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Background Drug reaction with eosinophilia and systemic symptoms (DRESS) is a cutaneous and systemic drug allergy disorder. Patients exist on a severity spectrum, with some experiencing a mild form of the disorder that fails to meet the Registry of Severe Cutaneous Adverse Reactions (SCAR) to Drugs diagnostic criteria for DRESS. Objective We sought to determine whether there were any cutaneous or dermatopathologic features that discriminate between the mild form of DRESS (DRESS minor) and the severe phenotype (DRESS major). Methods Hospitalized patients from a single center with a diagnosis of DRESS were prospectively recruited over a 7-year period. Clinical and dermatopathologic features were analyzed to discriminate between DRESS minor and DRESS major. Results Forty-five patients were included, of whom 19 had a Registry of Severe Cutaneous Adverse Reactions (SCAR) to Drugs score of ≤3 (DRESS minor) and 26 had a score of ≥4 (DRESS major). The mean latency period (P = .001), fever >38.5 °C (P = .001), and a reaction lasting >15 days (P = .010) discriminated DRESS major from DRESS minor. Facial edema was the sole discerning cutaneous feature (P = .025). Discriminating histopathologic features included basal squamatization (P = .005), dermal red blood cell extravasation (P = .009), and interface inflammation (P = .005). Conclusion We propose a new classification system—DRESS minor—to distinguish the milder illness from the severe form, DRESS major. Facial edema and certain histopathologic features can help discriminate between major and minor versions.

Purpose\ud Moderate hyperprolactinaemia (2–5 times upper limit of normal) occurring in a patient with a normal pituitary MRI is generally considered to be due to a lesion below the level of detection of the MRI scanner assuming macroprolactin and stress have been excluded. Most patients with mild-to-moderate hyperprolactinaemia and a normal MRI respond to dopamine agonist therapy. We present the rare case of a patient who had prolactin elevation typical of a prolactin-secreting pituitary macroadenoma,with a normal cranial MRI, and in whom the prolactin rose further with dopamine agonist treatment. Subsequent investigations revealed ectopic hyperprolactinaemia to a uterine tumor resembling ovarian sex cord tumor (UTROSCT) which resolved following tumor resection. Although mostly considered to be benign, the UTROSCT recurred with recurrent hyperprolactinaemia and intraabdominal metastases.\ud \ud Methods\ud We have systematically and critically reviewed existing literature relating to ectopic hyperprolactinaemia in general and UTROCST specifically.\ud \ud Results\ud Fewer than 80 cases of UTROSCTs have been reported globally of which about 23% have shown malignant behaviour. There are fewer than 10 cases of paraneoplastic hyperprolactinaemia originating from uterine neoplasms including one other case of ectopic hyperprolactinaemia to a UTROSCT.\ud \ud Conclusions\ud Our case demonstrates the importance of screening for extracranial hyperprolactinaemia in the context of: (1) substantially raised prolactin (10× ULN) and (2) normal cranial MRI assuming macroprolactin has been excluded. The majority of extracranial ectopic prolactin-secreting tumors occur in the reproductive organs.Methods: We have systematically and critically reviewed existing literature relating to ectopic hyperprolactinaemia in general and UTROCST specifically. \ud Results: Fewer than 80 cases of UTROSCTs have been reported globally of which about 23% have shown malignant behaviour. There are fewer than 10 cases of paraneoplastic hyperprolactinaemia originating from uterine neoplasms including one other case of ectopic hyperprolactinaemia to a UTROSCT. \ud Conclusions: Our case demonstrates the importance of screening for extracranial hyperprolactinaemia in the context of: (1) substantially raised prolactin (10xULN) and (2) normal cranial MRI assuming macroprolactin has been excluded. The majority of extracranial ectopic prolactin-secreting tumors occur in the reproductive organs.

We herein present a case report of a 60-year-old male patient diagnosed with squamous-melanocytic tumour (SMT) in his anal region, comprised of two intermingled different phenotypic lesions. This dual tumour is quite uncommon and could potentially be challenging on both diagnose and also management. It is the first case reported on this location, moreover, the lack of consensus for these lesions makes it difficult to classify them. We reviewed the literature of similar SMT’s and discussed its histogenesis. As they are rare, their biological behavior and potential metastasis remain unclear. Therefore, close follow-up is advised.

Background Histopathological features associated with coexistent invasive adenocarcinoma in large colorectal adenomas have not been described. This study aimed to determine the association of histopathological features in areas of low-grade dysplasia with coexistent invasive adenocarcinoma. Methods High-grade lesions (containing high-grade dysplasia or adenocarcinoma) from a cohort of large (at least 20 mm) colorectal adenomas removed by endoscopic resection were subjected to detailed histopathological analysis. The histopathological features in low-grade areas with coexistent adenocarcinoma were reviewed and their diagnostic performance was evaluated. Results Seventy-four high-grade lesions from 401 endoscopic resections of large adenomas were included. In the low-grade dysplastic areas, a coexistent invasive adenocarcinoma was associated significantly with a cribriform or trabecular growth pattern (P, Histopathological features associated with coexistent invasive adenocarcinoma in large colorectal adenomas have not been described. This study found several histopathological features identified in low grade areas of large adenomas were predictive of the presence of coexistent invasive cancer elsewhere in the lesion. An increasing number of these features is a strong predictor of coexistent invasive adenocarcinoma with an AUROC of 0.92 and ≥2 of these adverse histopathological features in low-grade areas had a sensitivity of 86% and specificity of 84% for coexistent invasive adenocarcinoma.

Heterogeneidad intratumoral; Inteligencia artificial; Terapias antitumorales Heterogeneïtat intratumoral; Intel·ligència artificial; Teràpies antitumorals Intratumor heterogeneity; Artificial intelligence; Antitumor therapeutics In this review, we highlight the role of intratumoral heterogeneity, focusing on the clinical and biological ramifications this phenomenon poses. Intratumoral heterogeneity arises through complex genetic, epigenetic, and protein modifications that drive phenotypic selection in response to environmental pressures. Functionally, heterogeneity provides tumors with significant adaptability. This ranges from mutual beneficial cooperation between cells, which nurture features such as growth and metastasis, to the narrow escape and survival of clonal cell populations that have adapted to thrive under specific conditions such as hypoxia or chemotherapy. These dynamic intercellular interplays are guided by a Darwinian selection landscape between clonal tumor cell populations and the tumor microenvironment. Understanding the involved drivers and functional consequences of such tumor heterogeneity is challenging but also promises to provide novel insight needed to confront the problem of therapeutic resistance in tumors. SRYC received support from Fondo de Investigaciones Sanitarias (PI14/01320 and PI17/02247), Redes Temáticas de Investigación Cooperativa en Salud (RD12/0036/0057), CIBERONC (CB16/12/00363), and Generalitat de Catalunya (AGAUR, 2017 SGR 1799 and 2014 SGR 1131). TA received support from Instituto de Salud Carlos III (grants PI16/00772 and CPII16/00042), co-financed by the European Regional Development Fund (ERDF).

