Morphometric evaluation of the human prostate

Morphometric evaluation of the human prostate

MARIÂA I ARENAS,* EVA ROMO,* MAR ROYUELA,* ANTONIO RUIZ, BENITO FRAILE,* MANUEL SAÂ NCHEZ-CHAPADO  and RICARDO

PANIAGUA*

*Department of Cell Biology and Genetics, University of AlcalaÂ, and  Department of Pathology,

Hospital Principe de Asturias, Alcala de Henares, Madrid, Spain

SummaryIn order to clarify the ageing-related histological changes in the human prostate, a

quantitative morphometric analysis was performed. Complete prostates were obtained at

autopsy from 281 men (aged 20±84 years) who died in traf®c accidents and presented no

clinical symptoms of prostatic disease. The prostates were classi®ed as: histologically

normal (n � 182), with nodular hyperplasia (n � 42), with intraepithelial neoplasia

(n � 40) and carcinomatous with low Gleason grade (n � 20). Each prostate was divided

into three regions (periurethral, central and peripheral) and the volume of each region, as

well as the average volume occupied by stroma and epithelium in each region were

quanti®ed. For each parameter, the average values for each age group were compared. In

the histologically normal prostates, an increase with ageing in the total volume and the

volume occupied by the central region were observed; these increases were mainly

caused by an increase in the stromal volume of the central region in men after 30 years of

age. No histologically normal prostates were found in men older than 70 years of age.

Nodular prostatic hyperplasia was found in men over 30 years of age and a ¯uctuation in

the total volume throughout ageing was observed. Prostates with intraepithelial neoplasia

(PIN) and carcinoma were observed in men aged >20 years and the total volume and

those of each prostatic region showed multiple variations, except for the eighth decade

where a marked increase with regard to that of the previous decades was observed.

Keywords: ageing, morphometry, normal prostate

IntroductionThe histology of the normal prostate is well documented

(McNeal, 1988) and the histological changes with age in the

transition zone and periurethral tissue (McNeal, 1978) have

also been studied. According to Bartsch et al. (1979), the

prostate can be histologically divided into two major

components: the ®bromuscular part (stroma) and the

parenchymal or glandular part (epithelium plus lumen).

Weibel & Gomez (1962) demonstrated that it is possible to

quantitate morphological data using a stereological approach.

Bartsch et al. (1979) subsequently showed that this approach

may be successfully applied to the study of the normal and

the pathologically altered prostates.

Although morphological quantitation of normal prostates

has been reported (Bartsch et al., 1979; Shapiro et al., 1997),

these studies were performed in men under 40 years of age.

Quantitative studies in benign prostatic hyperplasia (BPH)

(Siegel et al., 1990; Ishigooka et al., 1996; Shapiro et al.,

1997) have usually been made in ageing men, however, the

control prostates used in these studies were commonly from

men younger than 40 years of age.

In the present study, we have performed a morphometric

analysis of prostatic tissues from men in the age range

Correspondence: Ricardo Paniagua, Department of Cell Biology

and Genetics, University of AlcalaÂ, 28871 Alcala de Henares,

Madrid, Spain.

international journal of andrology, 24:37±47 (2001)

Ó 2001 Blackwell Science Ltd.

Table 1. Age-related changes in volume (mm3) in histologically normal human prostates

20±30 years 31±40 years 41±50 years 51±60 years 61±70 years

Number of prostates 56 60 24 23 19Total volume of the prostate 23854 � 3055a 31363 � 2205b 35984 � 3820c 29494 � 3429b 30648 � 4170b

Periurethral regionTotal volume 4346 � 329a (18.2) 4279 � 850a (13.6) 6113 � 680b (16.9) 4538 � 937a (15.4) 3429 � 372c (12.2)Volume of stroma 2033 � 413a 2656 � 280b 4578 � 412c 2581 � 290b 2562 � 350b

