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Thymic hyperplasia in newly diagnosed testicular germ cell tumors.

Thymic hyperplasia has been reported as a rebound phenomenon in children and young people, most commonly following chemotherapy for cancer. Although thymic hyperplasia has been documented in testis cancer patients after chemotherapy, to our knowledge it has not previously been reported in newly diagnosed cases before systemic therapy. A retrospective review of 362 testicular germ cell tumor patients treated at a single tertiary care center between January 1, 1980 and August 1, 1993 was performed, with special review of 221 who underwent computerized tomography staging of the chest. Thymic hyperplasia was detected in 4 of the 221 patients (1.8%) including 3 of 100 (3.0%) with seminoma and 1 of 121 (0.8%) with nonseminoma. All 4 patients had low stage (I or IIa) disease with a delay in diagnosis (5 to 24 weeks) and thymic hyperplasia was discovered at staging evaluation 18 to 37 days after orchiectomy but before other cancer therapy was administered. Of the 4 patients 2 underwent thymectomy, revealing histological thymic rebound hyperplasia. All 4 patients had no evidence of recurrence at 1 to 54 months after treatment. In addition to the well known post-chemotherapy phenomenon, thymic hyperplasia may also occur in nonsystemically treated, newly diagnosed testicular cancer patients. An anterior mediastinal mass in an otherwise low stage newly diagnosed testicular cancer patient may represent thymic hyperplasia and not necessarily metastatic disease.

Adult↗

Stimulation of epithelial hyperplasia in rat urinary bladder by Escherichia coli cystitis.

Using heterotopically transplanted rat urinary bladder, experiments were conducted to develop a reproducible animal model of bacterial cystitis-associated urothelial hyperplasia without calculus formation, and to elucidate which bacterial component(s) might induce urothelial hyperplasia. Bladder instillation of live Escherichia coli (E. coli) resulted in persistent infection and inflammation and also diffuse urothelial hyperplasia. Instillation of killed E. coli also induced diffuse hyperplasia. Hyperplastic changes regressed following withdrawal of the killed E. coli treatment. Urothelial hyperplasia was also induced by repeated instillation of protein-rich lipopolysaccharide (LPS), the endotoxin derived from gram-negative bacterial wall component, but not by protein-free LPS. A finding common to bladders showing hyperplasia was the infiltration of neutrophils into intercellular spaces of the urothelium. We conclude that urothelial hyperplasia is induced by E. coli cystitis, that LPS plays a significant role in the hyperplastic response, and that neutrophils may mediate the response.

Animals↗

Ultrasound and menstrual history in predicting endometrial hyperplasia in polycystic ovary syndrome.

OBJECTIVE: To assess the role of endometrial thickness on vaginal ultrasound assessment and menstrual history in predicting endometrial hyperplasia in women with polycystic ovary syndrome (PCOS) who presented with infertility due to anovulation. METHODS: This was a prospective study in a university referral-based fertility and endocrine clinic. Fifty-six women with PCOS presenting with infertility due to anovulation underwent both vaginal ultrasound assessments and endometrial biopsies. The main outcome measures were the predictive value of sonographic endometrial thickness (primary objective) and the menstrual history with other clinical characteristics (secondary objective) for proliferative endometrium and endometrial hyperplasia in logistic regression analysis. Their predictive value was further examined by receiver operating characteristic curve analysis. RESULTS: Thirty-six PCOS patients (64.3%) had proliferative endometrium and 20 (35.7%) had endometrial hyperplasia. Five of the latter (25%) had cytologic atypia. Endometrial thickness less than 7 mm or intermenstrual interval less than 3 months (corresponding to more than four menstrual periods yearly) was associated with proliferative endometrium only. The endometrial thickness correlated positively with endometrial hyperplasia (P =.018) and, together with the average intermenstrual interval, were significant predictors of endometrial hyperplasia (P <.001). CONCLUSION: These findings point to the usefulness of obtaining a detailed menstrual history in women with PCOS by identifying those at increased risk of endometrial hyperplasia and who require an endometrial biopsy. The endometrial thickness corroborates this clinical impression and is particularly useful when the menstrual history is uncertain. Endometrial hyperplasia in this population is effectively excluded when the endometrial thickness is less than 7 mm.

