Virgil Gadaleanu

Inflammatory Pseudotumor and Sarcoma of Urinary Bladder: Differential Diagnosis and Outcome in Thirty-Eight Spindle Cell Neoplasms

We assessed diagnostic criteria among 38 spindle cell tumors of the urinary bladder and obtained follow-up in 36 patients. Patients comprised 28 males and 10 females aged 2.5 months to 87 years. Hematuria was the commonest presenting symptom (27 patients). After review and immunohistochemical workup, 17 patients had inflammatory pseudotumor (myofibroblastic tumor), 4 postoperative spindle cell nodule, 1 leiomyoma, 13 sarcoma (7 low-grade; 6 high-grade), and 3 carcinoma. Mean age was 38 years for pseudotumor (range 15 to 74), 65 for postoperative spindle cell nodule, 51 for sarcoma, and 76 for carcinoma. Size of pseudotumor averaged 4.4 ± 0.7 cm (range 1.5 to 13.0), similar to sarcoma, 4.0 ± 0.6 cm (range 0.5 to 7.0). Similar proportions of benign tumors and sarcomas had muscularis propria invasion. The criteria that best differentiated sarcoma from inflammatory pseudotumor were presence of necrosis at the tumor-detrusor muscle interface in muscle-invasive cases, and nuclear atypia. Sarcoma also had less prominent microvasculature, less variable cellularity, consistently ≥1 mitotic figure per 10 high-power fields, and predominant acute inflammation without plasma cells. p53 protein nuclear immunostaining was moderate, unlike the rare to absent staining in pseudotumors. Because all 12 sarcomas were desmin-negative, we did not call them leiomyosarcoma; they overlapped with benign tumor in epithelial, mesenchymal, and actin immunostaining. Among 12 sarcoma patients, 2 died of tumor (at 3 months). Two of four experienced tumor recurrence after partial cystectomy (2 and 26 months). No pseudotumors recurred after transurethral resection or partial cystectomy, although one patient, 5 months after transurethral resection, had histologically identical pseudotumor that the surgeon considered residual. Another patient with pseudotumor, not a candidate for tumor ablation after transurethral resection, had continued tumor growth and he died of urosepsis. In conclusion, inflammatory pseudotumor, although overlapping with sarcoma in presentation, age range, and size, does not metastasize and remains histologically distinct from low-grade sarcoma.

Localization and mRNA expression of somatostatin receptor subtypes in human prostatic tissue and prostate cancer cell lines.

Somatostatin (SST) plays an important regulatory role in the physiological control of various organs including the prostate. Somatostatin receptors (SSTRs) and SST analogs are potential targets for prostate cancer treatment, especially since it has been shown that SST analogues are clinically effective in the treatment of advanced prostate cancer. The presence of SST containing neuroendocrine (NE) cells in the epithelium of the human prostate and their suggested role in the paracrine regulation of this gland prompted us to study the potential expression of somatostatin receptors (SSTRs) in human prostatic tissue and prostate cancer cell lines. Using the reverse transcriptase polymerase chain reaction (RT-PCR), we found the SSTR subtypes 1-3 in stromal cells and in prostate cancer cell lines LNCaP, PC-3 and DU 145. Immunohistochemical analysis of 27 radical prostatectomy specimens demonstrated the presence of hSSTR1 in a subpopulation of cancerous and NE cells, whereas hSSTR2 was found in the stroma, peritumoral blood vessels and tumor cells. Receptor subtype 3 was demonstrated to be present on the cell membrane of BPH and malignant areas. A strong immunoreaction (IR) of hSSTR4 was found in tumor cells, as compared with a less intense IR in adjacent BPH areas. Somatostatin receptor subtype 5 was not detectable. Western blot analysis revealed immunoreactive bands of molecular weight between 44-60 kDa. In summary, the present study clearly demonstrates the presence of hSSTR1-3 in tumoral and nontumoral epithelial cells as well as in the stromal compartment, whereas hSSTR4 was found to be confined to epithelial cells, and SSTR5 was not detectable.

