Expression of hypoxia-associated proteins in sporadic medullary thyroid cancer is associated with desmoplastic stroma reaction and lymph node metastasis and may indicate somatic mutations in the VHL gene.

Medullary thyroid carcinomas (MTCs) are mostly aggressive but slowly growing malignant tumours that metastasize early to loco-regional lymph nodes. Desmoplastic stroma reaction is a strong risk factor associated with lymph node metastases. We evaluated immunohistochemically the expression of two hypoxia-associated proteins, carbonic anhydrase IX (CAIX) and hypoxia-induced factor 1α (HIF1α), and ki-67, intercellular matrix adhesion molecule E-cadherin and the stroma remodelling marker tenascin C in a series of 100 sporadic MTCs and corresponding lymph node metastases, if present. Moderate to strong expression of CAIX was seen in 53 cases, and of HIF1α in 51 cases, showing a strong correlation (p < 0.001; Spearman's coefficient of correlation, 0.59). Expression correlated with the degree of desmoplasia (pCAIX = 0.001 and pHIF1α = 0.001), with tenascin C expression (pCAIX = 0.001,pHIF1α = 0.038), with the ki-67 proliferation index (pCAIX = 0.001, pHIF1α = 0.001) and with the presence of lymph node metastases (pCAIX < 0.001 and pHIF1α = 0.007). The absence of membranous E-cadherin staining was significantly associated with the grade of desmoplasia, tenascin expression and lymph node metastases(p ≤ 0.05) but not with ki67 proliferation index or expression of hypoxia-associated factors. Expression of hypoxia-associated proteins was in most cases identical between primary tumours and lymph node metastases.Two cases showed strong uniform expression of CAIX and HIF1α in the primary tumour as well as in the lymph node metastases, and sequencing revealed mutations in the coding regions of the Von-Hippel­Lindau gene (VHL ).Our findings suggest that despite of the fact that MTCs have only slowly growth, tumour hypoxia plays an important role in the development of loco-regional metastases. Since traditional cytotoxic chemotherapy has only little effect on MTCs, targeting hypoxia-associated and -regulated proteins might be of benefit for patients.

Desmoplastic stromal reaction in papillary thyroid microcarcinoma.

AIMS: To evaluate the value of a desmoplastic stromal reaction (desmoplasia) as an indicator of metastasis in papillary thyroid microcarcinoma. METHODS AND RESULTS: One hundred and nine cases of papillary thyroid microcarcinoma from the pathological archive of the Medical University of Vienna, Austria were analysed for the presence of desmoplasia in relation to other morphological and clinicopathological parameters. Eighty-one of 109 papillary microcarcinomas showed a desmoplastic stromal reaction. The desmoplasia was significantly associated with lymph node metastases (P = 0.001) and tumour diameter (P < 0.001). In addition, 'invasive parameters', such as peritumoral and vascular invasion, were associated with the presence of a desmoplastic stromal reaction (P < 0.001 and P = 0.006, respectively), and all pT3b tumours according to the UICC classification of 2002 (i.e. with perithyroidal infiltration) showed desmoplasia. Of all morphological parameters, the best indicator of lymph node metastasis was tumour calcification (P < 0.001). CONCLUSIONS: Our data indicate that a desmoplastic stromal reaction seems to be an indicator of invasive behaviour of papillary thyroid microcarcinomas significantly associated with lymph node metastases. Papillary microtumours without signs of invasion, e.g. desmoplasia, should not be regarded as invasive carcinoma, as they are more likely to be thyroidal intraepithelial neoplasias.

The 40bp Indel Polymorphism rs150550023 in the MDM2 Promoter is Associated with Intriguing Shifts in Gene Expression in the p53-MDM2 Regulatory Hub.

