Introduction

Prostate cancer is a large public health problem.¹ It is currently the most common neoplasm and the second leading cause of cancer death in males.² Prostate cancer is unique among the potentially lethal malignancies due to the wide discrepancy between the high prevalence of histological changes recognizable as cancer and the much lower prevalence of clinical disease.³

Nodular prostatic hyperplasia (NH) represents benign growth of the prostate that spontaneously develops in the aging population.⁴ Histological evidence of NH is rarely observed in males prior to the fifth decade of life. The development of NH is an unavoidable phenomenon for the majority of aging males, since 90% have evidence of microscopic NH.

Autopsy studies that have defined the incidence and morphological evolution of prostatic hyperplasia and carcinoma have been confined largely to hospital autopsy of men with more than 40 years of age. Benign hyperplasia and carcinoma of prostate are increasingly frequent with advancing age. Prostatic specimens thus constitute a good percentage of surgical pathology work load. The frequency of incidentally found carcinoma in autopsies of patients with no urological complaints varies from 6.6 to 66.7%.^5,6 It is likely that adenocarcinoma of the prostate is the most prevalent cancer in men although it is often discovered incidentally and may remain latent or pursue an indolent clinical course. This prompted us to investigate the spectrum of lesions in routine medicolegal autopsy specimens. Current theories of pathogenesis relate to abnormal hormonal influences and/ or recapitulation of embryonic events in the development of the prostate gland.

Materials And Methods

During the course of medico-legal autopsies, 100 consecutive prostates were collected and age ranged from 12 to 84 years. This study was a prospective study conducted in the Department of Pathology, Kasturba Medical College, Mangalore for 2 years from the period of August 2005 to July 2007. Most of the patients had died from traffic accidents in Mangalore, India. No clinical histories were available since these men had not been hospitalized.

The prostates were removed en block and immediately fixed in 10% formalin. After proper fixation, extracapsular connective tissue was dissected and prostates were weighed and measured. Any abnormalities like increase in weight / size and gross features like nodular and cystic changes were noted. Four sections (each 1mm thick) including the whole cut surface area was given for processing. The sections were processed routinely and embedded in paraffin. Sections were 4-6 um thick and stained with Hematoxylin and Eosin (H&E). Deeper sections were examined wherever necessary.

Results

100 autopsy cases were included in the study. The maximum numbers of cases were in the 41-50 years group followed by 21-30 years. There were 15 cases below 20 years of age, while 7 cases were seen in 61-70 and 2 cases in 71+ age groups (Fig.1).

Corresponding change in the weight was recorded according to the age. An increase in weight was observed with advancing age. The maximum weight of the prostate measured was 80 grams and minimum of 15 grams . The mean weight was 36.05gms with a standard deviation of 12.89 and the mean age was 39.44 with a SD of 16.04 (Table 1). Cases were grouped in decades and the mean weight expressed in grams ± standard deviation (SD).The mean weight in 11-20 age group was 18.13gms with a SD of 2.61; 24.9gms in 21-30 age group with SD 0f 2.17; 36.89gms with SD of 2.99; 45.72gms with SD of 2.57; 56.62gms with SD of 3.38; 66.71gms with SD of 2.36 and 82gms with SD of 2.83. (Table2).

Grossly, only 5 cases (5%) of prostate showed nodularity measuring 1 to 5cm in diameter. The nodules were noted mainly around the periurethral region and in the lateral lobes. It was solid and partially exhibited micro- or macrocystic pattern. Eight cases showed foci of hemorrhage which was also seen around the periurethral region. Hemorrhage may be however due to internal injury during traffic accidents. In the rest 87 cases, no gross abnormality was noted. Under microscopic examination, a total of 42 cases showed normal prostatic tissue. As the age increased, lesser numbers of normal prostatic tissue were seen.

A total of 64 cases showed prominent inflammation including both acute and chronic type. Acute inflammation was seen only in 2 cases, 1 each from 31-40 and 41-50 age groups. Chronic inflammation was seen in 62cases and the age group 41-50 was most affected. The inflammation was sparse in younger age groups and denser with advancing age. Granulomatous inflammation was not found in the present study. Inflammation was absent in 36 cases.

Transitional metaplasia only was seen in a total of 21 cases while 2 cases showed both transitional and mucinous metaplasia (Fig 2). Squamous metaplasia was not observed in any of the cases.

