A retrospective analysis of background lesions and tissue accountability for male accessory sex organs in Fischer-344 rats

Because the paired lobes (ventral, dorsal, lateral, and anterior) of the rat prostate have not been consistently sampled in many carcinogenicity and toxicity studies, comparison among different investigations has been compromised. The lack of specific site identification for prostatic lesions further lessens the value of incidences reported. We present here the lobe-specific incidences and degree of severity of background prostatic, seminal vesicular, and ampullary glandular lesions in 1768 control Fischer-344 rats from 35 recent National Toxicology Program 2-year carcinogenicity and toxicity studies conducted in 4 laboratories. The dorsal and lateral lobes were combined and considered the dorsolateral lobe where inflammation, epithelial degeneration, mucinous cysts, and edema were observed. Inflammation in the dorsolateral lobes was significantly associated with pituitary gland adenoma whose prolactin was suggested to play an important role in pathogenesis of prostatic inflammation. Epithelial degeneration, epithelial hyperplasia, inflammation, edema, and adenoma were conspicuous in the ventral lobes. Inflammation and edema occurred in the anterior lobes (coagulating glands). Inflammation, dilatation, epithelial hyperplasia, edema, and adenoma were observed in the seminal vesicles. Inflammation was also present in the ampullary glands. We suggest an optimal embedment and trimming method in rat prostate and seminal vesicle to ensure adequate, consistent sampling.     

Differential diagnosis of glandular proliferations in the prostate

 A variety of small acinar lesions of the prostate can mimic prostate cancer in punch biopsies and in transurethral resection material. The first part of this review deals with differential diagnostic problems of the central and transition zone, including atypical adenomatous hyperplasia of the prostate, atrophic processes, sclerosing adenosis, basal cell hyperplasia, and low-grade adenocarcinoma. The second part deals with differential diagnostic problems in the peripheral zone: prostatic intraepithelial neoplasia, postatrophic hyperplasia, Cowper’s glands, seminal vesicles, and ductal and intraductal carcinoma. Finally, atypical and small acinar proliferations are described. Diagnostic perspectives are discussed. Received: 23 June 1998 / Accepted: 13 August 1998     

Pathologic changes in the accessory sex glands of rats treated with a sympatholytic hypotensive agent (losulazine)

Groups of 25 male Sprague-Dawley rats were treated by gastric intubation with either vehicle control (modified methylcellulose) or a suspension of losulazine at 4, 8, 16, or 32 mg/kg/day for 1 yr. Ten rats/group were killed after 6 months of treatment. Reversibility of drug-induced changes was evaluated in 8 rats/group treated for 6 months and held without treatment for 5 months. Daily clinical signs and weekly body weight changes were monitored. Seminal vesicle/coagulating glands were weighed in rats treated for 6 months. Gross and microscopic evaluation of the accessory sex glands (ampullary glands, prostate, seminal vesicles and coagulating glands) was conducted in all rats killed at 6 months, after the recovery period, and in rats that survived through the one-yr treatment period. Ptosis, somnolence, and fecal softening were detected in all groups treated with losulazine. There was a nonreversible body weight gain retardation in groups treated with 8 to 32 mg/kg/day of losulazine for 6 months or 1 yr. Absolute and relative weights of the seminal vesicle/coagulating glands of treated rats were not significantly different from those of control rats. The ventral prostate in a few rats in all treated groups had yellow to tan granular foci. Treatment, but not dose-related sperm granulomas or glandular impaction with inspissated secretion (formation of corpora amylacia) in the ampullary glands, enhanced cellular exudation into the acini of the ventral prostate, and impaction of the seminal vesicles with altered granular to globular secretion were found in rats treated with losulazine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Expression of P-cadherin identifies prostate-specific-antigen-negative cells in epithelial tissues of male sexual accessory organs and in prostatic carcinomas. Implications for prostate cancer biology.

