Encapsulation status of papillary thyroid microcarcinomas is associated with the risk of lymph node metastases and tumor multifocality.

The management of papillary microcarcinoma (PMC) of the thyroid is controversial, especially after partial thyroid resection for benign thyroid disease. In order to detect prognostic factors for PMC, we analyzed 116 patients with PMC for encapsulation status and lymph node metastases. Between 10/1992 and 12/2010, 116 patients with PMC have been operated in our department (87 females, 29 males, median age 49 years). Eighty per cent of PMCs were diagnosed postoperatively. Seventy-six patients (66%) received a more extended resection with either thyroidectomy, near total thyroidectomy, or Dunhill operation either primarily or after completion operation, whereas 40 patients (34%) had only partial resection. Fifty patients (43%) received radioiodine (RIA) ablation. Lymph node metastases were found in 21 patients (18%). Univariate analysis showed four risk factors to be significantly associated with the risk of lymph node metastasis (p<0.05): male gender, younger age, age group<50 years and nonencapsulation of the tumor. Multivariate analysis demonstrated statistical significance for gender and tumor capsulation status. The tumor capsulation status also correlated with tumor multifocality. Our data show that the risk of lymph node metastases is significantly higher in partially or nonencapsulated PMC than in encapsulated specimens. We therefore suggest that the WHO classification should be extended to a compulsory notification of the encapsulation status in PMC.

Coincidence of primary hyperparathyroidism and nonmedullary thyroid carcinoma.

The incidence of primary hyperparathyroidism (pHPT) combined with nonmedullary thyroid carcinoma (NMTC) has been reported between 2-13%. To date, it remains controversial whether these 2 pathologies occur coincidental or are caused by specific risk factors or genetic changes. The aim of this study was to evaluate the clinical and histological characteristics of NMTC associated with pHPT. We reviewed prospective database records of 1 464 unselected, consecutive patients who were treated for pHPT in our institution between 1986 and 2012 and identified 41 NMTC (2.8%). The collective consisted of 35 papillary (PTC) and 6 follicular (FTC) thyroid carcinomas. Our collective of 41 NMTC including 34 single adenomas and 7 multiglandular diseases consisted of 33 females and 8 males. Patients with FTC demonstrated significant lower preoperative PTH levels compared to PTC. Interestingly, NMTC were predominantly located on the right side. FTC had significant larger tumors as well as demonstrated increased extrathyroidal growth and lymph node metastases. In 71% pHPT and NMTC were diagnosed synchronously. The comorbidity of pHPT and NMTC occurs in about 3%. As pHPT is often operated by a focal minimally invasive approach, we advocate a mandatory preoperative thyroid ultrasound for all patients with pHPT to be able to identify synchronous thyroid disease.

[Polyostotic fibro-osseus lesions associated with intramuscular soft tissue neoplasms]. / Polyostotische Knochenveränderungen mit assoziierten intramuskulären Weichteiltumoren.

A 40-year-old female patient presented with progressive painful soft tissue lesions in the left upper arm. Conventional radiography showed multicystic bone tumors of the left humerus, radius and ulna. The computed tomography (CT) scan showed no paraosteal spread. Magnetic resonance imaging (MRI) detected intramuscular tumors in the deltoid muscle, biceps humeri muscle and triceps humeri muscle which were T2-weighted hyperintense and T1-weighted hypointense. Postcontrast images showed a marginal enhancement. The findings corresponded to the rare Mazabraud's syndrome in which polyostotic fibrous dysplasia is associated with intramuscular myxomas.

Loss of PTEN expression in neuroendocrine pancreatic tumors.

PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a well established tumor suppressor gene, which was cloned to chromosome 10q23. PTEN plays an important role in controlling cell growth, apoptosis, cell adhesion, and cell migration. In various studies, a genetic change as well as loss of PTEN expression by different carcinomas has been described. To date, the role of PTEN as a differentiation marker for neuroendocrine tumors (NET) and for the loss of PTEN expression is still unknown. It is assumed that loss of PTEN expression is important for tumor progression of NETs. We hypothesize that PTEN might be used as a new prognostic marker. We report 38 patients with a NET of the pancreas. Tumor tissues were surgically resected, fixed in formalin, and embedded in paraffin. PTEN expression was evaluated by immunohistochemistry and was correlated with several clinical and pathological parameters of each individual tumor. After evaluation of our immunohistochemistry data using a modified Remmele Score, a widely accepted method for categorizing staining results for reports and statistical evaluation, staining results of PTEN expression were correlated with the clinical and pathological parameters of each individual tumor. Our data demonstrates a significant difference in survival with existence of lymph node or distant metastases. Negative patients show a significant better survival compared with positive patients. Furthermore, we show a significant difference between PTEN expression and WHO or TNM classification. Taken together, our data shows a positive correlation between WHO classification and the new TNM classification of NETs, and loss of PTEN expression as well as survival. These results strongly implicate that PTEN might be helpful as a new prognostic factor.