Objectives Experimental models of Graves hyperthyroid disease accompanied by Graves orbitopathy (GO) can be efficiently induced in susceptible inbred strains of mice by immunization by electroporation of heterologous human TSH receptor (TSHR) A-subunit plasmid. The interrelated pathological findings in the thyroid glands of Graves disease (GD) that explain the core changes classically include diffuse follicular hyperplasia and multifocal mild lymphocytic infiltrate. However, the relative contributions of different thyroid tissue components (colloid, follicular cells, and stroma) have not been previously evaluated. In this study, we characterize the thyroid gland of an experimental mouse model of autoimmune GD. Our objective was to define the relative contribution of the different thyroid tissue components to the pathology of glands in the experimental model. Methods Mice were immunized with human TSHR A-subunit plasmid. Antibodies induced to human TSHR were pathogenic in vivo due to their cross-reactivity to mouse TSHR. Results Autoimmune thyroid disease in the model was characterized by histopathology of hyperplastic glands with large follicular cells. Further examination of thyroid glands of immunized animals revealed a significantly increased follicular area and follicle/stroma ratio, morphometrically correlated with a noninflammatory follicular hyperplasia/hypertrophy. The increased follicle/stroma ratio was the most relevant morphometrically variable summarizing the pathological changes for screening purposes. Conclusion GD thyroid glands are enlarged and characterized by a noninflammatory diffuse follicular cell hyperplasia/hypertrophy and a significant increase in the follicles with an increased follicle/stroma ratio. Overall, this mouse model is a faithful model of an early hyperthyroid status of GD (diffuse glandular involvement and follicular expansion).

BACKGROUND Adrenocortical carcinoma (ACC) is a rare malignancy, with an annual incidence of 1 or 2 cases per million. Biochemical diagnosis is challenging because up to two-thirds of the carcinomas are biochemically silent, resulting from de facto enzyme deficiencies in steroid hormone biosynthesis. Urine steroid profiling by GC-MS is an effective diagnostic test for ACC because of its capacity to detect and quantify the increased metabolites of steroid pathway synthetic intermediates. Corresponding serum assays for most steroid pathway intermediates are usually unavailable because of low demand or lack of immunoassay specificity. Serum steroid analysis by LC-MS/MS is increasingly replacing immunoassay, in particular for steroids most subject to cross-reaction. METHODS We developed an LC-MS/MS method for the measurement of serum androstenedione, corticosterone, cortisol, cortisone, 11-deoxycorticosterone, 11-deoxycortisol, 21-deoxycortisol, dehydroepiandrosterone sulfate, pregnenolone, 17-hydroxypregnenolone, progesterone, 17-hydroxyprogesterone, and testosterone. Assay value in discriminating ACC from other adrenal lesions (phaeochromocytoma/paraganglioma, cortisol-producing adenoma, and lesions demonstrating no hormonal excess) was then investigated. RESULTS In ACC cases, between 4 and 7 steroids were increased (median = 6), and in the non-ACC groups, up to 2 steroids were increased. 11-Deoxycortisol was markedly increased in all cases of ACC. All steroids except testosterone in males and corticosterone and cortisone in both sexes were of use in discriminating ACC from non-ACC adrenal lesions. CONCLUSIONS Serum steroid paneling by LC-MS/MS is useful for diagnosing ACC by combining the measurement of steroid hormones and their precursors in a single analysis.

Background/Aim: Total mesorectal excision combined with neo-adjuvant chemoradiotherary (CRT) and adjuvant chemotherapy, has been the standard treatment of locally advanced rectal cancer (LARC). Although TNM (Tumor, Node, Metastasis) classification for malignant Tumors is still the cornerstone in rectal cancer staging, there has been an effort to identify molecular biomarkers with additional prognostic or predictive value. Materials and Methods: We retrospectively analyzed molecular biomarkers on prospectively collected histological specimens and clinical data from a cohort of 135 consecutive rectal cancer cases who underwent radical excision in a tertiary center between 2011-2014 (males=87, females=48, age range=22-89 years, mean=64,67 years, SD=13.40). Radiological, histopathological, molecular staging, treatment stratification by the multidisciplinary team (MDT), as well as prognostic outcome data were compared with various biomarkers including KRAS, BRAF, p16, b-catenin, MSI, MMR and MGMT. Results: The mean follow-up was 39.21 months (range=5-83 months, SD=21.34). Twenty-eight cases were Stage I (20.9%), n=30 Stage II (22.4%), n=45 Stage III (33.6%) and n=31 Stage IV (23.1%). Forty specimens were KRAS-mutant (mt) (37.4%) while n=67 (62.6%) wild type (wt). KRAS mt status was associated with female sex (n=20, p=0.021) and older age (69.62 vs. 62.27, p=0.005). Stage I Early Cancer Subgroup analysis showed that KRAS mt status is associated with distant recurrence of disease (n=4, p=0.045). Conclusion: KRAS mt status may affect the prognosis of early rectal cancer, as this is linked with distant recurrence.

Several autosomal dominant inherited tumour syndromes demonstrate prominent features in the oral and maxillofacial region. Although multiple organ systems are frequently involved, the target organs more frequently affected are the skin (nevoid basal cell carcinoma syndrome, Brooke-Spiegler syndrome, Birt-Hogg-Dube syndrome and Muir-Torre syndrome), gastrointestinal tract (Peutz-Jegher syndrome and Gardner syndrome) or endocrine system (multiple endocrine neoplasia type 2b and hyperparathyroidism-jaw tumour syndrome). In some syndromes, the disease is multisystem with skin index lesions presenting in the head and neck (Cowden syndrome and tuberous sclerosis complex). The pertinent features of these syndromes are reviewed with a systems-based approach, emphasising their clinical impact and diagnosis.

