Peter Earls

Renal Tumors Associated With Germline Sdhb Mutation Show Distinctive Morphology

Germline succinate dehydrogenase B (SDHB) mutation causes pheochromocytoma/paraganglioma syndrome type 4 (PGL4). PGL4 is characterized by pheochromocytoma and paraganglioma, type 2 (SDHB negative) gastrointestinal stromal tumors and renal tumors, which are usually classified as carcinoma. We report 4 kindreds with 5 PGL4-associated renal tumors. Four of the tumors occurred before the age of 30 years, 4 were in the left kidney, 3 were in female patients, and 4 demonstrated consistent but previously unrecognized morphology. The tumors were composed of cuboidal cells with bubbly eosinophilic cytoplasm and indistinct cell borders. Many of the cells displayed distinctive cytoplasmic inclusions, which were vacuolated or contained eosinophilic fluid-like material. The cells were arranged in solid nests or in tubules surrounding central spaces. The tumors were well circumscribed or lobulated and frequently showed cystic change. Benign tubules or glomeruli were often entrapped at the edges of the tumors. The fifth tumor lacked these features but displayed sarcomatoid dedifferentiation. Immunohistochemistry for SDHB was completely negative in all 4 available tumors. Death from metastatic disease occurred in the patient with dedifferentiated tumor 1 year after diagnosis, whereas the other 4 tumors were cured by local excision alone (mean follow-up, 11 y; range, 2 to 30 y). We conclude that morphology supported by negative immunohistochemistry for SDHB can be used to identify kindreds with germline SDHB mutations (PGL4 syndrome) presenting with this unique type of renal tumor. These renal tumors appear to have a good prognosis after complete excision unless there is sarcomatoid dedifferentiation.

Structured histopathology profiling of chronic rhinosinusitis in routine practice

Tissue eosinophilia in chronic rhinosinusitis (CRS) is a marker of inflammatory disorders recalcitrant to surgical intervention. Eosinophilic chronic rhinosinusitis (ECRS) is traditionally associated with asthma, polyps, aspirin sensitivity, high serum eosinophilia, and elevated immunoglobulin E (IgE). However, patients with ECRS may not present with these associations and there is a need to establish other surrogate markers. The objective of the study was to determine the associations between the histopathology, serology, and clinical characteristics in CRS patients.

Corticosteroid nasal irrigations after endoscopic sinus surgery in the management of chronic rhinosinusitis

Inflammatory dysfunction is considered an important part of chronic rhinosinusitis (CRS). Corticosteroid therapy has been widely used in CRS. Effective topical delivery has been previously problematic. The post–endoscopic sinus surgery (ESS) corridor is essential for adequate topical drug access. Devices delivering large volume with positive pressure allow better distribution to sinus mucosa. The objective of this study is to evaluate the efficacy of postoperative topical sinonasal steroid irrigations for CRS.

Papillomavirus-associated squamous skin cancers following transplant immunosuppression: one Notch closer to control

The frequent occurrence of cutaneous squamous cell carcinomas (SCCs) containing weakly tumorigenic human papillomaviruses (HPVs) following iatrogenic immunosuppression for organ transplantation remains incompletely understood. Here we address this problem in the light of recent insights into (1) the association of low-risk β-HPVs with skin SCCs in the rare genetic syndromes of epidermodysplasia verruciformis and xeroderma pigmentosum, (2) the frequent recovery of post-transplant tumor control on substituting calcineurin-inhibitory with mTOR-inhibitory immunosuppression, (3) the unexpectedly favorable prognosis of node-positive SCCs containing high-risk α-HPVs originating in the activated immune niche of the oropharynx, (4) the rapid occurrence of HPV-negative SCCs in ultraviolet (UV)-damaged skin of melanoma patients receiving Raf-inhibitory drugs, and (5) the selective ability of β-HPV E6 oncoproteins to inhibit Notch tumor-suppressive signaling in cutaneous and mesenchymal tissues. The crosstalk so implied between oncogenic UV-induced mutations, defective host immunity, and β-HPV-dependent stromal-epithelial signaling suggests that immunosuppressants such as calcineurin inhibitors intensify mitogenic signalling in TP53-mutant keratinocytes while also abrogating immune-dependent Notch-mediated tumor repression. This emerging interplay between solar damage, viral homeostasis and immune control makes it timely to reappraise strategies for managing skin SCCs in transplant patients.

Eosinophilic rhinosinusitis is not a disease of ostiomeatal occlusion

Ostiomeatal complex (OMC) occlusion may play a role in the pathogenesis of some chronic rhinosinusitis (CRS) subgroups, but its role in diffuse mucosal inflammation is strongly debated. The association between radiological OMC occlusion and its draining sinuses in patients with eosinophilic rhinosinusitis (ECRS) compared to non‐ECRS is investigated.

Interleukin-25 and interleukin-33 as mediators of eosinophilic inflammation in chronic rhinosinusitis.

