Basal cell hyperplasia, adenoid basal cell tumor, and adenoid cystic carcinoma of the prostate gland: An immunohistochemical study

Basal cell hyperplasia (BCH) is an uncommon proliferative lesion of the prostate gland. We studied ten cases of BCH, one case of an unusual adenoid basal cell tumor (ABT), and one case of a prostatic adenoid cystic carcinoma (ACC), using a panel of antibodies to define the histogenesis of these lesions. Monoclonal antibodies (MoAb) directed against a cytokeratin, which selectively stains basal cells (34 beta E12), and against muscle-specific actin, which stains myoepithelial cells (HHF35), were used. In addition, antibodies directed against prostatic acid phosphatase (PAP), prostate-specific antigen (PSA), S-100 protein, and vimentin were used. In the normal prostate, epithelial cells reacted positively with 34 beta E12, PAP, and PSA, and negatively with the actin, S-100 protein, and vimentin antibodies. In BCH, positive staining was seen for 34 beta E12, PSA, and PAP, with no reactivity for actin, S-100 protein, and vimentin. In ABT and ACC, positive reactivity was demonstrated for all antibodies except actin and vimentin. These findings indicate that the basaloid cells of BCH, ABT, and ACC are derived from basal cells of the normal prostate gland and suggest a continuum among the three lesions. The presence of S-100 protein in ABT and ACC may be related to the lack of this antigen's specificity for myoepithelial cells. The absence of reactivity with the HHF35 MoAb supports our belief that the S-100 positivity does not necessarily indicate myoepithelial cell differentiation.     

Cytokeratins, smooth muscle actin and vimentin in human normal salivary gland and pleomorphic adenomas. Immunohistochemical studies with particular reference to myoepithelial and basal cells.

The distribution of immunostaining in normal major salivary gland and in 12 pleomorphic adenomas was studied using monospecific monoclonal antibodies to a number of cytokeratins, including cytokeratin 14, to smooth muscle actin and vimentin. A number of these antibodies enabled a distinction to be made between structural components of the normal gland, and to relate this to the different structures of pleomorphic adenomas. In the normal gland, the luminal duct cells expressed cytokeratins 7, 8, 18 and 19. Three antibodies were of particular value for the characterization of normal myoepithelial and basal cells; while the antibody to smooth muscle actin and the cytokeratin antibody Ks8.12 mutually exclusively stained the myoepithelial (basket) cells and the basal duct (light) cells, respectively, the recently established monospecific antibodies to cytokeratin 14 showed specific immunostaining with both cell types. These three antibodies left luminal cells virtually unstained. Ck 13 was found occasionally in single luminal excretory duct cells. Antibodies to cytokeratins 1/2, 10 and 10/11 did not show any staining in the normal gland. In the pleomorphic adenomas, the staining pattern of the two-layered tubular formation resembled that of the normal gland ducts: tumour luminal cells showed the characteristic, although more irregular, expression of cytokeratins 7, 8, 18 and 19; the outer cells resembled normal ductal basal cells with their anti-cytokeratin 14/Ks8.12-epitope staining and in that they virtually lacked staining for smooth muscle actin. Trabecular formations and cells in myxoid areas were reactive with Ks8.12 and for cytokeratin 14, occasionally also for cytokeratins 7, 18 and 19. Epidermoid cell islets expressed mainly cytokeratin 14 and inconsistently the squamous epithelial cytokeratin 13 and the epidermal cytokeratin 10/11. Vimentin was found in cells of myxoid areas. The results support the postulate that some of the normal duct basal cells act as reserve cells and can give rise to tumour formation with a primitive myxoid or trabecular pattern and a more differentiated tubular or epidermoid configuration.     

Basal clear cells of the normal human breast

Summary The ductal system of the human breast consists of two major cell types: epithelial and myoepithelial. In some reports a third cell type, given various names is mentioned. In this study it is called a basal clear cell. The role of this cell, unlike that of the epithelial and myoepithelial cells, remains unclear, although it has been suggested that it may have a stem cell function. We illustrate here that there is an ultrastructural transition between the basal clear and myoepithelial cell; suggesting that it acts as a precursor of the myoepithelial cell, and may not be a stem cell for both epithelial and myoepithelial cells.     