Radiation enteropathy and leucocyte-endothelial cell reactions in a refined small bowel model

BackgroundLeucocyte recruitment and inflammation are key features of high dose radiation-induced tissue injury. The inflammatory response in the gut may be more pronounced following radiotherapy due to its high bacterial load in comparison to the response in other organs. We designed a model to enable us to study the effects of radiation on leucocyte-endothelium interactions and on intestinal microflora in the murine ileum. This model enables us to study specifically the local effects of radiation therapy.MethodA midline laparotomy was performed in male C57/Bl6 mice and a five-centimetre segment of ileum is irradiated using the chamber. Leucocyte responses (rolling and adhesion) were then analysed in ileal venules 2 – 48 hours after high dose irradiation, made possible by an inverted approach using intravital fluorescence microscopy. Furthermore, intestinal microflora, myeloperoxidase (MPO) and cell histology were analysed.ResultsThe highest and most reproducible increase in leucocyte rolling was exhibited 2 hours after high dose irradiation whereas leucocyte adhesion was greatest after 16 hours. Radiation reduced the intestinal microflora count compared to sham animals with a significant decrease in the aerobic count after 2 hours of radiation. Further, the total aerobic counts, Enterobacteriaceae and Lactobacillus decreased significantly after 16 hours. In the radiation groups, the bacterial count showed a progressive increase from 2 to 24 hours after radiation.ConclusionThis study presents a refinement of a previous method of examining mechanisms of radiation enteropathy, and a new approach at investigating radiation induced leucocyte responses in the ileal microcirculation. Radiation induced maximum leucocyte rolling at 2 hours and adhesion peaked at 16 hours. It also reduces the microflora count, which then starts to increase steadily afterwards. This model may be instrumental in developing strategies against pathological recruitment of leucocytes and changes in intestinal microflora in the small bowel after radiotherapy.

Local radiotherapy of exposed murine small bowel: Apoptosis and inflammation

BackgroundPreoperative radiotherapy of the pelvic abdomen presents with complications mostly affecting the small bowel. The aim of this study was to define the features of early radiation-induced injury on small bowel.Methods54 mice were divided into two groups (36 irradiated and 18 sham irradiated). Animals were placed on a special frame and (in the radiated group) the exteriorized segment of ileum was subjected to a single absorbed dose of 19 or 38 Gy radiation using 6 MV high energy photons. Specimens were collected for histology, immunohistochemistry (IHC) and ELISA analysis after 2, 24 and 48 hours. Venous blood was collected for systemic leucocyte count in a Burker chamber.ResultsHistology demonstrated progressive infiltration of inflammatory cells with cryptitis and increased apoptosis. MIP-2 (macrophage inflammatory protein) concentration was significantly increased in irradiated animals up to 48 hours. No significant differences were observed in IL-10 (interleukin) and TNF-α (tumour necrosis factor) levels. IHC with CD45 showed a significant increase at 2 hours of infiltrating leucocytes and lymphocytes after irradiation followed by progressive decrease with time. Caspase-3 expression increased significantly in a dose dependent trend in both irradiated groups up to 48 hours.ConclusionAcute small bowel injury caused by local irradiation is characterised by increased apoptosis of crypt epithelial cells and by lymphocyte infiltration of the underlying tissue. The severity of histological changes tends to be dose dependent and may affect the course of tissue damage.

The nested variant of urothelial carcinoma: a rare but important bladder neoplasm with aggressive behavior Three case reports and a review of the literature

OBJECTIVE To describe our experience with the nested variant of urothelial carcinoma (UC-NV) of the bladder, by characterization of the clinical picture and the prognostic implications of this rare form of bladder neoplasm. MATERIALS AND METHODS Three cases of UC-NV of the bladder treated in our institutions were revised and data compared with previously published case-reports. RESULTS Three patients presented with advanced muscle-invasive UC-NV, of which two had lymph node metastasis at cystoprostatectomy. The histopathology in the latter two cases showed the same picture in the lymph node metastasis as in the primary tumor with nests of tumor cells with mild-moderate atypia. In all three cases the tumor involved a ureteric orifice or the bladder neck. CONCLUSION UC-NV is a rare but important histopathologic entity. It has a poor prognosis. At early stage, tumors might be difficult to differentiate from benign conditions and awareness of the condition is of outermost importance.

