Nenavikine  ir  ikinavikine  patogija  prostatos  biopsijoje:  urologo  požiūris    

Stasys  Auškalnis  2014  

Druskininkai  

NENAVIKINĖ  PATOLOGIJA  Ê  Prostatitas    Ê  Prostatos  liaukinė  atrofija  -­‐  fokalinė  ir  difūzinė;  

Ê  Paprasta  atrofija    Ê  Post-­‐atrofinė  hiperplazija  Ê  Paprasta  atrofija  su  besiformuojančiomis  cistomis  Ê  Dalinė  atrofija  

Ê  Gerybinė  prostatos  hiperplazija;  Ê  Bazalinių  ląstelių  hiperplazija;  Ê  Šviesių  ląstelių  kribriforminė  hiperplazija;  Ê  Adenozė  Ê  Sklerozuojanti  adenozė;  Ê  Prostatos  liaukų  metaplazija;  Ê  Veromontanum  liaukinė  hiperplazija;  Ê  Prostatinės  uretros  dalies  pakitimai;  Ê  Mezonefrinė  hiperplazija;  Ê  Gerybinių  liaukų    perineurinis  plitimas.  

PROSTATE CANCER - UPDATE MARCH 2013 19

Epididymitis 0.7

Rectal bleeding > 2 days ± requiring surgical intervention 0.7

Urinary retention 0.2

Other complications requiring hospitalisation 0.3

* Adapted from NCCN Guidelines Prostate Cancer Early Detection. V.s.2012 (46).

6.5 Pathology of prostate needle biopsies6.5.1 Grossing and processingProstate core biopsies taken from different sites are usually sent to the pathology laboratory in separate vials and should be processed in separate cassettes. Before processing, number of cores per vial and length of each core should be recorded. There is a significant correlation between the length of prostate biopsy tissue on the histological slide and the detection rate of PCa (48). To achieve optimal flattening and alignment of individual cores, one should embed a maximum of three cores per cassette and use sponges or paper to keep the cores stretched and flat (49,50). To optimise the detection of small lesions, blocks should be cut at three levels (40). It is helpful routinely to mount intervening tissue sections in case additional immunostaining is needed.

6.5.2 Microscopy and reportingDiagnosis of prostate cancer is based on histological examination. Ancillary staining techniques (e.g. basal cell staining) and additional (deeper) sections should be considered if a suspect lesion is identified (51-53). Diagnostic uncertainty in biopsies may often be resolved by intradepartmental consultation or a second opinion from an external institution (51). Table 6 lists recommended concise terminology to report prostate biopsies (50).

Table 6: Recommended diagnostic terms to report prostate biopsy findings*

Benign/negative for malignancy. If appropriate, include a description (e.g. atrophy)

Active inflammation, negative for malignancy

Atypical adenomatous hyperplasia/adenosis, no evidence of malignancy

Granulomatous inflammation, negative for malignancy

High-grade PIN, negative for adenocarcinoma

High-grade PIN with atypical glands suspicious for adenocarcinoma

Focus of atypical glands/lesion suspicious for adenocarcinoma/atypical small acinar proliferation suspicious for cancer

Adenocarcinoma

*From Van der Kwast, 2003 (49).PIN = prostatic intra-epithelial neoplasia.

For each biopsy site, the proportion of biopsies positive for carcinoma and the ISUP 2005 Gleason score should be reported (54). A recent study has demonstrated the improved concordance of pattern and change of prognostic groups for the modified Gleason grading (55). According to current international convention, the (modified) Gleason score of cancers detected in prostate biopsy consists of the Gleason grade of the dominant (most extensive) carcinoma component plus the highest grade, irrespective of its extent (no 5% rule). When the carcinoma largely consists of grade 4/5 carcinoma, identification of a small portion (< 5% of the carcinoma) of Gleason grade 2 or 3 glands should be ignored. A diagnosis of Gleason score 4, or lower, should not be given on prostate biopsies (54). The presence of intraductal carcinoma and extraprostatic extension should be reported. In addition to a report of the carcinoma features for each biopsy site, an overall Gleason score based on findings in the individual biopsies is commonly provided.