Myoepithelial differentiation markers in salivary gland neoplasia]

Salivary gland tumors frequently present myoepithelial cell differentiation that is not always easily identified on routinely stained sections. Recently novel markers of myoepithelium have been studied, such as calponin (CALP), caldesmon (CALD), and smooth muscle myosin heavy chain. These markers, together with smooth muscle actin may be useful tools for identifying myoepithelial cells. We immunohistochemically studied a series of 23 benign and malignant salivary gland tumors using antibodies to these four markers. The tumors were classified as follows: pleomorphic adenoma (n = 8), basal cell adenoma (n = 3), myoepithelioma with plasmacytoid cells (n = 2), epithelial-myoepithelial cell carcinoma (n = 6) and adenoid cystic carcinoma (n = 4). All tumors were positive for at least one of the four markers. CALP and smooth muscle actin were the markers more frequently expressed. Positivity was mostly located in the myoepithelial cells that constitute the external layer of the glandular or tubular neoplastic structures. In poorly differentiated epithelial myoepithelial carcinomas, composed of solid sheets of neoplastic cells and sometimes of clear cells, immunohistochemical staining for myoepithelial markers evidenced rudimentary glandular structures. CALP and smooth muscle actin were positive in the two cases of myoepithelioma with plasmacytoid cells. In conclusion, the combined staining with four markers helps to disclose myoepithelial cell differentiation and can be a useful tool for the correct histopathological diagnosis of salivary gland tumors. Among the four markers studied, CALP and smooth muscle actin were the most useful to identify myoepithelial cell differentiation.     

Differential distribution of a carbohydrate epitope (Y) on human salivary gland cell membranes.

Monoclonal antibody 303 (mAb 303) reacts with the high molecular weight agglutinin present in human saliva. Its reactivity is periodate sensitive, and it has been shown to recognize the Y epitope. Immunogold labeling of thin sections of human parotid and submandibular glands with mAb 303 showed reactivity in secretory granules of serous acinar, intercalated and striated duct cells (Takano et al., 1988). We now report that the apical and basolateral membranes of salivary acinar and duct cells are labeled by mAb 303, but not myoepithelial cells, endothelial cells and other mesenchymal cells. Gold particles were confined to acinar and duct cell membranes even when myoepithelial cells were directly adjacent, suggesting that the epitope resides on a membrane glycoprotein and that the label does not represent secreted agglutinin bound to the cell surface. Although myoepithelial cells are thought to differentiate from epithelial stem cells, the present results indicate that substantial compositional differences exist between the membranes of myoepithelial cells and other salivary parenchymal cells. Earlier studies also showed that mAb 303 labels normal pancreatic acinar cells and certain salivary (pleomorphic adenoma) and mammary (lactating adenoma) tumors (Bogert et al., 1988). This antibody thus may be a useful reagent for characterizing the origin of exocrine gland-derived cell cultures and neoplastic cells. Further, localization studies may provide insight into the role of the Lewis blood group-related epitope in secretory cells.     

Hybrid sclerosing adenosis and basal cell hyperplasia of the prostate

Hybrid sclerosing adenosis and basal cell hyperplasia of the prostate is a rare lesion. Here we report the seventh case of such lesions. Histological examination of the transurethral resection of the prostate of a 83-year-old Japanese man showed a small lesion consisted of sclerosing adenosis and basal cell hyperplasia, in addition to the diffuse glandular and fibromuscular hyperplasia. Immunohistochemically, many basal cells in sclerosing adenosis and basal cell hyperplasia areas showed a positive reaction for p63, cytokeratin 5, and D2-40. Additionally, many basal cells in the sclerosing adenosis area and some basal cells in the basal cell hyperplasia area were positive for S-100 protein and alpha-smooth muscle actin, which are myoepithelial cell markers. Finally, we suggest that hybrid sclerosing adenosis and basal cell hyperplasia may be actually a special form of hyperplastic lesion of all components of prostatic tissue, reflecting the unbalanced distribution of glandular, stromal (sclerosing adenosis), and basal cell hyperplasia with the differentiation toward myoepithelial cells predominantly occurring in a sclerosing adenosis area. Additionally, this case showed that D2-40 is a useful marker of basal cells.     

