How I treat medullary thyroid cancer.

Medullary thyroid cancer (MTC) represents a rare neuroendocrine neoplasm originating from neoplastic C-cells in the thyroid gland. While localized disease is potentially curable with an optimized surgical approach, the number of relapses is high, and a considerable number of patients present with primary metastatic disease. Multidisciplinary management including standardized surveillance following surgery, but also early involvement of medical oncologists, is therefore important. Several oncogenic pathways are involved in the pathogenesis of MTC including vascular endothelial growth factor receptor, epidermal growth factor receptor, MET, and most importantly RET, and the multi-tyrosine kinase inhibitors vandetanib and cabozantinib have been approved for advanced MTC based on data from phase III studies. As activating RET mutations represent the most important driver, specific RET inhibitors were introduced and suggest high response rates with limited off-target toxicities. The current review provides a practical overview on clinical presentation and management from early to advanced MTC.

Omission of lateral lymph node dissection in medullary thyroid cancer without a desmoplastic stromal reaction.

BACKGROUND: Medullary thyroid cancer can be subdivided during surgery into tumours with or without a desmoplastic stromal reaction (DSR). DSR positivity is regarded as a sign of disposition to metastasize. The aim of this study was to analyse whether lateral lymph node dissection can be omitted in patients with DSR-negative tumours. METHODS: This was a retrospective cohort study of a prospectively maintained database of patients with medullary thyroid cancer treated using a standardized protocol, and subdivided into DSR-negative and -positive groups based on the results of intraoperative frozen-section analysis. Patients in the DSR-negative group did not undergo lateral lymph node dissection. Long-term clinical and biochemical follow-up data were collected, and baseline parameters and histopathological characteristics were compared between groups. RESULTS: The study included 360 patients. In the DSR-negative group (17.8 per cent of all tumours) no patient had lateral lymph node or distant metastases at diagnosis or during follow-up, and all patients were biochemically cured. In the DSR-positive group (82.2 per cent of all tumours), lymph node and distant metastases were present in 31.4 and 6.4 per cent of patients respectively. DSR-negative tumours were more often stage pT1a and were significantly smaller. The median levels of basal calcitonin and carcinoembryonic antigen were significantly lower in the DSR-negative group, although when adjusted for T category both showed widely overlapping ranges. CONCLUSION: Lymph node surgery may be individualized in medullary thyroid cancer based on intraoperative analysis of the DSR. Patients with DSR-negative tumours do not require lateral lymph node dissection.

Can quantitative diffusion-weighted MR imaging differentiate benign and malignant cold thyroid nodules? Initial results in 25 patients.

BACKGROUND AND PURPOSE: The characterization of cold nodules of the thyroid gland is mandatory because approximately 20% of these nodules are of malignant origin. The purpose of this study was to evaluate the distinction of cold thyroid nodules by using quantitative diffusion-weighted MR imaging (DWI). MATERIALS AND METHODS: In 25 patients with cold nodules on scintigraphy and suggestive findings at fine-needle aspiration, thyroid carcinoma was suggested. In these patients, cold nodules and the normal parenchyma of the contralateral thyroid lobe were prospectively investigated with quantitative DWI (echo-planar imaging sequence; maximum b-value, 800 s/mm(2)) before surgery. The differences in the mean apparent diffusion coefficient (ADC) values in benign and malignant nodules were tested by using a Mann-Whitney U test. RESULTS: Histologically, there were 20 carcinomas with a minimum size of 8 mm and 5 adenomas. The mean ADC values (in 10(-3) mm(2)/s) differed significantly among carcinoma, adenoma, and normal parenchyma (P < .05). The ranges (95% confidence interval) of the ADC values for carcinoma (2.43-3.037), adenoma (1.626-2.233), and normal parenchyma (1.253-1.602) showed no overlap. When an ADC value of 2.25 or higher was used for predicting malignancy, the highest accuracy of 88%, with 85% sensitivity and 100% specificity, was obtained. CONCLUSIONS: Quantitative DWI seems to be a feasible tool with which to differentiate thyroid carcinomas from adenomas; however, further studies are required including larger numbers of patients to confirm our results.

Sporadic hypercalcitoninemia: clinical and therapeutic consequences.