Most low-penetrance genetic risk factors for cancer are located in noncoding regions, presumably altering the regulation of neighboring genes. The poorly characterized Indel polymorphism rs150550023 (rs3730485; del1518) in the promoter of MDM2 (human homolog of mouse double minute 2) is a biologically plausible candidate genetic risk factor, which might influence the expression of MDM2, a key negative regulator of the central tumor suppressor p53. Here, we genotyped rs150550023 in a Central European hospital-based case-control study of 407 breast cancer patients and 254 female controls. mRNA levels of MDM2, p53, and the p53 target genes p21, BAX, and PERP were quantified with qRT-PCR, and p53 protein was assessed with immune histochemistry in ≈100 primary breast tumors with ascertained rs150550023 genotype. We found no evidence for an association of rs150550023 with the risk, age at onset, or prognosis of breast cancer. A possible synergism was observed with SNP309 in promoter P2 of MDM2. Mean mRNA levels of MDM2, p53, p21, and BAX were ≈1.5-3 fold elevated in TP53 wildtype tumors with the minor homozygous Del/Del genotype. However, systematic shifts in p53 protein levels or mutation rates were not observed, suggesting that the elevated p53 mRNA levels are due to regulatory feedback loops that compensate for the effects of rs150550023 on MDM2 expression.

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 patient's 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 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.

Neuroendocrine carcinomas arising in solid-organ transplant recipients: rare but aggressive malignancies.

Organ transplant recipients are at an increased risk of developing malignancies due to prolonged immunosuppression. However, the rate and clinical course of neuroendocrine tumors (NETs) following organ transplantation has not been assessed so far. We have retrospectively analyzed patients undergoing organ transplantation between 1985 and 2001 in order to assess the frequency and clinical course of NETs in organ transplant recipients. 3,190 organ transplant recipients with sufficient clinical data were identified (2,521 kidney and 669 heart transplants). In total, 161/3,190 patients (5%) developed malignancies, with 6 of them being classified as NETs (0.18%). Interestingly, all 6 patients were diagnosed with undifferentiated neuroendocrine carcinomas, while no indolent NETs were seen. Four of these patients had undergone renal, 1 patient heart and 1 patient both heart and renal transplantation. All 6 patients were given chemotherapy, but none of them responded, as all patients showed disease progression after a median of 3 cycles of chemotherapy (range 1-4) with the median survival being 4.8 months (range 2-11). The occurrence of NETs/undifferentiated neuroendocrine carcinomas following organ transplantation appears to be rare, with an incidence comparable with the normal population. Our data suggest a highly aggressive course with a dismal prognosis and unresponsiveness to chemotherapy.

Molecular characterization of the desmoplastic tumor stroma in medullary thyroid carcinoma.

Medullary thyroid carcinomas are aggressive neoplasias that metastasize very early to loco-regional lymph nodes, and tumors with a desmoplastic stromal reaction have a higher incidence of lymph node metastasis. In order to characterize the desmoplastic response in thyroid cancers, we evaluated the expression pattern of three molecular markers of activated fibroblasts/myofibroblasts, namely, fibroblast activation protein alpha (FAPalpha), tenascin-C (Tn-C), and alpha-smooth muscle actin (alpha-SMA), as well as the endothelial markers endoglyx-1, CD34 and CD31 in a series of 28 metastatic and non-metastatic medullary thyroid cancers. Immunohistochemical studies demonstrated that the three fibroblast activation markers (FAPalpha, Tn-C, alpha-SMA) are consistently expressed in the peritumoral and intratumoral stromal compartment of medullary thyroid carcinomas and expression of FAPalpha and Tn-C correlated with the degree of desmoplasia determined histologically (p=0.001 for FAPalpha and p<0.001 for Tn-C). Moreover, the extent of desmoplasia as well as the expression of FAPalpha and Tn-C correlated with the presence of lymph node (LN) metastases (p=0.002, p=0.005 and p=0.002, respectively). No correlation was found between the microvessel density (neoangiogenesis) in the tumor stroma, assessed with the endoglyx-1, CD34 and CD31 markers, and the degree of desmoplasia or incidence of LN metastases. Using a bioinformatics-based search of the BioExpresstrade mark database we found in a series of 48 thyroid cancers a significant correlation between FAPalpha RNA expression and incidence of LN metastases also in papillary cancers. These findings suggest that the link between specific molecular markers of tumor stromal reaction and locoregional metastasis extends from medullary to other thyroid cancer types.

Comparison of RNA amplification techniques meeting the demands for the expression profiling of clinical cancer samples.