Epithelial myoepithelial tumour of the tracheal gland.

A case of epithelial myoepithelial tumour originating from the tracheal gland in a 57 year old woman is described. The tumour was removed by segmental tracheal resection and end-to-end anastomosis. Histologically, the tumour comprised clear cells and presented a monophasic pattern. Immunohistochemical analysis showed that the tumour cells were positive for both S-100 protein and smooth muscle actin. suggesting that this tumour resembles a subtype of epithelial-myoepithelial carcinoma described in the 1990 WHO international classification of salivary glands. Although some reports describe a clear cell dominant epithelial myoepithelial carcinoma, in this case local invasiveness or regional lymphnode metastasis was not proved through investigation. It is therefore concluded that this was an epithelial myoepithelial tumour rather than a carcinoma.     

Single-cell RNA sequencing of human prostate basal epithelial cells reveals zone-specific cellular populations and gene expression signatures

Despite evidence of genetic signatures in normal tissue correlating with disease risk, prospectively identifying genetic drivers and cell types that underlie subsequent pathologies has historically been challenging. The human prostate is an ideal model to investigate this phenomenon because it is anatomically segregated into three glandular zones (central, peripheral, and transition) that develop differential pathologies: prostate cancer in the peripheral zone (PZ) and benign prostatic hyperplasia (BPH) in the transition zone (TZ), with the central zone (CZ) rarely developing disease. More specifically, prostatic basal cells have been implicated in differentiation and proliferation during prostate development and regeneration; however, the contribution of zonal variation and the critical role of basal cells in prostatic disease etiology are not well understood. Using single-cell RNA sequencing of primary prostate epithelial cultures, we elucidated organ-specific, zone-specific, and cluster-specific gene expression differences in basal cells isolated from human prostate and seminal vesicle (SV). Aggregated analysis identified ten distinct basal clusters by Uniform Manifold Approximation and Projection. Organ specificity compared gene expression in SV with the prostate. As expected, SV cells were distinct from prostate cells by clustering, gene expression, and pathway analysis. For prostate zone specificity, we identified two CZ-specific clusters, while the TZ and PZ populations clustered together. Despite these similarities, differential gene expression was identified between PZ and TZ samples that correlated with gene expression profiles in prostate cancer and BPH, respectively. Zone-specific profiles and cell type-specific markers were validated using immunostaining and bioinformatic analyses of publicly available RNA-seq datasets. Understanding the baseline differences at the organ, zonal, and cellular level provides important insight into the potential drivers of prostatic disease and guides the investigation of novel preventive or curative treatments. Importantly, this study identifies multiple prostate basal cell populations and cell type-specific gene signatures within prostate basal epithelial cells that have potential critical roles in driving prostatic diseases. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.     

Characterization of cytoskeletal proteins in basal cells of human parotid salivary gland ducts