Coincidence of mature cystic teratoma and serotonin-producing neuroendocrine tumor of the ileum.

Mature cystic teratomas are often found in gonadal sites, but are very rarely located extragonadally, for example, in retroperitoneum, mediastinum, central nervous system, lung, or liver. In the literature, only 10 cases of cystic teratoma originating from the diaphragm have been reported. Here, we report for the first time a metachronous occurrence of a benign mature cystic teratoma in the left diaphragm together with a serotonin-producing neuroendocrine tumor of the ileum. The 51-year-old, female patient received a partial resection of the ileum due to a neuroendocrine tumor (pT3N1M0) 4 years ago. Furthermore, she was operated for a benign cystadenoma of the right ovary 3 years ago. In her past medical history, she had an appendectomy in her childhood and a subtotal thyroidectomy 10 years ago. To our knowledge, this is the first report describing the metachronous occurrence of benign mature cystic teratoma in the diaphragm and a highly differentiated neuroendocrine tumor of the ileum. The possible coincidence of both diseases is discussed.

Global histone modification pattern predicts poor prognosis in organic hyperinsulinism.

Here we tested whether global histone modifications predict survival in organic hyperinsulinism and whether global histone modification pattern can be used to distinguish benign from malignant primary insulinoma. A tissue microarray (TMA) was built, using samples from 63 patients with organic hyperinsulinism. The TMA was classified according to the WHO classification of 2004 [WHO 1A: benign insulinoma (wdPET); WHO 1B: unknown behavior (wdPETub); WHO 2/3: malignant insulinoma (wdPEC/pdPEC)]. The TMA consisted of tissue cores from islands of Langerhans, primary insulinomas, lymph node metastases, and hepatic metastases. Immunohistochemistry was performed on consecutive TMA slides with antibodies against H3K9Ac, H3K18Ac, H4K12Ac, H3K4diMe, and H4R3diMe. The Remmele immunoreactive scoring system was used to classify the staining. The IHC staining results were correlated to the WHO-classification of 2004 as well as to clinical follow-up data (mean: 107 months; range: 1-312 months). A nuclear staining pattern was observed for all antibodies directed against histone H3 and H4 acetylation/methylation sites. We observed significant differences in the distribution of the medians across all investigated tissue types (H3K9Ac, p=0.004; H3K18Ac, p=0.001; H4K12Ac, p=0.006; H4R3diMe, p=0.002) except for H3K4diMe (p=0.183). Correlation of the histone modification with the WHO-classification and clinical follow-up data, showed in the dichotomized groups ["low" (score 0-3), "moderate" (4-7) vs. "high" (≥8)] that patients with lower H3K18Ac levels ("low + moderate") had a significantly decreased relapse-free survival vs. patients with high H3K18Ac levels (p=0.038). The WHO classification and age were also of significant prognostic impact upon univariate analysis. A backwards Cox proportional hazards model revealed the independent prognostic effekt of H3K18Ac levels. Our data revealed low K18 acetylation levels of histone H3 as independent prognostic factor in organic hyperinsulinism. This result warrants validation with independent data sets of organic hyperinsulinism, but is in line with several previous studies in different cancer entities. The broad applicability of this potential biomarker might lead to standardized diagnostic tests in near future and may help to manage insulinoma patients more effectively.

Standard-radical vs. function-preserving surgery of benign nodular goiter: a sonographic and biochemical 10-year follow-up study.

