Normal Acini Research Articles

Altered mucin expression is a field change that accompanies mucinous (colloid) breast carcinoma histogenesis

Mucinous carcinomas of the breast, so-called colloid carcinomas, exhibit better prognoses than their nonmucinous breast counterparts. This biological difference exhibited by mucinous breast carcinomas prompted us to examine the relationship of mucin expression to colloid carcinoma histogenesis. We studied 50 colloid carcinomas, 50 noncolioid cancers, and 50 normal breasts by hematoxylin-eosin (H&E) and Alcian blue staining, mucin immunohistochemistry, in situ hybridization with a battery of MUC riboprobes, and ancillary digital image analysis. We observed luminal mucin in normal ducts in 80% of colloid carcinomas compared with 10% of noncolloid carcinomas and 6% of normal breasts ( P < .01). In the cases of colloid carcinoma that showed mucin-filled ducts, luminal mucin was observed in 40% of the normal ducts and acini, 40% to 75% of the ducts involved by hyperplasia, atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), respectively, and in 50% of the co-incidental areas of cysts (mucoceles), adenosis, fibroadenoma, and intraductal papilloma ( P < .01). Immunohistochemistry showed that colloid carcinomas showed strong MUC2 cytoplasmic immunoreactivity and decreased MUC1 immunoreactivity compared with noncolloid carcinomas. In situ hybridization studies indicated fivefold increased MUC2 signals and twofold increased MUC5 signals within adjacent and remote normal epithelium in only the colloid carcinoma cases ( P < .01; P < .05). In these cases of colloid carcinoma, these increased MUC2 and MUC5 signals were also observed in areas of hyperplasia, ADH, DCIS, and invasive carcinoma. In contrast, the noncolloid carcinomas showed fivefold increased MUC1 signals but no increases in MUC2 or MUC5. In mixed colloid/noncolloid carcinomas, the colloid areas had identical mucin expression patterns as the pure colloid carcinomas, but there was a loss of MUC2 and MUC5 expression and a gain of MUC1 expression in the noncolloid areas that was therefore identical to the pattern observed in pure noncolloid carcinoma. In this study, we conclude that the altered expression of mucin so characteristic of colloid carcinoma is also a field change present in adjacent and remote normal breast epithelium.

Protein Kinase C Isoform Expression and Function in Transformed and Non-transformed Pancreatic Acinar Cell Lines

Members of the protein kinase C (PKC) family of multifunctional serine/threonine phosphorylating enzymes are believed to play a role in regulating cellular differentiation and proliferation in many cell types. In the present study, we examined the expression of PKC isoforms in non-transformed (BMRPA.430) and transformed (TUC3) rat pancreatic acinar cell lines and compared this to PKC expression in freshly dispersed acini from rat pancreas. BMRPA.430 cells maintain characteristics of normal acini and are not tumorigenic, whereas TUC3 cells do not express tight junctions or polygonal morphology and are tumorigenic. As reported previously, PKC α, δ, ϵ, and ζ are expressed in freshly prepared acini. Likewise, these isoforms were detected in both the BMRPA.430 and TUC3 cell lines. In addition, PKCθ, a novel isoform, was detected in all three cell types at low levels. We used two PKC inhibitors to examine the role of PKC in acinar cell proliferation. CGP 41 251, a selective PKC inhibitor, and Go 6976, an agent which specifically inhibits calcium-dependent PKC isoforms, inhibited cell proliferation of both cell lines. Translocation of PKCα to the membrane was not observed in either cell line. Hence, our data indicate that ras-induced transformation does not alter PKC isoform expression in pancreatic acinar cells and that activation of PKCα is involved with acinar cell growth.