Available ribonucleic acid (RNA) amplification methods are extensively tested for reproducibility, but only a few studies additionally deal with potential amplification bias. On targeted arrays, we evaluated three amplification protocols, which are less time consuming than the commonly used T7-RNA polymerase based in vitro transcription protocols and therefore may be more suitable for clinical use: Template-switching polymerase chain reaction (PCR), Ribo-single primer isothermal amplification and a random primer-based PCR. Additionally, a more sensitive labelling method, Dendrimer labelling, was evaluated. All methods were compared to unamplified RNA labelled at reverse transcription. From our results, we conclude that RNA amplification with template-switching PCR is highly reproducible and results in a reliable representation of the starting RNA population. We then assessed whether RNA amplification of clinical breast and thyroid cancer samples with template-switching PCR showed robust performance when altered cycle numbers or partially degraded RNA were used. Template-switching PCR proved to be a very reliable method for global RNA amplification, even when starting from partially degraded RNA down to a RNA Integrity Number of 4.3. In conclusion, template-switching PCR amplification promises to help micro-array expression profiling of limited amounts of human samples on its way to a clinical routine.

The value of intraoperative pentagastrin testing in medullary thyroid cancer.

BACKGROUND: The decrease of calcitonin levels after curative operation in patients with medullary thyroid cancer is characterized by individual variation; therefore, intraoperative calcitonin measurements to evaluate the completeness of the resection seem to not be feasible. The aim of this study was to evaluate whether an intraoperative pentagastrin test after thyroidectomy and central neck dissection is useful to predict lymph node involvement of the lateral neck. METHODS: A group of 30 consecutive patients underwent primary surgery. After thyroidectomy and dissection of the central lymph node compartment, an intraoperative pentagastrin test was performed. Biochemical and histologic data were compared retrospectively. RESULTS: Of the group, 20 patients (67%) showed no, or only central neck lymph node, involvement and no increase in calcitonin after intraoperative stimulation. Lymph node involvement was documented histologically in the lateral neck of 10 patients (33%), and 8 patients showed an increase of calcitonin as an indication of lymph node involvement. In two patients, each with 1 single micrometastasis in the lateral neck, the intraoperative pentagastrin test was negative. CONCLUSIONS: Intraoperative calcitonin monitoring after pentagastrin stimulation seems promising in predicting lymph node involvement of the lateral neck to aid selection of patients for lateral lymph node dissection. The development of a highly sensitive, quick calcitonin assay is imperative.

Expression of HER2 and the coamplified genes GRB7 and MLN64 in human breast cancer: quantitative real-time reverse transcription-PCR as a diagnostic alternative to immunohistochemistry and fluorescence in situ hybridization.

PURPOSE: Accurate testing of HER2 is centrally important for breast cancer therapy and prognosis. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are current standard testing methods. As a potential alternative for assessment of HER2, we explored quantitative real-time reverse transcription-PCR (RT-PCR), a fast and inexpensive method yielding quantitative results insensitive to interobserver variability and amenable to standardized scoring. EXPERIMENTAL DESIGN: We assessed HER2 status at the DNA, mRNA, and protein levels with FISH, quantitative RT-PCR, and IHC in 136 tumor samples from 85 breast cancer patients. Expression of GRB7, MLN64, and p21, genes coregulated with HER2, was also quantified with quantitative RT-PCR and correlated with the overall survival (OS) and disease-free survival (DFS) individually and in combination with HER2. RESULTS: Twenty-nine percent and 19% of the patients scored HER2 positive with IHC and quantitative RT-PCR, respectively. In 18 of 19 cases, HER2 statuses in tumors and lymph node metastases were identical. HER2 status significantly correlated with DFS when determined by IHC (P < 0.01), quantitative RT-PCR (P < 0.003), but not with FISH (P = 0.09). The combination of HER2 with MLN64, but not with GRB7 or p21, enhanced the prognostic power for the DFS (P < 0.00005) and OS (P < 0.0008). CONCLUSIONS: Quantitative RT-PCR seems to be clinically as useful in the assessment of HER2 status as IHC and FISH, yielding comparable correlations of HER2 status with the OS and DFS. Thus, quantitative RT-PCR analysis of HER2 or HER2 plus MLN64 is a promising complement or alternative to current methods for HER2 testing, particularly in laboratories lacking FISH or IHC technology.

