Endothelin-1 overexpression: a potential biomarker of unfavorable prognosis in non-metastatic muscle-invasive bladder cancer.

Endothelin-1 (ET-1) is a multifunctional peptide exerting its effects via receptors A and B. ET-1 and its receptors, endothelin axis (ET axis), play a promoting role in cancer biology. Alterations of proteins of ET axis have been detected in non-metastatic muscle-invasive bladder cancer (NMMIBC). The objective of this study is to investigate the potential role of ET-1 tumor expression as a biomarker of prognosis, compared to other prognostic parameters (epidemiologic and pathologic), in NMMIBC. We prospectively included 40 consecutive, primary, high-grade NMMIBC patients. Tumor specimens after initial transurethral resection were stained immunohistochemically for ET-1. The ET-1 evaluation of expression was based on staining intensity (SI) of ET-1. SI was classified according to an arbitrary four-tiered scale (negative = 0, mild = 1, moderate = 2, strong = 3). Epidemiologic and pathologic parameters were analyzed, using univariate and multivariate statistics, for disease progression, progression-free survival (PFS), and overall survival (OS). ET-1 overexpression (SI = 3) was the unique parameter which associated significantly, both in univariate (log-rank test, p = 0.033) and multivariate (Cox regression analysis, p = 0.045, HR = 4.849, 95 % CI: 1.039-22.624) analysis, with an increased hazard ratio of progression. ET-1 overexpression (SI = 3) was also the unique parameter which associated, marginally significantly in univariate analysis (log-rank test, p = 0.056) and highly significantly in multivariate analysis (Cox regression analysis, p = 0.005, HR = 7.001, 95 % CI: 1.782-27.501), with an increased hazard ratio of death. Overexpression of ET-1 may be a potential biomarker of unfavorable prognosis in NMMIBC patients.

Lack of prognostic significance of p16 and p27 after radical prostatectomy in hormone-naïve prostate cancer.

BACKGROUND: Loss of normal cell cycle control is an early event in the evolution of cancer. The expression of cyclin-dependent kinase (CDK) inhibitors p16 and p27 has been previously associated with progression of prostate cancer (PC). 70 patients diagnosed with early stage PCwere treated with radical prostatectomy (RP) at our institution and their tumor specimens were immunohistochemically evaluated for expression of p16 and p27. Available clinical data of time to PSA recurrence were correlated with the examined parameters and combined with pre-operative PSA level, Gleason score and pathological TNM (pT) stage assessment. RESULTS: Nuclear overexpression of p16 was not associated with time to biochemical failure (BF) (p = 0.572). Same was the case for nuclear p27 overexpression (p = 1.000). Also, no significant correlations were found between either p16 or p27, and pre-operative PSA level, pT stage and Gleason grade. pT stage emerged as the only independent prognostic factor for biochemical recurrence (p = 0.01). CONCLUSIONS: These data question previously reported data supporting the prognostic relevance of both p16 and p27 proteins in early PC.

CD10 is inversely associated with nuclear factor-kappa B and predicts biochemical recurrence after radical prostatectomy.

INTRODUCTION: The cell surface endopeptidase CD10 (neutral endopeptidase) and nuclear factor-κB (NF-κB) have been independently associated with prostate cancer (PC) progression. We investigated the correlations between these two factors and their prognostic relevance in terms of biochemical (prostate-specific antigen, PSA) relapse after radical prostatectomy (RP) for localized PC. PATIENTS AND METHODS: The immunohistochemical expression of CD10 and NF-κB in samples from 70 patients who underwent RP for localized PC was correlated with the preoperative PSA level, Gleason score, pathological stage and time to PSA failure. RESULTS: CD10 expression was inversely associated with NF-κB expression (p < 0.001), stage (p = 0.03) and grade (p = 0.003), whereas NF-κB was directly related with stage (p = 0.006) and grade (p = 0.002). The median time to PSA failure was 56 months. CD10 and NF-κB were directly (p < 0.001) and inversely (p < 0.001) correlated with biochemical recurrence-free survival, respectively. CD10 expression (p = 0.022) and stage (p = 0.018) were independently associated with time to biochemical recurrence. CONCLUSION: Low CD10 expression is an adverse prognostic factor for biochemical relapse after RP in localized PC, which is also associated with high NF-κB expression. Decreased CD10 expression which would lead to increased neuropeptide signaling and NF-κB activity may be present in a subset of early PCs.