Background The initiating mediators of T-helper 2 inflammation, often seen in eosinophillic chronic rhinosinusitis (CRS), remains poorly understood. Interleukin (IL) 25, IL-33, and thymic stromal lymphopoietin (TSLP) are epithelial-derived cytokines implicated in the initiation of T-helper 2 inflammation and eosinophilia in other diseases. The expression of these cytokines was compared with phenotypic and histopathologic markers to investigate the factors that may drive eosinophilic inflammation in CRS. Method Sinus mucosal samples from patients with CRS who were undergoing sinus surgery as part of their management were analyzed for IL-25, IL-33, and TSLP messenger RNA (mRNA) expression by quantitative polymerase chain reaction. Patients with tumor and who were undergoing surgery via an endonasal approach with normal sinus mucosa were controls. The mRNA expression was compared with CRS phenotype and histopathologic measures of eosinophilic inflammation. Immunohistochemical staining was used to confirm mRNA expression. Results Thirty-nine patients (mean ± standard deviation age; 48.2 ± 15.0 years, 38% women), 12 patients with CRS with nasal polyps, 20 patients with CRS without nasal polyps, and 7 controls were recruited. Higher IL-25 (p = 0.005) and IL-33 (p = 0.003) mRNA and protein expression was observed in patients with >10 eosinophil/hpf. TSLP showed no significant associations (p = 0.39). Similar overexpression was seen in eosinophilic dominated inflammation (IL-25, p = 0.01; IL-33, p = 0.02) and patients with greater inflammatory severity. Conclusion IL-25 and IL-33 overexpression was observed in eosinophilic CRS, The release of these cytokines by dysfunctional endothelium may perpetuate the eosinophillic inflammation in CRS.

Osteitic bone: a surrogate marker of eosinophilia in chronic rhinosinusitis.

BACKGROUND Causes of osteitis in chronic rhinosinusitis (CRS) other than previous surgery are poorly defined. Patients with eosinophilic CRS (ECRS) have more severe disease and poorer outcomes despite repeated surgery. Associations between osteitis and markers of ECRS are not well described. METHODS A cross-sectional study of CRS patients undergoing sinus surgery was conducted. Osteitis was scored radiologically using previously published measures. Associations between osteitis and histopathology, symptoms, endoscopy, CT mucosal score and seromarkers were analyzed. RESULTS Eighty-eight patients were assessed of whom forty-five had osteitis. Patients undergoing revision surgery recorded higher osteitis scores. Patients with mucosal eosinophilia had higher osteitis score than those without. Patients with osteitis had higher serum eosinophil. Similar relationships were also found in primary surgery. Osteitis was associated with endoscopic and radiologic, but not symptomatic disease severity. CONCLUSIONS Osteitis is associated with tissue and serum eosinophilia in both patients with and without prior surgery. Patients with these features may benefit from post-operative corticosteroid therapy to prevent osteitis.

Pancreatic solid pseudopapillary tumours – EUS FNA is the ideal tool for diagnosis

Background:  Solid pseudopapillary tumour (SPT) is a rare tumour of the pancreas with low malignant potential affecting mainly young women difficult to diagnose preoperatively. The aim of this study is to describe the endoscopic ultrasound (EUS) features and utility of EUS‐guided fine needle aspiration (FNA) in diagnosing these tumours.

Correlation of the Kennedy Osteitis Score to clinico-histologic features of chronic rhinosinusitis.

Osteitis is a feature of chronic rhinosinusitis (CRS) and often associated with recalcitrant disease. Radiological characteristics of osteitic sinus changes are commonly reported in practice but the clinical and pathologic significance is poorly defined. The objective of this study was to correlate the Kennedy Osteitis Score (KOS) to clinico‐histologic features of CRS.

IL-21 Contributes to Fatal Inflammatory Disease in the Absence of Foxp3+ T Regulatory Cells

The cytokine IL-21 has been shown to influence immune responses through both costimulatory effects on effector T cells and opposing inhibitory effects on T regulatory cells (Tregs). To distinguish the effect of IL-21 on the immune system from that of its effect on Tregs, we analyzed the role of IL-21/IL-21R signaling in mice made genetically deficient in IL-2, which exhibit a deficit in IL-2–dependent Foxp3 regulatory T cells and suffer from a fatal multiorgan inflammatory disease. Our findings demonstrate that in the absence of IL-21/IL-21R signaling, Il2−/− mice retained a deficiency in Tregs yet exhibited a reduced and delayed inflammatory disease. The improved health of Il2−/−Il21r−/− mice was reflected in reduced pancreatitis and hemolytic anemia and this was associated with distinct changes in lymphocyte effector populations, including the reduced expansion of both T follicular helper cells and Th17 cells and a compensatory increase in IL-22 in the absence of IL-21R. IL-21/IL-21R interactions were also important for the expansion of effector and memory CD8+ T cells, which were critical for the development of pancreatitis in Il2−/− mice. These findings demonstrate that IL-21 is a major target of immune system regulation.