The proportion (%) or length (mm) of tumour involvement per biopsy core correlates with tumour volume, extraprostatic extension, and prognosis after prostatectomy (56-58), and an extent of > 5 mm or > 50% of adenocarcinoma in a single core is used as a cut-off triggering immediate treatment versus active surveillance in patients with Gleason score 6 carcinoma. For these reasons a measure of the extent of cancer involvement (mm or %) should be provided for each core. Length of carcinoma and percentage of carcinoma involvement of the biopsy have equal prognostic impact (59). The extent of a single, small focus of adenocarcinoma, which is located in only one of the biopsies, should be clearly stated (e.g. < 1 mm or < 1%), as this might be an indication for further diagnostic work-

 Guidelines  for  processing  and  reporting  of  prostatic  needle  biopsies  

Th  H  van  der  Kwast,  C  Lopes,  C  Santonja,  C-­‐G  Pihl,  I  Neetens,  P  Martikainen,  S  Di  Lollo,  L  Bubendorf,  R  F  Hoedemaeker,  

members  of  the  pathology  committee  of  the  European  Randomised  Study  of  Screening  for  Prostate  Cancer  (ERSPC)  

    Suspect  for  but  not  diagnostic  for  adenocarcinoma,  if  the  lesion  is  too  small  and/or  lacks  sufficient  criteria  to  be  able  to  make  a  definite  diagnosis  of  adenocarcinoma.  The  pathology  committee  of  the  ERSPC  recommends  none  of  the  acronyms  that  have  been  proposed  recently,  such  as  AAP  (atypical  acinar  proliferation)  or  ASAP  (atypical  small  acinar  proliferation).  First,  lesions  suspicious  for  adenocarcinoma  do  not  represent  a  separate  entity  and  second,  their  morphology  may  vary  from  a  few  single  atypical  cells  to  strands  of  abnormal  cells  or  glands  with  atypical  features.  This  diagnosis  is  followed  by  repeat  biopsies  directed  at  the  site  of  the  initial  lesion.  

Guidelines  for  processing  and  reporting  of  prostatic  needle  biopsies  

Th  H  van  der  Kwast,  C  Lopes,  C  Santonja,  C-­‐G  Pihl,  I  Neetens,  P  Martikainen,  S  Di  Lollo,  L  Bubendorf,  R  F  Hoedemaeker,  

members  of  the  pathology  committee  of  the  European  Randomised  Study  of  Screening  for  Prostate  Cancer  (ERSPC)    

NENAVIKINĖ  PATOLOGIJA  

Ê  Prostatitas:  ūminis,  lėtinis,  granuliomatozinis  Ê  Prostatos  liaukinė  atrofija  -­‐  fokalinė  ir  difūzinė;  

Ê  Paprasta  atrofija    Ê  Post-­‐atrofinė  hiperplazija  Ê  Paprasta  atrofija  su  besiformuojančiomis  cistomis  Ê  Dalinė  atrofija  

Ê  Gerybinė  prostatos  hiperplazija  (maligninių,  navikinių  pokyčių  nėra);  Ê  Bazalinių  ląstelių  hiperplazija;  Ê  Šviesių  ląstelių  kribriforminė  hiperplazija;  Ê  Adenozė  (atipinė  adenomatozinė  hiperplazija  –  nerekomenduojamas  terminas)  Ê  Sklerozuojanti  adenozė  Ê  Prostatos  liaukų  metaplazija;  Ê  Veromontanum  liaukinė  hiperplazija;  Ê  Prostatinės  uretros  dalies  pakitimai  Ê  Mezonefrinė  hiperplazija  Ê  Gerybinių  liaukų    perineurinis  plitimas.  

Proliferacinė  uždegiminė  atrofija  

PROSTATOS  KARCINOMOS  PATOGENEZĖ  

Nelson  WGJ  Urol.  2004;172(5,  pt  2):S6–S11.      

IKI  NAVIKINĖ  PATOLOGIJA:  HGPIN  IR  ASAP  

Ê  Nuo  5%  iki  10%  visų  biopsijų  nustomi  ikinavikiniai  pakitimai  -­‐  HGPIN  ir/ar  ASAP.  

Ê  Epstein  JI,    J  Urol  2006;  

Ê  Istoriškai  buvo  manoma  ,  kad  nustačius  HPIN,    Ca  rizika  sekančiose  biopsijose  svyruoja  nuo  22-­‐79%.  Paskutiniu  metu  manoma,  kad  ši  rizika  varijuoja  nuo  2.3%  iki  23%  ir,  kuri  praktiškai  nesiskiria  nuo  PCa  dažnio  esant  GPH.  

Ê  Epstein  JI,.  Hum  Pathol  2007  

Ê  PCa  rizika  kartotinėse  biopsijose,  nustačius  ASAP,  varijuoja  nuo  26.7%  iki  42%  .  

Ê  Lepowitz  GK.  J  Urol  2002;    Ê  Epstein  JI,    J  Urol  2006;  

KOKIA  HPIN  REIKŠMĖ?      

Ê  Nediagnozuoto  vėžio  žymuo?  