Adult↗

Analysis of K-ras oncogene mutations in chronic pancreatitis with ductal hyperplasia.

BACKGROUND: K-ras oncogene mutations have been identified in up to 95% of pancreatic cancers, implying their critical role in their molecular pathogenesis. However, the earliest stage in which K-ras mutations can be detected in potential precursor lesions of pancreatic cancer remains unclear. This study evaluates pancreatic ductal hyperplasia in the setting of chronic pancreatitis, which predisposes to pancreatic cancer development, for K-ras codon 12 and 13 mutations. METHODS: Paraffin-embedded surgical specimens from 42 patients with chronic pancreatitis were examined microscopically for the presence of ductal hyperplasia. Both hyperplastic and nonhyperplastic ducts were microdissected from the specimens that contained hyperplasia (11 of 42). Four of the remaining specimens without hyperplasia served as controls. Genomic DNA was extracted, and polymerase chain reaction and amplification of the K-ras oncogene was performed. Polymerase chain reaction products were evaluated by means of hybridization to mutant specific oligonucleotide probes and by means of automated DNA sequencing. RESULTS: K-ras codon 12 mutations representing glycine to valine substitutions were present in 2 of (18%) 11 patients with ductal hyperplasia. No mutations were found in the controls without ductal hyperplasia. CONCLUSIONS: Our study supports the premise that K-ras mutations develop in a subset of chronic pancreatitis associated hyperplasia and provides a genetic basis for the potential progression of chronic pancreatitis to pancreatic cancer.

Adult↗

Mechanisms involved in the evolution of progestin resistance in human endometrial hyperplasia--precursor of endometrial cancer.

BACKGROUND: Successful treatment of endometrial hyperplasia with progestins is commonly accompanied by the finding of an inactive or suppressed endometrium after therapy. However, approximately 30% of the endometrial hyperplasia cases do not respond to progestins and hyperplastic glands persist. The Fas/FasL system is known to play a role in tissue remodeling as a result of changes in menstrual hormone levels. The aims of this study are to examine Fas/FasL expression in endometrial hyperplasia of pre- and postprogestin treatment samples and to study the Fas/FasL regulation in vitro with Ishikawa cells after progestin stimulation. DESIGN: Pre- and posttreatment paraffin-embedded endometrial hyperplasia tissue samples from 26 women were examined by immunohistochemistry for changes in Fas/FasL expression related to the administration of progestins. Among 26 patients, 18 were successfully treated with progestins and 8 failed treatment. Fas/ FasL positivity was defined by the presence of 10% or more immunoreactive epithelial cells in each specimen. In positive cases, a percentage or an immunoscore of immunoreactive cells was given by counting 500 cells. Cell viability was evaluated by the MTT assay. The in vitro effects of progesterone on Fas/FasL expression and apoptosis in Ishikawa cells were examined by using Western blot and TUNEL assays, respectively. RESULTS: Fas immunoreactivity was present in 4/26 (15%) preprogestin cases with an average of 16% of the epithelial cells expressing Fas. FasL was expressed in 21/26 (80%) pretreatment cases with an average of 42% of the hyperplastic glandular cells being positive. In postprogestin cases, an increase of Fas expression (14/18, 77%) with an average of 47% stained cells was seen in responders (P < 0.001), while FasL was found in 16/18 (89%) responders with an average of 65% of cells positive (P = 0.587). In nonresponders, no significant changes in Fas/FasL expression were detected compared to pretreatment samples. With in vitro Ishikawa cells, a slight increase (10-20%) of Fas and FasL protein expression was detected after 24 h of progesterone treatment, but a more significant increase (220-343%) of both Fas and FasL expression was found after 48 h of withdrawing progesterone, which parallels apoptotic activity. CONCLUSIONS: The Fas/FasL system may be involved in the development of endometrial hyperplasia. Part of the molecular mechanisms of progestin therapy for endometrial hyperplasia is through upregulation of Fas/FasL expression. Dysregulation of Fas/FasL expression in hyperplastic endometrium may be part of the molecular mechanisms for nonresponders to progestin treatment. Intermittent, rather than continuous, progestin treatment may be more effective clinically for the treatment of endometrial hyperplasia.

