Frequent promoter methylation of tumor-related genes in sporadic and men2-associated pheochromocytomas.

Hypermethylation of CpG island promoters is associated with transcriptional inactivation of tumor suppressor genes in neoplasia. Inactivation of p16 and Pten was related to the development of pheochromocytomas. In this report, we investigated the methylation status of the p16INK4a cell cycle inhibitor gene and other prominent tumor-related genes ( PTEN, RASSF1 A, CDH1, MSH2, MLH1, VHL, and TIMP3) in sporadic and multiple endocrine neoplasia type 2 (MEN2) pheochromocytomas by methylation-specific PCR. Hypermethylation was detected in 48 % of pheochromocytomas for RASSF1 A, 24 % for p16, 36 % for MSH2, 16 % for CDH1, and 8 % for PTEN. No VHL, MLH1, and TIMP3 methylation was observed. Interestingly, the frequency of p16 inactivation in familial tumors was higher (5 out of 12, 42 %) than in sporadic tumors (1 out of 13, 8 %; p = 0.047) and RASSF1 A inactivation was more common in the hereditary tumors (58 %) compared to the sporadic tumors (38 %). Combined methylation of RASSF1 A and p16 was found only in MEN2-related pheochromocytomas. Thus, a subset of hereditary pheochromocytomas displays preferential methylation of p16 and RASSF1 A.

[Recurrent operations on the adrenal glands]. / Wiederholungseingriffe an den Nebennieren.

Repeat adrenalectomy may be required due to ipsilateral recurrence of benign or malignant adrenal tumors after previous total or subtotal adrenalectomy. Even for multivisceral resection in patients with adrenocortical carcinoma, complete resection of local recurrent tumor offers results similar to those of primary resection (5-year survival 40-60%). In contrast, since no benefit on long-term survival has been shown so far by tumor debulking, palliative tumor resection should only be performed individually for control of severe endocrine symptoms. The effect of endoscopic adrenalectomy in patients with large tumors (>5 cm) or suspected malignancy has still not been well examined. Further studies are required. In any case, during open or endoscopic approach, tumor spillage must be avoided to prevent local tumor cell implantation. Following subtotal adrenalectomy, the risk of ipsilateral recurrence correlates with disease, follow-up, localization, size of the adrenal remnant, and, in case of familial pheochromocytoma, probably with genotype.

CYP2C and IL-6 expression in breast cancer.

Besides hepatic P450 (cytochrome P450) metabolism, there is increasing interest in the possibility of intratumoral activation of oxazaphosphorines by P450. Therefore, we investigated the expression of P450 (CYP2C8, CYP2C9, CYP2C18, and CYP2C19) by RT (reverse transcriptase)-polymerase chain reaction (PCR) and of CYP2C9 by Western blotting in 10 different breast tumor samples. Since P450 may be down regulated by interleukin (IL) IL-6, the receptor (R) for IL-6 was analyzed by RT-PCR and IL-6 in supernatants was calculated from ELISA data. None of the breast tumors was positive for CYP2C18 and CYP2C19 mRNA, whereas CYP2C8 and CYP2C9 were detected in all 10 breast tumors. Correspondingly, all breast tumors tested (9 of 10) revealed low, but nevertheless positive, staining of the CYP2C9 protein. All 10 samples were positive for the IL-6 receptor mRNA. ELISA measurement of IL-6 cytokine in supernatants revealed that all measured samples (8 of 10) were producing IL-6, the amounts ranging from 0.004 to 3.1 ng/g(tumor tissue). In summary, we have demonstrated that tumors of the breast express two out of four members of the CYP2C family, indicating that activation of such prodrugs as oxazaphosphorines may take place intratumorally. The presence of the IL-6 receptor and of IL-6 cytokine, which is produced in an autocrine manner, opens up the possibility that the well-known down regulating effect of IL-6 also takes place in breast tumors and might explain the weak or even absent expression of different CYP2C members.

IL-1 receptor type I expression in breast cancer.

