Reza Asari

Hypoparathyroidism After Total Thyroidectomy: A Prospective Study

HYPOTHESIS Combined measurement of intact parathyroid hormone (iPTH) and serum calcium (sCa) levels is useful for predicting postoperative hypocalcemia with minimal laboratory effort and low costs. DESIGN Prospective analysis of 170 consecutive patients. SETTING University hospital referral center. PATIENTS One hundred seventy patients underwent total thyroidectomy. Defining hypoparathyroidism as albumin-adjusted sCa levels of less than 1.9 mmol/L with or without clinical symptoms or subnormal sCa levels (1.9-2.1 mmol/L) with neuromuscular symptoms, the influences of central lymph node dissection, experience of the surgeon, and parathyroid autotransplantation were observed. We measured the sCa and iPTH levels separately and in combination and the postoperative sCa slope to predict patients who were at risk of hypoparathyroidism. MAIN OUTCOME MEASURES Predictive values for iPTH and sCa levels were compared to identify postoperative hypoparathyroidism. RESULTS Of the 170 study patients, 41 developed transient hypoparathyroidism and 2 developed permanent hypoparathyroidism. The morphologic features and function of the thyroid gland, central neck dissection, experience of the surgeon, and parathyroid autotransplantation did not influence development of postoperative hypoparathyroidism. The best sensitivity for predicting postoperative hypoparathyroidism was 97.7% for measurement of iPTH levels, and the best specificity was 96.1% for measurement of sCa levels. Negative and positive predictive values reached their best (99.0% and 86.0%, respectively) when we combined sCa and iPTH values. CONCLUSIONS Patients with iPTH levels of 15 pg/mL or less and sCa levels of 1.9 mmol/L or less are at increased risk of developing postoperative hypoparathyroidism. Measuring iPTH levels 24 hours after total thyroidectomy in combination with sCa levels on the second postoperative day allows the prediction of hypoparathyroidism with a high sensitivity, specificity, and positive predictive value.

Immunohistochemical Detection of the BRAF V600E-mutated Protein in Papillary Thyroid Carcinoma

The V600E mutation of the B-type Raf kinase (BRAF) gene is a common event in papillary thyroid carcinoma (PTC) and seems to play a key role in the development and progression of this disease. We evaluated the expression of the mutated BRAF V600E protein in 144 cases of PTC using a novel mutation-specific antibody. Seventy-six PTCs (52.8%) showed unequivocal diffuse cytoplasmic expression of the mutated BRAF protein, and the T1799A point mutation was confirmed by sequencing analysis in selected cases. No statistical difference in V600E BRAF protein expression was seen between microcarcinomas and macrocarcinomas. Further, no significant correlation of V600E expression with clinicopathologic parameters of aggressiveness such as lymph node metastasis, peritumoral infiltration, or perithyroidal infiltration was found. BRAF V600E protein expression was significantly more common in tumors with tall cell or oncocytic features but was less common in tumors with follicular growth pattern. Diffuse sclerosing, solid and follicular variants did not show the mutated BRAF protein. Immunohistochemical detection of the mutated V600E BRAF protein in PTC may facilitate mutational analysis in the clinical setting. Our data show that the expression of the mutated BRAF V600 protein and thus the corresponding BRAF mutation seems not to be per se a marker of aggressiveness but is already seen in clinically indolent microcarcinomas. Nevertheless, the investigation of BRAF V600E protein expression might be of clinical interest especially in therapy-resistant disease, as new therapeutics inhibiting the mutated protein are clinically available.

Follicular thyroid carcinoma in an iodine-replete endemic goiter region: a prospectively collected, retrospectively analyzed clinical trial.

