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Frequency of impalpable prostate adenocarcinoma and precancerous conditions in Greek male population: an autopsy study

Frequency of impalpable prostate adenocarcinoma and precancerous conditions in Greek male population: an autopsy study
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  ORIGINAL ARTICLE Frequency of impalpable prostate adenocarcinomaand precancerous conditions in Greek malepopulation: an autopsy study K Stamatiou 1 , A Alevizos 1 , D Perimeni 2 , F Sofras 3 and E Agapitos 4 1 Department of Urology, Tzaneion General Hospital, Greece;  2 Department of Microbiology, National School of Public Health, Greece; 3 Department of Urology, University of Crete, School of Medicine, Greece and  4 Department of Pathology, University of Athens, Schoolof Medicine, Greece A series of 212 prostate specimens of men dead between August 2002–August 2004, have beensectioned in consecutive autopsies and subjected to whole mount analysis in purpose to determine theepidemiology of impalpable prostate cancer in Greece. Impalpable prostate carcinomas were found in40 cases (18.8%) most in the peripheral region. In all, 29 of 40 impalpable cancers (70.7%) had volumeless than 1cm 3 . Most of impalpable carcinomas were of favorable (Gleason score 2–4) or intermediate(Gleason score 5 and 6) histological type (55 and 27.7%, respectively) while only five (12.5%) wereundifferentiated (Gleason score 7 and 8). In all, 24 (60%) of the 40 impalpable carcinomas weremultifocal and consisted of two or more foci, most of small size ( o 0.5cm 3 ). Most of the impalpablecancers found in this autopsy study were potentially insignificant tumors (relatively low volume,favorable or intermediate histological pattern and absence of invasiveness). Prostate intraepithelialneoplasia (PIN) coexisted with impalpable carcinomas, in almost half of the cancer-positivespecimens. There was a positive correlation between PIN foci and coexistent cancer foci in most ofthe cases. Frequency rate and pathological features of both entities show significant variations inmedical literature. Since the incidence of clinical prostate cancer in Greece is relatively low, andaccording to our autopsy findings, it is plausible that the frequency of clinical prostate cancer in acertain population could be related to the prevalent model of impalpable cancer as well as to thefrequency and extend of the precancerous lesions. Prostate Cancer and Prostatic Diseases  (2006)  9,  45–49. doi:10.1038/sj.pcan.4500847; published online29 November 2005 Keywords:  impalpable prostate carcinoma; precancerous lesions; PIN; autopsy Introduction Autopsy performed for epidemiological purposesprovides an accurate measure of the occurrence of prostate carcinoma. There are quite few studies pub-lished up-to-date, with significant differences on thestudied variables and occurrence of prostate carcinoma.Furthermore, it is generally agreed that racial andgeographic characteristics play an important role onthe incidence of the disease. To our knowledge, thereis only one autopsy study for the Greek populationand studies on prostate cancer pathology are scarce inGreek literature. Purpose The present study investigates the incidence andhistological features of impalpable prostate carcinomaand of prostate intraepithelial neoplasia (PIN) in autopsymaterial in Greek male population and also comparesour results with current medical literature. Materials and methods Study population The study was done in 212 consecutive autopsies of menabove 30 and  o 98 years of age, born and living inGreece, who died, (between August 2002 and August2004), of diseases other than carcinoma of the prostateand related conditions. Patients with abnormal pre-necropsy digital rectal examination (DRE), patients withhistory suspicious of prostate cancer and patients found Received 11 March 2005; revised 18 July 2005; accepted 28 September2005; published online 29 November 2005Correspondence: Dr K Stamatiou, 2 Salepoula str., 18536 Piraeus,Greece.E-mail: Prostate Cancer and Prostatic Diseases (2006) 9,  45–49 &  2006 Nature Publishing Group All rights reserved 1365-7852/06  $30.00  with macroscopic foci of cancer in any organ wereexcluded. There was no discretion in profession, socialclass, place of birth and death cause. The associations of prostate cancer and precancerous conditions wereassessed with parametric and nonparametric statisticalmethods. A comparison