Ê  Karcinomos    prekursorius  ?  

Ê  HPIN  nereikšminga?  

KOKIA  HPIN  REIKŠMĖ?      

Ê  Nediagnozuoto  vėžio  žymuo?  

Ê  Karcinomos    prekursorius?  

Ê   HPIN  nereikšminga?  

Autorius  Metai  n  Stulpelių  skaičius  pradinėje  biopsijoje  Stulpelių  skaičius  pakartotinėje  biopsijoje  Vėžio  dažnis  (proc.)  Laikas  tarp  biopsijų  (mėn.)  Borboroglu  ir  bendraautoriai    2001  45  6  22,5  44  3,9  (vidurkis)  Alsikafi  ir  bendraautoriai    2001  21  6  6  9,5  2  Moore  ir  bendraautoriai  2005  33  10  10  4,5  —  Gallo  ir  bendraautoriai  2008  65  6-­‐10  10  21,5  —  Lepowitz  ir  bendraautoriai    2001  43  12  12  2,3  4,15  (mediana)                          HPIN  REIKŠMĖ:NEDIAGNOZUOTO  VĖŽIO  ŽYMUO  

PCa  DAŽNIS  PAKARTOTINĖSE  BIOPSIJOSE  

PCa  DIAGNOZAVIMO  DAŽNIO  PRIKLAUSOMYBĖ  NUO  BIOPSINIŲ  STULPELIŲ  SUMINIO  ILGIO  

length of the biopsy sets was noted among different centres.The number of adequate needle biopsies for each case also dif-fered. The average total amount of prostatic tissue for eachparticipant and the detection rate of prostate cancer in theindividual centres correlated well (fig 1). It was noted thatmany biopsies were fragmented, which impeded a properevaluation. In line with these data, Iczkowski et al demon-strated that the length of the biopsy correlates with the pros-tate cancer detection rate.8 Although these observations stressthe importance of adequate tissue processing by the pathologylaboratory, these data also show that the biopsy technique andthe skill of the urologist can greatly influence the diagnosticoutcome. Therefore, it is strongly recommended that the uro-logical work up and the biopsy procedure should be performedby a limited number of experienced specialists in each screen-ing centre.

A learning curve may exist for pathologists who report pro-static needle biopsies. Therefore, it was initially agreed withinthe ERSPC that each ERSPC centre would institute a“reference” pathologist who is responsible for prostate needlebiopsy diagnostics. Centres with a large, multistaff pathologylaboratory have adopted the policy that the biopsies would beexamined by the general pathologists, but that cases withmalignancy, suspect lesions, or PIN would be reviewed by areference pathologist. Data from one of the ERSPC centresrevealed that after the review of approximately 1000 cancercases, the diagnosis of prostate cancer was reversed by the ref-erence pathologist in five cases. In two cases of a misdiagnosisof prostate cancer an exchange of material during the report-ing had been made and in the remaining three casespostatrophic hyperplasia in needle biopsies had been mis-taken for prostate cancer. In one additional case, where aprostate cancer was not found in the corresponding radicalprostatectomy specimen, an exchange of one of the sixbiopsies between two different participants was eventuallyconfirmed by molecular pathological analysis. Five of these sixserious mistakes were avoided by the institution of the refer-ence pathologist.

An obvious and simple measure to avoid mixing of biopsiesby the pathologist is to deliver needle biopsies of one patienteach on a separate plateau. For the cases of misdiagnoses bymisinterpretation, it is likely that continued training of

general pathologists by the reference pathologist and a lowthreshold consultation function of the reference pathologistcan largely avoid false positive diagnoses.

GUIDELINES FOR ADEQUATE PROSTATIC TISSUEPROCESSINGThe following processing issues have proved to be importantfor achieving a maximum amount of evaluable prostatic tissuein the prostatic needle biopsies.

The number of biopsies embedded in one cassetteUrologists want to know at which site the prostate cancer islocated. This information may help to decide whether aunilateral nerve sparing prostatectomy is possible. In cases oflesions suspect for adenocarcinoma, it is important to knowtheir localisation for site specific repeat biopsy. It is muchpreferable that each biopsy core should be embeddedseparately, but the consensus minimum requirement of thepathology committee of the ERSPC is that biopsies obtainedfrom one side of the prostate should be embedded separatelyfrom those obtained from the other side. It is noted that sepa-rate embedding of each biopsy core was not explicitly recom-mended by the World Health Organisation pathology com-mittee during the second international consultation9 or theRoyal College of Pathologists UK.10 Obviously, if there areadditional biopsies taken from a suspect lesion based on dig-ital rectal examination or transrectal ultrasound they shouldalways be embedded separately.