Volume of epithelium 1294 � 159a 856 � 89b 932 � 127b 910 � 97b 331 � 55c

Central regionTotal volume 6079 � 711a (25.5) 7868 � 732b (25.1) 8255 � 776c (23.9) 9924 � 834d (33.6) 10543 � 1362d (34.4)Volume of stroma 2519 � 308a 3493 � 391b 4615 � 458c 4969 � 409d 6767 � 644e

Volume of epithelium 2220 � 293a 2134 � 356a 2311 � 298a 2818 � 292b 1771 � 164c

Peripheral regionTotal volume 13284 � 1626a (56.2) 19324 � 2508b (61.6) 20543 � 2521b (57.1) 14831 � 1574a,c (50.3) 15952 � 1612c (52.1)Volume of stroma 5561 � 687a 9830 � 990b 9457 � 973b 6934 � 646c 10716 � 944b

Volume of epithelium 4165 � 448a 5066 � 635b 7580 � 753c 4205 � 532a 2355 � 234d

Values are expressed as mean � SD. For each parameter measured (line) differences among values with different superscript letters are signi®cant (p < 0.05). Values between brackets represent the percentage ofeach region in relation to the total volume in each age-group.

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Table 2. Age-related changes in volume (mm3) in human prostatic glandular hyperplasia

31±40 years 41±50 years 51±60 years 61±70 years 71±80 years 81±90 years

Number of prostates 8 6 4 15 4 5Total volume of the prostate 24081 � 2861a,* 19411 � 2361b,* 37459 � 4254c,* 31645 � 3315d 28722 � 3076d 39857 � 4069c

Periurethral regionTotal volume 3522 � 428a,* (14.6) 3451 � 758a,* (15.8) 5983 � 881b,* (16) 4748 � 442c,* (15) 4663 � 568c (16.2) 5162 � 825d (13)Volume of stroma 2160 � 234a,* 2397 � 236a,b,* 2830 � 258b 2642 � 242b 2714 � 228b 3076 � 322c

Volume of epithelium 865 � 58a 590 � 63b,* 1502 � 126c,* 1419 � 193c,* 835 � 81a 1228 � 142d

Central regionTotal volume 8376 � 913a (34.8) 7469 � 928a (35.5) 8751 � 998a,* (23.4) 10984 � 2193b (33.7) 10338 � 2477b (36) 18815 � 2658c (45.2)Volume of stroma 4066 � 470a,* 3614 � 375a,b,* 3354 � 340b,* 5828 � 550c,* 4617 � 432d 9115 � 926e

Volume of epithelium 3048 � 363a,* 2562 � 286b 3319 � 375a,c,* 3375 � 404a,c,* 3777 � 375c 7136 � 938d

Peripheral regionTotal volume 12165 � 1857a,* (50.5) 10407 � 1406a,* (53.6) 21679 � 1691b,* (57.9) 18082 � 2504c,* (55.1) 13865 � 2841a (48.3) 19819 � 2059c,b (47.7)Volume of stroma 6193 � 611a,* 4529 � 510b,* 13135 � 2109c,* 8835 � 902d,* 4427 � 541b 7775 � 874a,d

Volume of epithelium 4186 � 413a 4558 � 443a,* 4926 � 344a,* 7715 � 776b,* 4361 � 466a 6688 � 856c

Values are expressed as mean � SD. For each parameter measured (line) differences among values with different superscript letters are signi®cant (p < 0.05). Values with asterisk are signi®cant in relation tothose of the normal prostate. Values between brackets represent the percentage of each region in relation to the total volume in each age-group.

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Table 3. Age-related changes in volume (mm3) in human prostates with intraepithelial neoplasia

20±30 years 31±40 years 41±50 years 51±60 years 61±70 years 71±80 years 81±90 years

Number of prostates 3 9 6 5 11 4 2Total volume of the prostate 21062 � 1928a,* 16372 � 2110b,* 30182 � 4182c,* 30561 � 2989c 32298 � 2982c 28722 � 3076c 49224 � 6781d

Periurethral regionTotal volume 2887 � 385a,*

(13.7)2340 � 226a,*(14.3)

3772 � 437b,*(12.5)

4465 � 626c

(14.6)5124 � 624d,*(15.9)