of prevalence rates of cancer andPIN in our study’s Greek male population has also beenmade in confront to other Caucasian male populations asreported by other autopsy studies. Sample removal and processing The whole prostate and seminal vesicles were removedwith accuracy. The specimens were weighted, measuredin three dimensions (width  height  length), numberedand registered. The surface of the two lobes wascolored in different colors (red and blue ink for rightand left lobe, respectively) and fixed in acetic acid. A 10%solution of formalin was injected uniformly per cm 3 intothe gland and every single specimen was then immersedin formalin solution allowed to rest for 3 days for fixationpurposes. Seminal vesicles were removed and sectionedthrough the base. Base and apex were also removed bytransversal sections and the slices were cut at 4mmintervals. The rest of the two lobes were divided and stepsectioned at 4mm intervals perpendicular to the longaxis of the gland. Pieces were postfixed, resectioned,dehydrated, cleared in xylene and embedded inparaffin. 1 Microscope slides were numbered, registeredand examined by an expert pathologist.  Histological assessment The presence of impalpable cancer and PIN wasrecorded. The diagnosis of prostate cancer was basedon a constellation of histological (irregular acinar growth,irregular edge and arrangement, different dimensions,with varied distance between acini and absence of basiccells) and cytological features (large hypercromaticnuclei, sizeable nucleoli, and frequent mitoses) accordingto the WHO classification system. 2 Cancers wereclassified according to the Gleason scoring system. Casesof multifocal tumors were classified according to theprevalent histological model of the larger focus (indextumor). 3 The diagnosis of PIN was also based on aconstellation of histological features. 2,4 Results As 40 of the 212 specimens, were positive for prostatecancer, the frequency of impalpable carcinoma of theprostate in our study population was 18.8%. Anincreasing frequency according to age was observed.Major prevalence of impalpable cancer was observed inmen of the eight and ninth decade. Difference inprevalence between age groups 4, 5, 6, 7 (30–69 y.o.)and 1, 2, 3 ( 4 70 y.o.) was found to be of statisticalsignificance ( P o 0.001) (Table 1).Carcinomas obtained from specimens of age groups 1,2, and 3 ( 4 70 y.o.) showed notable differences inhistological differentiation (Gleason score 2–8), whilecarcinomas found in the prostates of younger menshowed a notable similarity on histological grade withthe majority of them being highly differentiated (Gleasonscore 2–4) (Table 2).Most cancers found in specimens obtained fromelderly men had a tumor volume above 1cm 3 , whilealmost all specimens obtained from younger individualscarried cancers of volume o 1cm 3 ; however, no statisticalsignificance was found between age, tumor volume, andhistological differentiation ( P ¼ 0.215 and 0.211) (Table 3).Of 40 impalpable cancers, 87.5% (35 cases) were foundexclusively in the peripheral zone, 2.5% (one case)exclusively in the transitional zone and 10% (four cases)in both peripheral and transitional zones (multifocaltumors). Transitional and peripheral zone cancers werenearly equivalent in terms of tumor volume and Gleasonscore. In all, 29 out of 40 cancers (70.7%) had an overallvolume o 1cm 3 . The largest impalpable prostate cancerwas a multifocal tumor which had an overall volume of 4.2cm 3 and was found in a prostate of 105cm 3 . Mostcarcinomas had a Gleason score between 2 and 6 (87.5%)while only five carcinomas (12.5%) had a seven or eightGleason score. There was a clear correlation ( P o 0.001) between tumor volume and histological differentiation:most tumors  4 1cm 3 in volume showed intermediateand poor differentiation while most tumors smallerthan 1cm 3 in volume showed histological characteristicsof favorable type (Table 4).Of the 40 cancers, 36 (90%) occupied less than the 5%of the total volume of the prostate gland and would beclassified as of stage T1a if diagnosed during lifetime.Most of these hypothetical T1a cases (27) would probablyhave been considered as insignificant tumors becauseof their histological features (relatively low volume, Table 1  Age and Prostate cancer  Age group Number of Specimens Positive SpecimensN % 1  4 90 16 9 56.22 80–89 30 12 403 70–79 36 11 30.54 60–69 36 5 13.85 50–59 38 2 5.26 40–49 38 1 2.67 30–39 18 0 —Total 212 40 — Table 2  Age and