'Calcitonin screening' is not accepted as the standard of care in daily practice. The clinical and surgical consequences of 'calcitonin screening' in a series of patients with mildly elevated basal calcitonin and pentagastrin stimulated calcitonin levels are presented. 260 patients with elevated basal (>10 pg/ml) and stimulated calcitonin levels (>100 pg/ml) were enrolled in this prospective study. None of the patients was member of a known medullary thyroid carcinoma family. Thyroidectomy and bilateral central and lateral neck dissections were performed. Testing for the presence of germ-line mutations was performed in all patients. Histological and immunohistochemical findings were compared with basal and stimulated calcitonin levels. All patients were subsequently followed biochemically. C-cell hyperplasia (CCH) was found in 126 (49%) and medullary thyroid cancer was found in 134 (51%) patients. RET proto-oncogen mutations were documented in 22 (8%) patients (medullary thyroid cancer:18, CCH:4). In 56 (46%) of 122 patients, sporadic CCH was classified neoplastic ('carcinoma in situ'). Of 97 (72%; 10 with hereditary medullary thyroid cancer) had pT1 (International Union against Cancer recommendations 2002) and 33 (25%) had pT2 or pT3 and 4 (3%) pT4 tumors. Of 39 (29.1%) had lymph node metastases. 106 (79.1%; 15 (38.5%) with lymph node metastases) patients were cured. Evaluation of basal and stimulated calcitonin levels enables the prediction of medullary thyroid cancer. All patients with basal calcitonin >64 pg/ml and stimulated calcitonin >560 pg/ml have medullary thyroid cancer. Medullary thyroid cancer was documented in 20% of patients with basal calcitonin >10 pg/ml but <64 pg/ml and stimulated calcitonin >100 pg/ml but <560 pg/ml.

Desmoplasia in medullary thyroid carcinoma: a reliable indicator of metastatic potential.

AIMS: To evaluate the reliability of desmoplasia as a reproducible morphological parameter indicating the metastatic potential of medullary thyroid carcinoma (MTC). METHODS AND RESULTS: One hundred and twenty cases of MTC of the Medical University of Vienna, Austria and 76 cases from the School of Medicine of Marseille, France were analysed for the presence of desmoplastic stroma reaction by four endocrine pathologists. Intra- and interobserver concordance was assessed. The Austrian cases were also analysed for various morphological parameters. Intra- and interobserver concordance were highly significant with a kappa value of 0.883 for intra-observer reliability and 0.837, 0.79 and 0.758, respectively, when pathologists N.N., C.D.M. and K.W.S. reviewed the Austrian cases. The cases from France were reviewed by C.D.M. and K.K. with a kappa value of 0.759. None of the cases that were categorized as desmoplasia negative by any of the investigators showed lymph node metastasis. No other distinct morphological characteristics could be assigned to the MTCs without desmoplasia. CONCLUSIONS: Our data indicate desmoplasia to be a reliable and highly reproducible parameter with regard to lymph node metastatic potential.

Importance of tumour size in papillary and follicular thyroid cancer.

BACKGROUND: The most controversial change in the new pathological tumour node metastasis (pTNM) classification of thyroid tumours is the extension of the pT1 classification to include tumours up to 20 mm. METHODS: Four hundred and three patients with pT1 or pT2 differentiated thyroid carcinomas were divided into three groups according to tumour diameter (group 1, 10 mm or less; group 2, 11-20 mm; group 3, 21-40 mm). They were analysed retrospectively with respect to carcinoma-specific and disease-free survival. RESULTS: No patient in group 1 died from papillary thyroid carcinoma, compared with three patients in group 2 and six in group 3. There was a statistically significant difference in carcinoma-specific survival between groups 1 and 2 (P = 0.033). Two patients in group 1, six in group 2 and eight in group 3 developed recurrence. The difference in disease-free survival between groups 1 and 2 was significant (P = 0.025). One patient in group 1, three in group 2 and four in group 3 died from follicular thyroid carcinoma, but there were no significant differences in survival between the three groups. CONCLUSION: Extension of the pT1 classification to cover all tumours up to 20 mm does not appear to be justified for papillary thyroid carcinoma.

Cytotoxic activity of camptothecin and paclitaxel in newly established continuous human medullary thyroid carcinoma cell lines.