4306 � 469c

(15)5684 � 857d

(13.5)Volume of stroma 1512 � 259a,* 1585 � 280a,* 2340 � 297b,* 871 � 99c,* 2755 � 244d 2714 � 227d 3660 � 376e

Volume of epithelium 530 � 87a,* 415 � 59b,* 747 � 88c,* 258 � 30d,* 1794 � 201e,* 835 � 101c 1316 � 212f

Central regionTotal volume 8000 � 935a,*

(38)5422 � 494b,*(33.1)

9389 � 993c,*(31.1)

8128 � 905a,*(27.6)

11196 � 1374d

(34.7)10338 � 2477c,d

(36)16400 � 1414e

(35.3)Volume of stroma 2164 � 129a,* 2726 � 222a,* 3987 � 362b,* 5994 � 484c,* 5292 � 593c,* 4617 � 532c 7675 � 852d

Volume of epithelium 4015 � 508a,* 1792 � 235b,* 3322 � 360a,* 841 � 77c,* 4039 � 578a,* 3777 � 475a 5647 � 660d

Peripheral regionTotal volume 10512 � 1715a,*

(50)8901 � 817b,*(54.4)

17170 � 2027c,*(56.9)

16931 � 2162c,*(56.4)

16099 � 2731c

(49.8)13865 � 3841d

(48.3)19759 � 4090e

(42.9)Volume of stroma 3751 � 601a,* 4196 � 518a,* 3579 � 412a,* 6067 � 650b,* 6771 � 581b,* 4427 � 541a 6671 � 736b

Volume of epithelium 3610 � 577a 2822 � 311a,* 7104 � 842b 3632 � 394a,* 5804 � 702c,* 4361 � 466a 5791 � 669c

Values are expressed as mean � SD. For each parameter measured differences among values with different superscript letters are signi®cant (p < 0.05). Values with asterisk are signi®cant in relation to those ofthe normal prostate. Values between brackets represent the percentage of each region in relation to the total volume in each age-group.

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Table 4. Age-related changes in volume (mm3) in human prostates with low grade carcinoma (Gleason grade 1 or 2)

20±30 years 31±40 years 41±50 years 51±60 years 61±70 years 81±90 years

Number of prostates 3 8 3 2 2 2Total volume of the prostate 19343 � 3243a,* 15613 � 3769a,* 33476 � 784b,* 18950 � 4096a,* 21600 � 825a,* 39125 � 4881b

Periurethral regionTotal volume 1585 � 167a,* (8.2) 2438 � 110b,* (15.6) 4266 � 958c,* (12.7) 1794 � 676a,* (9.5) 2782 � 525b (12.9) 5599 � 736c (14.3)Volume of stroma 1182 � 127ã,* 1640 � 292ã,b,* 2622 � 384c,* 871 � 129d,* 1944 � 286b 3490 � 412e

Volume of epithelium 281 � 32a,* 520 � 47b,* 925 � 108c 258 � 60a,* 518 � 96b 1488 � 222d

Central regionTotal volume 6488 � 650a (33.5) 5136 � 453b,* (32.9) 10995 � 1208c,* (32.8) 7306 � 587a,* (38.5) 10474 � 627c (48.5) 16150 � 626d (41.2)Volume of stroma 3413 � 365a,* 1970 � 262b,* 3733 � 108a,* 5993 � 484c,* 2290 � 299b,* 7250 � 471d

Volume of epithelium 1616 � 114a,* 2158 � 375b 3900 � 333c,* 841 � 77d,* 5184 � 590e,* 4025 � 474c

Peripheral regionTotal volume 11270 � 1487a,* (58.3) 9597 � 982a,b,* (61.5) 17144 � 888c,* (51.2) 9381 � 1650b,* (49.5) 8343 � 1217b,* (38.6) 17793 � 2090c (45.4)Volume of stroma 7430 � 624a,* 2813 � 234b,* 4083 � 520c,* 3345 � 426b,* 2052 � 215d,* 9133 � 875e

Volume of epithelium 2226 � 332a,* 3519 � 339b,* 8200 � 656c 3632 � 294b,* 3586 � 589b 6592 � 793d

Values are expressed as mean � SD. For each parameter measured differences among values with different superscript letters are signi®cant (p < 0.05). Values with asterisk are signi®cant in relation to those ofthe normal prostate. Values between brackets represent the percentage of each region in relation to the total volume in each age-group.