Nodular prostatic hyperplasia (NH) was noted only after 30 years of age and was present in all cases above 50 years (Fig 3). Predominantly adenomatous hyperplasia was seen in 2 cases, 1 each from 31-40 and 51-60 age groups. Both stromal and adenomatous hyperplasia was seen in most cases (55 cases). NH in the present study was also seen in association with low grade PIN, high grade PIN, atypical adenomatous hyperplasia and atrophy associated hyperplasia. NH with LGPIN was seen in 12 cases, NH with LGPIN and atrophy associated hyperplasia was seen in 1 case and NH with LGPIN and AAH was seen in 1 case. NH with HGPIN was seen in 1 case. (Table 3)

A total of 15 cases of low grade prostatic intraepithelial neoplasia (LGPIN) were seen (Fig 4). Out of these cases, 14 cases showed associated NH, 2 cases showed atrophy associated hyperplasia and 1 case showed atypical adenomatous hyperplasia (AAH) (Fig 5). High grade PIN (HGPIN) was seen in 1 case with 84 years of age (Fig 6).

Atrophy associated hyperplasia was seen in a total of 4 cases. LGPIN with atrophy associated hyperplasia was seen in 65 years old subject. AAH (atypical adenomatous hyperplasia) was seen in 4 subjects. NH with AAH was seen in a 45years old subject while AAH was seen in 2 cases aged 35and 48 years. AAH was characterized by a relatively well circumscribed nodule of closely packed small glands with a lobular growth appearance . Focal basal cell hyperplasia was seen in 25 cases.

Corpora amylacea (CA) was absent in 11 cases in 11-20 age group. It was also absent in the cases of PIN. Cystic dilatations of the glands were seen in 14 cases and were associated predominantly with NH. Calcification was seen in 1 case in a 65 years old subject.

Figure 1

Table 1: Distribution of age and weight of all cases– Range, Mean with standard deviation

Figure 2

Table 2: Distribution of weight of all cases – Mean with standard deviation

Figure 3

Table 3: Distribution of NH with PIN and associated lesions

Figure 4

Table 4: Comparison of average weight of the human prostate with age distribution

Figure 5

Table 5: Comparison of inflammation

Figure 6

Table 6: Comparison of Benign Prostatic Hyperplasia

Figure 7

Table 7: Comparison of Atypical Adenomatous Hyperplasia (AAH)

Figure 8

Table 8: Comparison of Atrophy Associated Hyperplasia

Figure 9

Table 9: Comparison of incidence of PIN

Figure 10

Fig 1: No of cases according to age distribution

Figure 11

Fig 2. Mucinous metaplasia seen in the prostate (H&E x 100)

Figure 12

Fig 3. Pattern of distribution of NH

Figure 13

Fig 4. Low grade PIN (H&E x 100)

Figure 14

Fig 5. Atypical adenomatous hyperplasia of prostate (H&E x 40)

Figure 15

Fig 6. High grade PIN (H&E x 100)

Discussion

Nodular prostatic hyperplasia and carcinoma of the prostate are increasingly frequent with advancing age.

The minimum weight seen in a study done by Pradhan and Chandra⁷ was 1.6 grams in 1-10 age group; 1.8 grams in study done by Swyer⁸ and 2.28 grams in study done by Murty and Roy⁹ for the same age group. Present study showed the minimum weight of 25.5 grams in 21-30 age group which was higher than other studies as cases below 10 years were not present in the study. The present study showed that normal prostate gains its maximum weight in men between 21-30 years of age and the weight remains fairly constant till 50 years of age. The human prostate undergoes two kinds of growth: the first one is related to puberty, the second one to the development of NH. The weight was seen constant from 3 ^rd to 5 ^th decade in a study done by Murty and Roy.⁹ In the studies done by Murty and Roy⁹ and Tornblom et al¹⁰ the maximum average weight were 40.3 gm and 34.5 gm respectively, both seen above 71 years. The present study showed maximum weight of 60grams in 84 years old subject and it was slightly higher as only 1 case was present above 80years. The present study showed 40 grams of weight in 71-80 age group correlating well with the study done by Murty and Roy.⁹ (Table 4).

Prostatits may be divided into several categories: acute and chronic bacterial prostatitis and chronic abacterial prostatitis and granulomatous prostatitis. Chronic abacterial prostatitis is the most common form of prostatitis seen.

In present study, acute prostatitis was seen in 2 cases, the age being 35 and 50 years respectively. One case was observed in association with AAH and the other with NH. Chronic inflammatory changes (62 cases) were seen in 75% of cases in 31-60 years age group and in all cases above 61years. Only 31.4% of cases below 30 years of age showed chronic prostatitis. Mittal et al¹¹ studied 185 consecutive prostatic specimens and found 57.83% showing inflammation. The present study showed 64% of cases showing inflammation having similar findings with Mital et al.¹¹ Kohen et al¹² showed the maximum percentage of inflammation being 98.1%, followed by Rekhi at al¹³ being 78.5% and Jonathan et al¹⁴ being 77.7%. The percentages were high in these studies as they included all cases of NH. Granulomatous prostatitis was not seen in any group in the study. Mittal et al¹¹ found only 3% of granulomatous inflammation as his number of cases were higher than the present study (Table 5).

