[Monstrous scrotal leiomyoma: case report and literature survey]. / Monströses scrotales Leiomyom; Fallbericht und Überblick über die Literatur.

The scrotal leiomyoma is a rare benign tumour, deriving from the smooth muscle. This tumour entity constitutes a differential diagnosis to malignant testicular tumours. Up to now, only 8 cases have been reported in the literature. We report on a 63-year-old European patient, presenting in our clinic for further treatment with a now monstrous mass of the left testis (about 8 kg) that has been growing for about 30 years, After partial scrotalectomy and orchiectomy pathological analysis confirmed a left-sided leiomyoma of the testicular/paratestical tissue. This case shows that even rare tumours should be included in the differential diagnosis of a testicular tumour.

[Space-occupying lesion of the ribs]. / Raumforderung in der Rippe.

An osteolytic tumor of the 7(th) rib was surgically removed from a 40-year-old patient. Immunohistochemical investigations showed that neither epithelial markers nor B and T cell markers were expressed in the tumor tissue; however, there was strong expression of VS38 and vimentin. These results were compatible with a solitary plasmocytoma of the bone. Further immunohistochemical investigations detected an expression of the melanoma markers S-100 and melan-A. The diagnosis of a metastasis of an amelanotic malignant melanoma could therefore be verified.

[Pathological work-up of rectal cancer following partial/total mesorectal excision]. / Pathologische Aufarbeitung von Rektumkarzinomen mit partieller/totaler mesorektaler Exzision.

Total mesorectal excision (TME) refers to the anatomically accurate surgical resection of the rectum from its surrounding fascias and has become the gold standard for treating rectal cancer. The pathologist plays a key role in the assessment of these specimens and good pathological reporting of rectal cancer is essential to achieving the optimum possible results for patients with rectal cancer. In experienced hands, these techniques result in a dramatic improvement in cancer-related cure rates from 45% to 75% and a reduction in pelvic recurrences from 40% to 5%-10%. Moreover, preservation of sexual and urinary functions is possible in the majority of cases. This article reviews the pathological assessment of the TME specimen in detail with regards to current international guidelines and describes its anatomical background. In addition, particular issues relating to margins, lymph node dissection and effects of neoadjuvant therapy are discussed.

Differential expression of microRNA-675, microRNA-139-3p and microRNA-335 in benign and malignant adrenocortical tumours.

BACKGROUND: For the clinical management of adrenocortical neoplasms it is crucial to correctly distinguish between benign and malignant tumours. Even histomorphologically based scoring systems do not allow precise separation in single lesions, thus novel parameters are desired which offer a more accurate differentiation. The tremendous potential of microRNAs (miRNAs) as diagnostic biomarkers in surgical pathology has recently been shown in a broad variety of tumours. METHODS: In order to elucidate the diagnostic impact of miRNA expression in adrenocortical neoplasms, a cohort of 20 adrenocortical specimens including normal adrenal tissue (n=4), adrenocortical adenomas (ACAs) (n=9), adrenocortical carcinomas (ACCs) (n=4) and metastases (n=3) was analysed using TaqMan low density arrays to identify specific miRNA profiles in order to distinguish between benign and malignant adrenocortical lesions. Results were validated in a validation cohort (n=16). RESULTS: Concerning the differential diagnosis of ACAs and ACCs, 159 out of 667 miRNAs were up- and 89 were down-regulated in ACAs. Using real-time PCR analysis of three of the most significantly expressed single key miRNAs allowed separation of ACAs from ACCs. ACCs exhibited significantly lower levels of miR-139-3p (up to 8.49-fold, p<0.001), miR-675 (up to 23.25-fold, p<0.001) and miR-335 (up to 5.25-fold, p<0.001). A validation cohort of 16 specimen with known Weiss score showed up-regulation of miR-335 and miR-675 in the majority of cases with probable malignant course, although overlapping values exist. CONCLUSION: miRNA profiling of miR-675 and miR-335 helps in discriminating ACCs from ACAs. miRNA analysis may indicate malignant behaviour in cases with indeterminate malignant potential.