Cadherins constitute a family of calcium-dependent cell-cell adhesion molecules the individual members of which are essential for the sorting of cells into tissues during development. In this study, we examined the expression of E-cadherin, N-cadherin, and P-cadherin in tissues obtained from radical prostatectomies. Epithelial cells of prostatic glands, ejaculatory ducts, and seminal vesicles expressed E-cadherin but not N-cadherin. P-cadherin was expressed in epithelial cells of the seminal vesicles and ejaculatory ducts. In the prostate it was limited to the basal cells of prostatic acini, glands with basal cell hyperplasia, and atrophic glands denuded of the luminal cells. All P-cadherin-positive cells were negative for prostatic-specific antigen. Prostatic cancers were mostly P-cadherin negative, but some tumors had P-cadherin-positive areas frequently located close to ejaculatory ducts and negative for prostatic-specific antigen. The mutually exclusive expression of P-cadherin and prostatic-specific antigen suggests that these proteins are involved in differential mechanisms of cell regulation in prostate cancer. P-cadherin may become a useful marker in the diagnosis and management of patients with prostate cancer and low levels of prostatic-specific antigen.     

The spectrum of morphology in non-neoplastic prostate including cancer mimics

The spectrum of morphology in non-neoplastic prostate includes lesions of prostatic epithelial origin, the most common being atrophy, including partial atrophy, adenosis (atypical adenomatous hyperplasia), basal cell hyperplasia and crowded benign glands, as well as those of non-prostatic origin, such as seminal vesicle epithelium. These lesions often mimic lower-grade prostatic adenocarcinoma whereas others, such as granulomatous prostatitis, for example, are in the differential diagnosis of adenocarcinoma, Gleason grades 4 or 5. Diagnostic awareness of the salient histomorphological and relevant immunohistochemical features of these prostatic pseudoneoplasms is critical to avoid rendering false positive diagnoses of malignancy.     

A human prostatic bacterial isolate alters the prostatic microenvironment and accelerates prostate cancer progression

Inflammation is associated with several diseases of the prostate including benign enlargement and cancer, but a causal relationship has not been established. Our objective was to characterize the prostate inflammatory microenvironment after infection with a human prostate‐derived bacterial strain and to determine the effect of inflammation on prostate cancer progression. To this end, we mimicked typical human prostate infection with retrograde urethral instillation of CP1, a human prostatic isolate of Escherichia coli. CP1 bacteria were tropic for the accessory sex glands and induced acute inflammation in the prostate and seminal vesicles, with chronic inflammation lasting at least 1 year. Compared to controls, infection induced both acute and chronic inflammation with epithelial hyperplasia, stromal hyperplasia, and inflammatory cell infiltrates. In areas of inflammation, epithelial proliferation and hyperplasia often persist, despite decreased expression of androgen receptor (AR). Inflammatory cells in the prostates of CP1‐infected mice were characterized at 8 weeks post‐infection by flow cytometry, which showed an increase in macrophages and lymphocytes, particularly Th17 cells. Inflammation was additionally assessed in the context of carcinogenesis. Multiplex cytokine profiles of inflamed prostates showed that distinct inflammatory cytokines were expressed during prostate inflammation and cancer, with a subset of cytokines synergistically increased during concurrent inflammation and cancer. Furthermore, CP1 infection in the Hi‐Myc mouse model of prostate cancer accelerated the development of invasive prostate adenocarcinoma, with 70% more mice developing cancer by 4.5 months of age. This study provides direct evidence that prostate inflammation accelerates prostate cancer progression and gives insight into the microenvironment changes induced by inflammation that may accelerate tumour initiation or progression. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Differenzialdiagnose des Prostatakarzinoms