Metaplastic changes in the glandular lining epithelium were a common finding. In present study, 23 cases showed metaplastic changes, transitional metaplasia being the commonest (21%) followed by mucinous metaplasia (2%). Both the cases of mucinous metaplasia were observed together with transitional metaplasia. Taizo et al¹⁵ and Grignon et al¹⁶ found 12 cases (0.7%) and 11 cases (0.8%) of mucinous metaplasia respectively in their studies. The percentage was slightly less than the present study as their numbers of cases were high. It gives an idea that mucinous metaplasia is rare.Grignon et al¹⁶ also noted 3 cases of mucinous metaplasia in association with transitional metaplasia although number of transitional metaplasia was not mentioned in the study as it was based only on mucinous metaplasia. Present study showed both the cases of mucinous metaplasia were below 30 years of age and transitional metaplasia was almost equally distributed in all age groups. Mittal et al¹¹ found 13 cases (7.02%) transitional metaplasia and 6 cases (3.24%) of squamous metaplasia. The percentage for transitional metaplasia was less than the present study as he had included biopsy specimens in his study. Squamous metaplasia was not found in the present study.

In the present study, NH was seen in 55 cases (55%). In NH, proliferation of the glands as well as the stroma was noticed. Compact stroma was always associated with the smooth muscle hypertrophy. The relative proportion of smooth muscle was increased in comparison to the collagen fibers. In normal cases, the surrounding stroma was loose, comprising mainly of collagen fibers^. NH was noted only after 30 years of age in this study and was increasing frequently with the advancing age. It was noticed in 93.6% of cases after 40 years of age. The highest percentage of NH was seen in a study done by Mittal et al¹¹ being 92.97%, followed by Rekhi et al¹³ being 88.5% and Kapoor et al¹⁷ being 83.6%. The percentage was high in these studies as studies were based on prostatectomy done on symptomatic patients. In an autopsy study done by Konstantinos et al¹⁸ the percentage of NH was 65.5%. The present study showed similar percentage correlating with the autopsy studies. Fritz et al¹⁹ in their study mentioned that NH changes can be noted as early as 30 years of age (Table 6).

Adenosis of the prostate also referred to as atypical adenomatous hyperplasia and atypical adenosis is a benign glandular proliferation that may be confused with low grade adenocarcinoma of the prostate. It is a well circumscribed nodule of closely packed gland with a lobular growth pattern.²⁰ The significance of identification of AAH lies in the fact that marked small glandular proliferation present in this condition may be confused with carcinoma. These microglandular proliferation may even show few large glands with CA and the basement membrane is intact in AAH whereas, CA and basement membrane will be absent in carcinoma. Present study showed only 4 cases (4%) of AAH. 2 cases of AAH were seen with benign glands, 1 was seen in association with NH and 1 with LGPIN. Gaudin et al²¹ found AAH in 44 cases (100%) of the study. The percentage was very high as the diagnosis was based on constellation of histologic features and confirmed with the use of antibodies to high molecular weight cytokeratin. Kovi et al²² have observed AAH in 86.8% of the prostate with carcinoma but only in 37.9% of prostates with benign glands. Mittal et al¹¹ had noted only 4 (2.16%) cases of AAH along with NH. The present study showed similar percentage as Mittal et al¹¹ and lower percentage than other studies as the number of cases were high in other studies (table 7).

After 30 years, many prostates begin to show a variety of focal deviation from the normal morphology. Early morphologic studies concluded that focal atrophy of the prostate was a manifestation of aging and was seen as early as age 40 years. In fact, focal atrophy in the prostate is almost always the consequence of previous inflammation rather than aging.^23,24 Atrophy associated hyperplasia is seen as small glands with flattened epithelium predominantly in the periphery of the gland. Among 4 cases with atrophy associated hyperplasia, 1 case was of age 40 years and the rest was after 60 years of age. Atrophy associated hyperplasia was observed in association with low grade PIN in 1case and with NH in 3 cases. Present study correlated well with the study done by Mittal et al¹¹ where he found 3.78% cases of atrophy associated hyperplasia. Ruska et al²⁵ found 51.45% of atrophy associated hyperplasia , the percentage was high as it was a review study done for 103 prostate needle biopsy specimens with atrophy (Table 8).