The procedure of embedding of needle biopsies intoparaffin waxBecause needle biopsies tend to become curved after fixation,flat embedding of the biopsy cores can enhance the amount oftissue that is examined by the pathologist. Flattening ofbiopsy cores can be achieved by stretching the needle biopsiesbetween two nylon meshes or by wrapping them in a piece ofpaper.6 11 This can be done even after initial formalin fixation.If multiple cores are embedded in one cassette, it is necessaryto take care that all are separated from each other. This willprevent multiple entangled biopsies from being representedonly partially in the mounted sections. An advantage of sepa-rate embedding of individual cores is that additional handlingis avoided, reducing a source of damage to the biopsies.

Improvement for needle biopsy sectioningEasy visualisation of the core biopsy in the paraffin waxgreatly helps the cutting of sections without losing too muchprostatic tissue. In some laboratories it is common practice toadd eosin or another colour solution to the biopsies beforeembedding to allow easy visualisation for the histotechnicianduring sectioning of the paraffin wax block.

The number of sections from each biopsy core (levels ofsectioning)Earlier reports3 11 12 have shown that so as not to miss smallfoci of adenocarcinoma it is mandatory to cut several sectionsof each biopsy core at different levels. Cutting biopsy cores atdifferent levels may allow a definite diagnosis of adenocarci-noma when a small focus is found at a single level. Because itwas not reported whether biopsy cores were flattened beforeembedding the recommendation of these studies to cut threedifferent levels may probably not be necessary in the case ofadequately flattened cores. Therefore, within the pathologycommittee of the ERSPC it is recommended that subsequentsections of a core at two different levels should be sufficient.Ribbons between the two levels can be stored for cases whereadditional histological slides or immunohistochemistry arerequired.

Figure 1 The relation between the cumulative length of sextantbiopsies and the detection rate of prostate cancer in men whounderwent sextant needle biopsy. Each letter in the figure representsa separate centre participating in the ERSPC

Processing and reporting of prostatic biopsies 337

www.jclinpath.com

Th  H  van  der  Kwast,  J  Clin  Pathol  2003    

HPIN  REIKŠMĖ:  PCa  PREKURSORIUS  

Autorius Metai n

Stulpelių skaičius

pradinėje biopsijoje

Stulpelių skaičius

pakartotinėje biopsijoje

Vėžio dažnis (proc.)

Laikas tarp

biopsijų (mėn.)

Lefkowitz ir bendraautoriai

[97] 2001 43 12 12 2,3 4,15

(mediana)

Lefkowitz ir bendraautoriai

[98] 2002 31 12 12 25,8 36

HPIN  REIKŠMĖ:  PCa  PREKURSORIUS  

Ê  Studijoje  (n=112)  pacientams,  kuriems  diagnozuotas  HPIN  po  12  –tainės  prostatos  biopsijos,  prostatos  vėžys  buvo  diagnozuotas  22.3%    ir  23.4%  atvejų  atitinkamai  po  34.4  ir  66.2    mėn.  

Ê  63.6%  (n=33)      Gleason  ≥7;  

Ê  9  iš  11  (81.8%)  operuotų  pacientų  nustatytas  kliniškai  reikšmingas  vėžys  (Gleason  ≥7  ir/ar  tumoro  tūris  >5%).  

 Guilherme  Godoy  Urology  2011    

 

 

HPIN  REIKŠMĖ:  PCa  PREKURSORIUS  

increase in hazard ratios with number of cores pos-itive for HGPIN (table 2). Laterality was assessedwith hazard ratios of 1.67 (95% CI 1.18, 2.37; p!0.0041) for unilateral disease and 2.20 (95% CI1.51, 3.21; p !0.0001) for bilateral disease.

A modified Kaplan-Meier plot, based on the builtCox regression models and stratified by HGPIN sta-tus, adjusting for other risk factors, was created toestimate the probability of detected CaP over time.When divided into unifocal and multifocal diseasethe estimated cancer rate by years 1, 3 and 5 was0.037, 0.125 and 0.224 for patients without HGPIN;0.044, 0.147 and 0.261 for those with unifocalHGPIN; and 0.091, 0.290 and 0.478 for those withmultifocal HGPIN, respectively (part A of figure).When stratified by laterality the estimated cancerrate by years 1, 3 and 5 was 0.057, 0.189 and 0.325for patients without HGPIN; 0.094, 0.296 and 0.481for those with unilateral HGPIN; and 0.121, 0.370and 0.578 for those with bilateral HGPIN, respec-tively (part B of figure).