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Ó 2001 Blackwell Science Ltd, International Journal of Andrology, 24, 37±47

42 M. I. Arenas et al.

20±84 years who presented no clinical symptoms of prostatic

disease. The aim of the study was to gain precise quantitative

information on the ageing-related changes in the various

prostatic tissue components of the normal prostate and to

obtain morphological controls for each age. In addition, the

occurrence of histological alterations (nodular hyperplasia,

prostates with intraepithelial neoplasia (PIN) and low

Gleason grade carcinomas) in these men without clinical

symptomorphology led us to evaluate the in¯uence of these

alterations on the normal parameters.

Materials and methods

Tissue specimensThe complete prostatic glands of 284 men aged

20±84 years were obtained from forensic autopsies. They

were from men who died in traf®c accidents and whose

post-mortem examination did not reveal gross alterations of

the male genitourinary or endocrine system. The glands

were transversely cut into nine consecutive slides (approxi-

mately 8 mm in width), which were ®xed in buffered

formalin (pH 7.4) and embedded in paraf®n wax. Sections of

6 lm were cut and stained with haematoxylin and eosin and

reviewed by two pathologists. After this review, prostates

were classi®ed as follows: histologically normal (182 men),

PIN (40 men), carcinomatous with low Gleason grade (1 or

2) (20 men), prostates with nodular hyperplasia and neither

tumour nor PIN (42 men). The latter hyperplasia was

characterized by the occurrence of glandular nodules

consisting of both small and large acini, some of them

showing papillary infoldings and projections that contained

central ®brovascular cores (Kohnen & Drach, 1979).

Prostates with different pathological processes at the same

time were excluded.

Morphometric study of each prostateThe volume of the entire prostate was measured by water

displacement before ®xation. Morphometric analysis of

prostatic tissue was performed for each prostate using nine

6 lm thick histological sections (one section from each

slide). In each section, the areas occupied by each region

(periurethral, central and peripheral) (McNeal, 1988) were

measured using an automatic image analyser (MIP4 version

4.4, Consulting Image Digital, Barcelona, Spain), and the

surface density of each region was obtained for each section.

The volume occupied by each prostatic region was

calculated by multiplying its average surface density by the

total volume of the prostate and by a correction factor (0.73)

for shrinkage caused by ®xation and embedding. This factor

was previously calculated by measuring 50 prostates before

and after ®xation.

In order to obtain information about changes in prostatic

components (glands and stroma), the surfaces occupied by

the glands (epithelium plus lumen), the epithelium alone and

the stroma were also measured with the image analyser in 15

randomly selected microscopic ®elds (23 300 lm2) of each

region in each of the nine histological sections. The number

of microscopic ®elds per section studied was determined by

successive approaches to obtain the minimum number of

microscopic ®elds required to reach the lowest standard

deviation (SD). A greater number of microscopic ®elds did

not decrease the SD. Delimitation of surface areas corres-

ponding to each prostatic region and type of prostatic

component (epithelium, lumen and stroma) were carried out

manually using the mouse of the image analyser. The volume

occupied by each of these prostatic regions and components

was calculated by multiplying its respective surface density by

the total volume of each prostatic region.

Data processingIn order to obtain information about changes with age

and histological diagnosis, the prostates corresponding to

each diagnosis group were subgrouped according to the

decade of life. From the average values obtained for each

parameter and prostate, the mean values � SD for each age

and diagnostic group were obtained (Tables 1±4). Within

each diagnostic group, comparison of age subgroups was

performed using ANOVA and the signi®cance of differences

between these groups were determined by the Fisher and

Behrens' test.

For each parameter and diagnostic group, a correlation

between mean values and age was calculated using the non-

parametric Spearman correlation coef®cient (Figs 1±4). Data

retrieval and analysis were made using a personal computer

and a statistical program (GraphPad Prisme 3.0).