Summary From previous immunofluorescent, immunohistochemical and ultrastructural studies, myoepithelial cells have been reported to be absent from the striated and excretory ducts of human salivary gland. Yet recently, certain anti-cytokeratin monoclonal antibodies which specifically label the myoepithelium of salivary gland acini and intercalated ducts have also been found to stain basally situated cells in both striated and excretory ducts. In this study, we have used eight samples of normal human parotid gland (methacarn-fixed and frozen sections) to establish if basal cells of striated and excretory ducts have the cytoskeletal protein complement (actin and cytokeratins) of myoepithelial cells. Using a muscle-specific actin, HHF35, not only is the myoepithelium of acini and intercalated ducts stained in all cases, but stellate and spindle shaped cells are also detected all along the inter- and intralobular striated ducts in four of the eight examples. With double-labeled frozen sections and fluorescent microscopy, the actin-specific probe, phalloidin, and the myoepithelial-selective anti-cytokeratin 14 antibody, 312C8-1, confirm that the striated duct does have a population of basal cells with the cytoskeletal protein make-up of myoepithelium. The monoclonal antibody 8.12 (specific for cytokeratin 13 and 16) also stains some basal cells of striated and excretory ducts, as well as luminal cells of ducts at all levels, but does not label the myoepithelium of acini and intercalated ducts. Both the anti-cytokeratin antibodies and the actin-detecting mechanisms reveal that the basal cell population of striated and excretory ducts is more heterogeneous, and likely functionally more complex, than has been realized previously. Such findings are not in agreement with certain aspects of current theories of the histogenesis of salivary gland tumours.The authors appreciate the funding provided by the Moe Levin Family Foundation, Montreal, Canada     

Actin containing cells in normal human salivary glands

Summary A study of actin distribution in human salivary glands was performed, using smooth muscle antibodies from a patient with active chronic hepatitis.Immunoperoxidase labelling methods were found to give a good staining intensity for actin containing cells. The peroxidase antiperoxidase (PAP) method gave a stronger reaction than the double layer method, but the latter was sensitive enough for our purpose and was less time consuming. Sections from formalin fixed and paraffin embedded specimens were negative for actin staining while frozen sections showed good staining results. Sections from specimens which were washed for 12 h at 4 ° C showed less background staining.Strong staining was found in myoepithelial cells lying around the acini, intercalated ducts and parts of the striated ducts. The number of myoepithelial cells around acini increased in the following order: the parotid gland, the submandibular gland, the sublingual gland and the small glands of the lip. This distribution indicates the importance of myoepithelial cells in the process of physical expression of saliva. Cytoplasmic staining in the basal epithelial cells of the striated ducts illustrates that these cells may be involved in some sort of secretion. This staining might also suggest a histogenetic origin for myoepithelial cells.     

Myoepithelial carcinoma (malignant myoepithelioma) of the parotid gland arising in a pleomorphic adenoma.

A myoepithelial carcinoma, a rare malignant salivary gland neoplasm, arose in a pleomorphic adenoma of the parotid gland. The initial tumour was a pleomorphic adenoma with epithelial and myoepithelial elements. Subsequently the tumour recurred twice and was characterised by invasion of the mandible. Histological examination of the second recurrence showed a malignant spindle cell neoplasm with an infiltrative growth pattern and a high mitotic rate. There was involvement of local lymph nodes. The immunophenotype was characteristic of myoepithelial differentiation: tumour cells stained positively with anticytokeratin antibodies, S-100 protein, alpha smooth muscle actin, and vimentin. Electron microscopy confirmed myoepithelial differentiation, with small foci of keratinocytic phenotype. Large numbers of tumour cell nuclei were reactive with the anti-p53 antibody, DO-7, in contrast to the two previous resections. Thus malignant transformation of a pleomorphic adenoma may involve myoepithelial as well as epithelial elements. Accumulation of p53 protein, perhaps through mutational events, may have played a role in this malignant transformation.     

The cell with a thousand faces: detection of myoepithelial cells and their contributions in the cytological diagnosis of salivary gland tumors

Myoepithelial cells are an important component of salivary gland tumors and are partly responsible from the diverse histology of them. In this study, we focus on the myoepithelial cell differentiation by using cytological morphology in a various types of salivary gland tumors especially with regard to their contribution to the diagnosis. The relation of myoepithelial cells with stromal matrix and the associated epithelial cells were evaluated. Cytologic slides of one hundred and forty one benign and twenty malignant salivary gland tumors were examined for identification of morphologically different myoepithelial cells such as; spindle-stellate, polygonal-epitheloid, plasmacytoid, basal and clear types. The best examples of myoepithelial cells were detected in pleomorphic adenomas, in some monomorphic adenomas and in the adenoid cystic carcinoma cases. Most of the pleomorphic adenomas were composed more than one type of myoepithelial cells and epitheloid-spindle cell combination was frequent. Basal and clear cell types of myoepithelial cells closely resembled the epithelial cells and their identification was relatively difficult. Identification of myoepithelial cell types was easier when they were associated with stromal matrix material and stood as a secondary layer around tubule-forming epithelial cells. Myoepithelial cell components of various salivary gland tumors may be quite different and identification of myoepithelial cell types may pose difficulties. A confident cytologic identification of myoepithelial cells may be critical part of diagnosing salivary gland tumors.     

