Unexpected borderline malignant and malignant smooth muscle cell tumors of the uterine corpus in women treated with LH-RH analogues

In this report, two cases of uterine smooth muscle cell tumors, one of uncertain malignant potential and one clearly malignant, are described in women treated for prolonged periods with luteinizing hormone-releasing hormone (LH-RH) analogues. Due to lengthy monitoring of LH-RH therapy, surgical intervention and histologic classification of these tumors was late in the course of disease, resulting in a delay in definite treatment. The risk to these women is discussed. The effects of LH-RH analogue therapy on fibroids is reviewed. Suggestions are put forward for monitoring LH-RH analogue therapy

Diagnostic accuracy of endoscopic ultrasonography-guided tissue acquisition prior to resection of pancreatic carcinoma:a nationwide analysis

Introduction: Endoscopic ultrasonography guided tissue acquisition (EUS + TA) is used to provide a tissue diagnosis in patients with suspected pancreatic cancer. Key performance indicators (KPI) for these procedures are rate of adequate sample (RAS) and sensitivity for malignancy (SFM). Aim: assess practice variation regarding KPI of EUS + TA prior to resection of pancreatic carcinoma in the Netherlands. Patients and methods: Results of all EUS + TA prior to resection of pancreatic carcinoma from 2014–2018, were extracted from the national Dutch Pathology Registry (PALGA). Pathology reports were classified as: insufficient for analysis (b1), benign (b2), atypia (b3), neoplastic other (b4), suspected malignant (b5), and malignant (b6). RAS was defined as the proportion of EUS procedures yielding specimen sufficient for analysis. SFM was calculated using a strict definition (malignant only, SFM-b6), and a broader definition (SFM-b5+6). Results: 691 out of 1638 resected patients (42%) underwent preoperative EUS + TA. RAS was 95% (range 89–100%), SFM-b6 was 44% (20–77%), and SFM-b5+6 was 65% (53–90%). All centers met the performance target RAS>85%. Only 9 out of 17 met the performance target SFM-b5+6 > 85%. Conclusion: This nationwide study detected significant practice variation regarding KPI of EUS + TA procedures prior to surgical resection of pancreatic carcinoma. Therefore, quality improvement of EUS + TA is indicated

Core biopsies of renal tumors: a study on diagnostic accuracy, interobserver, and intraobserver variability

OBJECTIVE: The diagnostic accuracy of in-bench core biopsies (CBs) from renal masses, and the interobserver and intraobserver variability in pathological subtyping of renal tumors were assessed. METHODS: We performed two CBs in 62 consecutive renal masses suspected for renal cell carcinoma (RCC), obtained after radical or partial nephrectomy and, in one case, after autopsy. Routine hematoxylin-eosin (HE)-stained sections from each CB were evaluated by five pathologists on two occasions. The surgical specimen was the reference standard. Diagnostic accuracy and the generalized kappa for intraobserver and interobserver agreement were calculated. RESULTS: Five tumors were benign and 57 malignant. Eight percent to 16% of the CBs were considered inadequate for diagnosis. In 0-8% of the cases, the pathologist could not discriminate between a benign or malignant tumor. Overall accuracy ranged from 77% to 90%. Sensitivity (79-100%) and positive predictive value (100%) were high with narrow 95% confidence interval (95%CI). Specificity (100%) was high but negative predictive value (29%-100%) varied, with wide 95% CI. Interobserver agreement was fair to almost perfect (kappa=-0.010 to 0.830) for the different subtypes. In 64-81% of the CBs, the subtype was correctly classified. Intraobserver agreement was substantial (mean kappa=0.628) for all pathologists. CONCLUSION: Diagnostic accuracy of CBs was high, with a diagnostic yield varying between 84% and 92%. Pathological subtyping of CBs was highly reproducible with the exception of the chromophobe renal cell carcinoma, which was problematic on HE-stained sections onl

Diagnostic problems in the subtyping of renal tumors encountered by five pathologists

The diagnostic problems in the subtyping of renal tumors were evaluated by a panel of five pathologists studying a set of selected tumors. Five pathologists independently assessed a single hematoxylin-and-eosin (HE)-stained slide from 28 selected renal tumors. After this independent assessment, the pathologists reevaluated and discussed all discordant cases. Additional HE-stained sections and immunohistochemically (IHC) stained slides were available. The generalized kappa for interobserver agreement was calculated. After independent assessment of the HE-stained slides, the five pathologists unanimously reached an agreement in the decision between malignant and benign in 82% of the cases. Fifty percent of the cases were correctly subclassified. The overall generalized kappa value for the five pathologists was 0.320 (CI 95% 0.090-0.551), which is considered a moderate agreement. A 100% agreement was reached for all 28 cases after examination of more slides from different tumor areas and IHC-stained sections. An accurate histologic distinction between benign and malignant renal tumors is possible on one HE-stained section. Correct assignment of the subtype is difficult on one slide alone and relies on IHC-markers and additional slides. Tumors composed of an eosinophilic cell type and tumors with a papillary growth pattern were the major causes of an incorrect diagnosis on an HE-stained section alone. (C) 2008 Elsevier GmbH. All rights reserve

The vascular endothelial growth factor receptor inhibitor sunitinib causes a preeclampsia-like syndrome with activation of the endothelin system