Clear-cell renal cell carcinoma single urinary bladder metastasis: a case report and review of the literature.

Renal cell carcinoma (RCC) is the most frequent solid lesion accounting for ~90% of all kidney malignancies. Clear-cell RCC (ccRCC) represents the most frequent subtype. Urinary bladder is a rare metastatic site either synchronous or metachronous. Hereby, we report the case of an 85-year-old male patient with a single urinary bladder metastasis due to ccRCC and we present a review of the literature.

Poorly differentiated muscle-invasive giant cell tumor of the bladder leads to unfavorable clinical outcome.

Urothelial carcinoma of the urinary bladder is a common clinical entity. Recently, researchers focused on the emerging clinical significance of histologic variants, because they may need special therapy and their prognosis differs. Hereby, we describe a case of a giant cell osteoclast-like urothelial carcinoma of the urinary bladder.

Mixed epithelial and stromal tumor-adult cystic nephroma of the kidney: a case report with immunohistochemical analysis.

The mixed epithelial and stromal tumor family of kidney contain neoplasms with biphasic epithelial and stromal component. According to the 2016 World Health Organization Classification, they encompasses a spectrum of tumors ranging from predominantly cystic tumors (adult cystic nephroma) to tumors that are variably solid (Mixed epithelial and stromal tumor-MESTs). We present the case of a 20-year-old woman with an adult cystic nephroma which was verified by immunohistochemical examination.

Simultaneous clinical resolution of focal segmental glomerulosclerosis associated with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab.

BACKGROUND: Although renal involvement in advanced haematological malignancies is common, glomerulonephritis associated with lymphoproliferative disorders is rare, and the related pathogenetic mechanisms are still poorly understood. We present a rare case of chronic lymphocytic leukaemia(CLL)-associated focal segmental glomerulosclerosis with nephrotic-range proteinuria. CASE PRESENTATION: A 53-year-old Caucasian man, previously healthy, with no history of hypertension, alcohol use or smoking presented with rapid weight gain, massive peripheral oedema, and hypertension. Laboratory findings included a white blood cell count of 49,800 cells/mm3 with an absolute lymphocyte count of 47,000 cells/mm3, serum albumin of 2.3 g/dL, urea 65 mg/dL, and creatinine 1.5 mg/dL. A 24-hour urine collection contained 7.1 g protein and significant haematuria. A peripheral blood smear showed mature lymphocytosis and smudge cells. Diagnostic imaging showed mild paraaortic lymphadenopathy with no renal abnormalities. Bone marrow aspiration and trephine biopsy showed diffuse and focal infiltration with B-CLL lymphocytes. Percutaneous renal biopsy revealed total sclerosis in 3/21(14%) of the glomeruli and focal and segmental solidification and sclerosis in 4/21 (19%) glomeruli. A regimen of fludarabine, cyclophosphamide and rituximab was successful in inducing remission of the CLL and clinical resolution of the nephritic-range proteinuria. CONCLUSIONS: A multidisciplinary approach to monitor both the malignancy and the glomerular lesions is crucial for the optimal management of paraneoplastic glomerulonephritis. Although chemotherapy with fludarabine, cyclophosphamide and rituximab successfully treated CLL-associated nephrotic syndrome in our patient, further studies are required to confirm efficacy in this setting.

Endothelin-1 indicates unfavorable prognosis in primary high-grade non-muscle-invasive urothelial bladder cancer.