Protection from glycine at low doses in ischemia-reperfusion injury of the rat small intestine.

BACKGROUND: Glycine at high doses is known to protect the small intestine against ischemia-reperfusion (I/R) injury. Here, we studied whether glycine at low clinically applicable doses has a protective effect. METHODS: In series 1, intestinal I/R was induced in male Wistar rats by occlusion (90 min)/reopening (120 min) of the superior mesenteric artery. Glycine was intravenously infused for 30 min before ischemia (pre-ischemic infusion), and once again from 30 min before until 60 min after reperfusion. Total glycine doses applied over the 120-min infusion were 5, 10, 20, and 75 mg glycine/kg. In series 2, pre-ischemic blood plasma glycine concentrations were determined under the conditions of series 1. RESULTS: In series 1, attenuation of I/R injury was comparable at 10, 20, and 75 mg glycine/kg, but less at 5 mg/kg (as indicated by less intestinal hemorrhages and better preserved mean arterial blood pressure, among other signs). In series 2, pre-ischemic blood plasma glycine concentrations increased with increasing glycine doses from 280 to 330, 340, 380, and 680 µM, respectively. CONCLUSION: These results demonstrate that even at a dose 50 times lower than previously applied - and at only slightly elevated plasma concentrations - glycine provides full protection against I/R injury of the small intestine.

[Characterization of the EGF receptor status in penile cancer : retrospective analysis of the course of the disease in 45 patients]. / Charakterisierung des EGF-Rezeptorstatus beim Peniskarzinom : Retrospektive Auswertung der Krankheitsverläufe von 45 Patienten.

INTRODUCTION: Therapeutic success in metastasized squamous cell carcinoma is poor. Some entities, such as head-and-neck tumors or non-small-cell lung cancer, show an over expression of the EGF receptor. In latest studies target-specific substances against the EGF receptor have already been combined with chemotherapy or radiotherapy. Some studies showed a clear advantage of this combination concerning remission rates as well as survival. EGF receptor status has not yet been examined in penile cancer, therefore, a retrospective analysis of the receptor status was performed in patients treated over the last 14 years and correlations with the clinical course were investigated. PATIENTS AND METHODS: The analysis included 45 patients, who underwent primary or secondary treatment at the Department of Urology of the University of Essen during 1990 to 2004. Histological preparations existed for 44 patients. Using immunohistochemistry the expression of EGF receptors was determined. RESULTS: A total of 25 patients were primarily without positive lymph nodes (6 times cN0 and 19 times pN0), while 20 patients had pathologically proven lymph node metastases and 3 of them also had hematogeneous metastases. Out of 42 patients with follow-up 18 are still living of whom only 3 primarily had positive lymph nodes. These patients received adjuvant chemotherapy after resection. Out of the remaining 15 patients, 4 primarily N0 patients developed a lymphogenic recurrence, which was also resected and 3 patients also received adjuvant chemotherapy. Of the patients 24 died, 22 because of penile cancer. Of these 22 patients 16 primarily had positive lymph nodes and 5 of them also had an extensive primary tumor. Surgery was the treatment of choice in these cases and 10 patients also received chemotherapy. Nevertheless, 15 patients developed several recurrences. Distinguishing primarily node-negative and node-positive patients, the Kaplan-Meyer survival curves showed a significant difference (p<0.001). Median overall survival was 55.5 compared to 34 months and median 5-year survival was 76.9% compared to 15.8%. Of the tumors 40 out of 44 (91%) showed a positive or strong positive EGF receptor expression of the primary tumor as well as of the metastases. A correlation between EGF receptor expression and survival could not be shown. CONCLUSION: Clinical data underline the prognostic value of the primary lymph node status as well as the therapeutic value of an ileoinguinal lymphadenectomy and adjuvant chemotherapy. It could also be shown that inductive chemotherapy is not very successful. EGF receptor expression was high and comparable to other squamous cell carcinomas, but there was no correlation to survival.