At the time of diagnosis, more than one quarter of patients with medullary thyroid carcinoma (MTC) has distant metastases. Only few of these patients can be cured by surgery. Standard chemotherapy is characterized by low response rates and short response time. The establishment of eight human MTC cell lines provides a new basis for in vitro investigation of cytotoxic drugs. Camptothecin (CPT) and paclitaxel, which never have been investigated in the treatment of MTC, were tested for their cytotoxic profile in comparison with the clinically ineffective dacarbazine. Eight MTC cell lines were established from seven patients with MTC. IC(50) values were calculated from dose-response relationships using cell counts and a formazan dye assay (WST-1). IC(50) values were 3.5 +/- 1.2 nmol/liter for CPT and 8.2 +/- 1.9 nmol/liter for paclitaxel. Dacarbazine showed no reduction of cell proliferation at concentrations 10-fold higher than clinically achievable. Given peak plasma concentrations of 65 +/- 20 nmol/liter for CPT and 1 micro mol/liter for paclitaxel, these promising in vitro results provide a basis for the performance of clinical trials in patients with advanced MTC.

Prognostic factors of papillary and follicular thyroid cancer: differences in an iodine-replete endemic goiter region.

Papillary (PTC) and follicular thyroid carcinoma (FTC) are known as differentiated thyroid carcinoma (DTC). Nevertheless, according to the UICC/AJCC (TNM) classification PTC and FTC are frequently analyzed as one cancer. The aim of this study is to show differences in outcome and specific prognostic factors in an iodine-replete endemic goiter region. Six hundred and three patients with DTC treated within a 35-year-period were retrospectively analyzed with respect to carcinoma-specific survival. Prognostic factors were tested for their significance using univariate and multivariate analysis. The histological type (PTC versus FTC) was found to be a highly significant factor - carcinoma-specific survival both in univariate (P<0.001) and multivariate analyses (P=0.003) was significantly different. Univariate analysis revealed patients' age, extra-thyroid tumor spread, lymph node and distant metastases, increasing tumor size, and the tall cell variant to be significant prognostic factors for PTC patients. Age > or =45 years, positive lymph nodes and increasing tumor size were confirmed as independent prognostic factors. Univariate analysis of FTC patients revealed age at presentation, gender, extrathyroidal tumor spread, lymph node and distant metastases, increasing tumor size, multifocality, widely invasive tumor growth and oxyphilic variant to be factors bearing prognostic significance. The presence of distant metastases and increasing tumor size could be identified as independent prognostic factors for FTC patients. This study shows distinctive differences in prognostic factors of PTC and FTC: independent factors predicting poor prognosis are age > or =45 years, positive lymph nodes and increasing tumor size for PTC, and distant metastases and increasing tumor size for FTC. PTC and FTC patients should be analyzed and reported separately.

Nesidioblastosis in adults: a challenging cause of organic hyperinsulinism.

BACKGROUND: Nesidioblastosis in adults has been reintroduced into the differential diagnosis of organic hyperinsulinism by the description of 'noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS)'. MATERIALS AND METHODS: Pathologic specimens of all adult patients (n = 66) operated on for organic hyperinsulinism were re-examined. Five patients fulfilled the histomorphological criteria of nesidioblastosis. Retrospective review of clinical presentation, results of 72-h fasts, intravenous tolbutamide tolerance tests, pre- and intraoperative localization studies and surgical therapy was performed. RESULTS: In contrast to NIPHS, fasting tests became positive after 8-14 h. Tolbutamide tests were positive and preoperative imaging showed negative results in all patients. At first operation distal pancreatic resections were performed in three patients, resection of the pancreatic body in one patient and biopsy of the pancreatic tail in one patient. Two of three patients with recurrent disease had to be reoperated. One patient showed a coexistence of nesidioblastosis and multiple small insulinomas and is part of a kindred with autosomal dominantly inherited 'familial islet-cell adenomatosis'. CONCLUSIONS: Surgical exploration is indicated only after thorough biochemical diagnosis. An aggressive strategy for preoperative localization including selective arterial calcium stimulation testing seems justified. There may be a combination of nesidioblastosis and islet cell tumours. A link between beta-cell hyperplasia and progression to insulinoma based on not yet known genetic causes can be suspected.