Prostate cancer offers a wide range of growth patterns depicted in the classical Gleason diagram. For each Gleason pattern exist a number of benign and malignant mimickers that can simulate prostatic adenocarcinoma. In the present review, the use of immunohistochemical markers is discussed with emphasis to a pattern-based approach to differential diagnosis in prostate pathology. Basal cell markers (34betaE12 and P63) are very useful to analyze histo-architectural features of small and large glandular lesions. AMACR (P504 s) is helpful not only in identifying small amount of cancer in needle biopsies but also in the diagnosis of high grade prostatic intra epithelial neoplasia (HGPIN). A number of lesions which may be confused with small acinar adenocarcinoma (Cowper's gland, nephrogenic metaplasia, mesonephric glands) and poorly differentiated prostate cancer (urothelial neoplasia, mucinous colon cancer and other metastatic lesions) lacks convincing PSA immunoreactivity. Basal cell markers and the nuclear androgen receptors are important markers to differentiate Gleason grade 5 A und 5 B patterns from prostatic involvement by transitional cell carcinoma. Finally, a selected panel of markers is useful to classify prostatic stromal lesions. In each case, immunohistochemical findings should be interpreted in context with the various patterns on routine microscopy.     

Investigations of the estrogen (ER-ICA-test) and the progesterone receptor in the prostate and prostatic carcinoma on immunohistochemical basis

Summary Estrogen (ER) and Progesterone receptors (PR) were demonstrated immunohistochemically on frozen sections from 11 prostatectomy and 7 cystoprostatectomy specimens in the nuclei of various cell types. The periglandular fibrocytes and smooth muscle cells were extensively positive, the interglandular stromal cells were only partly so. Normal basal cells stained focally positive, hyperplastic basal cells stained extensively. The glandular secretory epithelium and atrophic glands were negative. The same findings were obtained in hyperplastic nodules. Both ER and PR also occurred in the urothelium of central prostatic ducts and of the prostatic urethra. The fibrous stroma around the ejaculatory ducts and seminal vesicles was extensively positive while the epithelium was negative. The smooth musculature of the seminal vesicles was only partly positive. On large field sections, the ER as well as the PR were numerically equally distributed throughout the inner zone of the prostate and the prostate proper. 12 prostatic carcinomas (G I–G III) were ER- and PR-negative. Estrogens may contribute to nodular hyperplasia by triggering a stromal proliferation with a secondary inductive epithelial growth. Obviously they do not act directly on prostatic carcinoma but inhibit growth via the hypophyseal-testicualr axis. The biological significance of the PR in the prostate is unknown.     

Real-time PCR analysis of leptin and leptin receptor expression in the rat prostate, and effects of leptin on prostatic acid phosphatase release

We have recently demonstrated the expression of leptin and leptin receptor (Ob-R) isoforms a, b, c, e and f in the rat seminal vesicles and prostate. The aim of the present study was to provide a semiquantitative real-time PCR estimation of leptin/Ob-R isoform mRNA expression in the seminal vesicles and individual components of rat prostate, and to ascertain the in vitro effects of leptin on prostate acid phosphatase release. The highest expression of the leptin and Ob-R genes was in the seminal vesicles and lateral prostate lobe, respectively. Of the various isoforms, Ob-Rb displayed the highest and Ob-Re the lowest expression. Leptin (10(-8) and 10(-6) M) enhanced acid phosphate release from seminal vesicles, and (10(-6) M) decreased it from the coagulating lobe. Taken together, our findings support the contention that leptin may be involved in the autocrine-paracrine functional regulation of rat seminal vesicles and prostate. The physiological relevance of the marked heterogeneity of the different prostate lobes in both their leptin/Ob-R expression and functional response to leptin remains to be addressed.     

Calcifications in prostate and ejaculatory system: a study on 298 consecutive whole mount sections of prostate from radical prostatectomy or cystoprostatectomy specimens