Histological differentiation  Age group Histological differentiation High (Gleasonscore 2–4) Intermediate(Gleason score5–6)Low (Gleasonscore 4 7) 1  4 90 5 2 22 80–89 6 4 23 70–79 7 3 14 60–69 3 2 05 50–59 2 0 06 40–49 1 0 0Total 24 11 5 Frequency of impalpable prostate adenocarcinoma and precancerous conditions K Stamatiou  et al 46 Prostate Cancer and Prostatic Diseases  favorable, or intermediate histological pattern andabsence of invasiveness). Other pathological features(capsular penentration, perineural, and perivascularinvasion) were also examined and cross-correlated withhistological differentiation and tumor volume. Capsularpenetration was observed in four, perineural invasion insix and perivascular invasion in three cancer cases. Therewas a positive correlation between tumor volume andthe aforementioned pathological features. ( P o 0.001 in both parametric and nonparametric tests for the capsularinvasion,  P o 0.001 ( t -Test) and  P o 0.001 (Mann–WhitneyTest) for perineural invasion,  P ¼ 0.002 ( t -Test) forperivascular invasion) (Table 5).Multifocality was frequent in impalpable prostatecancer: 24 (60%) of the 40 carcinomas were composedof two or more small tumour foci ( o 0.5cm 3 ). Multifocalcancers showed a relative homogeneity: primary Gleasongrade of the index tumor corresponds to the primaryGleason grade of the other foci in 65% of the specimens.It is worth noting that only the larger ( 4 1cm 3 ) multifocaltumors (composed by more than four foci) showed aconsiderable heterogeneity. PIN foci were found in theperipheral zone of the gland (91%), often in closeproximity to foci of adenocarcinoma of the prostate(Table 6).PIN began to manifest in the male population after the3rd decade, was more frequent in the prostates of agegroups 3 and 4, and less frequent in the prostates of elderly men men. Furthermore PIN was unifocal in theprostates obtained from younger men while becamemultifocal in the elderly. The PIN lesions showed anormal distribution within age groups (with a peak at70–79y.o.) when confronted to the linear distribution of prostate cancer. A statistically significant cross-correla-tion was found among PIN and prostate cancer volume(more evident in multifocal tumors,  P o 0.001 in bothparametric and non parametric analysis). There were nostatistically significant differences in Gleason score between tumors coexistent with PIN and of tumorswithout precancerous lesions ( P 4 0.05) (Table 7). Inspecimens that presented with both lesions (PIN andcancer), the presence of PIN lesions was related to thehistological differentiation of the concomitant tumor, butfurther analysis revealed no statistical significance( P 4 0.05). There was no relation between the presenceof PIN and local invasiveness of the concomitant tumor(capsular penentration and perineural as well as peri-vascular invasion). Although most cases of PIN werefound in enlarged prostates, no statistical significantcross-correlation was observed ( P 4 0.05), between PINand benign prostate hypertrophy. Discussion The incidence of prostate cancer in Caucasian Mediter-ranean males, 5,6 is substantially lower when compared Table 3  Age and tumor volume a  Age group Tumor volume o 1cm 3 4 1cm 3 1  4 90 5 42 80–89 7 53 70–79 9 24 60–69 5 05 50–59 2 06 40–49 1 0Total 29 11 a In multifocal cancers, overall volume expresses the sum of individual foci. Table 4  Tumor volume and Histological differentiation a  High (Gleasonscore 2–4) Intermediate(Gleason score5–6)Low (Gleasonscore 4 7) Overall tumorvolume o 1cm 3 19 8 1Overall tumorvolume 4 1cm 3 5 3 4 a In multifocal cancers, overall volume expresses the sum of individual foci. Table 5  Tumor invasion/penetration according to overall tumorvolume a CapsularpenetrationPerineuralinvasionPerivascularinvasion Tumor volume o 1cm 3 1 (2.5%) 1 (2.5%) 1 (2.5%)Tumor volume 4 1cm 3 3 (7.5%) 5 (12.5%) 2 (5%) a In multifocal cancers, overall volume expresses the sum of individual foci. Table 6  Age and PIN  Age group Number of Specimens Positive Specimensn % 1  4 90 16 6 37.52 80–89 30 10 33.33 70–79 36 17 47.24 60–69 36 13 36.15 50–59 38 8 216 40–49 38 2 5.27 30–39 18 1 5.5Total 212 57 Table 7  Percentage of PIN lesions among cancer-positive speci-mens by age group  Age group Ca-P PIN and Ca-P 1  4 90 9 42 80–89 12 63 70–79 11 84 60–69 5 35 50–59 2 1*6 40–49 1 1*7 30–39 0 0 *Inadequate for statistical significance estimation, due to the small sample. Frequency of impalpable prostate adenocarcinoma and precancerous conditions K Stamatiou  et al 47 Prostate Cancer and Prostatic Diseases  to that of Caucasian males of Central and NorthernEurope 7–10 and other Western countries. 