Immunohistochemical characterization of basal cell adenomas of the salivary gland

Seven cases of basal cell adenomas of the salivary gland were analyzed by immunohistochemical methods with a broad panel of routinely used antibodies. Histologically the epithelial elements were classified as tubuloglandular, trabecular and solid patterns. The authors' results indicated the following: 1) The duct lining cells of tubuloglandular and trabecular patterns have distinct epithelial features with cytokeratins (KL 1, PKK 1, *PKK 2 and PKK 3), alpha-one-antichymotrypsin (alpha 1-ACT), carcinoembryonic antigen (CEA) and S-100 alpha subunit positivity. 2) The basaloid cells in the trabecular and solid patterns expressed two immunophenotypes: one had actin, neuron-specific enolase (NSE), S-100 protein and S-100 beta subunit patterns typical of myoepithelial cells in normal glands. The other basaloid cells had vimentin and S-100 protein patterns. The former cell type could be found in 4 of 7 cases and the latter was found in 7 cases. This represents a minor participation of the myoepithelial cells in the basal cell adenoma. 3) The basement membrane and stromal connective tissue around the neoplastic cells were positive for alpha-one-antitrypsin (alpha 1-AT). This antibody is a good marker in identifying the basement membrane-like material.     

Detection of the apoptosis-suppressing oncoprotein bc1-2 in hormone-refractory human prostate cancers.

The oncoprotein encoded by bc1-2 is unique because of its intracellular location (a mitochondrial membrane protein) and apparent mode of action (suppression of apoptosis). To date, this oncogene has been associated only with the development of certain forms of human B-cell lymphoma. In this report, we describe our experience with a monoclonal antibody made against a synthetic peptide for bc1-2 that can recognize the bc1-2 protein and identify cells in human prostate glands expressing this proto-oncogene with in situ immunohistochemical procedures. These procedures were utilized to survey a series of 62 human tissues to evaluate whether bc1-2 might have a role in the developing prostate gland or in prostate oncogenesis. While all primordial epithelial cells in a fetal prostate gland immunostain for bc1-2, normal and hypertrophic prostate glands of the adult show bc1-2 expression restricted to the basal cells. All epithelial cells in areas of prostatic intraepithelial neoplasia were stained by this antibody, as were most (62%) localized invasive prostatic carcinomas. In contrast, all primary prostatic carcinomas and metastases obtained from metastatic prostate cancer patients after hormone treatment (hormone-refractory tumors) stained positive for bc1-2. This study demonstrates that the oncoprotein encoded by bc1-2 can be detected at sequential stages in the natural history of human prostate cancer. Since the bc1-2 oncoprotein is known to suppress the cellular response to apoptotic stimuli, it will be important to determine whether bc1-2 expression is a factor in the development of prostate cancers and in the survival of hormone-refractory prostate cancer cells.     

Myoepithelial cells in salivary gland tumors. An immunohistochemical study

Normal salivary glands and 55 salivary gland tumors were examined by immunostaining (immunoperoxidase [IMP] and immunofluorescence [IMF]) to identify myoepithelial cells (MCs) and speculate on their role in the histogenesis of the tumors. The classic (C) MCs of normal salivary glands stained by IMP with antibodies to cytokeratin and S100 protein and stained by IMF with the same antibodies and with antibodies to vimentin and actin. Modified (M) MCs of pleomorphic adenomas stained positively by IMP and IMF with all of the preceding antibodies. In many mucoepidermoid carcinomas, adenoid cystic carcinomas, and basal cell adenomas, variable numbers of CMCs and MMCs stained positively by IMP with anti-cytokeratin and anti-S100 protein antibodies. No MCs were detected in adenolymphomas or acinic cell carcinomas. We believe that MCs play a major role in the histogenesis of pleomorphic adenomas and may also be important in many mucoepidermoid carcinomas, adenoid cystic carcinomas, and basal cell adenomas.     