Introduction Safe and effective endoscopic resection (ER) relies on the endoscopic diagnosis of large lesions to predict the risk of invasive cancer. However, a detailed evaluation of histopathological features and the molecular profile of the polypoid dysplastic mucosa to predict coexistent invasive neoplasm is not available. Methods: Data from endoscopic resection of colorectal superficial neoplastic lesions performed at a UK tertiary referral center (2011-2016) were analyzed. Lesions were assessed using magnification chromoendoscopy and narrow band imaging. A subset of these lesions containing high-grade dysplasia, intramucosal cancer or invasive cancer was identified and further subjected to a detailed histopathological analysis: endoscopic type, ulceration, distribution of high-grade dysplasia, dysplastic nuclear grade, presence and distribution of necrosis, and distribution of tumor-infiltrating lymphocytes (TIL). The two areas with the highest morphological grade were microdissected from each lesion, using 5μm FFPE sections. DNA extraction and next-generation sequencing using a human clinically relevant tumor panel (Qiagen, Hiden, Germany) of 24 genes were performed for each of these areas separately. Genetic abnormalities for each locus were categorized by genetic impact according to its severity (low/moderate/high/modifier) and allele frequency. Results: ER was performed for 418 large (≥20mm) colorectal superficial neoplastic lesions (mean size 55.2mm, range 20mm-160mm), 81% being laterally spreading tumors (LST). The proportions harboring an area of invasive cancer by morphological subtype were as follows: LST non-granular 30.8%; LST granular mixed-nodular type 12.3%; LST granular homogeneous type 0.9% and Is/Isp 11.4%. The histopathological genetic evaluation was available in 70 cases; a coexistent adenocarcinoma significantly correlated with dysplastic adenomatous mucosa featuring ulceration, mixed interface/interstitial TIL, multifocal high nuclear grade, infiltrative edges, and multifocal intraluminal necrosis. Multifocal intraluminal necrosis and high nuclear grade in the adjacent low-grade dysplastic mucosa were driven by cooperative genetic abnormalities of high-impact (FLT4), moderate impact (KRAS/NRAS for infiltrative edges, FLT4, TP53, ERBB2), and low impact (FGFR3, PDGFA). Conclusions The dysplastic stage of high-grade adenomatous polyps is characterized by multiple cooperative genetic mutations. A subset of these markers identify a risk of coexistent adenocarcinoma with a close correlation between genetic markers of angiogenesis (FLT4), receptor activation (RAS/ERBB2), genome maintenance (TP53) and stromal reaction (FGFR3, PDGFRA) with morphological features defined by high nuclear grade, intraluminal necrosis, and inflammatory stromal reaction.

Introduction The grading of both neoplastic and dysplastic lesions is based on morphological and genetic changes of the epithelial cells. The inflammatory stromal changes are frequent findings that can contribute to the neoplastic progression, and their correlation is not fully established in high-grade adenomas of the colon as predictors of coexistent invasive malignancy. Methods: Data from endoscopic resection (ER) of colorectal superficial neoplastic lesions performed at a UK tertiary referral center (2011-2016) were analyzed. A subset of these lesions containing high-grade dysplasia, intramucosal cancer or invasive cancer was identified and further subjected to a detailed histopathological analysis: endoscopic type, ulceration, distribution of high-grade dysplasia, dysplastic nuclear grade, presence and distribution of necrosis, and distribution of tumor-infiltrating lymphocytes (TIL). The two areas with the highest morphological grade were microdissected from each lesion, using 5μm FFPE sections. DNA extraction and next-generation sequencing using a human clinically relevant tumor panel (Qiagen, Hiden, Germany) of 24 genes were performed for each of these areas separately. Genetic abnormalities for each locus were categorized by genetic impact according to its severity (low/moderate/high/modifier) and allele frequency. Results: ER was performed for 418 large (≥20mm) colorectal superficial neoplastic lesions (mean size 55.2mm, range 20mm-160mm), 81% being laterally spreading tumors (LST). The proportions harboring an area of invasive cancer by morphological subtype were as follows: LST non-granular 30.8%; LST granular mixed-nodular type 12.3%; LST granular homogeneous type 0.9% and Is/Isp 11.4%. The histopathological genetic evaluation was available in 70 cases; the extension of TIL positively correlated with the presence of coexistent adenocarcinoma, and multifocal intraluminal necrosis and high nuclear grade. The presence of multifocal high-grade dysplasia was driven by different cooperative sets of genetic abnormalities regarding the TIL pattern: high-impact (TP53), and moderate impact (FLT4, ERBB2, RET/RAS/RAF/ERK) for an interface pattern, and high-impact (TP53, PDFGRA, FGFR3), and moderate impact (TP53, ERBB2, KRAS, RET/FGFR3) for an interstitial pattern. Conclusions A more extensive lymphocytic response contributes to the progression of adenomatous polyps and is associated with morphological changes of increased risk of adenocarcinoma (multifocal necrosis and high nuclear grade and abnormal TP53). An interface pattern expresses proliferative (receptor kinase) and vascular (FLT4) profile and the interstitial pattern outlines predominantly stromal (PDGFRA, FGFR3) features.

Graves' disease (GD) and Graves' orbitopathy are associated with stimulating thyrotropin receptor (TSHR) autoantibodies and autoreactive T cells. Recent in vitro studies suggested that sphingosine-1-phosphate (S1P) signaling is involved in the pathogenesis of orbitopathy. In this study, we explored the immune modulatory potential of S1P receptor antagonist fingolimod in a murine model for GD. Fingolimod was orally administered preventively during disease onset or therapeutically after disease onset. Administration of fingolimod during disease onset completely prevented the formation of TSHR-stimulating autoantibodies. Intervention after disease onset rarely reduced TSHR-stimulating autoantibodies and blocking autoantibodies were induced in some animals. Consequently, autoimmune hyperthyroidism characterized by elevated serum thyroxin levels, hyperplastic thyroid morphology accompanied by T cell infiltration, weight gain, enhanced body temperature, and tachycardia did not manifest preventively and showed milder manifestation in therapeutically treated animals. Importantly, examination of orbital tissue showed significant amelioration of orbitopathy manifestations through reduction of T cell infiltration, adipogenesis, and hyaluronan deposition. Autoimmune hyperthyroidism and orbitopathy were accompanied by changes in peripheral and splenic T cell proportions with high CD3+, CD4+, and CD8+ T cells. Activated T cells CD4+CD25+ were elevated whereas regulatory T cells CD4+Foxp3+ cells remained unchanged in spleens. Fingolimod decreased elevated T cell levels and increased CD4+CD25+Foxp3+ regulatory T cell populations. Analysis of total disease outcome revealed that treatment during disease onset protected animals against autoimmune hyperthyroidism and orbitopathy. Of note, therapeutic intervention after disease onset suppressed disease in half of the animals and in the other half disease remained at mild stages. The results of this study support a clinical trial to investigate the immunologic and clinical benefits of early treatment with S1P-based drugs in GD.

