.



    “As the data has shown that the risk of progression who received BCG is lower than those who did not receive BCG,  the result (risk for progression)  from EAU review may over estimate compared to risk of those with BCG treatment. ” should read  ” As the data has shown that the risk of progression who received BCG is lower than those who were treated with intravesical chemotherapy,  the result (risk for progression)  from EAU review may over estimate compared to risk of those with BCG treatment.


    Thanks Joe. Are you aware of data from any studies that were done to determine the probability of LG NMIBC turning to HG?


    Hi Gopal,

    Most studies were on risk based, rather than on grade basis.   I have found one study in internet.   I hope you will take the result just as reference.  The study was done  in 2010 before genomic analysis wasn’t easily available.  Note that the first genomic analysis was published in 2014 for muscle invasive bladder cancer.

    There is a study done by Johns Hopkins back in 2010.  Johns Hopkins in Maryland is a well know known academic hospital for bladder cancer, especially for  their largest pathology department in the US and it is the go to hospital  for a second opinion for histopathology.   The turnaround time  for pathology reevaluation is 24 hrs.  According to Johns Hopkins, 20% results in different pathology result from the original pathology.   It costs US$300-400.   I think it is always preferable that specimens from TURBT are evaluated by pathologist who specializes in urological cancers.    John Hopkins received a private donation of US$15 million in 2014, and Johns Hopkins Medicine added $45 million dollars to establish The Greenberg Bladder Cancer Institute, which also launched a women’s bladder program led by two female doctors.   The reason I mentioned about Johns Hopkins is to establish credibility of their study on the subject even it is a single institute study.

    The clinical study was to find out about grade progression from LG ->HG, LG->CIS, LG->muscle, LG->Metastasis.

    104 patients with initially diagnosed LG were followed for mean length of 40 months (2-113 months).

    56 (53.8%) had recurrence with LG.   19(18.3%) had recurrence with HG.    Of 19 patients who had HG recurrence,  5 also developed invasive stage (T1,T2.., and 2 developed metastasis.

    None of 104 patients died from bladder cancer.

    The study found there were not significant difference in sex, age, tumour size, smoking history in terms of its effect on recurrence or progressions, but patients with multiple tumours had significantly higher incidents of recurrences.;


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