Although calcifications in the prostate are a common manifestation, the relationship between calcifications and prostate cancer is not clearly documented as in breast cancer. In addition, anatomical distribution of calcifications by zones of the prostate and ejaculatory system has not been systematically studied. To study the frequency and patterns of calcifications within the prostate and ejaculatory system, we reviewed the whole mount sections of 298 consecutive prostatectomy or cystoprostatectomy specimens. Calcifications were evaluated in the prostate (central, peripheral and transition zones, and verumontanum), ejaculatory ducts, and seminal vesicles. We graded the degree of calcifications as mild, moderate, or severe. Calcifications in the prostate and ejaculatory system were common, and their frequency in our series is as follows: 88.6% (264/298) of prostates, 58.1% (173/298) of seminal vesicles, and 17.1% (51/298) of ejaculatory ducts. The prostatic calcifications occurred mostly in benign glands and/or stroma of all zones and the verumontanum. Calcifications were more common in the transition zone than other zones. There were 4 cases of prostatic calcifications in the areas of prostatic adenocarcinoma: 3 cases with calcifications in the tumor glands and 1 case with calcifications in tumor stroma but not in the accompanying tumor glands. In conclusion, calcifications are a very common finding in prostatectomy specimens and seem mostly to be associated with benign prostatic hyperplasia. However, calcifications can occur in direct association with prostatic adenocarcinoma, although the incidence of this association is not as high as in breast carcinoma. Also, ejaculatory system calcifications are not an infrequent finding.     

Morphological changes in mouse accessory sex glands following neonatal estrogen treatment.

A single injection of beta-estradiol 17-cypionate into the mice within 5 hr after birth induced inflammation in all prostate lobes and the seminal vesicles. Neutrophils emigrated into the lumen through the basal lamina and epithelium of the seminal vesicle and the anterior prostate. Local infiltration of lymphocytes was observed in the stroma and epithelium of ventral prostates. Lymphocytes penetrated through smooth muscle cells into epithelium. This could support the hypothesis that smooth muscle cells are the target of the estrogen action of prostates in estrogenized animals.     

Localization of estrogen and androgen receptors in male reproductive tissues of mice and rats

Using immunohistochemical methods, we studied the cell-type- and species-specific expressions of estrogen receptor (ER) isoforms (ER alpha and ER beta) and androgen receptors (ARs) in the male reproductive tract and accessory sex glands of mature mice and rats. ER alpha and ER beta showed cell-type- and species-specific distributions, respectively. In contrast, AR was localized in the epithelial and stroma cells of all tissues examined in this study, in both species. In mice, the epithelial cells of the ductuli efferentes showed a strong ER alpha-immunoreaction, and those of the caput epididymis, coagulating glands, and prostate also exhibited a positive reaction. Stroma cells, except in the ductuli efferentes, showed a positive ER alpha-immunostaining. In rats, ER alpha was detected in very few cell types: the epithelial cells of the ductuli efferentes showed a strong reaction, and the stroma cells of the ampullary and urethral glands exhibited a weak reaction. ER beta was localized in the epithelial cells of the prostate in mice, while the reaction was faint or negative in both the epithelial and stroma cells of other tissues. In rats, the ER beta-immunoreaction was strongest in the epithelial cells of the ventral prostate. The epithelial cells of the corpus and cauda epididymis, ductus deferens, and urethral glands, and the stroma cells of the urethral glands were also positively ER beta-immunostained. Almost the same AR distribution pattern was observed in both species. In particular, strong AR-immunostaining was present in the epithelial cells of the caput and corpus epididymis, seminal vesicle, and ventral prostate. These results indicate that species and tissues differences should be taken into careful consideration in assessing the physiological and pharmacological effects of sex steroids (particularly estrogens) on the reproductive tissues of male rodents.     

Mature cystic teratoma of the ovary with male accessory sexual glands including seminal vesicles,prostatic tissue,and bulbo-urethral glands: a case report

We present an extremely rare case of a benign cystic ovarian teratoma with structures of male accessory sexual glands. The patient was a 30-year-old woman. A unilocular cystic tumor, measuring 5cm in the largest diameter, was found in her right ovary and was removed. The teratoma contained epidermis, skin appendages, respiratory and intestinal epithelia, cartilage, muscle, and nervous and connective tissue. In addition to these histologically mature tissues, there were nodules with prostatic acini, prostate duct-like structures strongly positive for prostate-specific antigen and acid prostatic phosphatase, structures resembling Cowper’s glands, and seminal vesicles surrounded by fibromuscular stroma. To our knowledge, this is the first case in the English literature describing seminal vesicles associated with prostatic tissue and bulbo-urethral glands in a mature ovarian teratoma.     