OBJECTIVE: To conduct a prospective study of the potential prognostic role of endothelin-1 (ET-1) in a cohort of primary high-grade non-muscle-invasive urothelial bladder cancer patients, who were treated with adjuvant intravesical Bacillus Calmette-Guérin (BCG). MATERIAL AND METHODS: Patients with primary high-grade nonmuscle- invasive urothelial bladder cancer, who received postoperatively induction and maintenance BCG therapy, were prospectively included. Recurrence and progression were histologically proven. Immunohistochemical staining for ET-1 was assessed. Epidemiological, pathological and clinical parameters as well as the expression of ET-1 in tumor specimens were statistically analyzed for recurrence, progression, recurrence-free survival (RFS) and progression-free survival (PFS). RESULTS: ET-1 associates significantly with recurrence (p = 0.000), progression (p = 0.000), RFS (p = 0.000) and PFS (p = 0.000). The patient's age is also significant for recurrence (p = 0.003, OR = 1.273 95% CI: 1.086-1.492) and RFS (p = 0.013). CONCLUSIONS: ET-1 seems to deteriorate prognosis in patients suffering from primary high-grade non-muscle-invasive urothelial bladder cancer, who are treated with adjuvant BCG instillations. Furthermore, the patient's age associates with an increased likelihood for recurrence.

Low-Grade Appendiceal Mucinous Neoplasm (LAMN) Primarily Diagnosed as an Ovarian Mucinous Tumor.

BACKGROUND: Low-grade appendiceal mucinous neoplasms (LAMN) are detected in 0.7 to 1.7% of all appendicectomies. The diagnosis can be challenging, particularly in female patients where the differential diagnosis of primary appendiceal and ovarian mucinous neoplasms is unclear. Case Presentation. A 71-year-old female was referred to our tertiary hospital with the working diagnosis of a right ovarian cystic tumor. The lesion was identified through a transvaginal ultrasound performed for vague lower abdominal pain symptoms. CT scan confirmed these findings. Intraoperatively, an appendiceal mucocele was identified and a right hemicolectomy was performed. The histopathology examination revealed a LAMN. Six months later, the patient remains disease-free. A close biannual oncological follow-up has been suggested. CONCLUSION: This case underlines the difficulty in determining the origin of mucinous neoplasms of the right pelvic area. Mucocele of the appendix should be considered in the differential diagnosis of a mass in the right iliac fossa.

INCENP (inner centromere protein) is overexpressed in high grade non-Hodgkin B-cell lymphomas.

Inner centromere protein (INCENP) is a member of the Chromosomal Passenger Complex (CPC), which is a four member protein complex essential for proper completion of mitosis and cell division (cytokinesis). Inappropriate chromosomal segregation and cytokinesis due to deregulated expression of chromosome passenger proteins may lead to aneuploidy and cancer including lymphomas. According to our knowledge this is the first study investigating immunohistochemical expression of INCENP in lymphoma cases and cancer tissues in general. Our purpose was to characterize the expression of INCENP in cases of non-Hodgkin B-cell lymphomas, to compare the immunoreactivity between low and high grades and to evaluate the correlation between INCENP and MIB-1 labeling indices. We examined INCENP and MIB-1 immunoreactivity in paraffin sections of 55 samples of non-Hodgkin B-cell lymphomas, obtained from 55 patients, 31 men and 24 women. Thirty were of high grade and 25 were of low grade. Our results showed significantly higher nuclear immunohistochemical expression of INCENP in high grade B-cell lymphomas versus low grade ones. Also INCENP expression was significantly correlated with MIB-1 labeling index. Taken together our results point to a possible association between increased INCENP immunostaining and B-cell lymphoma aggressiveness and also stress the need for further investigating the expression of INCENP and other mitotic regulatory proteins in lymphomas and other malignant neoplasms.

