A case of sarcomatoid carcinoma of the bladder (SCB) presenting as a giant intravesical mass in a 75-year-old man complaining of lower urinary tract swmptoms (LUTS), abdominal pain and fever is reported. SCB is a rare (0.1% of all primary bladder tumors), aggressive cancer with a complex histology (a biphasic tumor with malignant epithelial and mesenchymal elements) and poor prognosis.
Adrenomedullin (AM) is a hypotensive peptide, that acts via the calcitonin receptor-like receptor (CRLR), whose interaction with the subtypes 2 and 3 of a family of receptor activity-modifying proteins (RAMP) gives rise to two distinct AM receptors, named AM1 and AM2 receptors. AM derives from the post-translational proteolytic cleavage of pro(p)AM, the last step of which involves the conversion of the inactive AM to active AM by the peptidyl-glycine alpha-amidating monooxigenase (PAM). Compelling evidence suggests that AM, in addition to exerting its well-known regulatory action on blood pressure and water and electrolyte balance, also possesses a growth promoting effect in several normal and neoplastic tissues, including human prostate. Conventional reverse transcription (RT)-polymerase chain reaction (PCR) demonstrated the expression of pAM, PAM, CRLR and RAMP(1-3) mRNAs in both prostate hyperplasias (PH) and carcinomas (PC), and semiquantitative PCR showed that pAM, PAM and RAMP3 mRNA expression was higher in PCs than PHs. Radioimmunoassay measured higher concentrations of immunoreactive AM in PCs than PHs. The expression of pAM, CRLR and RAMP1,2 mRNAs was also detected in the PC-derived cell lines PC-3 and DU-145, RAMP3 expression being restricted to the latter line. AM did not affect the growth rate (duplication time) of PC-3 cells, but it did significantly increase that of DU-145 cells. The growth promoting effect of AM was found to ensue from both the rise in the proliferation rate and the lowering in the apoptosis rate of DU-145 cells. These effects of AM were counteracted by the AM receptor antagonists CGRP(8-37) and AM(22-52), the former antagonist, which is more selective for AM2 than AM1 receptors, being more effective than the latter one. Both antagonists were per se able to induce a slow, but significant decrease in the basal growth rate of DU-145 cells by inhibiting proliferation and enhancing apoptosis, again CGRP(8-37) being more effective than AM(22-52). Taken together, our findings allow us to suggest that: i) endogenous AM system plays an important autocrine-paracrine growth promoting action in the human prostate, being possibly involved in the development of the malignant phenotype of epithelial cells; and ii) the tumor promoting effect of AM in the human prostate is mainly mediated by the AM2 receptor (CRLR/RAMP3) subtype.
11beta-Hydroxysteroid dehydrogenase types 1 and 2 (11betaHSD1 and 11betaHSD2) are two isoenzymes that convert inactive glucocorticoids (e.g., cortisone) to their active forms (e.g., cortisol) and vice versa. Abundant evidence indicates that 11betaHSD2 is expressed as mRNA and protein in both adrenal cortex and adrenal tumors. In contrast, 11betaHSD1 has been investigated to a much lesser degree. We therefore studied and compared the expression and activity of the two isoenzymes in the human adrenal cortex (HAC) and cortisol-secreting adenomas (CSAs).Six HAC and six CSA specimens were studied. 11betaHSD1 and 11betaHSD2 gene expression was studied by conventional and semiquantitative reverse transcription-polymerase chain reaction. 11betaHSD1 and 11betaHSD2 activity was assayed by measuring the capacity of both microsomal fraction and tissue fragments to convert [3H]cortisone to [3H]cortisol and vice versa. Steroid hormones were separated and purified by high-performance liquid chromatography, and cortisol concentration was measured by radioimmunoassay.Semiquantitative reverse transcription-polymerase chain reaction and enzymatic assay demonstrated higher 11betaHSD1 expression and activity and lower 11betaHSD2 expression and activity in CSAs than in HACs. CSA slices secreted larger amounts of cortisol than did HAC specimens, and the cholesterol side-chain-cleaving enzyme inhibitor aminoglutethimide, by blocking the early step of steroid synthesis, reduced cortisol secretion by approximately 70%. Aminoglutethimide decreased [3H]cortisol production from [3H]cortisone and increased [3H]cortisone production from [3H]cortisol in both tissues, thereby annulling differences in 11betaHSD1 and 11betaHSD2 activity between HACs and CSAs.Collectively, our findings indicate that 1) both 11betaHSD isoenzymes are expressed as mRNA and proteins in the HAC and CSA, with 11betaHSD1 upregulated and 1betaHSD2 downregulated in CSAs; and 2) 11betaHSD1 and 11betaHSD2 activity is positively and negatively correlated with the intracellular concentration of steroid hormones. Hence, 11betaHSD isoenzymes could act as amplifiers of the secretagogue effect of agonists and could contribute to the elevated hormonal secretion of CSAs.