The most commonly observed atypical proliferative disorder is prostatic intraepithelial neoplasia (PIN), which affects ducts and acini, and is defined as abnormal proliferation with nuclear changes similar to prostate cancer of luminal secretory cells.²⁶

Present study showed the incidence of low grade PIN in 15 cases (15%) and high grade PIN in 1 case (1%). It was seen in 5 (27.7%) out of 18 cases in the 31-40 years age group. The incidence increased up to 50% as the age increases above 50 years. Troncoso et al²⁷ showed 72% of PIN with a mean age of 63.5 and Kovi et al²⁸ showed 46% of PIN with a mean age of 54.5%. Oyasu et al ²⁹ less percentage of PIN with mean age being higher than previous studies. The present study showed less percentage of PIN as the number of cases included was of younger age group with a mean age being below 50 years. Fourteen cases of LGPIN and 1 case of HGPIN were seen in association with NH. Autopsy studies have shown that PIN is present in 27% of 30 to 40 years old man and that this incidence increases to more than 60% in men in their eighties.⁹ However Sakr et al^30,31 have found the prevalence of prostate cancer and PIN in autopsy studies to be 26%, and even in the younger age group (Table 9).

Soos G et al³² in his autopsy study found 38.8% of incidental prostatic. Both prostatic carcinoma and HGPIN was detected in the 3rd decade. In the age group 81–95, 86.6% and 60% of men had carcinoma and HGPIN, respectively. In our study, the lowest age of LGPIN was 38 years.

Basal cell hyperplasia is a benign lesion that is often misdiagnosed as adenocarcinoma. It consists of a thickness of two or more basal cells at the periphery of the prostatic acini. The cells were cuboidal to low columnar with round to oval nuclei. It was seen as solid or cystically dilated gland. A minimum thickness of two basal cells is required for the diagnosis although the criteria are arbitrary.¹⁷ BCH sometimes appears as small nests of cells surrounded by a few concentric layers of compressed stroma, often associated with chronic inflammation. Present study showed 25 cases of BCH and was observed above 30 years age group. Two cases of BCH were seen in normal prostate and the rest (23) were associated with NH. Mittal et al¹¹ found 5.4% of BCH in his study done in 185 cases. The percentage was quite low than the present study as he had included 86 prostatectomy specimens, 81 TURP specimens and 18 needle biopsies.

Corpora amylacea (CA), formed from retained and stagnating secretions within the prostatic acini, increases in number with increasing age. CA in the glands with nodular hyperplasia may act as the nucleus for stone formation as a result of improper drainage, infection of the acini, and calculi deposition.³³ Present study also showed 1 case (1%) of prostatic calculi associated with NH. It was seen as a homogenous eosinophilic material. In the present study, CA was seen occasionally below 20 years of age group with 1-3 concentric rings and the maximum number within the acini being 6. It was seen in only 3 out of 14 cases in that age group. Increasing number of CA was observed with advancing age. Above 21years, CA was noted in large numbers. One acinus contained maximum of 50 CA or eosinophilic bodies; average being 4-6 per acini. These bodies were large, faceted and centrally homogenous, surrounded by 7-10 concentrically arranged distinct regular rings. Above 60 years, CA noted in the acini had dark concentric rings and more in number. Murty and Roy⁹ also observed many acini above 15 years with CA with 3-4 concentric rings. They noticed large number of CA above 21 years age group and the number of concentric rings as well as number within the acini increased as the age increases like in the present study. Corpora amylacea was absent in a case associated with PIN in the present study. Mittal et al¹¹ found CA in 72 cases (38.91%) in their study. They also noted that none of the cases with carcinoma revealed CA.

Prostatic calculi are seen in about 7% of prostates with nodular hyperplasia.³³ It should be distinguished from those found in the prostatic urethra, which may have origin in the bladder, ureter or renal pelvis.

Cystic changes were present in 14 cases (14%) in the present study . The glands were cystically dilated and were lined by flattened epithelium. Scant to moderate amount of secretions were noted within the lumen. Cystic atrophy is another common focal lesion that typically is found in the peripheral zone and is segmental in distribution. The markedly enlarged, nearly spherical acini with flattened epithelium and the segmental distribution suggest an obstructive cause; however, obstruction is not typically demonstrable and the cause is unknown.³⁵

Focal autolytic changes were also observed during the histopathological study of the autopsy prostates. It was seen in 9 cases (9%), where the partial denudation of the lining epithelium of the ducts and acini were noted Autolysis was seen due to the significant time interval between the persons’ death and the postmortem performed and not merely due to the processing of the specimens.

Conclusion

NH is known to be the commonest pathology in advancing age as in the current study. Lesions like AAH and atrophy associated hyperplasia were infrequent and were mostly seen in association with NH. Prostatitis was encountered in 64% of cases and older age group showed more dense inflammation compared to younger age group. Basal cell hyperplasia was seen in 25% of all cases and was more in association with NH. Low grade and high grade PIN was seen in 15% and 1% of all cases respectively. All cases of PIN were above 30 years of age but interestingly 56% of all PIN (9 cases) were seen below 50 years.