Regulation of transcription of the two cyclooxygenase isoforms in pancreas acini

Background and Aims: In earlier experiments we have shown that exogenous application of prostaglandin E2 inhibits secretagogue stimulated enzyme secretion in isolated rat pancreatic acini. Also specific receptors for prostaglandin E2 were characterized on acinar cell membrane (Am. J. Physiol. 1991, 260, G711-19). Prostaglandins as mediators of inflammation are synthesized by the key enzyme cyclooxygenase (Cox or prostaglandin H synthase), of which two isoforms have been identified, Cox-1 and Cox-2. We are interested in two aspects of regulation of cell function through prostaglandins: Modulation of prostaglandin synthesis dependent on diet and through induction of pancreatitis in an animal model. Since a number of prostaglandins might be involved in these processes it appears reasonable to look at the regulation of the two cyclooxygenase isoforms by which all prostaglandins have to be synthesized. Methods and Results: We have developed an RT-PCR method to determine changes in the expression of Cox-1 and Cox-2 isoforms. Pancreatitis was induced in rats by different concentrations of cerulein. An optimal concentration for the induction of pancreatitis was determined. Pancreatic acini were isolated employing a collagenase digestion method. Total RNA was isolated from these acini from cerulein treated and untreated rats. We could detect both, Coxl and Cox-2, mRNA in isolated rat pancreatic acini. Amounts of Cox mRNA were standardized by comparison with GAPDH and actin expression. We also looked at and could exclude leukocyte infiltration in these tissue preparations. We will present data an induction and repression of cyclooxygenase transcription dependent on induced pancreatitis. We will discuss the correlation of enzyme expression, synthesis of prostaglandins and a potential cytoprotective role of prostaglandins. Conclusion: Cox-1 and Cox-2 are expressed in acinus cells of the pancreas with pancreatitis and in normal acini. These enzymes synthesize prostaglandins which may play a roll in mediation of pancreatitis.

Tumor-associated glycoprotein (TAG-72) in chronic submandibular sialadenitis and normal minor salivary glands defined by monoclonal antibody B72.3.

Formalin-fixed, paraffin-embedded samples of three normal minor salivary glands, 10 chronic submandibular sialadenitis, and three normal submandibular glands were studied immunohistochemically using the monoclonal antibody (Mab) B72.3 in order to have a better understanding of the distribution of tumor-associated glycoprotein (TAG-72). Diffuse expression of TAG-72 was observed in the mucous cells of normal minor salivary glands, and in the ducts with goblet cell metaplasia and/or hyperplasia of chronic submandibular sialadenitis (eight of 10). Focal expression of TAG-72 was seen in the acinar mucous cells of normal submandibular gland (three of three), and in the mucous cells of normal or atrophic acini of chronic submandibular sialadenitis (eight of 10). These results should be considered in the cytologic diagnosis of the mucoepidermoid carcinoma using the Mab B72.3 as a diagnostic aid, as well as in future studies for the radiation immunolocalization and immunotherapy of submandibular gland tumors.

Expression of alpha-1-antichymotrypsin in prostate carcinoma.

Prostate specific antigen (PSA) is a glycoprotein with the enzymatic activity of serine protease, the gene which is encoded in the human glandular kallikrein gene locus. Catalytically active PSA released into serum may be inactivated by a complex formation with alpha 1ACT (ACT) and alpha 2MG (MG), two major protease inhibitors. The serum complex-to-total PSA ratio can be used as a marker for the differentiation between prostate carcinoma (PCa) and a benign lesion because of a significant elevation of PSA binding to ACT in PCa. Apparently higher immunohistochemical expressions of PSA and ACT have been reported in PCa of low Gleason scores when compared with benign lesions. The fact that only normal secretory epitheliums are capable of producing ACT was recently proved by immunohistochemical and in situ hybridization methods. Our immunohistochemical study of ACT showed a tendency toward stronger expression in high Gleason grade PCa than in low Gleason grade Pca. Prostate intraepithelial neoplasia (PIN), as well as BPH, seldom react to ACT. Expression of ACT in normal ducts or acini was influenced by their location. In a normal prostate, expression of ACT was predominantly in secretory epithelial cells, with a minority of basal cells and rarely in the interdigitating neuroendocrine cells. Whereas the potency of ACT production in epithelial cells almost always appeared to be suppressed under normal conditions, it was noted that a strong expression of ACT was apparent in the normal ducts or acini near a high grade carcinoma with a weak reaction to ACT. ACT expression is much more enhanced in high grade carcinomas and in the residual normal acini adjacent to carcinomas of low ACT expression, presumably representing scale down the elevated PSA.