Adult↗

Endometrial hyperplasia with secretory changes.

OBJECTIVE: Secretory changes in endometrial hyperplasia are uncommon. The aim of this study is to review the morphologic and clinical findings of 24 cases of endometrial hyperplasia with secretory changes. METHODS: In 24 patients diagnosed with endometrial hyperplasia with secretory changes during 6 years, clinical characteristics such as menopausal status and hormone treatment were correlated with morphological features. A matched age control group of 24 women with conventional endometrial hyperplasia was used to compare the hormonal effect. RESULTS: Nineteen patients were premenopausal. Nine women showed simple hyperplasia without atypia and 15 complex hyperplasia, 7 of them with atypia. Seventeen women were under hormonal treatment at the time of diagnosis, 10 of them with progestins. In 7 patients endometrial adenocarcinoma could be seen, 5 coexisting with endometrial hyperplasia with secretory changes and in 2 appearing after 1 and 4 months. In control group only 2 patients were undergoing progestin hormonal treatment. CONCLUSIONS: Secretory changes can be found in hyperplastic endometrium, particularly in premenopausal women under hormonal treatment with progestins, with the risk of misdiagnosis.

Adult↗

Stimulated pulmonary cell hyperplasia underlies resistance to alpha-naphthylthiourea.

The rodenticide alpha-naphthylthiourea (ANTU) causes pulmonary edema and pleural effusion that leads to death via pulmonary insufficiency. Rats become resistant to the lethal effect of ANTU if they are first exposed to a small, nonlethal dose of ANTU. Young rats are also resistant to ANTU. The mechanism by which rats develop resistance by a prior, small dose exposure has yet to be determined. Growth factor induced-pulmonary hyperplasia has been demonstrated to attenuate ANTU-induced lung leak. We hypothesized that a small dose of ANTU protects against a large dose through pulmonary cell hyperplasia induced by the protective dose. Furthermore, we hypothesized that this hyperplasia is associated with altered transcription of growth factors. Male Sprague-Dawley rats (175-225 g) were treated with a low dose of ANTU (5 mg ANTU/kg; ANTU(L)) 24 h before challenge with a 100% lethal dose of ANTU (70 mg ANTU/kg; ANTU(H)) resulting in 100% protection against the lethal effect of ANTU(H). ANTU(L) protection against ANTU(H) lasted for 5 days, slowly phased out, all being lost by day 20. Injury was assessed by estimating pulmonary vascular permeability and through histopathological examination. ANTU(H) alone resulted in an increase in pulmonary edema leading to animal death. However, injury was prevented if the rats were first treated with ANTU(L). There was a stimulation of pulmonary cell hyperplasia in the lungs of ANTU(L) treated rats as measured by [3H]-thymidine and bromodeoxyuridine incorporation. Treatment with the antimitotic agent colchicine abolished ANTU(L)-induced resistance to ANTU(H). ANTU resistant rats were also resistant to the lethal effect of paraquat. Paraquat is not taken up by pneumocytes if they are undergoing hyperplasia. ANTU(L) administration resulted in an up regulation of gene transcription for keratinocyte growth factor, transforming growth factor-beta, keratinocyte growth factor receptor and epidermal growth factor receptor as determined through reverse transcription-polymerase chain reaction. A significant increase in transforming growth factor-alpha was not observed. These findings collectively suggest that ANTU(L)-induced pulmonary cell hyperplasia underlies resistance to ANTU(H). Furthermore, the stimulation of hyperplasia may be due to altered growth factor and growth factor receptor expressions.

Animals↗

Differentiation of focal foveolar hyperplasia from hyperplastic polyps in gastric biopsy material.