Primary renal epithelioid hemangioendothelioma.

BACKGROUND: Epithelioid hemangioendothelioma (EH) is a rare vascular neoplasm with an unpredictable malignant potential that has been described mainly in soft tissue, liver, and lung. CASE REPORT: We report a case of a primary renal EH in a 54-year-old woman who presented with a 3-month history of abdominal pain. Abdominal ultrasound and computed tomography scan revealed a solitary mass of 4.0 x 3.2 cm in the outer surface of the right kidney. Nephron-sparing surgery was performed. On the basis of the histological and immunohistochemical findings, the diagnosis of EH was made. The patient was free of disease 6 months after surgery. CONCLUSIONS: Although EH may have a histologically benign appearance and can be treated using a nephron-sparing approach, this neoplasm is potentially malignant urging the need for a long-term follow-up in these patients.

Fine needle aspiration cytology of a primary malignant peripheral nerve sheath tumor arising in the parotid gland: a case report.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is an uncommon mesenchymal neoplasm showing nerve sheath differentiation, usually arising in large nerves of the trunk and extremities. Primary location in the parotid gland is rare. We describe fine needle aspiration (FNA) findings in a case of MPNST in the parotid gland. Differential diagnostic problems encountered in interpretation are discussed. CASE: A 39-year-old man underwent FNA of a well-circumscribed, painless, mobile mass of the parotid gland. Smears were cellular, with clusters of tightly packed spindle or oval cells arranged in a storiform or whorled pattern, showing clearly malignant features. Elongated nuclei with tapered ends and many angulated nuclei were encountered. The background contained abundant necrotic material with dispersed malignant nuclei. Neoplastic cells were positive for vimentin and weakly positive for S-100 and negative for cytokeratins 8 and 18 and HMB-45. Cytologic diagnosis was positive for malignant cells consistent with a spindle cell sarcoma, with morphologic features compatible to neural differentiation, confirmed by histologic examination. CONCLUSION: This case illustrates that attention to moiphologic criteria suggestive of nerve sheath phenotype supported by immunocytochemical data is extremely helpful and reliable in the diagnostic approach to MPNSTs, even in rare locations.

Primary High-Grade Non-Muscle-Invasive Bladder Cancer: High NFκB Expression in Tumor Specimens Distinguishes Patients Who are at Risk for Disease Progression.

To investigate the potential prognostic role of NFκB expression in primary high-grade non-muscle-invasive bladder cancer. Patients with primary high-grade non-muscle-invasive bladder cancer who received induction and maintenance BCG therapy were retrospectively included. Recurrence and progression were histologically proven. Intensity and extent of immunochemistry were assessed. The final evaluation of the NFκB staining was done by combining intensity and extent as ΄΄product΄΄ and expressing it as ΄΄low NFκΒ expression΄΄ or ΄΄high NFκB expression΄΄. Epidemiological, pathological, clinical parameters and NFκB expression were statistically analyzed for recurrence (REC), progression (PR), recurrence-free survival (RFS) and progression-free survival (PFS). NFκB is significantly associated with disease progression (p < 0,001 in univariate analysis and p = 0,001, Odds Ratio = 14,484, 95% Confidence Interval = 3187-65,821 in multivariate analysis), but not with recurrence. The median value of NFκB expression as ΄΄product΄΄ is significantly higher for the patients with progression in comparison to patients with recurrence only (p = 0,003) and patients without recurrence or progression (p = 0,001). Patients' age is significantly associated (p = 0,001 in univariate analysis and p = 0,003, Odds Ratio = 1273, 95% Confidence Interval = 1086-1492 in multivariate analysis) with disease recurrence. High NFκB expression in primary high-grade non-muscle-invasive bladder cancer, treated with postoperative intravesical BCG immunotherapy, could represent an unfavorable prognostic factor.

Giant abdominal osteosarcoma causing intestinal obstruction treated with resection and adjuvant chemotherapy.