Background/Aim: Transanal endoscopic microsurgery (TEMS) is emerging as an alternative treatment for rectal cancer Stage I. There remains a risk of local recurrence. The Aim of the study was to study the effect of biomarkers in local recurrence for Stage I rectal cancer following TEMS plus or minus radiotherapy. Materials and Methods: This is a case-control study where we compared ten early rectal cancers that had recurred, against 19 cases with no recurrence, total 29 patients (age=28.25-86.87, mean age=67.92 years, SD=14.91, Male, N=18, Female, N=11). All patients underwent TEMS for radiological Stage I rectal cancer (yT1N0M0 or yT2N0M0) established with a combination of magnetic resonance imaging (MRI) and endorectal ultrasound. We prospectively collected all data on tumor histology, morphological features, as well as follow-up parameters. Molecular analysis was performed to identify their status on BRAF, KRAS, p16 O6-methylguanine-DNA methyltransferase (MGMT) and β-catenin. Results: Out of 29 specimens analyzed, 19 were KRAS wild type (65.9%) and ten mutant (34.5%). Recurrence of the tumor was noted in 10 cases (34.5%) of which 60% were pT1 (N=6) and 40% pT2 (N=4). There was a statistically significant association between KRAS mutant status and local recurrence (N=6, p=0.037). P16 expression greater than 5% (mean=10.8%, min=0, max=95) is linked with earlier recurrence within 11.70 months (N=7, p=0.004). Membranous β-catenin expression (N=12, 48%) was also related to KRAS mutant status (p=0.006) but not with survival (p>0.05). BRAF gene was found to be wild type in all cases tested (N=23). Conclusion: KRAS/p16/β-catenin could be used as a combined biomarker for prediction of local recurrence and stratification of the risk for further surgery.

A 79-year-old woman presented with a 5-month history of a painful dermatosis affecting her hands and feet. This developed into inflammation with fissuring, affecting the fingers and toes. The patient was a current smoker with a 65-pack-year history. She had no other medical conditions, no respiratory symptoms and was otherwise systemically well. On physical examination, striking nail changes were seen. There was marked subungual hyperkeratosis on the hands and brown discolouration of the nails, with detachment from the nail bed and loss of the cuticle (Fig. 1a), as well as significant involvement of the toes (Fig. 1b). Examination of the soles revealed marked confluent hyperkeratosis (Fig. 1c). Although the primary site of involvement was acral, there was also a diffuse macular erythema of the legs. Laboratory investigations showed erythrocyte sedimen-tation rate of 49 mm/h (normal range 0–30 mm/h), but were otherwise unremarkable. Chest radiography revealed a subtle lesion projected over the seventh posterior rib. The patient subsequently underwent computed tomography (CT) of the chest followed by positron emission tomography (PET)-CT, which showed a metabolically active nodule in the right upper lobe (Fig. 2a) that was highly suspicious for lung malignancy. The patient went on to have a right upper lobec-tomy of the lung, making a full postoperative recovery. Following tumour resection, the dermatosis significantly improved (Fig. 2b). Histological findings Following lung resection, an incisional biopsy taken from the sole of the foot showed parakeratosis and lymphocyte exocytosis, with a psoriasiform spongiotic dermatitis (Fig. 3). Histology from the lung lesion confirmed an underlying diagnosis of squamous cell carci-noma (SCC). What is your diagnosis? (a) (b) (c) Figure 1 (a) Striking changes of the fingernails and (b) toenails, and (c) marked confluent hyperkeratosis of the soles.

Introduction Guidelines on endoscopic resection (ER) of colorectal superficial neoplastic lesions (CSNL) recommend against biopsy sampling but many are extensively sampled prior to referral, despite the deleterious effect on ER, to exclude adenocarcinoma or high grade dysplasia (HGD), reflecting a lack of understanding of the incidence and nature of adenocarcinoma or HGD within different morphological sub-types. It is therefore important to define the significance of HGD on biopsy samples and place this in the context of the histopathological characteristics of high risk lesions. Methods ERs of large (≥2 cm) CSNL were included. Sensitivity and specificity of HGD on biopsy and higher risk morphology (laterally spreading tumour (LST) non-granular/LST mixed nodular type/IIc component) for diagnosing covert invasive adenocarcinoma and confirmed HGD after ER were calculated and compared (Mcnemar’s test). In addition, 50 high risk lesions (containing HGD or invasive adenocarcinoma) were subjected to more detailed histopathological analysis. Results Results from prior biopsy sampling were available for 291 lesions (mean size 62.8 mm). Histopathology after ER revealed HGD in 85 (29%) and invasive adenocarcinoma in 26 (9%). Sensitivity and specificity of HGD on biopsy (n=60) for invasive adenocarcinoma were 50% (95% CI 32%–68%) and 82% (95%–CI 77%–86%), and for confirmed HGD after ER were 47% (95% CI 37%–57%) and 90% (95% CI 85%–94%) respectively. Sensitivity and specificity of high risk morphology (n=124) for HGD after ER were 71% (95% CI 60%–79%) and 69% (95% CI 62%­75%) respectively. The sensitivity of high risk morphology was significantly higher than HGD on biopsy sampling (p=0.002). Detailed histopathological analysis of high risk lesions revealed invasive adenocarcinoma in 40% but a further 18% had non-invasive areas with cytological and architectural features indistinguishable from invasive adenocarcinoma. HGD was multifocal in 56%. The mean size of the focus of HGD was only 5.6 mm, and of adenocarcinoma was 11.0 mm. Mean lesion size was 53.6 mm. Conclusion Biopsy sampling of large CSNL has no value in excluding high risk lesions and morphology alone has higher sensitivity for high risk lesions. Histopathological analysis of high risk lesions reveals that areas of HGD or adenocarcinoma are very small relative to the lesion size and many contain non-invasive areas which would be cytologically indistinguishable from invasive adenocarcinoma on a biopsy. Despite this, biopsy sampling remains extremely common. Understanding of these findings and improved education regarding accurate lesion assessment may help reduce rates of inappropriate sampling.

Introduction: Multi-modal therapy for adrenocortical carcinoma (ACC) includes surgery, therapy with the adrenolytic agent mitotane and systemic chemotherapy. Achievement of therapeutic mitotane concentrations (≥14 mg/l) has been related to improved outcomes. Aim: To evaluate the effectiveness of a defined* high dose protocol mitotane therapy in patients with advanced ACC (stages III and IV). Methods: Review of patients presenting to KCH with stage III or IV ACC and the mitotane concentration achieved through the Lysosafe monitoring service. Results: N=57 patients were referred and first diagnosed with ACC (2008-17) of whom 44 patients had stage III or IV disease at diagnosis and were managed actively with surgery and/or mitotane therapy. 40/44 patients underwent surgical resection of the primary tumour;11/22 patients with stage IV disease subsequently received systemic chemotherapy [10 patients received a combination of etoposide, doxorubicin and cisplatin (EDP) and 1 patient received a combination of carboplatin and etoposide]. 38/44 patients were initiated on mitotane therapy. The median overall survival of patients with stage IV disease was 25.3 months. The median survival for stage III has not been reached. An additional 9 patients had prior management, including surgery, elsewhere and were referred for mitotane initiation. A total of 47 patients were therefore included in the mitotane pharmacokinetic analysis. Six patients were excluded: 3 patients died shortly after mitotane initiation, 1 patient withdrew due to a severe reaction and 2 patients had not completed 12 weeks therapy at the time of submission. Of the remaining 41 patients, 33 commenced the ‘high dose’ protocol and the remainder the ‘low dose’ protocol. For patients on the high dose protocol, 25/33 (76%) reached a mitotane concentration ≥14 mg/l within 12 weeks of initiation of therapy, compared to 3 patients from the low dose protocol group (P=0.084). In the high dose protocol group, 21 patients (84%) maintained therapeutic drug concentrations in ≥50% of the subsequent follow-up samples and 12 patients (48%) maintained therapeutic drug concentrations in ≥75% of subsequent samples. Conclusion: The use of high dose protocol mitotane therapy is a successful strategy to achieve and maintain therapeutic drug concentrations when treating patients with advanced ACC (stages III and IV). In combination with an assertive surgical approach and optimal chemotherapy, this has resulted in outcomes that compare favourably (median OS 25.5 months in stage IV disease) with previously published series which describe a median OS