Our objective was to investigate the question as to whether focal foveolar hyperplasia and hyperplastic polyp can be differentiated in forceps biopsy material from the stomach. Morphometric determination of the height of the epithelium layer in forceps biopsy specimens was obtained from 35 hyperplastic polyps, and forceps biopsy material was obtained from 25 focal foveolar hyperplasias. The diagnosis of hyperplastic polyp was confirmed by subsequent polypectomy. The medians and scatter range of the epithelial layer height were calculated. Using the t-test for independent samples the question was examined as to whether there is any statistically significant difference between hyperplastic polyps and focal foveolar hyperplasia in terms of the parameter "height of the foveolar epithelial layer." The measurements revealed that the average height of foveolar epithelial cells in hyperplastic polyps is 37.70 microns +/- 7.41 microns. In the case of focal foveolar hyperplasia, the corresponding figure was only 24.26 microns +/- 5.11 microns. This difference was statistically highly significant (p < 0.0001). In conclusion, focal foveolar hyperplasia and hyperplastic polyp of the gastric mucosa can readily be differentiated on the basis of architectural and cytological criteria, even in forceps biopsy material. Since the hyperplastic polyp very probably does not evolve from focal foveolar hyperplasia, and the latter is not a pre-neoplastic condition or lesion, it is proposed that focal foveolar hyperplasia should no longer be referred to as "gastric polyp," which would avoid unnecessary follow-up examinations and possibly even surgery.

Diagnosis, Differential↗

Immunohistochemical staining with MIB1, bcl2 and p16 assists in the distinction of cervical glandular intraepithelial neoplasia from tubo-endometrial metaplasia, endometriosis and microglandular hyperplasia.

AIMS: Preinvasive endocervical glandular lesions, termed cervical glandular intraepithelial neoplasia, are increasing in incidence. The distinction of cervical glandular intraepithelial neoplasia from benign mimics, especially tubo-endometrial metaplasia, endometriosis and microglandular hyperplasia, can be difficult. This study investigates the value of immunohistochemical staining with MIB1, bcl2 and p16 in the distinction of cervical glandular intraepithelial neoplasia from these benign mimics. METHODS AND RESULTS: Immunohistochemical staining using the monoclonal antibodies MIB1, bcl2 and p16 was performed on cases of cervical glandular intraepithelial neoplasia (n = 21), tubo-endometrial metaplasia (n = 13), endometriosis (n = 7) and microglandular hyperplasia (n = 14). With tubo-endometrial metaplasia and microglandular hyperplasia staining with MIB1 was either negative or involved <10% of cells, while with cervical glandular intraepithelial neoplasia the majority of cases (86%) exhibited >10% positive cells. Two cases of endometriosis exhibited a MIB1 index of 10-30% while in the other cases <10% cells stained. With bcl2 the cells of microglandular hyperplasia were negative although there was staining of associated reserve cells in 43% of cases. All cases of tubo-endometrial metaplasia except one and all cases of endometriosis stained diffusely positive with bcl2. Cases of cervical glandular intraepithelial neoplasia were negative or exhibited focal staining. With p16 all cases of cervical glandular intraepithelial neoplasia exhibited diffuse strong positivity, generally involving 100% of cells, while all cases of microglandular hyperplasia were negative. Sixty-two percent of cases of tubo-endometrial metaplasia showed focal positivity, the remainder being negative. Cases of tubo-endometrial metaplasia were never diffusely positive with p16. In three cases of endometriosis there was staining of >50% of cells while the other cases were either focally positive or negative. CONCLUSIONS: A panel of antibodies, comprising MIB1, bcl2 and p16, is a useful adjunct to histology in distinguishing cervical glandular intraepithelial neoplasia from tubo-endometrial metaplasia, endometriosis and microglandular hyperplasia. Cases of cervical glandular intraepithelial neoplasia are diffusely positive for p16 and generally exhibit a high proliferation index with MIB1, while bcl2 is negative or, at most, focally positive. Tubo-endometrial metaplasia and endometriosis are characterized by strong diffuse positivity with bcl2 and a low proliferation index with MIB1 (although occasional cases of endometriosis show moderate proliferative activity). p16 is negative or exhibits focal positivity in tubo-endometrial metaplasia but in endometriosis there may be quite widespread positivity. Microglandular hyperplasia shows a low proliferation index with MIB1 and is negative for bcl2 and p16.

Antibodies, Monoclonal↗

Expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in parathyroid hyperplasia caused by chronic renal failure versus primary adenoma.