ResultsThe results for quantitative morphometric analyses for

each diagnostic group and age are shown in Tables 1±4 and

Figs 1±4.

Histologically normal prostatesValues obtained when the data were grouped in age-

decades are shown in Table 1. For each parameter, signi®-

cant differences (p < 0.05) are expressed with different

superscript letters. Normal prostates were not encountered in

men older than 70 years of age. An increase in the total

prostatic volume was observed from 20 to 50 years; after this

age a diminution in prostatic volume was found. The same

changes were observed in the volume of the periurethral and

peripheral regions. However, the volume of the central

region increased steadily from 20 to 70 years of age.

Figure 1. Correlation analysis between age and the volume of the wholeprostate, each prostatic region and of stromal and epithelial volume inhistologically normal prostates.

b

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Morphometric evaluation of the human prostate 43

The volume occupied by the stroma in the peripheral and

central regions also increased progressively with advancing

age, while the stroma of the periurethral region only increased

up to 50 years of age. The volume occupied by the epithelium

diminished from the fourth decade in the peripheral region

and only in the seventh decade in the other two regions.

Figure 2. Correlation analysis between age and the volume of the whole prostate and each prostatic region in BPH.

Figure 3. Correlation analysis between age and the volume of the whole prostate and each prostatic region in PIN.

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44 M. I. Arenas et al.

The increase in volume of the whole prostate was

correlated with age (Fig. 1). The changes in the volume of

the periurethral and peripheral regions were not correlated

with age. An increase with age in the volume of the central

region was observed, although the correlation was not

signi®cant.

Prostates with histological disordersFor each disorder, values obtained when the data were

grouped in age-decades are shown in Table 2 (nodular

prostatic hyperplasia), Table 3 (PIN) and Table 4 (low grade

prostatic carcinoma).

Prostates with nodular hyperplasia were not encountered

in men under 30 years of age. Multiple variations in the total

volume of these prostates among the age groups could be

observed. At the ®fth decade, this volume was particularly

increased because of an increase in the peripheral region

volume, which was caused by an enlargement of the stromal

compartment. In addition, from the ®fth decade, the volume

occupied by the central region appeared to be increased.

Comparison of the volume of prostates with nodular

hyperplasia and that of normal prostates revealed that in

the third and fourth decades, the volume of normal prostates

was higher than those with hyperplastia. However, from the

®fth decade onwards the volume of prostates with nodular

hyperplasia was higher than those that were normal.

In prostates with intraepithelial neoplasia or low grade

Gleason carcinoma a dramatic increase in the total volume in

the eighth decade was observed. In the preceding decades,

the total volume and the volume of each prostatic region

varied widely from one decade to another without a clear

tendency; although in both types of altered prostates, their

volume was lower than in the corresponding age-matched

normal prostates.

For the three types of altered prostates, the non-para-

metric correlation analysis revealed a correlation (although

not signi®cant) between volume increase and ageing. A non-

signi®cant correlation between ageing and the increases in

both epithelial and stromal volume was also found (Figs 2, 3

& 4).

DiscussionQuantitative morphometric analysis may provide infor-

mation on structural changes in the prostate with advancing

age. Such methodology provides objective and reproducible

values for several morphological structures and thus allows

statistical comparison. There have been several reports about

the morphometry of the normal prostate (Bartsch et al.,

1979; Shapiro et al., 1997), but most attention has been on

BPH (Deering et al., 1994; Marks et al., 1994; Robert et al.,

1995; Ishigooka et al., 1996). In these studies, the compar-

ison has been made between hyperplasic prostates and

normal prostates from men under 40 years of age. In our

study, a morphometric analysis of histologically normal

prostates from men aged 20±84 years has been performed to

establish the changing pattern of the different prostatic

regions and, in each region, the distribution of epithelium

Figure 4. Correlation analysis between age and the volume of the whole prostate and each prostatic region in PC with low Gleason grade (1 or 2).