The dermoscopic features of solitary storiform collagenomas (sclerotic fibromas) have not been previously described, as these are rare cutaneous soft tissue tumors. The presence of multiple lesions is considered a marker of Cowden’s disease. They can also present as single firm cutaneous nodules. We present an unusual single nodule with distinct dermoscopic and histologic features.

Summary Experimental models of Graves' hyperthyroid disease accompanied by Graves' orbitopathy (GO) can be induced efficiently in susceptible inbred strains of mice by immunization by electroporation of heterologous human TSH receptor (TSHR) A-subunit plasmid. In this study, we report on the development of a bona fide murine model of autoimmune Graves' disease induced with homologous mouse TSHR A-subunit plasmid. Autoimmune thyroid disease in the self-antigen model was accompanied by GO and characterized by histopathology of hyperplastic glands with large thyroid follicular cells. Examination of orbital tissues showed significant inflammation in extra-ocular muscle with accumulation of T cells and macrophages together with substantial deposition of adipose tissue. Notably, increased levels of brown adipose tissue were present in the orbital tissue of animals undergoing experimental GO. Further analysis of inflammatory loci by 19F-magnetic resonance imaging showed inflammation to be confined to orbital muscle and optic nerve, but orbital fat showed no difference in inflammatory signs in comparison to control β-Gal-immunized animals. Pathogenic antibodies induced to mouse TSHR were specific for the self-antigen, with minimal cross-reactivity to human TSHR. Moreover, compared to other self-antigen models of murine Graves' disease induced in TSHR knock-out mice, the repertoire of autoantibodies to mouse TSHR generated following the breakdown of thymic self-tolerance is different to those that arise when tolerance is not breached immunologically, as in the knock-out models. Overall, we show that mouse TSHR A-subunit plasmid immunization by electroporation overcomes tolerance to self-antigen to provide a faithful model of Graves' disease and GO.

Experimental models of hyperthyroid Graves’ disease (GD) and Graves’ orbitopathy (GO) are efficiently developed by genetic immunisation by electroporation with human thyrotropin hormone receptor (hTSHR) A-subunit plasmid in female BALB/c (H-2d) mice. We investigated susceptibility in C57BL/6 J (H-2b) animals to allow studies on disease mechanisms in transgenic and immune response gene knock-out mice. Higher numbers of female C57BL/6 J were positive for pathogenic thyroid stimulating antibodies, but induced hyperthyroidism remained at a low frequency compared to BALB/c animals. Assessment of hTSHR specific T cells showed reduced proliferation in C57BL/6 J animals accompanied with anti-inflammatory IL-10, with less pro-inflammatory IFN-γ compared to BALB/c. Whilst the orbital tissue from immune BALB/c mice showed inflammation and adipogenesis, in contrast C57BL/6 J animals showed normal pathology. We characterised the gut microbiota using 16 S ribosomal RNA gene sequencing to explore its possible pathogenic role in the model. Despite being housed under identical conditions, we observed significantly different organisation of the microbiota (beta-diversity) in the two strains. Taxonomic differences were also noted, with C57BL/6 J showing an enrichment of Operational Taxonomic Units (OTUs) belonging to the Paludibacter and Allobaculum, followed by Limibacter, Anaerophaga and Ureaplasma genera. A higher number of genera significantly correlating with clinical features was observed in C57BL/6 J compared to BALB/c; for example, Limibacter OTUs correlated negatively with thyroid-stimulating antibodies in C57BL/6 J mice. Thus, our data suggest gut microbiota may play a pivotal immunomodulatory role that differentiates the thyroid function and orbital pathology outcome in these two inbred strains undergoing experimental GO.

Graves' orbitopathy (GO) is a complication in Graves' disease (GD) but mechanistic insights into pathogenesis remain unresolved, hampered by lack of animal model. The TSH receptor (TSHR) and perhaps IGF-1 receptor (IGF-1R) are considered relevant antigens. We show that genetic immunization of human TSHR (hTSHR) A-subunit plasmid leads to extensive remodeling of orbital tissue, recapitulating GO. Female BALB/c mice immunized with hTSHR A-subunit or control plasmids by in vivo muscle electroporation were evaluated for orbital remodeling by histopathology and magnetic resonance imaging (MRI). Antibodies to TSHR and IGF-1R were present in animals challenged with hTSHR A-subunit plasmid, with predominantly TSH blocking antibodies and were profoundly hypothyroid. Orbital pathology was characterized by interstitial inflammation of extraocular muscles with CD3+ T cells, F4/80+ macrophages, and mast cells, accompanied by glycosaminoglycan deposition with resultant separation of individual muscle fibers. Some animals showed heterogeneity in orbital pathology with 1) large infiltrate surrounding the optic nerve or 2) extensive adipogenesis with expansion of retrobulbar adipose tissue. A striking finding that underpins the new model were the in vivo MRI scans of mouse orbital region that provided clear and quantifiable evidence of orbital muscle hypertrophy with protrusion (proptosis) of the eye. Additionally, eyelid manifestations of chemosis, including dilated and congested orbital blood vessels, were visually apparent. Immunization with control plasmids failed to show any orbital pathology. Overall, these findings support TSHR as the pathogenic antigen in GO. Development of a new preclinical model will facilitate molecular investigations on GO and evaluation of new therapeutic interventions.

Summary Varicella zoster virus (VZV) causes the common childhood isease chickenpox (varicella), or upon reactivation, the dermatomal vesiculopustular eruption seen in shingles (herpes zoster). The clinical course of herpes zoster in immunocompromised patients is often recurrent, protracted and multidermatomal, and it can result in myelitis, meningoencephalitis, and cerebral or small-vessel vasculopathic or vasculitic changes. Commonly, the vesicular rash settles with aciclovir therapy and does not involve motor neuropathy. We report a 63-year-old man with a prolonged, multidermatomal, nonvesicular rash, and limb paresis secondary to brachioplexitis. PCR for VZV was positive, and the histological results were consistent with granulomatous vasculopathy. Prolonged treatment with valaciclovir was required to resolve the eruption and help improve the patient's motor function. We discuss the problems faced in clinical decision-making about immunosuppressive treatment of granulomatous vasculopathy and motor neuropathy, when any increase in immunosuppressive therapy may increase the likelihood of central nervous system complications.