BACKGROUND: In primary hyperparathyroidism, certain genetic abnormalities responsible for parathyroid tumorigenesis are proposed, and it has been reported that the overexpression of PRAD1/cyclin D1 induced by a DNA rearrangement of the parathyroid hormone (PTH) gene is one of the genetic disorders in a number of primary parathyroid adenomas. However, in secondary hyperparathyroidism caused by uremia, the mechanism of monoclonal proliferation in nodular parathyroid hyperplasia is not well understood. To elucidate the mechanism, we examined the expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in primary adenoma and secondary hyperplasia. METHODS: In adenomas (N = 15) and associated glands (N = 7) with normal histology obtained from patients with primary hyperparathyroidism and in diffuse (N = 14), multinodular (N = 58), and single nodular (N = 28) glands from patients who underwent parathyroidectomy for renal hyperparathyroidism, the expression of these cell cycle regulators was evaluated by immunohistochemical technique. A labeling index was used to define the proportion of cells with positive nuclear staining by each antibody. RESULTS: In 6 out of 15 (40%) primary adenomas, PRAD1/cyclin D1 was overexpressed (a labeling index of more than 500), possibly because of the PTH gene rearrangement, but not in secondary hyperplasia, including single nodular glands. Compared with diffuse hyperplasia, nodular hyperplasia showed a significantly higher expression of PRAD1/cyclin D1 (P < 0.05), retinoblastoma gene products (P < 0.05), and Ki67 (P < 0.05). However, no statistically significant correlation between the expression of PRAD1/cyclin D1 and that of Ki67 was observed in both primary adenoma and secondary hyperplasia. CONCLUSIONS: These results suggest that in secondary hyperplasia caused by uremia, at least remarkable overexpression of PRAD1/cyclin D1 induced by PTH gene rearrangement may be not the major genetic abnormality responsible for tumorigenesis. Heterogenous genetic changes seem to contribute to monoclonal proliferation of parathyroid cells induced by the expression of PRAD1/cyclin D1 or by some other mechanism independent of the amplification of the proto-oncogene.

Adenoma↗

Differential diagnosis between normal endometrium and endometrial hyperplasia with immunostaining cytology using anti-LeY monoclonal antibody.

We have previously reported that both endometrial cancer and endometrial hyperplasia stain positively for the anti-LeY monoclonal antibody, whereas normal endometrium does not. Endometrial hyperplasia is a premalignant change associated with the eventual development of endometrial carcinoma. However, it can be difficult to differentiate hyperplasia from normal endometrium in cytology. This study illustrates the use of immunocytochemical cytology using anti-LeY monoclonal antibody to differentiate between endometrial hyperplasia and normal endometrium. Immunostaining using anti-LeY monoclonal antibody was performed on cytologic specimens obtained from 17 normal endometria, 25 endometria with endometrial hyperplasia, and 13 endometria with endometrial carcinoma. All normal endometria displayed negative staining for anti-LeY monoclonal antibody, whereas all endometria with endometrial carcinoma displayed positive staining. Of the endometrial hyperplasia cases, 21 displayed positive staining. However, four displayed negative staining due to the small number of cells available for diagnosis. We believe that immunostaining cytology using anti-LeY monoclonal antibody is a useful method for differentiating between normal endometrium and endometrial hyperplasia.

Antibodies, Monoclonal↗

The impact of high pressure vs low pressure stent implantation on intimal hyperplasia and follow-up lumen dimensions; results of a randomized trial.