Angiogenesis inhibition is an established treatment for several tumor types. Unfortunately, this therapy is associated with adverse effects, including hypertension and renal toxicity, referred to as "preeclampsia." Recently, we demonstrated in patients and in rats that the multitarget tyrosine kinase inhibitor sunitinib induces a rise in blood pressure (BP), renal dysfunction, and proteinuria associated with activation of the endothelin system. In the current study we investigated the effects of sunitinib on rat renal histology, including the resemblance with preeclampsia, as well as the roles of endothelin 1, decreased nitric oxide (NO) bioavailability, and increased oxidative stress in the development of sunitinib-induced hypertension and renal toxicity. In rats on sunitinib, light and electron microscopic examination revealed marked glomerular endotheliosis, a characteristic histological feature of preeclampsia, which was partly reversible after sunitinib discontinuation. The histological abnormalities were accompanied by an increase in urinary excretion of endothelin 1 and diminished NO metabolite excretion. In rats on sunitinib alone, BP increased (ΔBP: 31.6±0.9 mm Hg). This rise could largely be prevented with the endothelin receptor antagonist macitentan (ΔBP: 12.3±1.5 mm Hg) and only mildly with Tempol, a superoxide dismutase mimetic (ΔBP: 25.9±2.3 mm Hg). Both compounds could not prevent the sunitinib-induced rise in serum creatinine or renal histological abnormalities and had no effect on urine nitrates but decreased proteinuria and urinary endothelin 1 excretion. Our findings indicate that both the endothelin system and oxidative stress play important roles in the development of sunitinib-induced proteinuria and that the endothelin system rather than oxidative stress is important for the development of sunitinib-induced hypertension

SOX2 expression in the pathogenesis of premalignant lesions of the uterine cervix: its histo-topographical distribution distinguishes between low- and high-grade CIN

SOX2 expression in high-grade cervical intraepithelial neoplasia (CIN3) and cervical squamous cell carcinoma is increased compared to that in the normal cervical epithelium. However, data on the expression and histological distribution of SOX2 in squamous epithelium during progression of CIN are largely lacking. We studied SOX2 expression throughout the epithelium in 53 cases of CIN1, 2, and 3. In general, SOX2 expression increased and expanded from basal/parabasal to the intermediate/superficial compartment during early stages of progression of CIN. An unexpected, specific expression pattern was found in areas classified as CIN2 and CIN3. This pattern was characterized by the absence or low expression of SOX2 in the basal/parabasal compartment and variable levels in the intermediate and superficial compartments. It was significantly associated with CIN3 (p = 0.009), not found in CIN1 and only seen in part of the CIN2 lesions. When the different patterns were correlated with the genetic make-up and presence of HPV, the CIN3-related pattern contained HPV-positive cells in the basal/parabasal cell compartment that were disomic. This is in contrast to the areas exhibiting the CIN1 and CIN2 related patterns, which frequently exhibited aneusomic cells. Based on their SOX2 localisation pattern, CIN1 and CIN2 could be delineated from CIN3. These data shed new light on the pathogenesis and dynamics of progression in premalignant cervical lesions, as well as on the target cells in the epithelium for HPV infection

Bioengineering of living renal membranes consisting of hierarchical, bioactive supramolecular meshes and human tubular cells

Maintenance of polarisation of epithelial cells and preservation of their specialized phenotype are great challenges for bioengineering of epithelial tissues Mimicking the basement membrane and underlying extracellular matrix (ECM) with respect to its hierarchical fiber-like morphology and display of bioactive signals is prerequisite for optimal epithelial cell function in vitro We report here on a bottom-up approach based on hydrogen-bonded supramolecular polymers and ECM-peptides to make an electro-spun bioactive supramolecular mesh which can be applied as synthetic basement membrane The supramolecular polymers used self-assembled into nano-meter scale fibers while at micro-meter scale fibers were formed by electro-spinning We introduced bioactivity into these nano-fibers by intercalation of different ECM-peptides designed for stable binding Living kidney membranes were shown to be bioengineered through culture of primary human renal tubular epithelial cells on these bioactive meshes Even after a long-term culturing period of 19 days we found that the cells on bioactive membranes formed tight monolayers while cells on non-active membranes lost their monolayer integrity Furthermore the bioactive membranes helped to support and maintain renal epithelial phenotype and function Thus incorporation of ECM-peptides Into electro-spun meshes via a hierarchical supramolecular method is a promising approach to engineer bioactive synthetic membranes with an unprecedented structure This approach may in future be applied to produce living bioactive membranes for a I:no-artificial kidney (C) 2010 Elsevier Ltd All rights reserve

SOX2 expression in the pathogenesis of premalignant lesions of the uterine cervix:its histo-topographical distribution distinguishes between low- and high-grade CIN

SOX2 expression in high-grade cervical intraepithelial neoplasia (CIN3) and cervical squamous cell carcinoma is increased compared to that in the normal cervical epithelium. However, data on the expression and histological distribution of SOX2 in squamous epithelium during progression of CIN are largely lacking. We studied SOX2 expression throughout the epithelium in 53 cases of CIN1, 2, and 3. In general, SOX2 expression increased and expanded from basal/parabasal to the intermediate/superficial compartment during early stages of progression of CIN. An unexpected, specific expression pattern was found in areas classified as CIN2 and CIN3. This pattern was characterized by the absence or low expression of SOX2 in the basal/parabasal compartment and variable levels in the intermediate and superficial compartments. It was significantly associated with CIN3 (p = 0.009), not found in CIN1 and only seen in part of the CIN2 lesions. When the different patterns were correlated with the genetic make-up and presence of HPV, the CIN3-related pattern contained HPV-positive cells in the basal/parabasal cell compartment that were disomic. This is in contrast to the areas exhibiting the CIN1 and CIN2 related patterns, which frequently exhibited aneusomic cells. Based on their SOX2 localisation pattern, CIN1 and CIN2 could be delineated from CIN3. These data shed new light on the pathogenesis and dynamics of progression in premalignant cervical lesions, as well as on the target cells in the epithelium for HPV infection. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00418-022-02145-6