Anti-thrombin is expressed in the benign prostatic epithelium and in prostate cancer and is capable of forming complexes with prostate-specific antigen and human glandular kallikrein 2

Anti-thrombin, a member of the serpin family and an inhibitor of thrombin and blood coagulation factor Xa, was recently shown to inhibit angiogenesis and tumor growth. In the present study, we examined the expression of anti-thrombin in benign and malignant prostate gland. Using immunohistochemistry, anti-thrombin was found in prostate epithelium and stroma cells. Tissue microarrays of tumors (n = 112) and three different prostate cancer cell lines (PC-3, LNCaP, and DU-145) were all positive for anti-thrombin. Abundant expression in a population of prostatic tumor cells was further evidenced by in situ hybridization experiments. The immunostaining for anti-thrombin was confined to the cytoplasm, was most intense in Gleason grade 3 tumors, and in part overlapped with that of prostate-specific antigen. Western blotting of benign and malignant tissue homogenates revealed a predominant 58-kd anti-thrombin immunoreactive component. In vitro, anti-thrombin formed complexes more readily with human kallikrein 2, particularly in the presence of heparin, and less efficiently with prostate-specific antigen. Both complexes could be recognized by polyclonal and monoclonal IgGs against anti-thrombin. We conclude that anti-thrombin is widely expressed in prostate cancer but is gradually lost in tumors of high Gleason grade. Anti-thrombin may act as a local anti-angiogenic factor, the effect of which is partially lost in poorly differentiated prostatic tumors.

Aberrant expression of cystatin C in prostate cancer is associated with neuroendocrine differentiation.

To investigate the expression of cystatin C and the relationship with neuroendocrine differentiation and proliferation in benign and malignant prostatic tissues, as cystatin C, the most important inhibitor of human lysosomal cysteine proteases, is considered to be a major regulator of pathological protein degradation in inflammatory and neoplastic diseases.

Evaluation of DNA Ploidy Combined with a Cytometric Proliferation Index of Imprints from Core Needle Biopsies in Prostate Cancer

Objective: To evaluate if DNA ploidy analysis with a proliferation index (PI) derived from DNA cytometry of imprints from core needle biopsies predicts disease progression in patients with prostate cancer. Methods: Touch imprints were done on a consecutive series of core needle biopsies taken by the same urologist from 240 patients with suspected prostate cancer, 137 (46%) of whom were found to have prostate cancer and included in the study. Scattered cells to the right of the image cytometry (ICM) ploidy-establishing peak, the S-phase fraction, and those in the G2M area of the ICM DNA histograms, were counted in percent of the total number of tumor cells, this value being designated the ICM PI. Based on previous results in archival fine needle aspiration material, the following classification was used: DNA group I, diploid tumor with a low PI; DNA group II, diploid tumor with an intermediate PI and tetraploid tumor with a low or intermediate PI, and DNA group III, diploid or tetraploid tumor with high PI and all tumors with an aneuploid pattern. Results: Correlation was found to exist between DNA groups I–III and Gleason score (GS) (p < 0.0001), T-stage (p = 0.006), M-stage (p = 0.009) and disease progression (p < 0.0001). Among the 39 patients who had curative treatment and GS 5–7, the progression-free survival rate was 100% in DNA group I, as compared with only 38% in DNA group II and 55% in DNA group III within the follow-up period (p = 0.008). Conclusion: DNA ploidy combined with a PI derived from image cytometry of imprints from core needle biopsies yields additional prognostic information in patients with GS 5–7. Diploid tumors with a low PI (DNA group I) are associated with a low risk of disease progression.