AIMS: Histology and retrospective clinical studies have indicated that the amount of neointimal hyperplasia is dependent on the arterial injury induced during stent implantation. This study analysed, prospectively, the impact of high vs low pressure stent implantation techniques using a second generation stent on intimal hyperplasia and follow-up lumen dimensions. METHODS AND RESULTS: Post-intervention and follow-up (mean[+/-SD] 5.5+/-1.3 months) angiographic and intravascular ultrasound studies were performed on 120 Multi-Link HP stents randomized to implantation at either low (8-10 atm) or high (16-20 atm) pressure. Intravascular ultrasound measurements of the external elastic membrane, stent, and lumen cross-sectional area were performed at 1 mm axial increments. Peri-stent plaque+media cross-sectional area (external elastic membrane-stent cross-sectional area, intimal hyperplasia cross-sectional area (stent-lumen cross-sectional area at follow-up), intimal hyperplasia thickness and peri-stent tissue growth cross-sectional area (Deltapersistent plaque+media cross-sectional area) were calculated. Intravascular ultrasound demonstrated a larger minimal lumen cross-sectional area post-intervention in the high pressure group (7.3+/-2.0 vs 6.2+/-1.8 mm(2), P<0.001, high vs low pressure group, respectively). At follow-up, the mean intimal hyperplasia cross-sectional area (1.7+/-0.9 vs 1.5+/-0.8 mm(2), P=0.708), the mean intimal hyperplasia thickness (0.16+/-0.12 vs 0.16+/-0.12 mm, P=0.818) and peri-stent tissue proliferation cross-sectional area were not greater in the high pressure group. Thus, the minimal lumen cross-sectional area at follow-up continued to be greater (5.5+/-2.0 vs 4.7+/-1.7 mm(2), P=0.038) in the high pressure group. CONCLUSIONS: High pressure stent implantation results in greater stent expansion even with the less rigid second generation Multi-Link stent. Larger lumen dimensions persist at follow-up, while intimal hyperplasia is not significantly greater after high pressure implantation compared to the low pressure technique.

Coronary Angiography↗

Expression of the retinoblastoma-related gene Rb2/p130 is downregulated in atypical endometrial hyperplasia and adenocarcinoma.

The retinoblastoma-related gene Rb2/p130 encodes a protein that is a negative cell-cycle regulator normally expressed in a number of adult tissues. This protein shares many structural and functional features with the product of the retinoblastoma gene, one of the best-studied tumor-suppressor genes, and plays a fundamental role in growth control. The Rb2/p130 gene product associates with specific members of the E2F family and various cyclins, displaying a growth-suppressive activity specific for the G(0)/G(1) phases. It has been reported that Rb2/p130 is involved in the pathogenesis and progression of lung cancer and mesothelioma. We previously demonstrated for the first time that reduced immunohistochemical expression of Rb2/p130 was a strong independent predictor of poor outcome in endometrial cancer. The aim of the present study was to evaluate Rb2/p130 expression in normal, hyperplastic, and neoplastic endometrial lesions to determine whether the protein plays a significant role in endometrial carcinogenesis. We evaluated Rb2/p130 expression by immunohistochemistry staining in 102 specimens chosen to represent a spectrum of endometrial changes, including proliferative endometrium (n = 18), secretory endometrium (n = 18), simple or complex hyperplasia without atypia (n = 18), atypical hyperplasia (n = 18), and invasive carcinoma (n = 30). We found that Rb2/p130 was highly expressed in proliferative endometrium and in hyperplasia without atypia, the mean percentage of stained nuclei being 66% and 60%, respectively, but was downregulated in secretory endometrium, atypical hyperplasia, and carcinoma, with mean scores of 38%, 25%, and 22%, respectively. When categorized on a semiquantitative scale (negative v 1% to 50% v >50% positivity), endometrial cancer displayed significantly less staining than all other endometrial samples (P <.001). Poorly differentiated carcinomas (n = 9) showed a significantly lower immunoreactivity for Rb2/p130 than did well-differentiated carcinomas (n = 11; P =.005) and moderately differentiated carcinomas (n = 10; P =.03). In addition, atypical hyperplasia showed a significantly lower immunoreactivity than either proliferative endometrium (P =.003) or hyperplasia without atypia (P = 0.02). Our findings of a progressive decrease in Rb2/p130 expression from hyperplastic endometrium through atypical hyperplasia to poorly differentiated carcinomas suggest the involvement of this negative cell-cycle regulator in endometrial carcinogenesis. Furthermore, immunostaining for Rb2/p130 may prove diagnostically useful in the often difficult distinction between hyperplastic and atypical hyperplastic endometrium. HUM PATHOL 32:360-367.

Adenocarcinoma↗

Prostate cancer vs hyperplasia: relationships with prostatic and adipose tissue fatty acid composition.