Objective:To determine risk factors for presence of lymph node or distant metastases in patients with follicular thyroid cancer (FTC) at the time of diagnosis and whether there is a relationship between the type of tumor invasion and metastases. Summary Background Data:FTC often presents distant metastases at the initial diagnosis. As distant metastases are independent prognostic factors in a patients survival, determination of clinicopathologic characteristics for patients who are at higher risk for developing metastases is of greater clinical importance. Methods:The prognostic significance of gender (male vs. female), age (≤40 years vs. <40 years), tumor size (≤40 mm vs. >40 mm), number of lesions (uni- vs. multifocality), type of invasion (minimally invasive vs. widely invasive), and oncocytic changes (with vs. without) were analyzed in 207 patients, according to presence of lymph node and distant metastases at the time of initial surgery. According to the type of invasion, the carcinoma-specific survival and the disease-free survival of minimally invasive (MI) and widely invasive (WI) FTC were estimated and compared. Results:None of the 127 patients with MI growth presented with lymph node metastases but 9.4% distant metastases. Overall risk factors for the presence of lymph node metastases at the initial diagnosis were multifocality (P = 0.02) and widely invasion (P = 0.0001) and for distant metastases age >45 years (P = 0.007), tumor size larger than 40 mm (P = 0.03) and widely invasion (P = 0.0001). WI-FTC patients show larger tumors (P = 0.0001), older age (P = 0.0001), and are presented more frequently in recurrent goiter disease (P = 0.0001). The estimated 10 years carcinoma-specific survival and disease-free survival for MI-tumors were significantly better than for WI-tumors (P = 0.0001). Conclusions:Total thyroidectomy is recommended in all patients with FTC because of early distant metastases. Patients with WI-FTC need a more aggressive surgical treatment because of higher tendency for lymph node metastases. MI-FTC has an excellent prognosis with no sign of lymph node metastases, which emphasizes a limited need for nodal surgery.

Desmoplastic stromal reaction in papillary thyroid microcarcinoma.

Koperek O, Asari R, Niederle B & Kaserer K
(2011) Histopathology 58, 919–924
Desmoplastic stromal reaction in papillary thyroid microcarcinoma

Desmoplastic Stromal Reaction in Medullary Thyroid Cancer—An Intraoperative “Marker” for Lymph Node Metastases

BackgroundMedullary thyroid cancer (MTC) disseminates early to lymph nodes (LN). There is no pre- or intraoperative marker to exclude LN involvement and thereby avoid lateral neck dissection in LN-negative patients.Materials and MethodsThis study was intended to verify the observation that patients with MTC lacking desmoplastic stromal reaction (DSR) never have LN metastases. In 120 patients undergoing primary operation for sporadic MTC the prognostic value of DSR with respect to LN involvement was evaluated.ResultsThirty-two (27%) of 120 tumors were DSR negative, and 88 (73%) were DSR positive. All 32 (100%) DSR-negative tumors were LN negative (N0), and all patients were biochemically cured. Of 88 DSR-positive tumors, 57 (65%) were staged N0, and 31 (36%) were staged N1(LN positive; Fisher’s exact test: P = 0.0001). In a comparison of the LN involvement to the DSR characteristics, 32 (36%) of the 89 N0 patients and none of the 31 N1 patients were DSR negative. The sensitivity of DSR in predicting N0 is 38% (95% confidence interval: CI 95% = 27 %–55%), the specificity is 100% (CI 95% = 88%–100%). The sensitivity and specificity for the parameter DSR to differentiate between N0 or N1 were 100% and 36%, respectively.ConclusionsThe desmoplastic stromal reaction appears to be an excellent intraoperative marker to predict LN involvement with a high specificity but low sensitivity. We therefore propose to avoid initial lateral neck dissection in MTC patients without DSR.