Extraskeletal osteosarcoma (ESOS) is an uncommon tumor that accounts for 1% of all soft tissue sarcomas and 4% of all osteosarcomas. Its presentation may be atypical, while pain has been described as the most common symptom. Radiological findings include a large mass in the soft-tissues with massive calcifications, but no attachment to the adjacent bone or periosteum. We present the case of a 73-year-old gentle man who presented with a palpable, tender abdominal mass and symptoms of bowel obstruction. Computer tomography images revealed a large space-occupying heterogeneous, hyper dense soft tissue mass involving the small intestine. Explorative laparotomy revealed a large mass in the upper mesenteric root of the small intestine, measuring 22 cm × 12 cm × 10 cm in close proximity with the cecum, which was the cause of the bowel obstruction. Pathology confirmed the diagnosis of an ESOS. ESOS is an uncommon malignant soft tissue tumor with poor prognosis and a 5-year survival rate of less than 37%. Regional recurrence and distant metastasis to lungs, regional lymph nodes and liver can occur within the first three years of diagnosis in a high rate (45% and 65% respectively). Wide surgical resection of the mass followed by adjuvant chemotherapy or radiotherapy has been the treatment of choice.

p53 and cyclooxygenase-2 expression are directly associated with cyclin D1 expression in radical prostatectomy specimens of patients with hormone-naïve prostate cancer.

Prostate cancer (PCa) is a potentially curable disease when diagnosed in early stages and subsequently treated with radical prostatectomy (RP). However, a significant proportion of patients tend to relapse early, with the emergence of biochemical failure (BF) as an established precursor of progression to metastatic disease. Several candidate molecular markers have been studied in an effort to enhance the accuracy of existing predictive tools regarding the risk of BF after RP. We studied the immunohistochemical expression of p53, cyclooxygenase-2 (COX-2) and cyclin D1 in a cohort of 70 patients that underwent RP for early stage, hormone naïve PCa, with the aim of prospectively identifying any possible interrelations as well as correlations with known prognostic parameters such as Gleason score, pathological stage and time to prostate-specific antigen (PSA) relapse. We observed a significant (p = 0.003) prognostic role of p53, with high protein expression correlating with shorter time to BF (TTBF) in univariate analysis. Both p53 and COX-2 expression were directly associated with cyclin D1 expression (p = 0.055 and p = 0.050 respectively). High p53 expression was also found to be an independent prognostic factor (p = 0.023). Based on previous data and results provided by this study, p53 expression exerts an independent negative prognostic role in localized prostate cancer and could therefore be evaluated as a useful new molecular marker to be added in the set of known prognostic indicators of the disease. With respect to COX-2 and cyclin D1, further studies are required to elucidate their role in early prediction of PCa relapse after RP.

Expression of neutral endopeptidase, endothelin-1, and nuclear factor kappa B in prostate cancer: interrelations and associations with prostate-specific antigen recurrence after radical prostatectomy.

Objective. To study the impact of the neutral endopeptidase (NEP)/neuropeptides (NPs) axis and nuclear factor kappa B (NFκB) as predictors of prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP). Patients and Methods. 70 patients with early-stage PC were treated with RP and their tumor samples were evaluated for expression of NEP, endothelin-1 (ET-1) and NFκB (p65). Time to PSA recurrence was correlated with the examined parameters and combined with preoperative PSA level, Gleason score, pathological TNM (pT) stage, and surgical margin (SM) assessment. Results and Limitations. Membranous expression of NEP (P < 0.001), cytoplasmic ET-1 (P = 0.002), and cytoplasmic NFκB (P < 0.001) were correlated with time to PSA relapse. NEP was associated with ET-1 (P < 0.001) and NFκB (P < 0.001). ET-1 was also correlated with NFκB (P < 0.001). NEP expression (P = 0.017), pT stage (P = 0.013), and SMs (P = 0.036) were independent predictors of time to PSA recurrence. Conclusions. There seems to be a clinical model of NEP/NPs and NFκB pathways interconnection, with their constituents following inverse patterns of expression in accordance with their biological roles and molecular interrelations.