Human Epithelial Related Antigen (hERA) in Salivary Glands and Their Tumors: Immunohistochemical Observations.

The expression of human epithelial related antigen (hERA), a 40 kD transmembrane glycoprotein assigned to one of the small cell lung cancer antigen was evaluated in normal salivary glands and their tumors using immunohistochemical methods.In normal salivary gland acini, hERA was seen in lateral borders and basal plasma membrane of serous cells of the parotid and submandibular glands and in the basal layer of mucous cells of the sublingual and minor oral glands, the luminally projecting cell membrane being consistently unreactive. In ductal segments, hERA was seen in basal infoldings and lateral borders of striated duct cells, excretory ducts or interlobular ducts and the ductal basal cells in particular, were devoid of hERA immunostaining.Salivary pleomorphic adenoma showed luminal borders of tubulo-ductal structures immunoreactive for hERA whereas the nonluminal or the neoplastic myoepithelial cells were consistently unreactive. A similar pattern of immunoreactivity was observed in Warthin's tumor where lateral borders of luminally located tall columnar tumor cells showed reaction products whereas the basal cells were unreactive. Mucoepidermoid carcinoma showed hERA in epidermoid and intermediate tumor cells, but not in mucous secreting cells. In adenoid cystic carcinoma reaction product for hERA was seen in a limited number of lumen-lining cells and again the non-luminally located neoplastic myoepithelial cells were unreactive. The results of the present study suggest that hERA may be a useful marker to detect luminal cell components in salivary tumor and, apart from the neoplastic myoepithelial cells or their counterparts, these luminally located cells may have a potential implication in salivary gland tumorigenesis.

Androgen receptor expression in prostatic dysplasia (prostatic intraepithelial neoplasia) in the human prostate: an immunohistochemical and in situ hybridization study.

To evaluate the role of androgens in the pathogenesis of prostatic dysplasia, we compared the localization of androgen receptor (AR) in proliferative and nonproliferative cells in normal and dysplastic acini. Basal cells, the only proliferating cells identified in normal acini, contained AR mRNA but lacked an immunodetectable receptor. Both AR mRNA and immunodetectable receptor were present, however, in secretory and stromal cells. Androgen receptor localization in dysplastic lesions was identical to normal but here the proliferative marker Ki-67 was found in both basal and secretory cells. Our findings suggest that androgens do not directly initiate the division of basal cells, the putative precursors of secretory cells. Instead, the hormone may act through its fully translated receptor to mainly mediate the differentiation of secretory cells. The presence of both AR and Ki-67 in dysplastic secretory cells may indicate an abnormal direct androgen-mediated proliferation in this compartment. This is consistent with previous evidence that secretory cell differentiation is impaired in dysplasia.

Location of 72-kd metalloproteinase (Type IV Collagenase) in untreated prostatic adenocarcinoma