An immunohistochemical study of the breast using antibodies to basal and luminal keratins,alpha-smooth muscle actin,vimentin, collagen IV and laminin

Summary The distribution of simple epithelial (K8/18/ 19) and basal (myoepithelial) (K5/14) keratins, -smooth-muscle actin, vimentin, collagen IV and laminin in normal mammary glands and in benign proliferative lesions was studied using monoclonal antibodies (mAbs). These antibodies (Abs) identified myoepithelial cells and luminal cells specifically. In lesions with adenosis and papillomas, the two-layered formation resembled that of normal glands with a purely myoepithelial-epithelial differentiation. In scleradenotic lesions, the main cell was of myoepithelial immunophenotype with intermixed trabecular-tubular proliferations of simple-type epithelium. The sclerosis seems to be the result of an irregular basal lamina synthesis by the myoepithelial cells. In contrast to these lesions, epitheliosis represents a purely intraluminal cell proliferation of clearly simple epithelial immunophenotype and of cells with a basal keratin phenotype, lacking myoepithelial differentiation antigen actin. The basal keratin type epithelium may represent post-stem or intermediate cells developing into luminal epithelium. Epitheliosis appears to be a purely epithelial hyperplasia with striking similarity to the regeneration of normal breast epithelium. The different proliferative patterns may give an explanation for differences in potential cancer risks of patients with these lesions.Dedicated to Prof. Dr. G. Seifert on the occasion of his 70th birthday     

CD109, a new marker for myoepithelial cells of mammary, salivary, and lacrimal glands and prostate basal cells

The CD109 gene encodes a glycosylphosphatidylinositol (GPI)-anchored cell surface protein. Herein it is shown that CD109 is highly expressed in myoepithelial cells of mammary, salivary, and lacrimal glands; and in prostate basal cells. The anti-CD109 antibody generated by the authors was available for formalin-fixed paraffin section, and it strongly stained myoepithelial cells and basal cells but not ductal, acinar, and secretory cells in these glands. CD109 expression was negative in examined breast ductal carcinomas and prostate adenocarcinomas. These findings indicate that CD109 is a useful marker for the diagnosis of invasive breast and prostate carcinomas.     

TRAF-4 expression in epithelial progenitor cells. Analysis in normal adult, fetal, and tumor tissues.

TRAF-4 was discovered because of its expression in breast cancers and is a member of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) family of putative signal-transducing proteins. In vitro binding assays demonstrated that TRAF-4 interacts with the cytosolic domain of the lymphotoxin-beta receptor (LT beta R) and weakly with the p75 nerve growth factor receptor (NGFR) but not with TNFR1, TNFR2, Fas, or CD40. Immunofluorescence analysis of TRAF-4 in transfected cells demonstrated localization to cytosol but not nucleus. Immunohistochemical assays of normal human adult tissues revealed prominent cytosolic immunostaining in thymic epithelial cells and lymph node dendritic cells but not in lymphocytes or thymocytes, paralleling the reported patterns of LT beta R expression. The basal cell layer of most epithelia in the body was very strongly TRAF-4 immunopositive, including epidermis, nasopharynx, respiratory tract, salivary gland, and esophagus. Similar findings were obtained in 12- to 18-week human fetal tissue, indicating a highly restricted pattern of expression even during development in the mammary gland, epithelial cells of the terminal ducts were strongly TRAF-4 immunopositive whereas myoepithelial cells and most of the mammary epithelial cells lining the extralobular ducts were TRAF-4 immunonegative. Of 84 primary breast cancers evaluated, only 7 expressed TRAF-4. Ductal carcinoma in situ (DCIS) lesions were uniformly TRAF-4 immunonegative (n = 21). In the prostate, the basal cells were strongly immunostained for TRAF-4, whereas the secretory epithelial cells were TRAF-4 negative. Basal cells in prostate hypertrophy (n = 6) and prostatic intraepithelial neoplasia (PIN; n = 6) were strongly TRAF-4 positive, but none of the 32 primary and 16 metastatic prostate cancer specimens examined contained TRAF-4-positive malignant cells. Although also expressed in some types of mesenchymal cells, these findings suggest that TRAF-4 is a marker of normal epithelial stem cells, the expression of which often ceases on differentiation and malignant transformation.     