AFP-producing hepatoid adenocarcinoma of the stomach: a case report.

Hepatoid gastric adenocarcinoma is a distinct variant of gastric carcinoma which represents a comparatively small percentage of the disease and in many cases is producing high serum alpha-fetoprotein (AFP). We report a case of an 85 year old woman who presented with epigastric and right upper quadrant pain and was found in a CT scan to have multiple liver nodules and a gastric antrum mass as well as an elevated AFP level of 155000 IU/ml. An endoscopic biopsy of the antral mass showed hepatoid variant of gastric adenocarcinoma. The patient refused any further treatment and died 4 months after diagnosis. Hepatoid gastric adenocarcinoma is considered to have a poor prognosis, although cases with survival of several years have been reported. Poor outcome in most of the cases is due to the fact that, as in our patient, metastatic disease is already present at diagnosis.

Fascin determination in urothelial carcinomas of the urinary bladder: a marker of invasiveness.

CONTEXT: Invasion and the depth of invasion affect significantly the prognosis in urothelial carcinomas. The histopathologic evaluation of invasion may be problematic in some cases. Application of new immunohistochemical markers may facilitate the assessment of invasion. Fascin, one of these markers, is an actin-bundling protein involved in tumor cell migration. Fascin expression is increased in various carcinomas. Prior to this research, to our knowledge, only one study exists regarding fascin expression in urothelial carcinomas. OBJECTIVE: To characterize the expression of fascin in additional cases of urothelial carcinoma and to verify statistically a relationship between fascin overexpression and invasiveness in these tumors. DESIGN: We examined fascin immunoreactivity in 116 specimens of urothelial carcinomas obtained from 116 patients including 96 men and 20 women. Fifty-eight cases were ranked as low-grade carcinomas, pTa stage, and 58 cases were ranked as high-grade carcinomas--11 were ranked as stage pTa, 21 were ranked as pT1, and 26 were ranked as pT2 carcinomas. Fascin immunoreactivity was assessed semiquantitatively in tumor cells. In each case, we ascribed 3 immunoreactivity scores, one for extent, one for intensity, and a combined immunoreactivity score. RESULTS: The combined immunoreactivity score was significantly higher in invasive carcinomas. In addition, strong staining was observed exclusively in invasive carcinomas. None of the pTa tumors demonstrated intense staining, including those ranked at the higher grade. CONCLUSIONS: Our results point to an association between fascin immunostaining and urothelial carcinoma invasiveness and suggest that fascin overexpression may be a marker of aggressive urothelial carcinomas.

Tubulointerstitial nephritis and uveitis (TINU) syndrome in a 52-year-old female: a case report and review of the literature.

Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare entity first described in 1975, affecting mainly young women and adolescents. We present a case of a 52-year-old female patient (one of the oldest in the literature) who complained of fever, anorexia, nausea, and vomiting. After she was admitted to our hospital, laboratory tests revealed tubular proteinuria, elevated erythrocyte sedimentation rate (ESR), anemia, and renal insufficiency (serum creatinine 4.2 mg/dL) with metabolic acidosis. Ophthalmologic examination revealed anterior uveitis (iritis) and renal biopsy showed acute tubulointerstitial nephritis. The diagnosis of TINU syndrome was established and the patient was treated with oral corticosteroids. All symptoms and ophthalmologic abnormalities disappeared after 6 weeks of treatment. Renal function also recovered completely and remained stable at follow-up. TINU syndrome should be considered in the differential diagnosis of unexplained tubulointerstitial nephritis, especially in the presence of ocular findings. Corticosteroid therapy is still controversial, but it helps in the quick resolution of renal and mainly eye abnormalities.