Cyclo-oxygenase-2 overexpression is a feature of early and well-differentiated hepatocellular carcinoma with a favourable prognosis.

AIMS: To determine the prognostic relevance of cyclo-oxygenase-2 (COX-2) expression in hepatocellular carcinoma (HCC) and its relationship to important clinicopathological parameters. METHODS: A series of 196 patients with HCCs treated either by surgical resection (n = 106) or liver transplantation (n = 90) was investigated. Immunohistochemically confirmed COX-2 expression was correlated with a series of clinicopathologically relevant parameters as well as proliferative activity and apoptosis. RESULTS: Overexpression of COX-2 correlated statistically with high histological tumour differentiation (p<0.001) and early TNM stage (p = 0.003). COX-2 overexpression was associated with lower apoptotic rates (p = 0.001), whereas proliferation activity did not differ significantly. In addition, COX-2 overexpression showed a significant correlation with favourable overall survival (p<0.001). In multivariate survival analysis, COX-2 expression qualified as an independent prognostic parameter (p = 0.030). CONCLUSIONS: Overexpression of COX-2 in HCC indicates early-stage cancer with less aggressive tumour behaviour and constitutes an independent prognostic factor.

"Preemptive" live donor liver transplantation for fibrolamellar hepatocellular carcinoma: a case report.

Fibrolamellar (FL) hepatocellular carcinoma (HCC) is a distinctive form of primary HCC that occurs principally in children and young adults. Although liver transplantation is not contraindicated for FL-HCC, noncirrhotic patients with large HCC tumors (including FL-HCCs) are not prioritized. Although hepatic resection is considered to be the primary treatment for FL-HCC, living donor liver transplantation is evolving into a potentially better alternative. Herein we have reported successful "preemptive" living donor liver transplantation for presumed recurrence of FL-HCC after an extended right hepatectomy with resection and synthetic graft replacement of the inferior vena cava.

Wegener's granulomatosis in the thyroid mimicking a tumour.

Wegener's granulomatosis (WG) is a systemic vasculitis characterised by the presence of necrotizing granulomas and classically manifests as a triad of upper and lower respiratory tract involvement along with glomerulonephritis. Other rather unusual presentations of WG include ocular, salivary gland, cutaneous, gastrointestinal and cardiac involvement. We report a case in a 51-year-old woman suffering from WG with positive antineutrophil cytoplasmic autoantibodies and antibodies directed against proteinase 3. Under maintenance therapy, the patient developed two thyroid nodules suspicious for malignancy which led to thyroidectomy. Postoperative histological examination revealed a tumour-forming WG mimicking a malignant thyroid tumour. We conclude that, although extremely rare, Wegener's. granulomatosis should be added to the list of differential diagnoses of tumours of the thyroid gland.

[Cutaneous basosquamous cell carcinoma]. / Basosquamöses Karzinom der Haut.

BACKGROUND: Basosquamous carcinoma (BSC) is a rare malignancy with specific histopathological features of both basal cell (BCC) and squamous cell carcinoma (SCC). Therefore, the histological diagnosis is challenging. Due to its low incidence there is no consensus on the surgical management of BSC. PATIENTS AND METHODS: We describe the (immunohistological) diagnostic and therapeutic aspects of nine cases (8 male symbol : 1 female symbol, on average 68.6 years of age (range: 47-81)) of BSC. Of these, seven were located on the pinna, one on the forehead and zygomatic region and one in the retroauricular region. RESULTS: Immunochemical staining for epithelial membrane antigen was negative (apart from the typical areas of epithelial pearl formation) and BerEP4 was positive in all cases. Therapy consisted of partial removal of the pinna in four, and total removal in three cases. One patient was treated by partial removal of the auricle with superficial parotidectomy and ipsilateral neck dissection. In the case of the carcinoma on the forehead, a local excision was performed. The median follow-up was 45 months. One patient had a local recurrence. CONCLUSIONS: The histological diagnosis of BSC is confirmed by the use of EMA and BerEP4 immunohistological staining. Clinically, BSC is a rare, aggressive skin tumor. Despite the histological similarity to basal cell carcinoma, BSC has an imminent risk of metastasizing. Hence, therapy should be similar to that for SCC, taking into consideration the age and general state of the usually elderly patient.