11,12 Accordingto our findings, the prevalence of impalpable prostatecancer found in autopsy in Greece, has increasedsince the last two decades (18.8% vs 14.8%), as indicated by the only evidence (to our knowledge), of an autopsystudy ever conducted in Greece. 13 This finding couldrepresent a global trend in prostate cancer frequency,due to a true increment in prevalence of thedisease itself and/or the ageing of the population. 14,15 It is worth noting that, most of the impalpablecancers, likely to progress and become clinicallysignificant (advanced Gleason score, greater volume)were found in elderly men. Age-related increase inthe prevalence of prostate cancer found in autopsy,has been well-documented in several studies but is notsimilar worldwide. 16 In addition, the frequency of smallcarcinomas found in autopsy is about 12% in all the areasinvestigated and does not vary with age. 6 On thecontrary, rates for larger carcinomas found in autopsy,increase with age and show an area-to-area variationresembling that of clinical carcinoma of prostate, 9 thuslarger tumors found in autopsy, are common amongWestern elderly men 10,17–19 while most elderly Asianmen have carcinomas less than 1cm in diameter. 20 Similarly, the frequency of infiltrative tumors is frequentin America (particularly among African-Americans)and Northern Europe, while is currently rare in Asiancountries. 24,21,22 The earlier onset of those cancersmore likely to become clinically significant (advancedGleason score, greater volume and extensiveness), whichis evident in some necropsy studies, explain theincrease in frequency of clinical prostate cancerin those countries. 23,24,25 The statistically significantdifference in age distribution and frequency of infiltra-tive cancer observed in our study, may explain therelatively low incidence of clinical prostate cancer inGreece. Since age groups 4–6 consist the main age groupof PSA (Prostate Specific Antigen) screening, the lowfrequency of prostate cancer in these groups, may reflectthe effect of PSA screening. Several studies examiningthe largest tumor perprostate have suggested that biologic behaviour is closely related to volume andhistological grade. 26,27 Reports on the level of homo-geneity among multifocal prostate cancers as found inliterature in several studies, show great variation,ranging from 41 to 68%. 27–29 In our study, multifocaltumors were frequent and composed of small foci( o 0.5cm 3 ). The level of homogeneity (as calculated bythe correspondence rate of the various foci with theprevalent histological model of the larger focus/indextumor), was 65%. Since, larger-volume cancers are thecarcinomas that progress more rapidly to becomeclinically significant, 30 the proportion of small volumehomogeneous multifocal tumors in a certain populationcould be related to the transformation rate fromhistological to clinically significant cancer and thus tothe frequency of clinical prostate cancer. Epidemiologicaland morphometrical characteristics of PIN (frequencyrate, age-specific autopsy prevalence, and number) varyin several studies: PIN is higher in African–Americanmales compared to Caucasian and Asian males, 31–34 while differences have been reported even amongCaucasian men, with a lower prevalence of PIN inMediterranean populations. 35 Conclusions Microscopic foci of impalpable cancer and precancerouslesions can be documented in Greek males from the 4thand 3rd decade of life-respectively-onwards. The lesions become more frequent and extensive as age increases.The frequency of both lesions seems to be similar to otherCaucasian Mediterranean males and significantly lower,than in northern European and American males in all theage groups evaluated. Since most impalpable cancersfound within the necropsy material were characterized by small volume, favorable histological type, and lowinvasiveness, the relatively low frequency of prostatecancer in Greece could be associated to the morphologicfeatures of impalpable cancer in Greek male population.Differences on number and extension of PIN foci amongautopsy studies on other ethnic groups may reflectsimilar associations in the epidemiology of clinicalprostate cancer. References 1 Henson DE, Hutter RP, Farrow G. 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