The objective of the present study was to study whether adipose tissue and prostatic tissue fatty acid composition differentiates between prostate cancer and benign hyperplasia patients. In addition, the present investigation aimed at exploring the extent to which prostatic tissue fatty acid composition differentiates between prostate-confined cancer and extraprostatic disease including possible metastasis. The subjects were 71 male patients from the island of Crete. Half the patients (n=35) had been diagnosed with benign hyperplasia of the prostate, half with prostatic malignancy (n=36). Patients were examined at the outpatient clinic of the urology unit, University Hospital, Medical School, University of Crete. Relative to benign hyperplasia patients, cancer patients had elevated adipose tissue saturated and reduced monounsaturated fatty acid levels. Cancer patients had reduced prostate tissue stearic to oleic acid ratios and stearic acid levels as opposed to hyperplasia patients. The most pronounced difference between cancer patients and hyperplasia patients was a 3-fold elevated prostatic palmitoleic acid in the former group. Relative to benign hyperplasia patients, cancer patients had reduced prostate tissue arachidonic and docosahexaenoic acid levels. Finally, there was a significantly reduced omega-3/omega-6 polyunsaturated fatty acid ratio in the prostate cancer patient as opposed to the benign hyperplasia group. The pronounced elevations in prostatic tissue palmitoleic acid in cancer patients highlight a possible role of this fatty acid in neoplastic processes. The decreased arachidonic acid levels in cancer patients possibly stem from enhanced metabolism of arachidonic acid via lipoxygenase and cyclooxygenase pathways, and the formation of derivatives such as 5-HETE, 15-HETE, 12(S)-HETE and PGE(2).

Adipose Tissue↗

Apoptosis and the expression of Bax and Bcl-2 in hyperplasia and adenocarcinoma of the uterine endometrium.

BACKGROUND: Apoptosis plays a crucial role in carcinogenesis in various tumours. This study was designed to investigate the occurrence of apoptosis and the expression of Bcl-2 and Bax proteins in endometrial tumours of corpus uteri. METHODS: Endometrial tissues were obtained from 20 patients with endometrioid adenocarcinoma, 16 patients with endometrial hyperplasia, and 4 patients with myoma uteri (which were used as controls). The occurrence of apoptosis was examined by using molecular biochemical techniques. The expression of Bcl-2 and Bax proteins was also investigated using immunohistochemical staining with appropriate antibodies. RESULTS: The labelling of DNA in situ indicated that apoptotic cells were sporadically seen in postmenopausal endometrium (5.2 +/- 2.1, n = 4) and endometrial hyperplasia without atypia (2.6 +/- 0.5, n = 9). In contrast, labelled cells were detected in atypical endometrial hyperplasia (15.9 +/- 2.2, n = 7), and their numbers increased intensely in adenocarcinoma (29.3 +/- 3.7, n = 20). Autoradiographic analysis revealed DNA laddering in many cases of carcinoma. Bcl-2 was highly immunopositive in hyperplasia without atypia (36.2 +/- 6.5%, n = 9), but was decreased in the atypical endometrial hyperplasia (16.3 +/- 4.8%, n = 7). Large fractions of the carcinoma (6.3 +/- 1.8%, n = 20) and normal endometrium (2.8 +/- 1.4%, n = 4) were immunonegative or slightly immunopositive to Bcl-2. In contrast, Bax immunoreactivity was more frequent and stronger in adenocarcinoma (43.6 +/- 4.1%, n = 20) than that in normal endometrium (17.6 +/- 6.7%, n = 4) and hyperplasia (7.2 +/- 2.2%, n = 16). CONCLUSIONS: These results suggest that cells in hyperplasia expressing Bcl-2 might have prolonged survival ability. Neoplastic cells in adenocarcinoma might show apoptosis in association with a decreased expression of Bcl-2 and an increased expression of Bax. Therefore, the frequency of apoptosis and the expression of Bcl-2 and Bax might be correlated with carcinogenesis in the uterine endometrium of humans.

Adenocarcinoma↗

Mammary tumorigenesis in chemical carcinogen-treated mice. IV. Induction of mammary ductal hyperplasias.