Sporadic versus familial medullary thyroid microcarcinoma: a histopathologic study of 50 consecutive patients.

By means of calcitonin screening programs, sporadic and hereditary medullary thyroid carcinoma (MTC) can be detected at an early stage. We investigated the histopathologic findings of 16 familial (mean age 32 +/- 21 years, female/male ratio 1.6:1) and 34 sporadic (mean age 58 +/- 15 years; female/male ratio 2.4:1) MTCs with stage T1 comparatively. Patients with hereditary tumors were younger. Hereditary tumors were more often found multifocal (13 of 16 vs 3 of 34; p < 0.001), bilateral (11 of 16 vs 3 of 34; p < 0.001), displaying desmoplastic stroma (14 of 16 vs 19 of 34; p = 0.02), and accompanied by C cell hyperplasia (16 of 16 vs 24 of 34; p = 0.01), but all of these factors were present in some sporadic patients. Only tumors with desmoplastic stroma showed lymph node metastasis, which was observed in eight of the 50 patients. After surgery all patients showed permanent normalization of calcitonin levels. We conclude that 1) morphologic parameters considered to indicate familial MTC risk are of no value in the individual patient, 2) many sporadic MTCs develop on the background of CCH, 3) tumors with desmoplastic stroma are more likely to develop lymph node metastasis, and 4) early detection of MTC permits curative surgery in the majority of patients.

[Surgery for non-colorectal and non-neuroendocrine liver metastases]. / Die chirurgische Therapie von nicht-kolorektalen und nicht-neuroendokrinen Lebermetastasen.

INTRODUCTION: Hepatic resection has been shown to prolong survival in selected patients with colorectal liver metastases. Due to slow tumor growth patients with neuroendocrine liver metastases tend to have a good prognosis and benefit from chemo-embolisation and symptomatic treatment. The role of surgery in treating non-neuroendocrine and non-colorectal liver metastases is discussed controversially, due to the limited knowledge on this subject. The aim of our study was, therefore, to evaluate our own experiences with hepatic surgery for non-neuroendocrine, non-colorectal liver metastases. METHODS: A retrospective review of 72 patients (median age 60.9 years) who underwent 73 hepatic resections for non-neuroendocrine, non-colorectal liver metastases between 1980 and 2000 at a single tertial referral center was carried out. RESULTS: Hepatic resection was combined with surgery for the primary tumor in 30 cases (41.1%). Hospital mortality was 4.2%. 35 patients (47.9%) developed complications. The mean hospital stay was 17.5 days. In 64.4% of the cases a potentially curative resection was reached. Overall actuarial survival was 52.1% at 1 year, 25.3% at 3 years and 9.9% at 5 years. The respective median overall survival times were 7.1 months (gastric cancer metastases; n = 15), 4.9 months (cholangiocellular cancer metastases; n = 9), 5.6 months (gall bladder, bile duct cancer metastases; n = 8), 35.4 months (kidney cancer metastases; n = 8), 14.4 months (breast cancer metastases; n = 4), 15.3 months (pancreas and other adenocarcinoma metastases; n = 11), 49.9 months (sarcoma metastases; n = 10) and 32.9 months (other metastases; n = 7). CONCLUSIONS: In isolated hepatic metastases originating from sarcoma and hypernephroma radical resection can prolong survival. However, surgery cannot improve the prognosis in patients with liver metastases originating from the pancreas, gallbladder and the biliary tract. In selected patients with liver metastases from gastric and breast cancer long term survival seems possible after resection.

Minimally invasive open parathyroidectomy in an endemic goiter area: a prospective study.