AKT and ERK1/2 signaling in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinomas (ICC) are neoplasms that originate from cholangiocytes and can occur at any level of the biliary tree. Surgical resection is the current therapy of choice for this highly aggressive cancer. However, the 5-year survival still is poor, with high recurrence rates. Due to the intrahepatic growth a significant proportion of patients present with advanced disease and are not candidates for curative surgery or transplantation. The existing palliative options are of limited benefit and there is a great necessity for novel therapeutic options. In this article we review the role of the phosphoinositide 3-kinase(PI3K)/AKT and extracellular regulated kinase (ERK) signaling pathways in ICC and present new data on the prognostic value of these protein kinases. Finally, we discuss future upcoming therapeutic options based on targeting these signaling pathways.

Activation of extracellular regulated kinases (ERK1/2) but not AKT predicts poor prognosis in colorectal carcinoma and is associated with k-ras mutations.

Signal transduction and modulation represent central mechanisms in cellular processes such as cell-cycle regulation, oncogenesis, and apoptosis. The aim of this study was to determine the prognostic relevance of two kinases important in the regulation of cell proliferation and apoptosis in 135 colorectal cancer cases: AKT and extracellular regulated kinases (ERK1/2). We investigated the relationship of phospho-ERK1/2 (pERK1/2) and phospho-AKT (pAKT) with associated parameters (EGFR, COX-2, cyclin-D1), proliferative activity (Ki-67), and apoptosis (TUNEL) using immunohistochemistry. Additionally, the k-ras gene was screened for mutations to determine its putative association with ERK1/2 activation. Activation of ERK1/2 but not AKT correlated statistically with the presence of k-ras mutations (P = 0.015). Survival analysis of phospho-ERK1/2 immunoexpression showed a significant correlation with decreased overall survival (OS). The multivariate Cox regression analysis identified pERK1/2 as an independent prognostic parameter (P = 0.005). Activation of ERK1/2 in colorectal cancer may indicate aggressive tumor behavior and may constitute an independent prognostic factor. Furthermore, our data suggest that mutations of the k-ras oncogene may induce activation of ERK1/2. We propose immunohistochemical determination of pERK1/2 status as a promising candidate for the identification of high-risk patients who would benefit from new anticancer drugs targeting the ERK pathway.

Overexpression of cyclo-oxygenase-2 is an independent predictor of unfavourable outcome in node-negative breast cancer, but is not associated with protein kinase B (Akt) and mitogen-activated protein kinase (ERK1/2, p38) activation or with Her-2/neu signalling pathways.

BACKGROUND AND AIM: The production of prostaglandins is regulated by cyclo-oxygenases (COXs), which also have a role in tumour development and progression in various malignancies, including breast cancer. The mechanisms by which COX-2 contributes to unfavourable prognosis are still poorly understood. The association between expression of COX-2 and possible linked signalling pathways-namely, Akt, extracellular regulated kinases (ERK1/2), the stress-activated kinase p38 or Her-2/neu-is assessed in a series of 113 node-negative breast cancers. RESULTS: COX-2 was identified as an independent prognostic factor (p = 0.034) in node-negative breast cancer by survival analysis. The lack of a relationship between COX-2 expression and activated Akt, Erk1/2, p38 and Her-2/neu was indicated by statistical analysis. CONCLUSIONS: The prognostic effect of COX-2 expression on lymph node-negative breast cancer is confirmed-COX-2 is probably not regulated by HER-2, Akt, Erk1/2 or p38. Further studies are necessary for the elucidation of the signalling pathways responsible for the modification of COX-2 expression and the increased aggressiveness of breast cancers overexpressing COX-2.

Relationship and prognostic significance of phospho-(serine 166)-murine double minute 2 and Akt activation in node-negative breast cancer with regard to p53 expression.