BALB/cCrgl, C57BL/Ki, and (C57BL/Ki X DBAf)F1 mice were treated with 7,12-diemthylbenz[a]anthracene (DMBA) or urethan to determine conditions that would induce a high frequency of ductal hyperplasias in the mammary gland. Among virgin BALB/c mice treated with either 3.0 or 4.0 mg DMBA, ductal hyperplasias and mammary tumors were present in 50% and 31% of the mice, respectively. These ductal hyperplasias were characterized by intraluminal epithelial hyperplasia and capped by endbud-like structures that appeared abnormal. Hyperplastic alveolar nodules were not seen. Most mammary tumors were adenocarcinomas rather than the adenocanthomas observed in DMBA-treated, pituitary isograft-bearing BALB/c mice. The predominant mammary lesions in urethan-treated, pituitary isograft-bearing C57BL and (C57BL X DBAf)F1 mice were terminal duct (lobular) hyperplasias characterized by intraluminal epithelial hyperplasia; the urethan-induced mammary tumors were a mixture of adenocarcinomas (36%), adenoacanthomas (5%), and fibroadenomas (59%). The induction by chemical carcinogens of intraductal hyperplasias in a relatively high incidence, with associated mammary neoplasms, provides a system for study of the process of tumor progression in lesions similar to suspected high-risk lesions occurring in human breast cancer.

9,10-Dimethyl-1,2-benzanthracene↗

Papillary urothelial hyperplasia. A precursor to papillary neoplasms.

Precursor lesions of papillary urothelial neoplasms have not been well characterized. We reviewed the surgical pathology files of the Johns Hopkins Hospital and three regional hospitals from 1992 to present. Sixteen cases of papillary hyperplasia, defined as undulating urothelium arranged into thin mucosal papillary folds, were identified (in 11 men and five women: age range, 40-89 years). Relative to the diagnosis of papillary hyperplasia, nine patients had a history of papillary urothelial neoplasms; in one of these cases, the patient also had subsequent papillary urothelial neoplasms, and two of these patients had concurrent papillary urothelial neoplasms with papillary hyperplasia. In one of these nine cases, papillary hyperplasia arose in the scar of a prior papillary urothelial neoplasm. In two cases, the patients had concurrent, yet no prior history, of papillary urothelial neoplasms. Of these 11 cases, three had multiple resections showing papillary hyperplasia over time. In case 12, the patient had a history of moderate urothelial atypia. The remaining four patients had no history of papillary urothelial neoplasms or urothelial atypia. We describe papillary hyperplasia as a well-defined entity that is usually asymptomatic and generally found on routine follow-up cystoscopy for papillary urothelial neoplasms. Papillary hyperplasia appears to be a precursor lesion of low-grade papillary urothelial neoplasms.

Adult↗

Postatrophic hyperplasia of the prostate gland: a detailed analysis of its morphology in needle biopsy specimens.

Postatrophic hyperplasia is a histologic pattern showing atrophic and hyperplastic glands, sometimes with a small acinar configuration. Because distinction from small acinar carcinoma may be challenging, particularly in needle biopsy specimens, we studied 56 needle biopsy specimens containing 68 foci to ascertain the morphologic spectrum of postatrophic hyperplasia. All foci showed a distinct lobular small acinar proliferation with varying proportions of atrophic and hyperplastic glands. Gland size was typically variable, predominantly of small caliber but occasionally of intermediate to larger caliber. Round, oval, elongated, slitlike and stellate glands were seen. The nuclei were generally regular without hyperchromasia, with rare small nucleoli seen in 10 (15%) foci. The cytoplasm was variable, ranging from scant in atrophic glands to moderate or abundant and clear or occasionally eosinophilic in hyperplastic glands. An irregular internal gland contour was noted in glands with features of both atrophy and hyperplasia. Basal cells were apparent by light microscopy in most foci, although their distribution within foci and between foci varied. This finding was confirmed in all 26 cases studied with the high molecular weight cytokeratin immunohistochemical stain (34betaE12). Associated pathology included adenocarcinoma (12%), high-grade prostatic intraepithelial neoplasia (3%), atrophy distinct from foci of postatrophic hyperplasia (55%), and atypical adenomatous hyperplasia (2%). Adjunctive features of cancer were not seen in any of the foci of postatrophic hyperplasia. Familiarity with the histologic features of postatrophic hyperplasia will allow its confident separation from cancer, especially in limited biopsy material.

Aged↗