The cytokine interleukin (IL)-1 is known to be involved in angiogenesis and metastasis. A prerequisite for IL-1 signalling is the presence of its receptor. Previously we have shown that glioblastoma cells express the IL-1 receptor type I (IL-1RI). In this study we analysed 11 breast tumour specimens for IL-1RI expression using the reverse transcriptase (RT) polymerase chain reaction (PCR). We found all the 11 breast tumours were positive for IL-1RI. This suggests that paracrine or autocrine produced IL-1 mediated signalling via IL-IRI might take place in breast tumours to control the production of pro-tumourigenic factors such as angiogenic factors and support further progression of tumour growth and metastasis.

Medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is subdivided into sporadic (75 %) and hereditary (25 %) forms. Several germline mutations in the RET proto-oncogene are the source of distinct clinical phenotypes in hereditary MTC including familial MTC (FMTC) and multiple endocrine neoplasia 2A (MEN 2A) and 2B (MEN 2B). The higher the penetrance of the MEN 2 phenotype the earlier the progression of MTC which forms the basis for the currently recommended codon-related concept of prophylactic thyroidectomy. In patients with sporadic MTC, routine calcitonin (CT) measurement in nodular goiter patients has been shown to reduce the frequency of advanced tumor stages. Patients with CT levels over 100 pg/ml after pentagastrin stimulation are recommended for total thyroidectomy. In patients with unexpected sporadic MTC after histological examination, completion thyroidectomy is currently only recommended when CT levels remain elevated. The extent of lymph node dissection in patients with MTC is controversial. However, with respect to lymphonodal micrometastases, systematic compartment-oriented microdissection has been shown to reduce the frequency of lymphonodal recurrence. On the other hand, to avoid unnecessary lymph node dissection, a more individualized concept is required in the future. New chemotherapeutic agents (tyrosine kinase inhibitors), therapeutic nuclids (90Yttrium-labeled octreotide), and chemoembolization of liver metastases are currently the most promising therapeutical concepts in patients with distant metastases.

[Subtotal bilateral adrenalectomy preserving adrenocortical function]. / Subtotale bilaterale Adrenalektomie mit adrenokortikalem Funktionserhalt.

This study analyzed the frequency of recurrence and postoperative adrenocortical function in 16 patients who had been operated on by bilateral subtotal adrenalectomy since 1995. Bilateral pheochromocytoma was found in 13 patients, bilateral adrenal metastases in 2 patients, and bilateral micronodular adrenocortical hyperplasia with primary aldosteronism in 1 patient. An endoscopic approach was performed in four patients. The remaining 12 patients were operated on by an open approach. In ten patients, unilateral subtotal adrenalectomy with contralateral total adrenalectomy (synchronous or metachronous) was performed. Six patients underwent bilateral subtotal adrenalectomy. In all patients, a total of residual adrenal tissue of at least 1/3 of a normal adrenal gland was left in situ. 15 patients were successfully weaned from exogenous steroid substitution. During a mean follow-up period of 24 months, no recurrences were observed. Three patients died without local recurrence. The present study provided evidence for the safety and benefit of subtotal bilateral adrenalectomy, which could guarantee sufficient adrenocortical function in adrenal remnant volume of more than one-third of one adrenal gland even after dividing the main adrenal vein. At our institution, particularly in patients with inherited pheochromocytoma, subtotal adrenalectomy has become a common surgical strategy.

[Multi-modality therapy concept in metastatic follicular thyroid carcinoma with hyperthyroidism]. / Multimodales Therapiekonzept bei metastasiertem folliculären Schilddrüsencarcinom mit Hyperthyreose.

The coincidence of hyperthyroidism and thyroid carcinoma seldom occurs. Only few reports on functionally metastases of thyroid carcinoma have been published. We report a 59-year-old man who underwent subtotal thyroidectomy for toxic nodular goiter. Histological examination revealed a follicular thyroid carcinoma. After thyroidectomy and cervical lymphadenectomy the patient developed a strong hyperthyreosis. Scintigraphy showed strong radioiodine uptake in the sacrum. De-bulking resection of the metastasis followed by high-dose radioiodine treatment was performed. After radioiodine therapy the patient became euthyroid. Treatment of hyperthyreosis in metastatic thyroid cancer requires a multimodal therapeutic concept.