Prostate Stem Cell Compartments : Expression of the Cell Cycle Inhibitor p27Kip1 in Normal, Hyperplastic, and Neoplastic Cells

The stem cells of rapidly renewing tissues give rise to transiently proliferating cells, which in turn give rise to postmitotic terminally differentiated cells. Although the existence of a transiently proliferating compartment has been proposed for the prostate, little molecular anatomical evidence for its presence has been obtained to date. We used down-regulation of the cyclin-dependent kinase inhibitor p27^Kip1 to identify cells capable of entering the proliferative phase of the cell cycle and, therefore, competent to fulfill the role of the transiently proliferating compartment. We examined the expression of p27^Kip1 in relation to its role in the development of prostatic carcinoma. Formalin-fixed paraffin-embedded specimens from matched samples of normal-appearing prostate tissue, benign prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia, primary adenocarcinomas, and pelvic lymph node metastases were evaluated by comparative immunohistochemistry against p27^Kip1. In normal-appearing prostate epithelium, moderate to strong nuclear staining of p27^Kip1 was present in greater than 85% of the terminally differentiated secretory cells. The normal basal cell compartment, believed to contain prostatic stem cells, showed distinctive p27^Kip1 expression; acini in epithelial benign prostatic hyperplasia tissue contained more p27^Kip1-negative basal cells than acini from non-benign prostatic hyperplasia tissue. A third layer of cells was identified that was sandwiched between the basal cells and the luminal cells, and this layer was consistently p27^Kip1 negative. This intermediate layer was accentuated in the periurethral region, as well as in prostate tissue that had been subjected to prior combined androgen blockade. We hypothesize that, on appropriate additional mitogenic stimulation, cells in this layer, and other p27^Kip1-negative basal cells, are competent for rapid entry into the cell cycle. Consistent with the fact that cancer cells are capable of cell division, all cases of high-grade prostatic intraepithelial neoplasia and invasive carcinoma also showed down-regulation of p27^Kip1 as compared with the surrounding normal-appearing secretory cells. In pelvic lymph node metastases, p27^Kip1 expression was also reduced. In summary, our results suggest that lack of nuclear p27^Kip1 protein may delineate a potential transiently proliferating subcompartment within the basal cell compartment of the human prostate. In addition, these studies support the hypothesis that reduced expression of p27^Kip1 removes a block to the cell cycle in human prostate epithelial cells and that dysregulation of p27^Kip1 protein levels may be a critical early event in the development of prostatic neoplasia.     

Somatostatin and/or somatostatin-like immunoreactive endocrine-paracrine cells in the human prostate gland

We demonstrated the presence of somatostatin and/or somatostatin-like immunoreactive (SSLI) endocrine-paracrine (EP) cells for the first time in the human prostate gland. Specimens from 26 prostates removed at radical cystectomies were studied using the unlabeled-antibody peroxidase-antiperoxidase technique. The SSLI cells were located predominantly in the prostatic ducts in widely scattered clusters and were mostly of the closed type. Some SSLI cells had processes that were prominent, suggesting a paracrine role. The SSLI cells were always associated with aggregates of numerous argyrophil cells. The finding of SSLI cells in the prostate gland (particularly in association with other EP cells) is circumstantial evidence that other polypeptide hormones are present. The SSLI and other prostatic EP cells may play major roles in the pathophysiology of the prostate gland and have an effect on such diverse conditions as infertility, nodular prostatic hyperplasia, and prostatic carcinoma.