Cytokeratin immunohistochemistry as a diagnostic tool for distinguishing malignant from benign epithelial lesions of the prostate.

The basal cell layer (BCL) is believed to be absent in malignant but present in nonmalignant epithelial lesions of the prostate. Using the avidin-biotin-peroxidase complex (ABC) immunoperoxidase method, we examined the value of the monoclonal antibody cocktail MA-903, which stains selectively the prostatic BCL layer, in the distinction between benign and malignant epithelial lesions of the prostate. We immunostained histologic sections of 63 prostates, containing 235 morphologic appearances: normal prostate glands, 43; benign prostate hyperplasia (BPH), 59; basal cell hyperplasia (BCH), 24; adenosis, seven; prostatic intraductal neoplasia (PIN 1), 21; PIN 2, 25; PIN 3, 16; and cancer, 40. Some degree (continuous, continuous with focal disruption, and disrupted patterns) of basal cell staining was demonstrable in all normal and BPH, BCH, and PIN 1 lesions, but was absent in 39 of 40 cancers. However, not every gland in benign lesions stained positively. Further, two of 25 PIN 2 and six of 16 PIN 3 lesions failed to reveal BCL. Our results suggest that the presence or absence of BCL, predicated on cytokeratin MA-903 immunoreactivity, may be a useful indicator in the distinction between benign and malignant epithelial lesions of the prostate.     

Localization of cathepsin B in normal and hyperplastic human prostate by immunoperoxidase and protein A-gold techniques

Cathepsin B, a lysosomal cysteine protease, was localized in normal prostate and benign prostatic hyperplasia (BPH) using immunoperoxidase and protein A-gold techniques. Our objective was to determine whether cathepsin B was involved in the prostatic epithelium affected by nodular hyperplasia. All samples were collected immediately after prostatectomy. Immunohistochemical studies showed that the enzyme was expressed in the supranuclear cytoplasm of columnar cells and in numerous basal cells of normal and BPH acini. The strongest localization of cathepsin B occurred in acinar basal cells; hence, it is possible that cathepsin B could be useful as a marker for such cellular elements. Stromal macrophages showed reaction products, but lymphocytes and neutrophils did not. In both normal and hyperplastic glands, the enzyme was localized by gold particles in lysosomes, secretory granules, and vacuoles of columnar epithelial acinar cells. Immunoelectron microscopic study also showed the presence of cathepsin B in the heterochromatin (condensed chromatin) and nuclear membranes of columnar and basal cells, but not in euchromatin or nucleoli. At present, the function of cathepsin B in the nuclei of basal and columnar cells remains unknown. However, the cathepsin B in the cytoplasmic compartment might be associated with the lysosomal function of the cells. The role of cathepsin B as a marker for basal cell participation in the development of prostatic lesions should be studied further.     

Utility of NKX3.1 immunohistochemistry in the differential diagnosis of seminal vesicles versus prostatic tissue in needle biopsy

NKX3.1 is considered a reliable immunohistochemical marker of prostatic origin with high specificity and sensitivity. However, NKX3.1 positivity has been described in other neoplastic and non-neoplastic tissues, such as mesenchymal chondrosarcoma, sex-cord stromal tumors, rete testis adenocarcinoma, lobular and ductal carcinoma of the breast, salivary glands, peribronchial submucosal glands, and Sertoli cells. We analyzed expression of two antibodies (mono and polyclonal) of NKX3.1 in a total of 63 non-neoplastic seminal vesicles. We used 52 resection materials (12 seminal vesicles without prostatic adenocarcinoma, 26 seminal vesicles with prostatic adenocarcinoma infiltration, and 14 cases of seminal vesicles infiltrated by urothelial carcinoma) and 11 prostatic core needle biopsies with incidentally sampled fragment of seminal vesicles. In all cases, tissues from seminal vesicles were completely negative for NKX3.1, despite using polyclonal and monoclonal NKX3.1 antibodies, and regardless of the detection system utilized (diaminobenzidine (DAB) versus alkaline phosphatase (AF)). However, prostatic adenocarcinoma was negative in several cases (n = 6), when AF detection system was used. Reaction with DAB was strong and robust in all cases. Based on our data, we can recommend NKX3.1 as a negative immunohistochemical marker of seminal vesicles.     