The aim of the study was to investigate the location of the expression of 72-kd metalloproteinase (MMP-2) in relation to the distribution of type IV collagen in untreated prostatic adenocarcinoma (PAc). Twenty formalin-fixed, paraffin-embedded PAc cases, in which high grade prostatic intraepithelial neoplasia (PINhigh) was occasionally present, were immunohistochemically examined. Type IV collagen immunoreactivity showed the presence of a basement membrane (BM) at the epithelial-stromal junction. In cribriform and solid/trabecular PAc, the staining was focally disrupted. In acinar PAc, the BM immunostained by anti-type IV collagen was observed around the individual acini, with occasional thinning and fragmentation. Immunostaining for MMP-2 was heterogeneous in intensity and location. Cribriform and solid/trabecular PAc showed weak cytoplasmic immunostaining for MMP-2; both moderately and intensely stained cells were seen in the cell layer adjacent to the stroma; intense immunostaining was shown by small clusters of neoplastic cells or single neoplastic cells located in the stroma which also showed thinning and fragmentation of BM staining. In acinar PAc, weak cytoplasmic immunostaining for MMP-2 was seen throughout most areas of the tumours, whereas moderately and intensely stained cells were observed less frequently than in cribriform and solid/trabecular adenocarcinoma. Intense immunostaining of single or small clusters of neoplastic cells located in the stroma was rarely observed and, as for cribriform and solid/trabecular PAc, mainly located towards the periphery of the tumour nodules. BM stained by anti-type IV collagen was preserved in normal prostate and in PIN, some thinning being present in the latter. The pattern and intensity of immunoreactivity for MMP-2 in PIN was similar to that of cribriform and solid/trabecular PAc, whereas normal ducts and acini showed weak immunostaining in most of the secretory cells and moderate to strong immunoreactivity in scattered basal cells. Thus, MMP-2 appeared basically expressed in cells which lie in direct contact with the stroma. This underlined the importance of evaluating the MMP-2 location in relation to basement membrane degradation and tumour invasion.

Solitary fibrous tumors of soft tissue. A clinicopathologic and immunohistochemical study of 12 cases.

We describe 12 cases of primary soft tissue neoplasms that showed the histologic and immunohistochemical features of solitary fibrous tumors of serosal surfaces (solitary fibrous mesothelioma, submesothelial fibroma). Nine patients were women and three were men whose ages ranged from 28 to 83 years. Seven lesions were located in the head and neck region, and the remainder were located in the back, buttock, perineum, and groin. The lesions measured from 1 to 6 cm in greatest diameter and presented grossly as well-circumscribed, unencapsulated, soft to rubbery tissue masses. Histologically they were characterized by a proliferation of spindle cells exhibiting a variety of growth patterns, including storiform, herringbone, neural with wavy nuclei, and hemangiopericytic admixed with areas of sclerosis. In two cases the lesions showed areas of increased cellularity with occasionally scattered mitotic figures. Three cases were located adjacent to a major salivary gland; in one, entrapment of normal salivary gland acini and ducts could be observed at the edges of the lesion. Immunohistochemical studies showed positive staining of the spindle cells with CD34 (anti-HPCA-1) and vimentin antibodies and negative staining with keratin, actin, desmin, S-100 protein, collagen type IV, and factor VIII related antigen. Follow-up from 6 months to 12 years has shown no evidence of recurrence or metastasis in any of our patients. Solitary fibrous tumors appear to represent ubiquitous mesenchymal neoplasms that may not be necessarily restricted to serosal surfaces. Identification of these lesions is of importance to avoid misdiagnosis with other more aggressive conditions in soft tissue locations.

Prostatic Intraepithelial Neoplasia and Well Differentiated Adenocarcinoma Maintain an Intact Basement Membrane

The status of the basement membrane in prostatic intraepithelial neoplasia (PIN) and adenocarcinoma is unsettled. Previous studies using antibodies directed against Type IV collagen have been hindered by intense staining around the stromal smooth muscle fibers, making interpretation of acinar staining difficult. We employed a monoclonal antibody to heparan sulfate proteoglycan (HSPG) to overcome this problem, recognizing that HSPG is present in the basement membrane of epithelial and endothelial cells, but not stromal smooth muscle cells. In 22 totally-embedded whole mount radical prostatectomies for adenocarcinoma which contained PIN, intense HSPG immunoreactivity was observed in the basement membrane of all normal and hyperplastic acini, 98% of acini with high grade PIN, and 100% of acini of well differentiated (Gleason score 5) adenocarcinoma; vessels served as the internal positive control, with consistent staining throughout each specimen. The extent of HSPG immunoreactivity in cancer decreased with increasing Gleason grade (measured as percent of acini staining, in 10% increments; p = 0.002). These findings indicate that HSPG is a consistent component of the basement membrane of benign, hyperplastic, and early neoplastic prostatic acini, and, unlike other extracellular matrix proteins such as type IV collagen, is not hindered by background staining around stromal smooth muscle cells. High grade PIN and well differentiated adenocarcinoma usually maintain an intact basement membrane, and loss of the basement membrane occurs with histologic dedifferentiation.