Background Drug reaction with eosinophilia and systemic symptoms (DRESS) describes a heterogeneous group of severe adverse reactions to medications. The cutaneous phenotype has a number of guises, accompanied by a variety of systemic features including fever, haematological abnormalities and visceral involvement, most commonly the liver. Clinical markers of prognosis have not been identified. Objectives To assess the cutaneous signs and dermatopathological features of DRESS in order to identify potential prognostic markers. Methods We reviewed the clinical features, dermatopathology and outcomes of 27 consecutive cases of DRESS presenting to a single unit. Results Four distinct patterns of cutaneous involvement were identified: an urticated papular exanthem (13 ⁄27 patients), a morbilliform erythema (three of 27), an exfoliative erythroderma (three of 27) and an erythema multiforme-like (EM-like) reaction consisting of atypical targets (eight of 27). All patients mounted a fever, most developed lymphadenopathy (24 ⁄27) and peripheral eosinophilia (25 ⁄27) and the most common organ involved was the liver (27 ⁄27). Review of the dermatopathic features of patients with DRESS demonstrated a superficial spongiotic dermatitis in the majority of cases (16 ⁄27). A smaller number of cases showed basal cell vacuolar degeneration and necrotic keratinocytes (nine of 27). The patients with these biopsy findings more commonly had an EM-like cutaneous phenotype, and more severe hepatic involvement. Three patients died, two following failed liver transplants. Conclusions Our series is the first in which a detailed dermatological assessment has been made of consecutive patients presenting with DRESS, and the largest U.K. series to date. Our results suggest a possible prognostic role of the cutaneous and dermatopathic findings in DRESS in predicting the severity of visceral involvement in this syndrome.

The REarranged during Transfection (RET) proto-oncogene is a receptor tyrosine kinase involved in growth and differentiation during embryogenesis and maintenance of the urogenital and nervous systems in mammals. Distinct mutations across hotspot RET exons can cause Multiple Endocrine Neoplasia Type 2A (MEN2A) characterised by development of medullary thyroid cancer (MTC), phaeochromocytoma (PCC) and primary hyperparathyroidism (PHPT), with a strong correlation between genotype and phenotype. Here, we report a 42-year-old man presented in the clinic with a unilateral PCC, with subsequent investigations revealing a nodular and cystic thyroid gland. He proceeded to thyroidectomy, which showed bilateral C-cell hyperplasia (CCH) without evidence of MTC. His brother had neonatal Hirschsprung disease (HSCR). Genetic testing revealed the presence of a heterozygous variant of unknown significance (VUS) in the cysteine-rich region of exon 10 in the RET gene (c.1846G>C, p.E616Q), in both affected siblings and their unaffected mother. Exon 10 RET mutations are known to be associated with HSCR and MEN2. Variants in the cysteine-rich region of the RET gene, outside of the key cysteine residues, may contribute to the development of MEN2 in a less aggressive manner, with a lower penetrance of MTC. Currently, a VUS in RET cannot be used to inform clinical management and direct future care. Analysis of RETE616Q reveals a gain of function mutant phenotype for this variant, which has not previously been reported, indicating that this VUS should be considered at risk for future clinical management.

We recently described a preclinical model of Graves' orbitopathy (GO), induced by genetic immunization of eukaryotic expression plasmid encoding human TSH receptor (TSHR) A-subunit by muscle electroporation in female BALB/c mice. The onset of orbital pathology is characterized by muscle inflammation, adipogenesis, and fibrosis. Animal models of autoimmunity are influenced by their environmental exposures. This follow-up study was undertaken to investigate the development of experimental GO in 2 different locations, run in parallel under comparable housing conditions. Functional antibodies to TSHR were induced in TSHR A-subunit plasmid-immunized animals, and antibodies to IGF-1 receptor α-subunit were also present, whereas control animals were negative in both locations. Splenic T cells from TSHR A-subunit primed animals undergoing GO in both locations showed proliferative responses to purified TSHR antigen and secreted interferon-γ, IL-10, IL-6, and TNF-α cytokines. Histopathological evaluation showed orbital tissue damage in mice undergoing GO, manifest by adipogenesis, fibrosis, and muscle damage with classic signs of myopathy. Although no inflammatory infiltrate was observed in orbital tissue in either location, the appearances were consistent with a “hit-and-run” immune-mediated inflammatory event. A statistically significant increase of cumulative incidence of orbital pathology when compared with control animals was shown for both locations, confirming onset of orbital dysimmune myopathy. Our findings confirm expansion of the model in different environments, accompanied with increased prevalence of T cell-derived proinflammatory cytokines, with relevance for pathogenesis. Wider availability of the model makes it suitable for mechanistic studies into pathogenesis and undertaking of novel therapeutic approaches.

Glucagon-like peptide-1 (GLP-1) is a gut peptide that promotes insulin release from pancreatic β-cells and stimulates β-cell hyperplasia. GLP-1 secretion causing hypoglycemia has been described once from an ovarian neuroendocrine tumor (NET) but has not been reported from a pancreatic NET (pNET).A 56-yr-old male with a previous diagnosis of diabetes presented with fasting hypoglycemia and was found to have a metastatic pNET secreting glucagon. Neither the primary tumor nor metastases stained for insulin, whereas the resected normal pancreas showed histological evidence of islet cell hyperplasia. We provide evidence that GLP-1 secretion from the tumor was the cause of hyperinsulinemic hypoglycemia.GLP-1 levels were determined in the patient, and immunohistochemistry for GLP-1 was performed on the tumor metastases. Ex vivo tissue culture and a bioassay constructed by transplantation of tumor into nude mice were performed to examine the tumor secretory products and their effects on islet cell function.The patient had high levels of glucagon and GLP-1 with an exaggerated GLP-1 response to oral glucose. Immunohistochemistry and primary tissue culture demonstrated secretion of glucagon and GLP-1 from the tumor metastases, whereas insulin secretion was almost undetectable. Ex vivo coculture of the tumor with normal human islets resulted in inhibition of insulin release, and transplanted mice developed impaired glucose tolerance.This is the first description of glucagon and GLP-1 secretion from a metastatic pNET causing sequential diabetes and hypoglycemia. Hypoglycemia was caused by insulin secretion from hyperplastic β-cells stimulated by tumor-derived GLP-1.