Premalignant lesions of the prostate

Two putative premalignant lesions of the prostate have been identified. Prostatic intraepithelial neoplasia (PIN) is characterized by proliferation and anaplasia of cells lining ducts and acini. Atypical adenomatous hyperplasia (AAH) consists of a localized proliferation of small round glands without cytologic atypia. PIN and AAH may be confused with well-differentiated carcinoma as well as florid hyperplasia, basal cell hyperplasia, transitional metaplasia, seminal vesicular epithelium, and atypia due to inflammation, infarction, and radiation. These premalignant lesions appear to have a high predictive value for carcinoma, and their presence on prostatic biopsy warrants further search for concurrent invasive adenocarcinoma. The use of strict morphologic criteria and uniform nomenclature will ensure standardization in the diagnosis of premalignant lesions of the prostate.     

Spontaneous mutation in mice provides new insight into the genetic mechanisms that pattern the seminal vesicles and prostate gland.

The seminal vesicles and prostate gland are anatomically adjacent male sex-accessory glands. Although they arise from different embryonic precursor structures and express distinct sets of secretory proteins, these organs share common features in their developmental biology. A key shared developmental feature is the elaboration of complex secretory epithelia with tremendous surface area from simple precursor structures with juxtaposed epithelial and mesenchymal cells. In this study, new insight into the nature of the biological processes that underlie glandular morphogenesis is achieved by analyzing the phenotypes present in mice that harbor a spontaneous mutation, seminal vesicle shape (svs), previously identified for causing altered seminal vesicle morphology in adults. An examination of seminal vesicle development in svs mice provides the first evidence that the concurrent processes of epithelial branching and epithelial infolding are distinct processes under separate genetic control. It also provides the first direct evidence that the thickness and topology of the smooth muscle layer in the seminal vesicles are determined by interaction with the glandular epithelium during the branching process. In addition, the seminal vesicle phenotype in svs mice is shown to phenocopy the morphologic form present in certain other mammals such as the guinea pig, raising the possibility that the svs mutation is the sort of variant that arises during evolution. By also including an investigation of the prostate gland, this study also identifies previously unrecognized phenotypes in svs prostates, including increased gland size and dramatically reduced levels of branching morphogenesis. Finally, this study advances the goal of identifying the svs gene by mapping the svs mutation relative to known molecular markers and testing Fgfr2 as a candidate gene. The finding that the svs mutation maps to a genomic region syntenic to a region frequently deleted in human prostate tumors, together with the prostatic phenotype present in svs mice, further raises the interesting possibility that the svs mutation will identify a candidate prostate tumor suppressor gene.     

Immunohistochemistry of a prostate membrane specific protein during development and maturation of the human prostate

An antiserum against secretory vesicles from human seminal fluid (prostasomes) was used to study the localisation and distribution of the respective antigen(s) during prenatal development and pubertal maturation of the human prostate. The crude antiserum stained both secretory and membrane proteins in the adult prostate and other glands, such as pancreas and parotid gland. An immunoaffinity purified fraction from the antiserum selectively reacted with the apical plasma membrane of prostatic epithelium adluminal cells, recognizing a 100 kDa antigen (PMS). Even in the earliest stages of embryonic prostate specimens studied, the adluminal plasma membrane of the epithelial cells from developing glandular anlagen reacted strongly. The occurrence of PMS immunoreactivity in prostatic anlagen was directly correlated with lumen formation. As the antigen is an androgen-independently synthesised membrane protein of the prostate, it may possibly be used as a marker of cell polarity in the normal and pathologically altered prostate.