Is minimally invasive parathyroidectomy without QPTH monitoring justified

BackgroundIt is matter of discussion if quick parathyroid hormone (QPTH) monitoring is helpful in patients with primary hyperparathyroidism (PHPT) and “localized single-gland disease” (SGD; concordant sestamibi and ultrasound results) to further increase the rate of success (permanent normocalcemia) of performing selective parathyroidectomy by minimally invasive parathyroid exploration (MIP). The aim of this study was to evaluate if a randomized controlled trial was justified in order to clarify this discussion.Materials and methodsThe prospective database of patients with sporadic PHPT, SGD, MIP, and QPTH monitoring (1999–2005) was evaluated regarding the “conversion rate” to bilateral exploration and permanent normocalcemia (“QPTH” group). Retrospectively, the patients were analyzed a second time “without” applying QPTH monitoring (“non-QPTH” group). Statistical differences between both groups were calculated (McNemar’s test).ResultsBy definition, 338 patients with “localized SGD” underwent MIP. MIP was finished in 308 (91.1%) patients. Five of 308 patients (1.6%) showed persisting (n = 1) or recurrent disease (n = 4). In 30 of 338 patients (8.9%), a conversion to bilateral exploration was necessary (false preoperative localization 15 patients—one patient not cured; multiple-gland disease correctly indicated by QPTH monitoring 15 patients—one patient not cured). Analyzing the “non-QPTH” group, 14 additional patients showed persisting disease. Thus, without using QPTH monitoring, the rate of persisting PHPT would increase from 0.9% (three patients) to 5.0% (17 patients; p = 0.0005).ConclusionIntraoperative QPTH assay seems necessary even in patients with “localized SGD” by two techniques in an endemic goiter region. Abandoning QPTH monitoring would more than double the rate of persisting disease. A randomized trial seems not to be justified.

Surgical treatment of GIST – An institutional experience of a high-volume center

BACKGROUND Discovery of the molecular pathogenesis of Gastrointestinal stromal tumors led to the development of targeted therapies, revolutionizing their treatment. However, surgery is still the mainstay of GIST therapy and the only chance for cure. AIM Here we present a single institutional consecutive case series of 159 GIST-patients. METHODS AND PATIENTS A total of 159 GIST-patients who underwent resection between 1994 and 2011 were reviewed for clinicopathohistological data, informations on surgical and medical therapy and further follow-up, outcome and survival data. RESULTS Laparoscopic (25.2%) and open (71.1%) GIST surgery achieved complete resection rates of 97.5% and 85.2%, whereas 44.4% of incomplete and 6.6% of complete resected patients died from GIST. Compared to open surgery laparoscopy significantly reduced duration of operation (183.4 vs. 130.6 min), length of hospitalization (16.1 vs. 8.3 d) and morbidity (23% vs. 7.5%). Mean survival time was 3.7 ± 2.7 years (R0: 5.1 a and R1: 2.6 a) and the mean overall survival was 4.5 ± 3.8 years. CONCLUSION Complete surgical resection is the primary goal and laparoscopy can be performed safely in a subset of GIST-patients with potential perioperative advantages. Although not proven by the present study the authors assume that multimodal GIST-treatment, as performed in reference-centers, is required for advanced or high risk disease. Our data suggest the potential for minimally invasive GIST resection to achieving comparable oncological outcomes as after open surgery while providing low morbidity rates.