BACKGROUND: The necessary extent of thyroid resection in benign nodular goiter is under debate. The aim of our study was to compare the long-term outcome of different thyroid resection modes with special interest in the incidence of recurrent nodules and the use of oral thyroid hormone medication. MATERIALS AND METHODS: We performed a follow-up examination of 109 patients (23 men and 86 women) having been operated for benign nodular goiter at our department 10 years ago. Unilateral resections and function-preserving resections of at least one thyroid lobe were classified as function-preserving (FP). Total thyroidectomy, Dunhill's operation and bilateral subtotal thyroidectomy were rated as standard-radical (STR). On follow-up, we recorded current oral thyroid hormone medication, thyroid function tests and ultrasound of the neck. RESULTS: Seventy-three patients had FP resection (67%), while 36 were STR-operated (33%). The subsequent medical treatment was performed by dedicated endocrinologists (n = 19), internists (n = 11) or primary-care physicians (n = 59). Twenty patients had no medical attendance. Recurrent nodules were found in 13 cases in the FP group (18.6%) vs. 3 cases in the STR group (2.5%; p < 0.001). In both groups, about 80% of patients used thyroid hormone medication 10 years after operation. CONCLUSION: There was no advantage in thyroid function tests nor lesser medication in the FP group. The risk for recurrent nodules was significantly higher in the FP than in the STR-operated patients.

Sandifer syndrome--a multidisciplinary diagnostic and therapeutic challenge.

Sandifer syndrome, named after the neurologist Paul Sandifer, was first reported by M. Kinsbourne in 1962 who noticed a disorder of the upper gastrointestinal tract with neurological manifestations occurring in children and adolescents. Sandifer syndrome is a combination of gastro-oesophageal reflux disease with spastic torticollis and dystonic body movements with or without hiatal hernia. It is hypothesised that the positioning of the head provides relief from abdominal discomfort caused by acid reflux. The true pathophysiological mechanisms of the condition are still unclear. We report the diagnosis of Sandifer syndrome in a 9-year-old boy with a history of chronic torticollis and dystonic episodes for 5 years associated with abdominal symptoms. The cause of the dystonic body movements had not been found, although multiple neuropsychiatric diseases were suspected. The patient had been seen by many different specialities including Paediatrics, Paediatric Neurology, Psychology, Orthopaedic Surgery and ENT but the reason for the torticollis remained elusive. Unclear abdominal discomfort was the indication for an endoscopy that revealed severe gastro-oesophageal reflux disease with oesophagitis III degrees and a hiatal hernia which led to the correct diagnosis of Sandifer syndrome. After medical treatment and laparoscopic floppy Nissen fundoplication the symptoms nearly resolved 3 months after operation. Few reports of this syndrome exist, but Sandifer syndrome is probably underrecognised. Children with torticollis, dystonic episodes or atypical seizures should be evaluated for GERD and Sandifer syndrome. Early surgery, for example a laparoscopic floppy Nissen fundoplication or a Toupet procedure, can resolve the symptoms.

Secondary malignancy in patients with sporadic neuroendocrine neoplasia.

The incidence of neuroendocrine neoplasias (NENs), especially of the gastro-entero-pancreatic (GEP), system relatively increased over the past decades, as a result of advanced diagnostic tools, a better clinical awareness, and distinguished pathological diagnostic recognition. Previous reports hypothesized an increased risk for secondary malignancies in patients with NEN especially in GEP-NENs. The present study was designed to investigate the coincidence of NENs and secondary malignancies in a large patient collective. A retrospective analysis was performed on 161 patients (85 female and 76 male) with NEN of various origins. Clinical data of these patients, different classification systems (TNM/WHO), proliferations-based grading, and clinical follow-up were collected and analyzed. Out of 143 patients with a sporadic NEN, 15 (10.49 %) patients were identified with secondary malignant tumors. Median age at the time of the primary operation for NEN was 65 years, whereas the median age of initial diagnosis of associated tumors was 59 years. Mean follow-up time was 61 months. The risk of developing a secondary malignancy was most elevated for patients with an NEN of the lung, the stomach, and the ileum (60, 50 and 20 %, respectively). The spectrum of secondary malignancies included various types of cancer. Kaplan-Meier survival analysis shows a difference suggesting that patients with a secondary malignancy demonstrate a worse survival compared to patients without a secondary tumor; no significance was detected (p = 0.349). Our data suggest that secondary malignancies in patients with NEN's especially in GEP-NENs are found more frequently than in general population. Therefore, patients with NEN need a continuous and detailed follow-up. The reason for the increased incidence of secondary malignancies in patients with NENs remains to be elucidated.