‘inflammation of parathyroid gland’, ‘lymphocytic infiltrate’, ‘tuberculosis of the parathyroid’, ‘sarcoidosis’, and ‘graulomatous inflammation’. Three autopsy series, 27 articles and 96 case reports with inflammatory parathyroid disorders were identified. Autopsy series showed lymphocytic infiltrates in up to 16% of all cases. The entire material reported lymphocytic infiltrates (n = 69), parathyroiditis with germinal centres (n = 15), sarcoidosis (n = 6), tuberculosis (n = 4), and other granulomatous diseases (n = 2). Conclusions: Distinct inflammatory and granulomatous processes in the parathyroid gland are rare. Scanty lymphocytic infiltrates are common, and occur in generalized inflammatory conditions or venous congestion. We note the surprising absence of an association between histological proof of parathyroiditis and hypoparathyroidism.

Atypical (dysplastic) melanocytic nevi are clinically heterogeneous malignant melanoma precursors, for which no topographic analysis of cell kinetic, cell cycle regulators and microsatellite profile is available. We selected low-grade atypical melanocytic nevi (92), high-grade atypical melanocytic nevi (41), melanocytic nevi (18 junctional, 25 compound) and malignant melanomas (16 radial growth phase and 27 vertical growth phase). TP53, CDKN2A, CDKN1A, and CDKN1B microsatellite patterns were topographically studied after microdissection; Ki-67, TP53, CDKN2A, CDKN1A, and CDKN1B expressions and DNA fragmentation by in situ end labeling for apoptosis were topographically scored. Results were statistically analyzed. A decreasing junctional-dermal marker expression gradient was observed, directly correlating with atypical melanocytic nevus grading. High-grade atypical melanocytic nevi revealed coexistent TP53-CDKN2A-CDKN1B microsatellite abnormalities, and significantly higher junctional Ki67-TP53 expression (inversely correlated with CDKN1A-CDKN1B expression and in situ end labeling). Malignant melanomas showed coexistent microsatellite abnormalities (CDKN2A-CDKN1B), no topographic gradient, and significantly decreased expression. Melanocytic nevi and low-grade atypical melanocytic nevi revealed sporadic junctional CDKN2A microsatellite abnormalities and no significant topographic kinetic differences. High-grade atypical melanocytic nevi accumulate junctional TP53-CDKN1A-CDKN1B microsatellite abnormalities, being progression TP53-independent and better assessed in the dermis. Melanocytic nevi and low-grade atypical melanocytic nevi show low incidence of microsatellite abnormalities, and kinetic features that make progression unlikely.

The best surgical approach to parathyroid cancer is disputed. Recommendations vary and are built on incoherent evidence. High rates of recurrence and death require an in-depth review of underlying findings. This retrospective study includes 11 patients with parathyroid cancer who underwent surgery with central and/or lateral neck dissection by a single surgeon between 2005 and 2010. The diagnosis was based on histopathological criteria in all patients. Patterns of lymph node and soft tissue involvement of these and formerly reported patients were analysed based on full-text review of all published cases of parathyroid cancer. In this series only 1 of 11 patients (9.1%) manifested lymph node metastasis. In the literature, lymph node metastases have been reported in only 6.5% of 972 published patients, or in 32.1% of the 196 in whom lymph node involvement was assessed by the authors. They were, with few exceptions, localised in the central compartment. Recurrence in soft tissue is more frequent than in locoregional lymph nodes. Oncological en bloc clearance of the central compartment with meticulous removal of all possibly involved soft tissues, including a systematic central lymph node resection, may improve outcomes and should be included in the routine approach to the suspicious parathyroid lesion. There is no need for a prophylactic lateral neck dissection.

Introduction: Congenital segmental emphysema (CSE) is a newly-recognised sub-type of congenital parenchymal lung anomaly. It is characterised by antenatal detection and post-natal evolution from an initially solid segmental appearance to a hyperlucent and hyperinflated segment. Methods: A retrospective review of a single-centre tertiary referral database between Jan 1994 and Dec 2007 was performed. Main Results: 130 infants had antenatally detected lung anomalies, and of these 12 (9.2 %) infants (initially labelled as congenital cystic adenomatoid malformation (CCAM)), showed features better defined as CSE. The lesions were described antenatally as non-progressive micro-cystic (n=6), hyperechogenic (n=2) or both (n=2). Early post-natal CT scans showed areas of solid segmental parenchyma, initial hyper-lucency or microcysts. Subsequent CT imaging, however, showed evolution to segmental hyper-lucency in areas previously solid and in 2 cases a central bronchocele was noted. Ten children underwent resectional surgery (segmentectomy n=4, lobectomy n=6) at a median age of 1 (range 0.4-5.2) year and the gross appearance of the resected specimen confirmed hyperinflated (not cystic) segments. Histological review showed localised abnormally dilated alveolar spaces in 7 cases. Adjacent areas consistent with type 2 CCAM were also seen (n=3). Conclusion: CSE lies within the spectrum of both CCAM and sequestration but there is a definite post-natal evolution and volume change which presage symptoms. This may be associated with segmental bronchial atresia and progressive air trapping via collateral airways such as the interalveolar pores of Kohn.

We report a 12-mm nodular, cream-coloured skin lesion that appeared on the left nasal ala in an 81-year-old man. This trabecular infiltrative tumour showed keratin microcysts, stromal hyalization, cytoarchitectural malignancy features, colonizing melanocytes, and immunoexpression of epithelial membrane antigen, cytokeratin 15/20, chromogranin, synaptophysin and CD56. To our knowledge, this is the first documented case of a trichilemmal carcinoma with neuroendocrine differentiation and melanocyte colonization, which is suggested by the trabecular growth pattern and requires immunohistochemical confirmation. The colonization of the epithelial nests by nonatypical dendritic or spindle melanocytes is a clue to morphological recognition of pilar neoplasms, along with the presence of stromal induction (CD34-positive peritumoral spindle cells), catagen-like apoptotic bodies, calcifications, keratin microcysts and cell balls.

Adrenocortical carcinoma is associated with a low cure rate and a high recurrence rate. The prognosis is poor, and at diagnosis 30-40% of cases are already metastatic. The current therapeutic options (surgical resection, followed by adjuvant mitotane treatment +/- chemotherapy) are limited, and the results remain unsatisfactory. Key molecular events that contribute to formation of adrenocortical cancer are IGF2 overexpression, TP53-inactivating mutations, and constitutive activation of the Wnt/b-catenin signalling pathway via activating mutations of the b-catenin gene. The underlying genetic causes of inherited tumour syndromes have provided insights into molecular pathogenesis. The increased occurrence of adrenocortical tumours in Li-Fraumeni and Beckwith-Wiedemann syndromes, and Carney complex, has highlighted the roles of specific susceptibility genes: TP53, IGF2, and PRKAR1A, respectively. Further studies have confirmed that these genes are also involved in sporadic tumour cases. Crucially, transcriptome-wide studies have determined the differences between malignant and benign adrenocortical tumours, providing potential diagnostic tools. In conclusion, enhancing our understanding of the molecular events of adrenocortical tumourigenesis, especially with regard to the signalling pathways that may be disrupted, will greatly contribute to improving a range of available diagnostic, prognostic, and treatment approaches. (Endokrynol Pol 2016; 67 (4): 427-440).