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Morphometric evaluation of the human prostate 45

and stroma. In addition, we have compared the evolution of

the histologically normal prostate with that of other prostates

that, in the absence of clinical symptoms, presented hidden

lesions whose detection was a fortuitous ®nding at autopsy.

Among these ®ndings, an interesting observation was the

high incidence of nodular prostatic hyperplasia in men from

30 years of age, however, intraepithelial neoplasia and

prostatic carcinomas (PC) with low degrees of development

were encountered even in the second decade of life. The

percentage of men that presented with PIN (14.1%) was

similar to the proportion of men with BPH (14.8%).

Semiquantitative studies of the human prostate have

reported data about the surface occupied by the different

prostatic regions and in each region the surface occupied by

the epithelium and the stroma. Shapiro et al. (1997)

evaluated the stromal surface/epithelial surface ratio in the

whole prostate of men from 21 to 40 years of age and they

found a value of 6.3. Bartsch et al. (1979) in their study of

normal prostates, established a morphological difference

between inner (periurethral) and outer (central and periph-

eral) parts of the gland encountering a ratio of 2:1 in the

outer part and of 2.5:1 in the inner part. The present report is

a quantitative study focused on the total volume of the

stromal and epithelial compartments. In the histologically

normal prostates, we have observed an increase in total

volume with age up to 50 years, followed by a decrease in

the following decade of life; afterwards the volume was

maintained, at least, up to the seventh decade. These changes

occurred in the periurethral and peripheral regions and the

prostatic compartment responsible for these changes in

volume was stroma rather than the epithelium, which

showed a tendency to diminish. In contrast, the central

region underwent a continuous hyperplasia, mainly in its

stroma while epithelial volume was maintained and only

diminished in the seventh decade. These differences were

not signi®cant when the data were evaluated by the non-

parametric correlation analysis. However, when the paired

t-test was applied, a signi®cant difference between age-

groups was observed for the periurethral, central and

peripheral regions. This observation suggests that there is a

natural tendency to prostatic hyperplasia throughout ageing

and this hyperplasia is caused by the stromal component.

Semiquantitative studies have shown that in BPH

the mean stromal surface/epithelial surface ratio increases,

although data reported in the literature vary widely: Bartsch

et al. (1979) and Rohr & Bartsch (1980) reported a ratio of

5:1, whereas Ishigooka et al. (1996) encountered a ratio

of 14:7 and Shapiro et al. (1997) found a ratio similar to that

of the normal gland (6:3). These discrepancies could be

explained either by the origin of the samples (transurethral

resection or prostatectomy) or the sample size. These authors

demonstrated a statistically signi®cant increase in stromal

tissue and in this compartment the ®brous component

predominates (Siegel et al., 1990). A reduction in the

vascular tissue has also been reported (Ishigooka et al.,

1996). In the present study, the prostates with nodular

hyperplasia showed, in comparison with their age-matched

normal prostates, an increase in the stromal compartment but

only in the periurethral region. However the prostates

studied here were not actually from men with BPH, but

were normal sized prostates with nodular hyperplasia. The

patients did not show any gross alterations and the nodular

hyperplasia was only diagnosed under microscopic observa-

tion.

No previous morphometric studies on PIN and PC are

reported. In these pathological processes we have observed

that the total volume of the prostate was lower than that in

the normal prostate in all age groups. The volume variations

of each prostatic region did not present a regular pattern. In

the eighth decade, there was a marked increase in the total

volume and that of each region when compared with that of

previous ages.

In summary, the normal prostate undergoes several

changes throughout ageing. These changes are re¯ected in

an increment of the central region volume and of the volume

occupied by stroma in the three prostatic regions. In our

study, the appearance of nodular prostatic hyperplasia was

observed in men over 30 years of age and prostatic

intraepithelial neoplasia and carcinoma were observed in

men over 20 years of age. Men older than 70 years presented

with pathological changes in the prostate.

AcknowledgementsThis work was supported by grants from the Fondo de

Investigaciones Sanitarias (98/0820), Sociedad MadrilenÄa de

UrologõÂa and University of AlcalaÂ.

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Morphometric evaluation of the human prostate 47