Review on novel concepts of columnar lined esophagus

SummaryBackgroundColumnar lined esophagus (CLE) is a marker for gastroesophageal reflux and associates with an increased cancer risk among those with Barrett’s esophagus. Recent studies fostered the development of integrated CLE concepts.MethodsUsing PubMed, we conducted a review of studies on novel histopathological concepts of nondysplastic CLE.ResultsTwo histopathological concepts—the squamo-oxyntic gap (SOG) and the dilated distal esophagus (DDE), currently model our novel understanding of CLE. As a consequence of reflux, SOG interposes between the squamous lined esophagus and the oxyntic mucosa of the proximal stomach. Thus the SOG describes the histopathology of CLE within the tubular esophagus and the DDE, which is known to develop at the cost of a shortened lower esophageal sphincter and foster increased acid gastric reflux. Histopathological studies of the lower end of the esophagus indicate, that the DDE is reflux damaged, dilated, gastric type folds forming esophagus and cannot be differentiated from proximal stomach by endoscopy. While the endoscopically visible squamocolumnar junction (SCJ) defines the proximal limit of the SOG, the assessment of the distal limit requires the histopathology of measured multilevel biopsies. Within the SOG, CLE types distribute along a distinct zonation with intestinal metaplasia (IM; Barrett’s esophagus) and/or cardiac mucosa (CM) at the SCJ and oxyntocardiac mucosa (OCM) within the distal portion of the SOG. The zonation follows the pH-gradient across the distal esophagus. Diagnosis of SOG and DDE includes endoscopy, histopathology of measured multi-level biopsies from the distal esophagus, function, and radiologic tests. CM and OCM do not require treatment and are surveilled in 5 year intervals, unless they associate with life quality impairing symptoms, which demand medical or surgical therapy. In the presence of an increased cancer risk profile, it is justified to consider radiofrequency ablation (RFA) of IM within clinical studies in order to prevent the progression to dysplasia and cancer. Dysplasia justifies RFA ± endoscopic resection.ConclusionsSOG and DDE represent novel concepts fusing the morphological and functional aspects of CLE. Future studies should examine the impact of SOG and DDE for monitoring and management of gastroesophageal reflux disease (GERD).ZusammenfassungHintergrundZylinderepithel-Ösophagus (engl. columnar lined esophagus; CLE) zeigt gastroösophagealen Reflux und bedingt bei jenen mit einem Barrett Ösophagus ein erhöhtes Krebsrisiko. Rezente Studien beschreiben ein integriertes morphofunktionales CLE Konzept.MethodikDiese PubMed basierte Analyse gibt eine Übersicht zu neuen histopathologischen Konzepten zu CLE ohne Dysplasie.ErgebnisseUnsere neue Vorstellung zu CLE wird anhand von zwei neuen histopathologischen Konzepten dargestellt: dem Mukosasegment zwischen Plattenepithel und oxntischer Magenschleimhaut (engl. squamo-oxntic gap; SOG) und dem dilatierten distalen Ösophagus (engl. dilated distal esophagus; DDE). Als Folge des Reflux entsteht das SOG zwischen dem von Plattenepithel ausgekleideten Ösophagus und des von oxyntischer Mukosa ausgekleideten proximalen Magens. SOG beschreibt die Histologie des CLE im tubulären Ösophagus und DDE, welcher auf Kosten des durch den Reflux verkürzten unteren Ösophagussphinkters entsteht und damit vermehrten Rückfluss des sauren Mageninhalts begünstigt. Morphologische Untersuchungen des Ausgangs der Speiseröhre zeigten, dass der DDE Reflux-geschädigter, dilatierter, magenähnliche Falten bildender Ösophagus ist und in der Endoskopie nicht vom proximalen Magen unterschieden werden kann. Während die proximale Grenze des SOG der endoskopisch definierbaren Platten-Zylinderepithelgrenze entspricht, kann die untere Grenze des SOG nur mittels Fusion von Biopsie-Lokalisation und der Histologie von aus diesem Bereich entnommenen Gewebeproben bestimmt werden. Im SOG ordnen sich die CLE Typen entsprechend einer typischen proximalen-distalen Verteilung mit intestinaler Metaplasie (IM, Barrett Ösophagus) ± Kardia Schleimhaut (CM) an der Platten-Zylinderepithelgrenze und Oxyntokardia (OCM) Mukosa im distalen Abschnitt des SOG. Die Ausrichtung folgt dem Reflux-bedingte pH Gradienten entlang des unteren Ösophagus. Die Diagnose von SOG und DDE erfolgt mittels Endoskopie, Histologie von Multi-Level Biopsien aus dem Ausgang der Speiseröhre sowie Funktionstests und Röntgenuntersuchungen. CM und OCM an sich bedürfen keiner Therapie und sollen in 5 Jahren nachuntersucht werden, nur assoziierte Reflux Beschwerden, welche die Lebensqualität beeinträchtigen, sollen medikamentös oder chirurgisch behandelt werden. Bei entsprechendem Krebsrisiko ist es gerechtfertigt, bei IM ohne Dysplasie eine Radiofrequenzablation (RFA) im Rahmen klinischer Studien zu erwägen, um damit die Entstehung von Dysplasie und Karzinom zu verhindern. Dysplasie rechtfertigt eine RFA ± endoskopischer Resektion.SchlussfolgerungenSOG und DDE sind neue Konzepte, welche Morphologie und Funktion des Zylinderepithel-Ösophagus integrieren. Die Zukunft wird zeigen, welche Bedeutung diese neuen Konzepte für Diagnose und Therapie der gastroösophagealen Refluxkrankheit haben.