[Medical palliative therapy of meningiosis carcinomatosa of breast carcinoma with dissociated response in lumbar methotrexate instillation]. / Palliativmedizinische Therapie einer Meningiosis carcinomatosa bei Mammakarzinom mit dissoziierter Response unter lumbaler Methotrexat-Instillation.

CASE REPORT: We report the case of a 51-year-old woman who suffered from breast cancer and developed meningeal carcinomatosis of the brain stem with deafness and blindness. Radiotherapy was given but led to remarkable deterioration of the condition and strong headache. We performed intrathecal therapy with methotrexate (MTX) via lumbar application. Under this regimen, the patient immediately showed complete improvement of the headache and a partial recovery of hearing. There were no side effects apart from alopecia. MTX concentrations in liquor and blood were remarkably inconsistent. 4 weeks after MTX therapy, MRT revealed partial remission of the meningiosis of the brain stem but progression on both hemispheres. 5 weeks after the beginning of the intrathecal therapy, the patient died. CONCLUSION: Despite pharmacokinetic problems we consider lumbar intrathecal therapy with MTX a suitable procedure for patients with leptomeningeal carcinomatosis and poor performance status.

[Function-preserving adrenalectomy for adrenal tumors]. / Funktionserhaltende Adrenalektomie bei Nebennierentumoren.

Organ preserving resection (subtotal adrenalectomy) or adrenocortical autotransplantation can preserve adrenocortical stress capacity in bilateral adrenal surgery. After adrenocortical autotransplantation approximately 30% of patients do not need exogenous steroids. Organ preserving surgery avoids steroid supplementation in more than 80% of cases. After organ preserving resections in secondary or familial diseases, however, there is a relevant risk of recurrent disease: the rate of ipsilateral recurrence in familial pheochromocytoma is approximately 20% during a follow-up of 20 years. Routine administration of exogenous steroids should be avoided after subtotal adrenalectomy as functional restitution of the residual tissue might be disturbed. Approximately 80% of patients, however, present with impaired adrenocortical stress capacity directly after surgery. Within a few weeks some 80% of patients show a sufficient functional restitution of the adrenocortical stress capacity. Organ preserving adrenal surgery should be performed endoscopically. The adrenal remnant should not be devascularized; the adrenal vein, however, can be divided without functional consequences. About one third of a normal adrenal gland usually provides sufficient adrenocortical function.

[Current TNM system of the UICC/AJCC : the prognostic significance for differentiated thyroid carcinoma]. / Aktuelles TNM-System der UICC/AJCC : Prognostische Bedeutung beim differenzierten Schilddrüsenkarzinom.

BACKGROUND: The aim of study was an evaluation of prognostic factors of the current TNM version (UICC/AJCC 2009, 7th revision) for differentiated thyroid carcinoma (DTC). PATIENTS AND METHODS: A total of 368 patients with DTC (papillary thyroid carcinoma [PTC] n = 269, follicular thyroid carcinoma [FTC] n = 99) were included. Disease-specific survival (DSS) was calculated based on the different TNM stages (mean follow-up 60 ± 37.5 months). RESULTS: When compared to patients with FTC, PTC patients had smaller tumors (diameter 19 mm versus 33 mm), more often lymph node metastases (40.9% versus 9.1%) but less frequent distant metastases (2.6 versus 13.1%) and poorly differentiated variants (PDTC 3.0% versus 8.1%). The 5-year and 10-year DSS for PTC versus FTC were 97.3% versus 91.5% and 96.2% versus 91.5% (p = 0.086), respectively. When comparing different TNM categories between well-differentiated PTC and FTC, no statistically significant differences were found but PDTCs, had a significantly worse DSS. CONCLUSIONS: The current TNM system is a sufficient tool for predicting DSS in well-differentiated PTC. In FTC, the extent of capsular and vascular invasion should also be considered. The implementation of a specific TNM system for PDTC needs to be confirmed in further studies.