Clinical recurrence in the absence of biochemical PSA failure is uncommon and accounts for less than 1%; we report a rare case of solitary lung metastasis in a patient with undetectable PSA level (<0.1 ng/mL) after radical prostatectomy (RP) for prostate cancer (PCa). An asymptomatic 75-year-old man nine years after RP showed a solitary lung mass (about 2 cm) at chest radiography; the 18-FDG-PET/CT confirmed the presence of an isolated mass suspicious for primitive pulmonary cancer. The initial histological specimen after RP showed a mixed acinar and ductal PCa (Gleason score 7, pT3aNO stage, negative surgical margins). A segmental pulmonary resection was performed and definitive specimen demonstrated a single ductal PCa metastasis; after six months from surgery the patient was free from recurrence. In conclusion, in patients with atypical PCa variants imaging studies may be considered in the follow up even in presence of undetectable PSA because they could benefit from early salvage therapy.
To evaluate accuracy of Ki-67 expression on biopsy specimens in comparison with quantitative histology findings for preoperative prostate cancer (PCa) staging. From January 2008 to January 2010, 126 patients (median age 63 years) underwent radical retropubic prostatectomy; median PSA was 9.1 ng/mL; 98 and 28 patients had a clinical stage T1c and T2, respectively. The following variables of quantitative histology were evaluated as predictive of non organ-confined (OC) PCa: Gleason score > 6, TPC > 20%, GPC > 50%, cancer-positive cores > 2, presence of cancer-positive cores in both lateral margins and bilateral PCa. Value of Ki-67% staining in all cancerous cores was calculated. Sixty (47.7%) patients had a non OC-PCa with positive nodes in 12 (20%) cases. The mean Ki-67 score was 4.4%: 3.7% in OC-PCa and 5.6% in non-OC-PCa, respectively. Predictive positive value (PPV) of quantitative histology, Ki-67 (cut-off > 5%) and both parameters to predict a non-OC-PCa vs an OC-PCa was equal to 90%, 40% and 93.4%, vs 36.6%, 78.8% and 78.8%, respectively. Ki-67 staining on biopsy specimens does not improve quantitative histology in predicting non-OC-PCa; moreover, the low expression of Ki-67, even in presence of advanced disease, decreases its prognostic value in predicting an OC-PCa.
Transrectal ultrasound (TRUS), routinely performed by urologists to guide prostate biopsy, could be usefully employed in atypical cases. We report our experience in some patients in whom TRUS allowed to obtain a diagnosis in a faster and easier way in comparison to other instrumental procedures usually recommended.
Abstract —Proadrenomedullin N-terminal 20 peptide (PAMP) is a 20–amino acid hypotensive peptide expressed in the adrenal medulla. We investigated the localization and function of PAMP receptors in the human adrenal gland. Autoradiography showed the presence of [ 125 I]PAMP-binding sites in both zona glomerulosa and adrenal medulla that were displaced by cold PAMP and PAMP(12–20) but not by other preproadrenomedullin-derived peptides. PAMP, but not PAMP(12–20), counteracted, in a concentration dependent manner, both aldosterone response of zona glomerulosa cells and catecholamine response of adrenal medulla cells to BAYK-8644, the selective agonist of voltage-activated Ca 2+ channels, as well as to K + and angiotensin II. PAMP(12–20) partially reversed this antisecretagogue effect of PAMP. Collectively, these findings suggest (1) that PAMP inhibits Ca 2+ -dependent, agonist-stimulated aldosterone and catecholamine secretion, acting via specific receptors and through a mechanism involving the impairment of Ca 2+ influx; and (2) that PAMP(12–20) acts as a weak antagonist of PAMP receptors, thereby suggesting that both C- and N-terminal sequences of the PAMP molecule are required for this peptide to exert its antisecretagogue action on the human adrenal gland.
11beta-Hydroxysteroid dehydrogenase type 1 and type 2 (11betaHSD1 and 11betaHSD2) isozymes catalize the conversion of inactive glucocorticoids (e.g. cortisone) to their active forms (e.g. cortisol) and vice versa, respectively. Reverse transcription-polymerase chain reaction allowed the detection of 11betaHSD1 and 11betaHSD2 mRNAs in the human adrenal cortex, liver, kidneys, as well as in six aldosterone-secreting adenomas. 11betaHSD1 and 11betaHSD2 activity, as evaluated by the capacity of the microsomal fraction to convert [3H]cortisone to [3H]cortisol and vice versa, was detected in both human adrenal cortex and aldosteronomas, although it was less elevated than in liver and kidneys. Aldosteronomas possessed more intense 11betaHSD1 activity and less intense 11betaHSD2 activity than the normal adrenal cortex. The hypothesis is advanced that the elevated local concentration of steroid-hormone intermediates occurring in aldosteronomas up-regulates 11betaHSD1 and down-regulates 11betaHSD2, thereby contributing to their enhanced steroidogenic function.