Expression of somatostatin receptor 2A in medullary thyroid carcinoma is associated with lymph node metastasis.

Medullary carcinoma (MTC) is an aggressive tumour that derives from the thyroid parafollicular calcitonin-secreting cells (C cells). Lymph node metastasis may occur early in disease pathogenesis and is one of the most important negative prognostic parameters. Surgery is the only curative therapy while chemotherapeutic options are limited. Neuroendocrine differentiated C cells may express somatostatin receptors (SSTR), which have a wide range of biological actions including inhibitory effects on cell survival and angiogenesis and antiproliferative effects on cancer cell lines. Moreover, they are a potential target for various somatostatin analogues. Aim of this study was to analyse the protein expression of SSTR2A and 5 in MTCs with or without the presence of lymph node metastases in correlation with various clinicopathological parameters. This retrospective immunohistochemical analysis included 97 patients with medullary thyroid carcinomas. Protein expression was detected by immunohistochemistry for somatostatin receptors 2A and 5. Various clinicopathological parameters, such as Ki-67 proliferation index or presence of desmoplasia, were included for statistical analysis. SSTR2A protein expression significantly correlated with the presence of lymph node metastases (p = 0.009), locally advanced MTCs staged according to the TNM (p < 0.001) and degree of desmoplasia (p = 0.029). Although SSTR5 protein expression significantly correlated with advanced stages of MTCs (p = 0.023) and degree of desmoplasia (p = 0.020), no correlation was found with the presence of lymph node metastases. Our results provide additional information concerning the aggressiveness of MTCs and reveal that a high SSTR2A and SSTR5 expression might be a poor prognostic feature.

Frequency and relevance of elevated calcitonin levels in patients with neoplastic and nonneoplastic thyroid disease and in healthy subjects.

Routine measurement of serum calcitonin (CT) has been recently proposed for all patients with neoplastic thyroid disease to detect clinically occult medullary thyroid carcinoma (MTC). Data on the prevalence of elevated CT levels in nonneoplastic thyroid disease or in healthy subjects have not been reported to date. Four hundred and fourteen consecutive patients with suspected thyroid disease and 362 healthy controls underwent thyroid examination with measurement of basal serum CT. Whenever serum CT was 10 pg/ml or more, a pentagastrin (PG) stimulation test was performed. Twenty-eight of 414 patients (6.8%) showed elevated basal serum CT levels, 15 of them with nonneoplastic thyroid disease, and the remaining 13 subjects with neoplastic thyroid disease. Four patients with abnormal PG testing (stimulated CT, > or = 100 pg/ml) were identified. Three of them had biochemical and sonographical evidence of thyroiditis. Elevated basal CT levels were significantly more frequent in patients with Hashimoto's thyroiditis (HT; P < 0.05). One female patient with HT had a 5-mm nodule, which was classified as MTC. None of the 6 out of 362 healthy controls with elevated basal CT (1.7%) presented an abnormal PG test. Our data suggest that basal CT measurements can be of use in the detection/screening of MTC not only in subjects with neoplastic thyroid disorders, but also in patients with immunological evidence of HT. They also confirm earlier reports on the essential value of PG stimulation testing, even when basal plasma CT levels are only modestly elevated, with regard to establishing the diagnosis of MTC or its premalignant associated conditions (micro-MTC and neoplastic C cell hyperplasia).

Cytogenetic and molecular analyses of multiple endocrine neoplasias of the MEN1 syndrome.

A pancreas carcinoid, an adrenocortical adenoma, three parathyroid adenomas and a parathyroid hyperplasia of 5 MEN1 patients were used for loss of heterozygosity (LOH) and comparative genomic hybridization (CGH) studies. The MEN1 gene is located in the region 11q13, approximately 30 kb distal to PGYM. Four tumors showed LOH on chromosome 11q13 (D11S11335, PGYM, D11S1883, FGF3, D11S937) however LOH was also found beyond 11q13. The pancreas carcinoid and adrenocortical adenoma, both from the same patient, showed LOH at marker 11q23.3 and 11q25. In the three parathyroid adenomas LOH was detected in five different markers: 11q21, 11q22.3, 11q23.2, 11q23.3 and 11q25. No LOH was found in parathyroid hyperplasia. CGH analysis showed in case of the pancreas carcinoid losses on chromosomes 1p, 2q, 3, 6, 9p, 11 and 12p. Gains were found at 4, 5, 7, 8, 13, 14, 15q, 18, 19. The parathyroid adenoma of the third patient showed losses only on chromosome 11 in the region 11p12-p15 and 11q12-q23. Our data indicate that other genes are involved in the tumorigenesis of the MEN1 syndrome. Especially the numerous allelic losses between markers 11q23 and 11q25 (D11S938 and D11S910) are a hint for further tumor suppressor genes on chromosome 11.