[Genetics of pheochromocytoma]. / Genetik der Phäochromozytome.

About one third of all patients with a pheochromocytoma are carriers of germ line mutations of 1 of the 10 susceptibility genes. Thus, these patients can be diagnosed and classified with specific tumor syndromes. This group is composed of the entities of multiple endocrine neoplasia type 2 (MEN2) due to mutations in the RET gene, von Hippel-Lindau disease (VHL, VHL gene), the paraganglioma syndromes types 1-4 (PGL1-4) due to mutations of the genes SDHD, SDHAF2, SDHC, SDHB, neurofibromatosis type 1 (NF1) due to mutations of the NF1 gene and familial pheochromocytoma syndromes due to mutations of the SDHA, TMEM127 and MAX genes. Patients with hereditary pheochromocytomas run a lifelong risk of relapse of pheochromocytoma. In addition extraparaganglial tumors are frequent and include medullary thyroid carcinoma in MEN2 or renal cancer or neuroendocrine pancreatic cancer as well as hemangioblastomas of the retina and the central nervous system in VHL. Furthermore, renal cancer may be associated with PGL4 and PGL3. In conclusion, molecular genetic screening is essential for the diagnosis of pheochromocytoma-associated cancer syndromes and is thus the cornerstone for successful lifelong preventive medicine of such patients and their relatives.

Peritoneal carcinosis in apparently benign cortisol producing adrenal adenoma ≥ 5 cm in diameter: the need of regular postoperative surveillance.

BACKGROUND: Clinical and histopathological distinction between benign and malignant adrenocortical tumors can be a challenge.Report on 2 patients with cortisol producing apparently benign adrenal adenomas ≥ 5 cm in diameter with local malignant recurrence and peritoneal carcinomatosis after endoscopic surgery. RESULTS: Case 1: The 59-year-old male presented with adrenal hypercortisolism due to a 5.0 cm large adrenal tumor on the left side. A retroperitoneoscopic total adrenalectomy was performed. Histologically, a benign adrenal adenoma (Weiss score 1, Ki-67 < 2%) was found. 6 months later, the patient developed clinically and biochemically recurrent disease with recurrent tumor in the left adrenal region and peritoneal carcinomatosis. The patient died 5 months after second surgery. Case 2: The 32-year-old female was pregnant in 27th week when presenting with adrenal hypercortisolism due to a 5.5 cm large adrenal tumor on the left side. She was operated on using a laparoscopic approach and a total adrenalectomy was carried out. Histological examination revealed a benign adrenocortical adenoma (Weiss score 1, Ki-67 < 5%). 4 years later, the patient came back with clinically and biochemically recurrent disease. Imaging showed a 10 cm large tumor in the left retroperitoneum and a diffuse peritoneal carcinomatosis. The patient died 2 months after diagnosis. CONCLUSION: Cortisol producing adrenal tumors ≥ 5 cm in diameter are at risk to be misdiagnosed as apparently benign. Regular surveillance should be considered in patients presenting with large cortisol producing tumors.

[Extrathyroidal thyroid cancer : results of tracheal shaving and tracheal resection]. / Organüberschreitende schilddrüsenkarzinome : ergebnisse nach trachealem shaving und trachearesektion.

Extrathyroidal thyroid cancer invading the laryngotracheal system (UICC stage pT4a) represents a progressive process of infiltration of the tracheal wall layers from the outer to the inner parts of the trachea. These tumors usually present with high proliferation activity correlating with a reduced long-term prognosis. In contrast to intraluminal manifestation requiring complete wall resection, in cases of non-transmural invasion, complete tumor removal can be sometimes achieved by extraluminal tangential resection (shaving). Tangential resections, however, are associated with a higher frequency of microscopically invaded resection margins (R1 resection rate >40%). The available comparative studies (all retrospective, maximum EBM level 3) analyzing oncological outcome show inconsistent results. In more recently published studies, however, complete wall resection in well-differentiated thyroid cancer with tracheal invasion only was found to be associated with longer recurrence-free and tumor-specific survival when compared to shaving. Deep larynx invasion is associated with reduced long-term prognosis when compared to invasion of the trachea. Salvage resections should therefore be performed in selected cases only.