Microfluorometric studies of intracellular Ca2+ and Na+ concentrations in normal human labial gland acini

The responses of human labial salivary acini to muscarinic, adrenergic, and substance P peptidergic stimulation were studied using the fluorescent indicators fura 2 for intracellular Ca2+ concentration ([Ca2+]i) and sodium-binding benzofuran isophthalate for intracellular Na+ concentration ([Na+]i). Of the agents tested (carbachol, epinephrine, isoproterenol, and substance P) only the muscarinic agonist carbachol increased [Ca2+]i substantially above basal levels (three to fourfold; half-maximal effect approximatley 1 microM). Experiments with the Ca(2+)-adenosinetriphosphatase inhibitor thapsigargin indicated the presence of both thapsigargin-sensitive and thapsigargin-insensitive intracellular Ca2+ stores, both of which were mobilized by carbachol. [Na+]i in resting labial acini was approximately 20 mM. On stimulation with carbachol, [Na+]i rose transiently to more than three times this value and then partially recovered. This carbachol-induced rise in [Na+]i was largely blocked by bumetanide, a specific inhibitor of the Na(+)-K(+)-2Cl- cotransporter. These results are consistent with an intact muscarinic fluid secretory response in human labial acini with transepithelial Cl- secretion driven via Na(+)-K(+)-2Cl- cotransport and the secretion of fluid presumably following Cl- loss via an apical Ca(2+)-dependent anion channel, as observed in salivary acini from other species.

The proliferative function of basal cells in the normal and hyperplastic human prostate.

To obtain more insight into the proliferative function of basal and secretory cell types in human prostate, we studied the immunoprofile of three well-characterized proliferation-associated antigens (Ki-67, PCNA, MIB 1) in normal and hyperplastic prostate tissue. Distinction between labeled basal and secretory cell types was made by simultaneous demonstration of the proliferation-associated antigens and basal cell-specific cytokeratins in identical sections. In normal and hyperplastic acini, approximately 70% of labeled cells were of the basal cell phenotype. These data clearly suggest that the proliferative compartment of the normal and hyperplastic epithelium is located in the basal cell layer. Compared to normal and hyperplastic conditions, severe proliferative abnormalities were detected in high-grade prostate intraepithelial neoplasias (PIN), as documented by the extension of the proliferative compartment up to the luminal border. Conversely, approximately 70% of proliferating cells detected in atypical hyperplasias that progressed in invasive carcinomas were localized in the remaining basal cell layer. These findings may indicate the proliferative role of basal cells in the epithelial renewal, and the development of hyperplastic and neoplastic disorders in the human prostate.

Immunohistochemical localisation of pS2 protein in ductal carcinoma in situ and benign lesions of the breast.

The expression of pS2 was examined histochemically in paraffin sections taken from biopsy material from patients diagnosed with ductal carcinoma in situ (DCIS). Often intense immunoreactivity, to an anti-pS2 monoclonal antibody, was observed in comedo, solid, cribriform and micropapillary types of DCIS, with significant positivity found in 63-67% of cases. In 15 samples analysed, we found a good correlation between pS2 expression and presence of progesterone receptor positive cells, but not with estrogen receptor. There was only a limited degree of correspondence between the cells staining with these anti-sera. Some pS2 positive cells were also seen in normal acini in areas adjacent to cancer but much less frequently in sections of normal breast from reduction mammoplasty. Most normal areas were negative, as were cysts. In benign proliferative conditions (seen in sections with and without DCIS) such as adenosis, sclerosing adenosis, mild and florid ductal epithelial hyperplasia, significant pS2 positivity was seen in about 50% of cases. These results suggest that there is a progressive increase in pS2 from normal to benign to cancer cells and that this gene is expressed in both the invasive and pre-invasive forms of breast cancer.