Autoimmune thyroid disease is the most common organ-specific autoimmune disorder which consists of two opposing clinical syndromes, Hashimoto's thyroiditis and Graves' (hyperthyroidism) disease. Graves' disease is characterized by goiter, hyperthyroidism, and the orbital complication known as Graves' orbitopathy (GO), or thyroid eye disease. The hyperthyroidism in Graves' disease is caused by stimulation of function of thyrotropin hormone receptor (TSHR), resulting from the production of agonist antibodies to the receptor. A variety of induced mouse models of Graves' disease have been developed over the past two decades, with some reproducible models leading to high disease incidence of autoimmune hyperthyroidism. However, none of the models show any signs of the orbital manifestation of GO. We have recently developed an experimental mouse model of GO induced by immunization of the plasmid encoded ligand binding domain of human TSHR cDNA by close field electroporation that recapitulates the orbital pathology in GO. As in human GO patients, immune mice with hyperthyroid or hypothyroid disease induced by anti-TSHR antibodies exhibited orbital pathology and chemosis, characterized by inflammation of orbital muscles and extensive adipogenesis leading to expansion of the orbital retrobulbar space. Magnetic resonance imaging of the head region in immune mice showed a significant expansion of the orbital space, concurrent with proptosis. This review discusses the different strategies for developing mouse models in Graves' disease, with a particular focus on GO. Furthermore, it outlines how this new model will facilitate molecular investigations into pathophysiology of the orbital disease and evaluation of new therapeutic interventions.

Background Gastroschisis associated intestinal dysmotility (GAID) is poorly understood. Animal experiments suggest that interstitial cells of Cajal (ICC), play an important role. Methods Infants with gastroschisis (GS) and GAID (time to full feed > 42 days) were selected. Age matched GS and control (NEC, ileal atresia, malrotation, and volvulus) samples from primary (T1) and secondary (T2) time points underwent standard histopathology and immunohistochemistry for identification of ICC, followed by evaluation of ICC numbers, distribution, morphology, relation to ganglion cells, and myenteric plexus architecture. Groups were compared using parametric and non-parametric tests. Main Results Twelve patients had samples available for histopathological evaluation. GAID patients had a significantly lower total number of ICC than controls (3 vs. 8, P < 0.0029). ICC number at T1 was 2.5 vs. 6, P=0.0629 and significantly lower at T2. (3.5 vs. 11, P=0.0124). GAID patients did not show a significant increase of ICC from T1 to T2. Controls showed a significant increase of ICC over time (6 vs. 11, P=0.0408). Conclusion Intestinal samples from infants with GAID who underwent stoma formation demonstrated fewer ICC than controls. There was no improvement or cell recovery during the study period. The ability to modulate ICC may have significant implications for the management of GAID.

Clonal seborrheic keratoses are uncommon, are usually pigmented, and cannot be clinically differentiated from ordinary seborrheic keratoses. The histologic hallmark is the presence of sharply demarcated intraepithelial nests of basaloid cells (Borst-Jadassohn phenomenon). Although dermoscopy is a helpful diagnostic tool for atypical seborrheic keratoses, the clonal variant may represent a dermoscopic pitfall. Clonal seborrheic keratoses present with blue- brown globules and milia-like cysts on dermoscopy, but vascular structures have not been described to our knowledge.We present an unusual acquired red patch in a young patient, showing polymorphic vessels on a diffuse pink and whitish background with white network. Polymorphic vessels on dermoscopy suggest malignancy, as they may appear in squamous cell carcinomas, Spitz nevi, and melanomas. Clonal seborrheic keratoses may present as nonpigmented patches and should be considered in the differential diagnosis of acquired erythematous vascularized lesions. Biopsy is mandatory to confirm the diagnosis.

We retrieved 50 cutaneous epithelial pilar neoplasms from The Royal London Hospital archives (1980–2003), 46 benign (39 trichoepitheliomas ⁄ seven trichoblastomas) and four malignant (trichilemmal carcinomas). The pilar differ- entiation criteria included organoid, lobular or folli- culo-centric growth pattern, few or no connections with the epidermis, keratinous microcysts and ‘cell balls’, hyalinized stroma and catagen-like apoptotic bodies.1,2 Malignancy criteria included infiltrative margins, nuclear pleomorphism, necrosis and mitotic figures including atypical ones.1,2 Two haematoxylin and eosin (H&E) levels were reviewed by two histo- pathologists (Z.A. and S.D-C.) to systematically assess growth pattern, catagen-like apoptotic bodies, dual cell population, pigment, stromal reaction (myxoid, lamel- lar fibrosis, hyalinization), calcification, nuclear fea- tures, mitotic figures ⁄ 10 high-power fields (equivalent to 1.52 mm2), and immunostaining for CD34, S100 and HMB-45. As controls, adnexal neoplasms (eight sebaceous adenomas, two sebaceous carcinomas, seven poromas ⁄ nodular hidradenomas, three porocarcinomas ⁄ hidradenocarcinomas) were identified according to standard criteria.2 Basal cell carcinomas (n 1⁄4 10) were also included in the control group because they are frequently considered in the differential diagnosis. Conclusion: Melanocytes are invariably found within the epithelial nests of CEPN (both benign and malignant) and can be used along with the presence of CD34+ stromal induction as clues for pilar differenti- ation, in the absence of epithelial cell melanin during routine histological examination.

Summary objective Clinical acromegaly is characterized by elevated GH secretion in the presence of high circulating IGF-I levels. We hypothesized that the physiological IGF-I/GH negative feedback loop may be reset in somatotroph adenomas, specifically in terms of the level of expression of these receptors or mutations of the GH receptor (GH-R) in such tumours. methods We therefore investigated the full coding sequence of the GH-R in a series of somatotroph and other pituitary adenomas. We also investigated the mRNA expression of these putative feedback receptors in a series of pituitary adenomas and normal pituitary tissue, and their protein expression by immunostaining. Real-time RT–PCR assay was used for the quantification of the type 1 IGF receptor (IGF-R) and GH receptor (GH-R) mRNA, and sequence analysis was performed on the coding region of the GH-R gene. results No somatic mutations of the GH-R mRNA were detected in 18 GH-secreting tumours or two nonfunctioning pituitary adenomas (NFPAs). However, the levels of GH-R mRNA were significantly lower in both somatotroph tumours and NFPAs compared to the normal pituitary (P