Organic hyperinsulinism and endoscopic surgery

SummaryBACKGROUND: Experience with minimally invasive surgery for organic hyperinsulinism is limited. No criteria for patient selection with special regard to sporadic, hereditary, multiple and malignant tumors have been defined. METHODS: The estimated success rate of endoscopic surgery was retrospectively calculated by analysing 34 consecutive patients with organic hyperinsulinism operated on by open surgery. A literature search was undertaken to better define indications for endoscopic procedures. Differences in postoperative outcome (morbidity) between endoscopic and open procedures were analysed. RESULTS: Twenty-eight of 31 patients (90%) with solitary insulinomas and one of three patients with multiple insulinomas were correctly localized preoperatively. Twenty-six enucleations (76%) and eight distal resections (24%) including one endoscopic tail resection were performed. Theoretically only 14 out of 34 patients (41%) would have been suitable for endoscopic surgery (8 enucleations and 6 patients for distal resections which were enucleated using an open approach). Pancreatic fistulas were documented in three patients (9%). Reviewing 34 publications, 49 enucleations, 36 distal resections and 15 conversions to open surgery were performed, showing a higher proportion of distal resections in endoscopic surgery. The spleen was preserved in 88% of cases. Fourteen fistulas occurred after enucleations. CONCLUSIONS: Only solitary insulinomas localized in the pancreatic tail or superficially in the body or head may be candidates for endoscopic procedures. Patients with multiple insulinomas, MEN-1 syndrome or malignancy should undergo open surgery.

A pilot study of the endomicroscopic assessment of tumor extension in Barrett’s esophagus–associated neoplasia before endoscopic resection

Background and study aims: Barrett’s esophagus (BE) – associated neoplasia can be treated endoscopically, but accurate assessment before intervention is challenging. This study aimed to investigate the role of confocal laser endomicroscopy (CLE) as an adjunct in the endoscopic treatment of BE-associated neoplasia by assessing lateral tumor and subsquamous tumor (SST) extension. Patients and methods: In the context of a prospective, single-arm pilot clinical trial, patients referred for endoscopic resection of BE-associated neoplasia (high grade dysplasia and esophageal adenocarcinoma) underwent high definition, white light endoscopy with narrow-band imaging (NBI). Then, CLE mapping of suspected neoplastic lesions was performed by another endoscopist, partially blinded to the previous findings, before the patients underwent endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD), depending on lesion size and anticipated histology. Results: In 7 of 38 patients (18 %), CLE revealed additional neoplastic tissue compared with prior white light endoscopy and NBI: 2 concomitant lesions, 2 cases of lateral tumor extension within the Barrett’s epithelium, and 3 cases of previously undetected SST extension. Overall, en bloc resection (tumor-free lateral margin) was achieved in 28 of 34 neoplastic lesions (82 %), and complete resection (tumor-free lateral and basal margins) in 21 of 34 neoplastic lesions (62 %). Conclusions: CLE-assisted endoscopic resection of BE-associated neoplasia was safe and effective in this study, as proved by a high additional diagnostic yield of CLE (including visualization of occult SST extension) and a favorable rate of en bloc resection. The clinical value of CLE for assisting endoscopic therapy of BE-associated neoplasia deserves further evaluation in randomized controlled trials.