Follicular variant of papillary thyroid carcinoma: a long-term follow-up.

HYPOTHESIS: The clinical behavior of the follicular variant of papillary thyroid carcinoma (FVPTC) is similar to pure papillary thyroid carcinoma (PPTC) and completely different from follicular thyroid carcinoma (FTC). DESIGN: Retrospective analysis of prospectively documented data. SETTING: Referral center of a university hospital. PATIENTS: Two hundred thirty-seven consecutive patients with follicular cell-derived thyroid carcinomas were operated on in our institution during a 15-year period, from January 1, 1980, to December 31, 1994. Of the 154 PTC patients, 37 (24%) had FVPTC. The mean follow-up was 128.2 months (10.7 years). MAIN OUTCOME MEASURES: Demographic features, tumor characteristics, local and distant spread, persistence or recurrence of disease, and carcinoma-related mortality were compared between the groups with FVPTC, PPTC, and non-Hürthle cell FTC (NHFTC). RESULTS: The frequency of multicentricity was significantly higher in the FVPTC group than in the PPTC group (P =.03) or in the NHFTC group (P =.01) (12 [32%] of 37 patients vs 17 [15%] of 117 patients vs 6 [10%] of 58 patients, respectively). The incidence of cervical lymph node metastases was lower in the FVPTC group than in the PPTC group (P =.30) and higher than in NHFTC group (P =.004) (12 [32%] of 37 patients vs 53 [45%] of 117 patients vs 6 [10%] of 58 patients, respectively). At diagnosis, no patient with FVPTC showed distant metastases, compared with 5 patients (4%) with PPTC (P =.34) and 19 (33%) with NHFTC (P<.001). There was no carcinoma-related death in the FVPTC group. The strikingly poorer prognosis for the NHFTC group was statistically significant (P<.001), whereas the difference in carcinoma-specific survival between the PPTC and the FVPTC groups did show a trend toward better survival in the FVPTC group. CONCLUSION: The clinical behavior of the FVPTC group did not differ significantly from that of the PPTC group, whereas compared with the NHFTC group, the FVPTC group showed statistically significant differences for most of the analyzed variables.

Cystic echinococcosis of the thyroid gland in children and adults.

In humans, cystic echinococcosis is one of the most serious helminthic diseases worldwide. The larval stages (cysts) of Echinococcus granulosus are mainly located in the liver and the lung. Other locations of infection are rare, which may occasionally hinder its diagnosis. A 14-year-old girl from Kosovo presented with a cystic lesion in the left thyroid lobe of 4 years duration. Although two percutaneous punctures had been performed, she developed a recurrence and therefore had to undergo thyroid surgery. The results of the histopathologic examination revealed a hydatid cyst, and consequently, the patient received a long-term course of medication, namely, albendazole. Imaging of the cranium and chest were normal. A computed tomography of the abdomen detected a further cyst in the liver which did not show the typical signs of cystic echinococcosis. An echinococcus cyst in the thyroid gland is rare, especially in children. In a review of the literature published since 1965, only 12 children have been reported. Although by definition percutaneous drainage is contraindicated to avoid the spread of protoscolices, it is documented in eleven patients without complications. Surgical extirpation is mandatory. Chemotherapy with benzomidazole derivatives is necessary to avoid recurrence.

Evaluation of MUC1 splice variants as prognostic markers in patients with ductal carcinoma in situ of the breast.