DISCUSSIONThe role of HGPIN as a risk factor for CaP remainspoorly elucidated. While HGPIN is pathogenicallyassociated with CaP, a greater disparity is reported

in the literature of the incidence of CaP after adiagnosis of HGPIN, ranging from an uninterpret-able 2% to 100%.9,10 The shift from sextant biopsiesto extended biopsy protocols further complicates theissue. Our results demonstrate that patients diag-nosed with multifocal and/or bilateral HGPIN oninitial prostate biopsy are at greater risk for CaPthan those with a benign diagnosis on initial pros-tate biopsy in the extended (minimum 10 cores) bi-opsy era. The risk is independent of age, PSA, ab-normal DRE and number of cores obtained onbiopsy.

The overall incidence of CaP on repeat biopsy was45.2% higher (36.3% vs 25.0%) in the HGPIN vsbenign initial biopsy groups. Our incidence of CaPafter initial diagnosis of HGPIN falls slightly abovethe range of previously reported studies in the ex-tended biopsy era (25% to 33%).9,10 The CaP rate inour benign group (25.0%) was consistent with pub-lished positive biopsy rates for men undergoing re-peat biopsy after benign initial biopsy.11 Limited bythe retrospective nature, we attempted to create theclosest comparable control group, men who on initialbiopsy did not have atypia, HGPIN or CaP, butultimately underwent another biopsy based on theknown approximately 23% to 25% false-negativerate of even extended biopsy.12,13 While we con-trolled for abnormal DRE we were unable to assessfamily history and PSA trends, which are often con-sidered in clinical decision making especially in thesetting of repeat prostate biopsy.

The CaP detection rate when men with PIN un-dergo repeat biopsy has decreased from 40% to 50%in the earlier 1990s to 25% to 33% in recent stud-ies.9,10 This change has been attributed to the shiftaway from sextant biopsies to extended biopsy pro-

Table 2. Number of cores with HGPIN and prostate cancer risk

No. HGPIN Cores No. Pts Hazard Ratio (95% CI) p Value

0 335 1.00 Not applicable1 155 1.20 (0.79, 1.82) 0.40382 104 2.73 (1.83, 4.09) !0.00013 37 2.11 (1.18, 3.75) 0.01124" 28 2.70 (1.56, 4.65) 0.0004

Modified Kaplan-Meier curves stratified by focal disease (A) and laterality (B) derived from Cox regression model after adjusting forother risk factors.

HIGH GRADE PROSTATIC INTRAEPITHELIAL NEOPLASIA AND RISK OF PROSTATE CANCER1960

increase in hazard ratios with number of cores pos-itive for HGPIN (table 2). Laterality was assessedwith hazard ratios of 1.67 (95% CI 1.18, 2.37; p!0.0041) for unilateral disease and 2.20 (95% CI1.51, 3.21; p !0.0001) for bilateral disease.

A modified Kaplan-Meier plot, based on the builtCox regression models and stratified by HGPIN sta-tus, adjusting for other risk factors, was created toestimate the probability of detected CaP over time.When divided into unifocal and multifocal diseasethe estimated cancer rate by years 1, 3 and 5 was0.037, 0.125 and 0.224 for patients without HGPIN;0.044, 0.147 and 0.261 for those with unifocalHGPIN; and 0.091, 0.290 and 0.478 for those withmultifocal HGPIN, respectively (part A of figure).When stratified by laterality the estimated cancerrate by years 1, 3 and 5 was 0.057, 0.189 and 0.325for patients without HGPIN; 0.094, 0.296 and 0.481for those with unilateral HGPIN; and 0.121, 0.370and 0.578 for those with bilateral HGPIN, respec-tively (part B of figure).

DISCUSSIONThe role of HGPIN as a risk factor for CaP remainspoorly elucidated. While HGPIN is pathogenicallyassociated with CaP, a greater disparity is reported

in the literature of the incidence of CaP after adiagnosis of HGPIN, ranging from an uninterpret-able 2% to 100%.9,10 The shift from sextant biopsiesto extended biopsy protocols further complicates theissue. Our results demonstrate that patients diag-nosed with multifocal and/or bilateral HGPIN oninitial prostate biopsy are at greater risk for CaPthan those with a benign diagnosis on initial pros-tate biopsy in the extended (minimum 10 cores) bi-opsy era. The risk is independent of age, PSA, ab-normal DRE and number of cores obtained onbiopsy.