The stimulatory effects and binding characteristics of PACAP27 in rat dispersed pancreatic acini.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a recently isolated active peptide of the VIP (vasoactive intestinal peptide) family. Two bioactive forms, PACAP38 and PACAP27, a shorter N-terminal amidated peptide of PACAP38, have been identified. In this study, we explored the action of PACAP27 in rat dispersed pancreatic acini and the characteristics of its binding sites. PACAP27 stimulated amylase secretion and intracellular cAMP production in a dose-dependent manner. Adding 0.5 mM IBMX increased the potency of PACAP27 on the amylase secretion, but did not change the efficacy. The biological action of PACAP27 was mediated via intracellular cAMP as is also the case with PACAP38 or VIP. The time course study, however, revealed that PACAP stimulated the initial amylase secretion greater than VIP, suggesting an involvement of mechanisms other than intracellular cAMP. Binding studies using 125I-PACAP27 and 125I-VIP indicated that the binding sites for PACAP27 interacted with PACAP27 and VIP with a similar affinity. These observations suggested the presence of type II PACAP-binding sites in the normal acini of the rat pancreas which may be functionally coupled with acinar enzyme secretion.

Altered expression of ABO (H) carbohydrate antigens is seen in pleomorphic adenomas.

Cell surface carbohydrate antigens show changes in relation to differentiation, maturation and malignant transformation. The expression of type 2 chain ABH carbohydrate structures of the ABO histo-blood group system was investigated in 28 pleomorphic adenomas (PA) and normal parotid glands in order to study possible changes in the glycosylation pattern. The distribution of carbohydrate structures was investigated by immunohistological stainings of formalin-fixed paraffin-embedded material using monoclonal antibodies (MAbs) with well-defined specificity. A strong interindividual variation was found in the normal tissue as well as in the tumors. In normal tissue, acinus and duct cells all expressed elongated carbohydrate structures. The yoepithelial cells did not stain with any of the MAbs investigated. In the PAs, staining was seen in the ductular structures and myoepithelial cells. In contrast to normal tissue, the tumors expressed the short precursor molecule sialylated N-acetyllactosamine. Furthermore, the PAs showed loss of H and A antigens, and a reduced expression of Le(y) compared to normal tissue. The ductular structures as well as the modified myoepithelial cells expressed binary N-acetyllactosamine, which in the normal tissue could only be found in the striated and excretory ducts. Thus our study has shown that aberrant glycosylation is not only a feature of malignant neoplasms but also occurs in pleomorphic adenomas.

Putrescine and spermidine uptake is regulated by proliferation and dexamethasone treatment in AR4-2J cells

Polyamines are essential for cell growth and differentiation. Their specific uptake contributes to the regulation of intracellular polyamine levels. In this study, we describe the modulation of this transport mechanism in a rat tumoral pancreatic acinar cell line (AR4-2J) and analyze the transport system characteristics of the normal rat pancreatic acini. Normal acini had a common carrier for spermidine and spermine, like AR4-2J cells, but not a specific putrescine carrier. Intracellular polyamine deprivation enhanced putrescine and spermidine uptake of AR4-2J cells with no modification of polyamine carrier affinity. Uptake was modulated during growth and decreased for both polymaines at confluence. AR4-2J cell differentiation with dexamethasone prevented cell proliferation and diminished uptake of both putrescine and spermidine without affecting their respective carrier affinities. Our data show, first, that the polyamine transport system could be modulated by polyamine metabolism with no change in its affinity characteristics. Second, in rat pancreatic acinar cells, neoplastic transformation was partly characterized by induction of a high-affinity putrescine carrier. This phenotype was not reversed by dexamethasone-induced cell differentiation.

Monoclonal antibody B72.3 in benign breast lesions.