Despite intense research in the field of breast cancer it still remains the most common cancer in women in the Western world. A decreasing trend in mortality was mainly achieved by improved early detection which led to an increased incidence of ductal carcinoma in situ (DCIS) of the breast. For the patient's prognosis and the administration of a patient-tailored therapy strategy it is crucial to identify diagnostic and prognostic markers for high-risk DCIS patients. MUC1 is associated with tumour aggressiveness in human breast cancer. Recent studies used MUC1 splice variant A to identify malignant thyroid cancer. In the present study we have examined the usefulness of MUC1 splice variants as prognostic markers in DCIS. We used laser capture microdissection of paraffin-embedded tissue to isolate RNA from isolated tumour cells and determined the MUC1 splice variant distribution by RT-PCR. In the majority of cases variant B was more highly expressed than variant A. This was true for pure DCIS (66%) as well as for DCIS with adjacent invasive cancer (66%). In 7 out of 18 cases (38%) of pure DCIS variant A was not expressed at all. In DCIS with adjacent invasive cancer only 2 samples out of 12 showed this expression pattern (16%). The situation that variant A was more highly expressed than B, or that variant B was not expressed at all, was similar for pure DCIS (27%) and for DCIS with adjacent invasive cancer (33%). The present study describes the differences of MUC1 splice variant expression in pure DCIS compared to DCIS with adjacent invasive cancer. A discriminating pattern of MUC1 splice variants could not be demonstrated.

How accurate is MR imaging in characterisation of adrenal masses: update of a long-term study.

OBJECTIVE: The purpose of this study was to update a long-term study that evaluates the accuracy of MR imaging in the characterisation of adrenal tumours. In all patients, MR imaging findings were correlated with histopathologic results. PATIENTS: In 204/560 patients who underwent MR imaging for characterisation of an adrenal mass, histopathologic results were available. The final study group consisted of 229 adrenal masses in 204 patients. MR imaging was performed using T2-weighted fast spin-echo imaging and unenhanced and gadolinium-enhanced T1-weighted spin-echo imaging in all patients. In addition, chemical shift imaging was performed in 182 patients and dynamic gadolinium-enhanced studies in 198 patients. Chemical shift images and dynamic studies were qualitatively assessed. All images were reviewed by an experienced investigator (Gertraud Heinz-Peer) who was blinded to the clinical history and the results of prior imaging studies. RESULTS: The sensitivity of MR imaging for the differentiation of benign and malignant adrenal masses was 89%, the specificity 99%, and the accuracy was 93.9%. This results in a positive predictive value (PPV) of 90.9% and a negative predictive value (NPV) of 94.2%. These results are comparable to the data published previously by our study group with a lower number of cases. CONCLUSION: Large study numbers show that MR imaging is a reliable method in characterisation of benign and malignant adrenal masses. Since laparoscopic adrenalectomy has become the new gold standard in the surgical treatment of benign adrenal lesions, the high accuracy of MR imaging in characterisation of those lesions offers even patients with large adrenal masses (>5 cm) the advantages of the minimally invasive technique.

[Pathologic-anatomic diagnosis of endocrine neoplasms: new trends and applications]. / Pathologisch-anatomische Diagnostik endokriner Tumore: neue Trends.

The pathologic-anatomical diagnosis of endocrine diseases mainly relies on established techniques of histology and cytology. Additional immunhistochemical tests an the expression analysis may lead to a higher specificity of the morphological diagnosis. For thyroid tumours so-called high-throughput methods have been established in clinical routine successfully. Calcitonin screening tests can be performed routinely in patients with or without an increased risk of familiar dominance. For the neuroendocrine neoplasms of the pancreas and the gastrointestinal tract a new WHO classification has been established.

Multiple endocrine neoplasia type 1 (MEN1) in Austria.

Multiple endocrine neoplasia type 1 (MEN1) is a rare cancer predisposition syndrome. It results from the autosomal dominant inheritance of inactivating germ-line mutations of the MEN1 tumor suppressor gene. Mutation carriers are prone to develop tumors, preferentially, of the parathyroid and anterior pituitary glands as well as the enteropancreatic endocrine tissues. Because such tumors also occur without the MEN1 context, we have set up a molecular genetic screening program in Austria to discriminate between heritable and non-heritable tumor forms. Following the recognition of a MEN1-specific germ-line mutation in a tumor patient, we extend the screening to all first-degree relatives. To date, we have studied 42 individuals by sequencing the coding exons 2 to 10 of the MEN1 gene. A germ-line mutation was discovered in four of seven families suspected, clinically, to have MEN1, and in 3 of 22 (13.6%) patients with a presumed sporadic endocrine tumor. The respective mutations were also detected in three first-degree relatives of whom only one 6-year-old boy was asymptomatic at the time of investigation. The possibility to clearly discriminate between genetically predisposed and non-predisposed individuals has a significant impact on the diagnosis and clinical management of both patients and their relatives. Both symptomatic and asymptomatic mutation carriers can be closely monitored, thereby allowing early recognition and treatment of developing tumors. Non-affected relatives, on the other hand, do not require further controls. Finally, this approach also provides the information necessary for reliable genetic counseling.