The overall incidence of CaP on repeat biopsy was45.2% higher (36.3% vs 25.0%) in the HGPIN vsbenign initial biopsy groups. Our incidence of CaPafter initial diagnosis of HGPIN falls slightly abovethe range of previously reported studies in the ex-tended biopsy era (25% to 33%).9,10 The CaP rate inour benign group (25.0%) was consistent with pub-lished positive biopsy rates for men undergoing re-peat biopsy after benign initial biopsy.11 Limited bythe retrospective nature, we attempted to create theclosest comparable control group, men who on initialbiopsy did not have atypia, HGPIN or CaP, butultimately underwent another biopsy based on theknown approximately 23% to 25% false-negativerate of even extended biopsy.12,13 While we con-trolled for abnormal DRE we were unable to assessfamily history and PSA trends, which are often con-sidered in clinical decision making especially in thesetting of repeat prostate biopsy.

The CaP detection rate when men with PIN un-dergo repeat biopsy has decreased from 40% to 50%in the earlier 1990s to 25% to 33% in recent stud-ies.9,10 This change has been attributed to the shiftaway from sextant biopsies to extended biopsy pro-

Table 2. Number of cores with HGPIN and prostate cancer risk

No. HGPIN Cores No. Pts Hazard Ratio (95% CI) p Value

0 335 1.00 Not applicable1 155 1.20 (0.79, 1.82) 0.40382 104 2.73 (1.83, 4.09) !0.00013 37 2.11 (1.18, 3.75) 0.01124" 28 2.70 (1.56, 4.65) 0.0004

Modified Kaplan-Meier curves stratified by focal disease (A) and laterality (B) derived from Cox regression model after adjusting forother risk factors.

HIGH GRADE PROSTATIC INTRAEPITHELIAL NEOPLASIA AND RISK OF PROSTATE CANCER1960

PCa  diagnozavimo  dažnis  HPIN  vs  GPH  -­‐  35.67%  vs  25.07%,  P=.014)  -­‐  HR  1.89  95%  CI  1.39,  2.55  (p=0.00004).    

•  Monofokalinė  –  HR  1.19  (95%  CI  0.87,  1.82;  p=0.41)  ;  •  Multifokalinė  –  HR  2.56  (95%  CI  1.83,  3.60;  p<0.0001)  .  

   Michael  C.  Lee  J  Urol  2010      

HPIN  REIKŠMĖ:  PCa  PREKURSORIUS  

1m.   3m.   5m.  

GPH   3.6%   12.5%   22.4%  

Monofokalinė   4.4%   14.7%     26.1%    

Multifokalinė   9.1%   29.0%     47.8%    

   Michael  C.  Lee  J  Urol  2010      

PCa  diagnozavimo  dažnis  pakartotinėse  biopsijose  

ASAP  REIKŠMĖ  

shown that thorough sampling of the prostate gland,ie with extended PNB protocols, correlates with anincreased cancer detection rate14–17 and the contem-porary approach to PNB typically yields 10 or moreprostate cores. We have completed an analysis of asubset of patients with 10 or more cores on initialand followup biopsy.18 In that study, as in the largerstudy population, patients with multifocal HGPINwere at increased risk for subsequent PCa comparedto patients with benign findings or unifocal HGPINon initial PNB.

In our study biopsies were interpreted by experi-enced urological pathologists. HGPIN is a morpholog-ical diagnosis and 1 group reported that nonexpertpathologists show significant variability in making

this diagnosis (! statistic ! 0.45).9 Our results may notbe reliably transferred to all practice settings.

There is bias in this study with a high rate of PCadevelopment in the benign group (crude risk 22.0%).Of 4,938 patients with benign findings in the data-base only 845 (17.1%) went on to another biopsyduring the study period. Patients in the benigngroup who underwent followup PNB were slightlyyounger and had slightly less extensive sampling oninitial PNB than those who did not undergo followupPNB (data not shown). PSA upon initial PNB waslower in patients with a benign diagnosis who didnot undergo repeat PNB (data not shown). Possiblyclinicians noted lower PSA and more extensive sam-pling on initial PNB, and were more confident of abenign diagnosis, electing not to repeat PNB in suchpatients. Since we did not analyze complete PSAprofiles (serial values over time), it is difficult tocomment on PSA trends that may have promptedclinicians to rebiopsy some patients despite benignfindings on initial PNB. Also, detailed DRE findingsand family history data were not available, whichare typically considered in clinical decision making.Regardless, our control group was not ideal andshowed a high rate of PCa, likely higher than onewould find in a more representative sample.

CONCLUSIONSTo our knowledge we report the first study compar-ing outcomes in different ASAP subgroups stratifiedby HGPIN pattern and extent. Patient numbers inthe ASAP subgroups are small but this was due tothe relative paucity of these diagnoses in clinicalpractice and the introduction of an immunoperoxi-dase stain to confirm small volume PCa. Regardless,our data reveal that multifocal HGPIN and ASAPcarry a significant risk of subsequent PCa. Further-more, when multifocal HGPIN is diagnosed withASAP, the risk of subsequent PCa further increases.