[Cervicovisceral resection in invasive thyroid tumors]. / Zervikoviszerale Resektionen beim organüberschreitenden Schilddrüsenkarzinom.

About 6% of patients with thyroid cancer present with life-threatening tumor invasion of the trachea and/or esophagus. The extent of resection depends on tumor diagnosis and stage (indication only in differentiated and perhaps medullary thyroid cancer without extrapulmonary metastases), extent of aerodigestive invasion, and general health state of the patient. After complete tumor resection, 5-year and 10-year survival rates of 40-75% can be achieved. Incomplete tumor resection however has a negative effect on prognosis. Tangential tumor resection (shaving) is indicated if no transmural invasion of trachea/esophagus has occurred. Tracheal resection can be subdivided into six standard procedures--types 1 and 2: laryngotracheal or tracheal window resection; types 3 and 4: circular resection with primary reconstruction infraglottic or tracheal; and types 5 and 6: laryngectomy and cervical evisceration.

Intraoperative monitoring of the recurrent laryngeal nerve in thyroid surgery.

BACKGROUND: Recurrent laryngeal nerve (RLN) palsy ranks among the leading reasons for medicolegal litigation of surgeons because of its attendant reduction in quality of life. As a risk minimization tool, intraoperative nerve monitoring (IONM) has been introduced to verify RLN function integrity intraoperatively. Nevertheless, a systematic evidence-based assessment of this novel health technology has not been performed. METHODS: The present study was based on a systematic appraisal of the literature using evidence-based criteria. RESULTS: Recurrent laryngeal nerve palsy rates (RLNPR) varied widely after thyroid surgery, ranging from 0%-7.1% for transient RLN palsy to 0%-11% for permanent RLN palsy. These rates did not differ much from those reported for visual nerve identification without the use of IONM. Six studies with more than 100 nerves at risk (NAR) each evaluated RLNPR by contrasting IONM with visual nerve identification only. Recurrent laryngeal nerve palsy rates tended to be lower with IONM than without it, but this difference was not statistically significant. Six additional studies compared IONM findings with their corresponding postoperative laryngoscopic results. Those studies revealed high negative predictive values (NPV; 92%-100%), but relatively low and variable positive predictive values (PPV; 10%-90%) for IONM, limiting its utility for intraoperative RLN management. CONCLUSIONS: Apart from navigating the surgeon through challenging anatomies, IONM may lend itself as a routine adjunct to the gold standard of visual nerve identification. To further reduce the number of false negative IONM signals, the causes underlying its relatively low PPV require additional clarification.

Advances in the management of hereditary medullary thyroid cancer.

This work draws on recent advances during the era of codon-oriented prophylactic surgery for hereditary medullary thyroid cancer (MTC). Milestones included identification of RET (REarranged during Transfection) as the susceptibility gene, introduction of prophylactic surgery on evidence of a RET germline mutation, revelation of genotype-phenotype correlations within the MEN 2 spectrum and demonstration of age-related progression of MTC. Novel surgical techniques, notably systemic microdissection and compartment-oriented surgery, have greatly enhanced surgical cure. Uncovering molecular pathways from RET genotype to MEN 2 phenotype should provide treatment options for RET mutation carriers whose MTC currently is too advanced for cure.

[Emergency management of a monstrous inguinal hernia]. / Notfallversorgung eines monströsen Leistenbruchs.

We report the case history of a 59 year old male patient, who suffered from a giant congenital inguinal hernia, which was operated because of a rapid increase of size and imminent obstruction of intestines. The treatment was carried out with non absorbable mesh. A part of the hernial sac was left in place. After a wound infection the non absorbable prosthetic mesh was substituted by absorbable material. The postoperative monitoring in the intensive care unit with artificial ventilation and the further treatment are described.