The Akt signalling pathway plays a central role in tumourigenesis. Activation of Akt is related to a more aggressive phenotype in various human cancers, including breast cancer. Its activation contributes to cancer progression via pleiotropic effects, including suppression of apoptosis and modulation of cell cycle regulation. Murine double minute 2 (MDM2) is an oncoprotein that inhibits the function of p53 tumour suppressor protein. Cell culture studies show that Akt-related phosphorylation of MDM2 at serine 166 allows MDM2 to gain nuclear entry and fulfil its p53 regulating function. This study was designed to analyse the relationship of phospho-MDM2 (pMDM2) expression with Akt activation to determine a possible prognostic relevance of pMDM2 in node-negative breast cancer with respect to Akt activation and p53 status. pMDM2, phospho-Akt (pAkt) and p53 protein expression status were analysed immunohistochemically in 121 paraffin-embedded breast cancer cases. Expression of pMDM2 correlated with Akt activation (P<0.001). Univariate analysis identified pMDM2 as a prognostic factor (P=0.0458) in node-negative breast cancers. The unfavourable prognostic significance was even more pronounced in tumours with a pMDM2(+)/pAkt(+) immunophenotype (P=0.0205). Stratification into a p53-negative subgroup further strengthened the adverse prognostic influence. These data confirm that MDM2 phosphorylation at serine 166 is mediated by Akt kinase. Besides the prognostic impact of pMDM2, our findings suggest that Akt-mediated modulation of the MDM2/p53 complex contributes to increased tumour aggressiveness especially in p53-negative breast cancers. However, due to the relatively small number of patients in this cohort, the results obtained need to be confirmed by larger cohorts.

[Histological criteria and metastasis of squamous cell carcinoma of the pinna]. / Histologische Kriterien und Metastasierungshäufigkeit von Plattenepithelkarzinomen der Ohrmuschel.

INTRODUCTION: According to the guidelines for cancer of the skin in the head and neck region of the German association of Otolaryngology, Head and Neck surgery squamous cell carcinoma (SCC) of the pinna are classified by using the current TNM system of skin cancer. As soon as cartilage is infiltrated, irrespective of other criteria like tumour size, SCC of the thin skin of the pinna are classified as T4 category. As therapy considerably depends on the TNM stage a review of the prognostic value of cartilage infiltration as well as other histological criteria seems to be justified. METHODS: Medical records of all patients (n = 36) being operated for SCC of the pinna between August 1988 and January 2004 at our department were retrospectively analysed with regard to a statistical correlation of histological criteria, cervical lymph node metastases and prognosis. RESULTS: In 36 cases a histological re-evaluation could be performed on the original tumour samples (34 male symbol : 2 female symbol; average age was 76 years, with an age interval of 54 - 99 years). 26 SCC cases were smaller than 2 cm, 8 cases between 2 and 5 cm and 2 cases bigger than 5 cm of size. 36 % of SCC cases had infiltration of the auricular cartilage. Statistical analysis did not show a statistical correlation of either cartilage infiltration, tumour size bigger than 2 cm or 1 cm, tumour grading and tumour depth with regard to lymph node metastases. DISCUSSION: According to our results, cartilage infiltration as single criterion of inclusion into a T4 category should be analysed cautiously. The anatomical peculiarity of the pinna where cartilage lies directly beneath very thin skin should be taken into account. A survey of a bigger group of patients e. g. as a multicenter study would be desirable for such a rare malignancy.

ETV6-NTRK3 gene fusion in a secretory carcinoma of the breast of a male-to-female transsexual.

Secretory carcinomas of the breast were first described as "juvenile carcinoma" by McDivitt and Stewart in a cohort of children. This term has been replaced by the term "secretory breast carcinoma", because the entity can occur at any time of life. Carcinoma of the male breast is uncommon and accounts for approximately 1% of all cancers in men. Recently, it has been reported that human secretory breast carcinoma expresses the ETV6-NTRK3 gene fusion that was previously cloned in pediatric mesenchymal cancers. We present the case of a 46-year-old male-to-female transsexual in whom a secretory breast carcinoma was an incidental finding. As confirmation of the histopathological diagnosis we detected the novel ETV6-NTRK3 gene fusion in this tumor.