Figure 2. PCa risk by HGPIN extent. A, ASAP diagnostic subgroups. B, all study groups. u, unifocal. m, multifocal.

Table 5. Logistic regression OR and Cox regression HRpredicting PCa by initial PNB pathological findings

Initial Diagnosis

HGPIN Extent*

Absent Unifocal Multifocal

Benign:No. pts 845OR 1.00HR 1.00

HGPIN:No. pts 287 277OR 1.02 1.73HR 1.79 2.78

ASAP alone:No. pts 90OR 2.71HR 3.48

PIN-ASAP:No. pts 5 15OR 2.37 1.77HR 10.2 4.82

ASAP " PIN:No. pts 36 42OR 2.53 8.86HR 3.75 6.45

* Logistic and Cox regression models p #0.00005.

MODEL TO PREDICT PROSTATE CANCER AFTER ATYPICAL FINDINGS IN BIOPSY1244

OR-­‐8.86  

Jennifer  L.  Merrimen,  J  Urol  2011      

PROSTATOS  VĖŽIO  PREVENCIJA  5  -­‐ALFA  REDUKTAZĖS  INHIBITORIUMI  DUTASTERIDU  ESANT  AUKŠTAI  PROSTATOS  VĖŽIO  SUSIRGIMO  RIZIKAI  

Per  6  ir  12  mėn.  biopsijas  nustatyta  81,1%  visų  PCa  

NCCN Guidelines IndexTable of Contents

Discussion

Version 2.2012, 05/02/12 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .®®

NCCN Guidelines Version 2.2012Prostate Cancer Early Detection

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

PROSD-5

Managementof biopsyresults

hIn patients using finasteride or dutasteride, failure to have a substantial decrease (approximately 50%) in PSA or an increase while on medication can be associatedwith an increased risk for prostate cancer.

Cancer See NCCN Prostate Cancer Treatment Guidelines

Atypia,suspiciousfor cancer

Extended pattern rebiopsy (within 6 mo) withincreased sampling of the atypical small acinarproliferation (ASAP) site and adjacent areas. If nocancer is found, close follow-up with PSA and DREis recommended

High-gradeprostaticintraepithelialneoplasia(PIN)

Benign

Follow-up, based on DRE and PSA findings:

!

!

!

!

Positive DRE (See PROSD-4)High Risk (See PROSD-5)PSA 4-10 (See PROSD-7)PSA > 10 (See PROSD-8)

TRUS-GUIDED BIOPSY

Initial and Repeat

Number of cores:Sextant (6) ,Lateral peripheral zone (6), andLesion-directed at palpable nodule orsuspicious image

Anteriorly directed biopsy is not supported inroutine biopsy. However, the addition of atransition zone biopsy to an extended biopsyprotocol may be considered in a repeatbiopsy if PSA is persistently elevated.After 2 negative extended TRUS biopsies,prostate cancer is not commonly found atrepeat biopsy. Additional MRI imaging (T2plus diffusion weighting) may help identifyregions of cancer missed on prior biopsiesand should be considered in selected cases.For high-risk men with multiple negativebiopsies, consideration can be given to asaturation biopsy strategy.Local anesthesia can decreasepain/discomfort associated with prostatebiopsy.

Extended-pattern biopsy (12 cores)!

!

!

!

!

!

!

!

If initial sextant biopsy used,rebiopsy using extended pattern

Repeat biopsy within the firstyear, if high-grade PIN is

multi-focal ( 2 cores)"

If no cancer isfound, closefollow-up withPSA and DRE isrecommended

MANAGEMENT OF BIOPSY RESULTS

Printed by stasys auskalnis on 1/27/2014 3:35:09 PM. For personal use only. Not approved for distribution. Copyright © 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

Išvados  

Ê  Reikalingas  standartizuotas  histologinės  medžiagos  ištyrimas  -­‐  nuo  paėmimo  iki  histologinio  ištyrimo:  

Ê  Kokybiška  biopsija  ir  medžiagos  surinkimas;  

Ê  Teisinga  biopsijos  technika;  

Ê  Pakankamas  bioptatų  skaičius;  

Ê  Tinkamas  laikas  kartotinai  biopsijai.  

Ê  Pat.medžiagos  aprašymas,papildoma  nuomonė,  centrinis  vertinimas.  