Multiple endocrine neoplasia 1--current recommendations for diagnosis and treatment.

BACKGROUND: The principally affected glands in the MEN 1 syndrome (parathyroids, pancreas, pituitary and adrenal glands) are often diffusely or multi-centrically involved, making different therapeutic approaches necessary. METHODS: In a retrospective analysis of 10 patients with genetically proven (n = 7) or clinically suspected (n = 3) MEN 1 syndrome, recommendations for diagnosis, timing of interventions and surgical procedures are reviewed. RESULTS: All patients had primary hyperparathyroidism (PHPT). An extended bilateral exploration localized 4 or more enlarged glands in 6 patients and subtotal parathyroidectomy (SPTX) was performed. In 4 patients, only one (n = 2) or two (n = 2) enlarged glands were removed. Two patients were reoperated for persistent PHPT and one patient developed recurrent PHPT. In 3 out of 6 patients, neuroendocrine pancreatic tumors were the first manifestation. 2 patients had solitary, one patient multiple benign and one patient multiple malignant insulinomas. Tumors were removed by enucleation, distal pancreatic resection or a combination of both. Out of the 2 patients with gastrinomas, one underwent partial pancreatoduodenectomy and the other has refused operation up to now. During follow-up, no persistence or recurrence of hormone excess was diagnosed. Three patients had non-functioning bilateral lesions of the adrenal glands, and one of these additionally had a small, clinically insignificant pheochromocytoma. Adrenalectomy was performed during pancreatic surgery in 2 patients, and endoscopically in one patient. Pituitary tumors were treated in 3 patients. CONCLUSION: A high index of clinical suspicion, biochemical screening and menin gene testing, according to current guidelines, is mandatory for early diagnosis of MEN 1. In PHPT with multiglandular involvement and neuroendocrine pancreatic tumors, meticulous surgery can achieve a long-term cure in the majority of patients, with low morbidity.

Recommendations for reporting C cell pathology of the thyroid.

BACKGROUND: Calcitonin screening programs have proved to be effective in early detection of medullary thyroid carcinoma, not only in patients with known risk factors for the development of hereditary tumors. Thus, more thyroidectomies, based on an abnormal pentagastrin test, can be expected. Here we give summarizing recommendations for reporting C cell pathology. METHODS: All patients underwent total thyroidectomy and were tested for germ-line mutations in the RET-Protooncogene. The entire surgical specimens were blocked and C-cell disorders were assessed using conventional histology and immunohistochemistry. RESULTS: Among 110 patients with an abnormal pentagastrin test, 60 (55%) had medullary thyroid carcinoma (T1 34% [n = 37], T2 14% [n = 16], T4 6% [n = 7]), and 50 (45%) had C cell hyperplasia only. C cell hyperplasia accompanying medullary thyroid carcinoma was found in 13 of 15 familial and in 28 of 45 sporadic patients. All C cell changes were found in the upper two thirds of the thyroid lobes and 83% of the medullary thyroid carcinomas could be identified with frozen sections. CONCLUSION: 1. Abnormal pentagastrin stimulation is always associated with either medullary thyroid carcinoma or C cell hyperplasia. 2. Blocking of the entire upper two thirds of the thyroid lobes is essential for reliable detection of C cell hyperplasia and small medullary thyroid carcinomas. 3. Most medullary thyroid carcinomas can be detected with intraoperative frozen sections. 4. The presence of C cell hyperplasia should always be reported; however its usefulness for indicating familial risk is limited and its role as a preneoplastic condition in patients without RET-protooncogene mutations remains to be elucidated.