Immunohistochemical differentiation of eosinophilic heart diseases using antibodies against eosinophil activation markers.

AIMS: Eosinophilic heart syndromes are rare in Western countries and include endocarditis parietalis fibroplastica (EPF) and hypersensitivity myocarditis (HM). There are striking differences in natural history and morphological findings. Since diagnosis can be difficult when analysing small myocardial biopsies lacking the characteristic histological features, we studied a set of immunohistochemical markers in order to characterize the activation status of the infiltrating eosinophils to distinguish between these two entities. METHODS AND RESULTS: This study is based on the investigation of seven explanted hearts and one left ventricular specimen collected during implantation of a left ventricular assist device from a total of seven patients with HM. Also investigated were three right and three left ventricular specimens from five patients with EPF. We used antibodies (Ab) against EG1, and EG2, CD44, and CD69 which have been described as markers to distinguish between resting and activated eosinophils. The EG1 to EG2 ratio of eosinophils and the immunoreactivity against CD44 showed no differences between the two entities. However, eosinophils in the EPF were completely negative for CD69, whereas eosinophils reacted positively within the HM group. CONCLUSION: The immunohistochemical investigation of eosinophilic heart diseases using antibodies against CD69 can be a useful tool to distinguish between hypersensitivity myocarditis and endocarditis parietalis fibroplastica.

[Two cystic retroperitoneal lesions mimicking adrenal cysts]. / Retroperitoneale Zysten, die Nebennierenzysten imitieren können.

Adrenal cysts are uncommon lesions and most of them are found incidentally during abdominal imaging. We report on two benign extraadrenal lesions mimicking adrenal tumors in abdominal imaging. The histopathological investigation of the lesions revealed a foregut duplication cyst of the lesser gastric curvature and an epithelial inclusion cyst (epidermoid cyst) in an intrapancreatic accessory spleen respectively.

Standardized in situ AgNOR analysis in breast pathology: diagnostic and cell kinetic implications.

The aim of the present study was to assess the diagnostic value of the recently standardized morphometric analysis of silver-stained nucleolar organizer region-associated proteins (AgNORs) [30] in a variety of 155 routinely processed benign and malignant breast lesions. 5 normal breast samples, 21 adenoses, 20 ductal hyperplasias, 10 atypical ductal hyperplasias, 20 in situ and 43 invasive ductal carcinomas, 10 in situ and 26 invasive lobular carcinomas were investigated. A statistically highly significant difference was found between normal/ordinary hyperplastic and neoplastic breast lesions with all 4 consensus AgNOR parameters (mean area, mean number, CV of area, CV of number) evaluated. AgNOR quantity was significantly related to histological grade of both in situ and invasive carcinomas. However, variable overlap was found between AgNOR values in different diagnostic groups. We conclude that standardized AgNOR analysis is a prerequisite for objective and reproductible AgNOR assessment in archival tissues. Despite its limited diagnostic utility for individual breast lesions, standardized AgNOR analysis bears a significant potential for characterizing cell kinetic and metabolical activity of breast lesions. This may give insight into the biological background of breast carcinogenesis, differentiation and tumor progression and may also underlie the independent prognostic value of AgNORs in breast cancer.

Folate supplementation and neural tube defects: a review of a public health issue.

Folate deficiency is one of today's most common vitamin deficiencies in women. Women who consume a low level of folate during pregnancy are at risk for poor pregnancy outcomes including neural tube defects (NTD). However, other factors such as heredity, social class, maternal age, birth order, maternal diet, length of time between pregnancies, maternal zinc deficiency, use of anticonvulsant drugs, abnormal homocysteine metabolism and the use of oral contraceptives, have also been implicated as causes of NTD. Animal studies have shown that fetuses are highly dependent on the folate status of the mother. In addition, several retrospective and prospective human studies have provided evidence that folate lowers the incidence of NTD.