It has been suggested that the monoclonal antibody B72.3 may be useful as a diagnostic tool in fine needle aspirates of breast masses because it recognises "tumour associated glycoprotein (TAG)-72". The antigen was sought in paraffin wax sections of 43 normal and benign breast biopsy specimens, using the avidin-biotin complex technique, to assess the extent of its presence in non-malignant tissue. Strong focal staining was seen in 21 (49%) cases. In 29 cases of fibrocystic change staining was present in 17 (59%). All areas of apocrine metaplasia were positive, as well as a few normal ducts and acini and occasional areas of adenosis. Focal positivity was present in five out of 12 foci of ductal epithelial hyperplasia and in three out of seven radial scars. Staining was absent in two areas of lobular hyperplasia, three areas of sclerosing adenosis, and in a focus of lactational change. Focal positivity was also seen in two out of five fibroadenomas and in two out of three intraduct papillomas. Five normal subareolar sections and a section of normal lactating breast were negative. It is concluded that B72.3 monoclonal antibody can show focal reactivity with a variety of normal and benign epithelial mammary structures, and it is doubtful that its use would be of any help in differentiating benign from malignant cells in fine needle aspirates.

Nucleolar prominence as a diagnostic variable in prostatic carcinoma

The diagnosis of well-differentiated adenocarcinoma of the prostate can be difficult on needle biopsy specimens. Nucleolar prominence has proven to be a useful diagnostic variable, but its objective evaluation has had limited study. To find nucleolar criteria that might differentiate benign from malignant conditions, we examined 41 open prostatectomy specimens, 25 of which were removed for well-differentiated adenocarcinoma and 16 of which were removed for benign prostatic hypertrophy (BPH). Four acini of carcinoma, prostatic intraepithelial neoplasia (PIN), atypical adenomatous hyperplasia (AAH), nodular hyperplasia, and normal tissue were examined. The total number of nuclei with nucleoli 3 microns or greater (N'), the fraction of nuclei with nucleoli 3 microns or greater (N'/N), and the average diameters of nucleoli 3 microns or greater (AVG) were recorded. Hyperplastic and normal areas, when compared with carcinoma, had significantly smaller N',N'/N, and AVG values (P less than 0.005). The N' and N'/N values were significantly higher in hyperplasia when compared with normal acini (P less than 0.005). In addition, N' and N'/N values in PIN were significantly greater than those in AAH (P less than 0.0001). In comparing prostates with and without carcinoma, N' and N'/N were significantly different for hyperplastic areas. In only two cancer areas and one PIN area was the N'/N ratio less than 0.31, which was the highest value for either hyperplastic or normal areas. Although AVG also were significantly different, they did not improve discrimination between the groups. We conclude that N'/N ratios are useful in diagnosing well-differentiated prostatic adenocarcinoma on small tissue samples.

Pathologic Basis of the Sonographic Appearance of the Normal and Malignant Prostate

The hypoechoic nature of prostatic cancer is now well recognized. In fact, not all cancers are purely hypoechoic; many are isoechoic, and some have a mixed echogenicity. Rarely, we have seen a cancer that was predominantly hyperechoic. Other signs of disturbance of the normal internal anatomy of the prostate may suggest the diagnosis of prostate cancer and are particularly valuable in assessing patients with more advanced disease. Approximately one third of early-stage cancers detected by palpation or transurethral resection are isoechoic. These tumors are anteriorly located, small, and well differentiated and infiltrate among normal glands or are composed of malignant glands similar in size to normal acini. Not all hypoechoic areas within the prostate are cancer; both normal anatomic structures and various benign conditions may appear less echogenic than the normal prostatic parenchyma. A comprehensive understanding of normal prostatic anatomy and the morphology of prostate cancer is essential to the accurate interpretation of the sonogram. Precise interpretation of prostatic sonograms requires detailed correlations of high-quality images with pathologic examinations of the whole prostate. The development of accurate criteria for the sonographic diagnosis of both malignant and benign prostatic diseases can be achieved only by such studies. As the possibilities and limitations of transrectal ultrasonography become apparent from pathologic correlation, the role of ultrasound in the diagnosis of prostate cancer will be placed on a more rational basis.

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.