Išvados  

Ê  Jei  nebuvo  atlikta  išplės2nė  biopsija,  HPIN  diagnozė  atspindi  didelį  šansą  nenustatytos,  jau  esančios  PCa.  

Ê  Mul2fokalinė    HGPIN  yra  PCa  prekursorius  ir  susijusi  su  reikšminga  rizika  (maždaug  pusei  pacientų)  PCa  išsivysty2  per  5-­‐6  metus.  

Ê  ASAP,  ypač  jei  kartu  yra  nustatyta  ir  mul2fokalinė  HPIN,  susijusi  su  labai  didele  rizika  nustaty2  karcinomą.  

AČIŪ  UŽ  DĖMESĮ  

�  Is  HGPIN  a  marker  of  unidentified  prostate  cancer,  a  precursor  to  the  malignancy,  or  an  insignificant  finding?      The  answer  is  all  three,  with  a  few  critical  caveats,  of  course.  The  explanation  for  this  seeming  contradiction  lies  in  some  critical  details  that  are  easy  to  overlook  in  this  discussion.        

Ê  Prostatitis  occurs  in  approximately  10%  to  15%  of  men  and  is  a  costly,  psychologically  and  physically  debilitating  disease  Sharp  VJ,  et  al.  Am  Fam  Physician.  2010;82(4):397–406.    

Ê  Patients  who  undergo  needle  core  biopsies  of  the  prostate  for  elevated  prostate-­‐specific  antigen  (PSA)  levels  show  evidence  of  prostatitis  on  histology  in  approximately  27%  of  the  cases.Nickel  JC  et  al.  BJU  Int.  2001;87(9):797–805.    

Ê  Chronic  inflammation  of  the  prostate  has  been  invoked  as  a  predisposing  factor  in  the  pathogenesis  of  prostatic  adenocarcinoma,  and  future  studies  are  necessary  to  further  elucidate  this  association.  Nelson  WG  et  al  J  Urol.  J  Urol.  2004;172(5,  pt  2):S6–S11.    

Ê  Granulomatous  inflammation  can  be  seen  in  the  prostate  in  less  than  1%  of  needle  core  biopsies.7    

Ê  Benign/negative  for  malignancy.  If  appropriate,  include  a  description  (e.g.  atrophy)    

Ê  Active  inflammation,  negative  for  malignancy    

Ê  Atypical  adenomatous  hyperplasia/adenosis,  no  evidence  of  malignancy    

Ê  Granulomatous  inflammation,  negative  for  malignancy    

Ê  High-­‐grade  PIN,  negative  for  adenocarcinoma    

Ê  High-­‐grade  PIN  with  atypical  glands  suspicious  for  adenocarcinoma    

Ê  Focus  of  atypical  glands/lesion  suspicious  for  adenocarcinoma/atypical  small  acinar  proliferation  suspicious  for  cancer    

Ê  Adenocarcinoma    

Van  der  Kwast  TH,  Lopes  C,  Santonja  C,  et  al.  Members  of  the  pathology  committee  of  the  European  Randomised  Study  of  Screening  for  Prostate  Cancer  (ERSPC).  Guidelines  for  processing  and  reporting  of  prostatic  needle  biopsies.    J  Clin  Pathol  2003  May;56(5):336-­‐40.      

Ê  The  role  of  prostate  biopsies  (PBs)  has  changed.  Their  importance  has  evolved  from  pure  cancer  detection  to  assisting  clinical  patient  management.  Biopsy  as  a  critical  part  of  active  surveillance  (AS)  protocols  emphasises  the  necessity  of  reproducible  and  standardised  staging  and  grading  strategies.  The  increase  in  sampled  tissue  may  achieve  a  more  complete  picture  of  the  disease  burden.    

Figure  1.  Nonspecific  granulomatous  prostatitis  characterized  by  periglandular  granulomatous  inflammation  with  multinucleated  giant  cells  (hematoxylin-­‐eosin,  original  magnification  3200).      

Ê  For  example,  in  the  mid-­‐1990s,  several  experts  recommended  that  patients  with  HGPIN  should  undergo  repeat  biopsy  every  three  months  for  some  duration.  This  was  based  on  reports  showing  that  up  to  half  of  these  patients  would  be  found  to  have  prostate  cancer  with  this  progressive  biopsy  strategy.  The  caveat  is  that  these  patients  had  undergone  initial  sextant  biopsy,  which  in  retrospect  has  been  shown  to  identify  only  about  half  of  all  tumors.  Multiple  repeat  biopsies  in  these  patients  clearly  would  have  found  cancer  in  about  half  of  the  cases  based  not  on  coexistent  HGPIN,  but  on  the  aggressive  biopsy  strategy.