An update on thyroid surgery.

Surgery has been the treatment of choice for many disorders of the thyroid gland, both benign and malignant, for many decades. However, surgery has not been invariable but has continued to change in accordance with research results. In benign cases, surgery has generally evolved to be as organ preserving as possible. In several instances, however, a more radical extent of resection seems justified in order to ensure that the risk of recurrence is as low as possible. For instance, total thyroidectomy may be beneficial in patients with endemic multinodular goitre or young patients with Graves' disease and accompanying cold nodules or high levels of autoantibodies. Several tools, e.g. magnifying glasses, bipolar coagulation forceps and neuromonitoring, are available to identify and preserve the recurrent laryngeal nerve and the parathyroid glands, hence keeping the morbidity at a low level. Most recently, minimally invasive surgery has been successfully used in treating both benign and malignant disorders of the thyroid gland. In the case of malignant disorders, minimally invasive surgery may become an attractive alternative to open surgery if a limited surgical extent is justified, e.g. in patients with micro-PTC (papillary thyroid carcinoma, diameter less than 1 cm). Whether a limited surgical approach is also justified in other cases, e.g. in any patient with intrathyroidal PTC or patients with micro-FTC (follicular thyroid carcinoma), remains to be shown and is the subject of ongoing investigations. One of the most intriguing recent discoveries is the identification of genotype-phenotype correlations in patients with hereditary medullary thyroid carcinoma. In these patients, the timing and extent of surgery may depend not only on the patient's age and serum levels of the tumour marker calcitonin but also on the specific germline RET proto-oncogene mutation. Surgery will certainly continue to play an important role in the treatment of thyroid diseases and may be increasingly based on individual findings instead of general recommendations.

Calcitonin kinetics in the early postoperative period of medullary thyroid carcinoma.

INTRODUCTION: Calcitonin is a sensitive marker for medullary thyroid carcinoma. Normalisation of calcitonin levels following resection of medullary thyroid carcinoma has been described after a few hours; however, it may be observed more than 4 weeks after surgery. The aim of this study was to correlate the postoperative calcitonin kinetics with preoperative calcitonin levels and tumour stage. Furthermore, we wanted to test the prognostic impact of the calcitonin kinetics. Therefore, only patients with postoperative normalisation of calcitonin levels (biochemical cure) were included in this study. METHODS: Fourteen biochemically cured patients were analysed, including measurement of postoperative basal and pentagastrin-stimulated calcitonin concentration. With respect to the time of postoperative basal calcitonin normalisation, patients were classified into two groups: (A) patients with normalisation of basal calcitonin levels within 24 h and (B) patients with normalisation of basal calcitonin levels later than 24 h postoperatively. RESULTS: Eight patients were found to have normalisation of basal calcitonin levels within 24 h (group A). In the remaining six patients (group B), the period to normalisation of basal calcitonin levels varied from 6 days to 14 days and longer. There were no differences between the two groups with regard to tumour size, number and pattern of lymph node metastases and tumour stage. However, preoperative basal calcitonin levels were significantly different (258 ng/ml vs 955 ng/ml, P<0.01). In the group with slow-decreasing calcitonin levels, no strong correlation between the preoperative level and the postoperative time to normalisation of basal calcitonin levels could be established, which may be due to the small number of patients. After a median follow-up of 21 months, no patient developed tumour recurrence. However, an increased basal calcitonin level was observed in one patient from group B. All other patients had normal basal and peak calcitonin levels. CONCLUSION: Using a highly sensitive calcitonin assay, we demonstrated that normalisation of basal calcitonin levels may be delayed in patients suffering from medullary thyroid carcinoma. The lack of correlation of preoperative levels and the time to normalisation of the basal calcitonin levels, as well as the positive pentagastrin test in some of the patients, argues that this phenomenon is not simply due to prolonged biochemical calcitonin elimination. Nevertheless, a prognostic influence could not be shown in this study due to the short follow up-period. Further investigations and a longer follow-up are necessary to determine the nature and the prognostic impact of delayed normalisation of calcitonin levels.