HYPOTHESIS: Single-gland disease identified by preoperative localization studies in combination with rapid intraoperative parathyroid hormone monitoring seems to allow a limited exploration of the neck in sporadic primary hyperparathyroidism. Minimally invasive open parathyroidectomy by lateral approach (oMIP) in sporadic primary hyperparathyroidism seems feasible in an endemic goiter region. DESIGN: One hundred consecutive patients with sporadic primary hyperparathyroidism underwent preoperative double-phase technetium Tc 99m sestamibi scanning with single-photon emission computed tomography and high-resolution ultrasonography with color Doppler imaging of the cervical region. All patients were operated on with the use of quick parathyroid hormone assay to confirm the surgical success "on-line." Patients with localized single-gland disease, irrespective of additional ipsilateral thyroid disease requiring surgery, were selected for oMIP. Success of the preoperative localization studies, postoperative (at least 6 months) serum calcium levels, and operating time were analyzed. SETTING: University hospital, section of endocrine surgery. RESULTS: Of 100 patients, 83 (83%) were considered suitable for oMIP. In 69 patients, oMIP was finished successfully. Nine of these had had previous neck surgery, and another 24 underwent additional ipsilateral thyroid resection. Permanent normocalcemia was achieved in 67 (97.1%) of 69 patients and 98 (98%) of 100 patients. CONCLUSION: The oMIP in combination with quick parathyroid hormone assay may become the treatment of choice for sporadic primary hyperparathyroidism in an endemic goiter region in centers with high experience in thyroid and parathyroid surgery. It allows treatment of concomitant ipsilateral thyroid disease and is feasible in reoperations.

Diagnostic efficacy of unconjugated plasma metanephrines for the detection of pheochromocytoma.

BACKGROUND: Recently, measurement of plasma metanephrines was suggested to improve the detection of pheochromocytoma compared with the other common biochemical tests. OBJECTIVE: To examine the diagnostic precision of measurements of plasma metanephrines, plasma catecholamines, and urinary catecholamines and to assess their variability. METHODS: Plasma metanephrine as well as plasma and urinary catecholamine concentrations were measured by high-performance liquid chromatography with electrochemical detection. Before surgery, responses of plasma metanephrines and catecholamines to change of posture were determined. Intraoperatively, metanephrines and catecholamines were measured before skin incision, during maximal mechanical tumor manipulation, and repetitively after the tumor was separated from the circulation. Patients were reexamined 1 and 3 months after surgery. Patients with pheochromocytoma (n = 17) and with histologically proved other adrenal tumors (n = 14) were studied before, during, and after surgery. RESULTS: Measurement of plasma metanephrines and plasma and urinary catecholamines provided 100% and 82% sensitivity, respectively, for the detection of pheochromocytoma (P<.001). Levels of plasma catecholamines but not metanephrines increased in response to change of posture (norepinephrine, P =.03; epinephrine, P =.07) and intraoperative stress (norepinephrine, P =.002; epinephrine, P =.009). CONCLUSIONS: Plasma metanephrines offer improved efficacy for the diagnosis of pheochromocytoma. Less variability in response to external factors may favor plasma metanephrines in the screening for this disease. Arch Intern Med. 2000;160:2957-2963

Prevalence of C-cell hyperplasia in patients with normal basal and pentagastrin-stimulated calcitonin.

The prevalence of thyroid C-cell hyperplasia (CCH) was investigated prospectively in 57 patients with normal preoperative pentagastrin-stimulated plasma concentrations of calcitonin (hCT, range, 1-60 pg/mL; normal, 100 pg/mL) who subsequently underwent total thyroidectomy due to thyrotoxicosis (n = 18) or to nodular thyroid disease in the presence (n = 9) or absence (n = 30) of cytological follicular neoplasia. CCH was seen in 28 of 57 (49%) of all patients. CCH was more common in hyperthyroid (12/18 [66%]) than in euthyroid (16/39 [41%] patients. No age- or gender-related differences in the occurrence of CCH was seen. There was no histological evidence of medullary thyroid carcinoma (MTC) in any patient. CCH classified histologically as neoplastic was encountered in two instances. It was concluded that CCH may be expected in almost 50% of normocalcitonemic patients with various thyroid disorders. Although the potential clinical importance of this histological finding and specifically its neoplastic variety remains unknown, these results are in keeping with the assumption that pentagastrin-stimulated plasma concentrations of hCT within the normal range do not exclude the presence of CCH.

Intrathoracic fluid volumes and pulmonary function during orthotopic liver transplantation.

BACKGROUND: Impaired pulmonary function is a frequent finding in patients undergoing orthotopic liver transplantation (OLT). Experimental data suggest an essential contribution of splanchnic ischemia and reperfusion as a result of intraoperative volume shifts, i.e., the accumulation of extravascular lung water (EVLW). Increases of intrathoracic blood volume (ITBV) and pulmonary blood volume (PBV) might additionally influence pulmonary capillary fluid filtration. The main objective of this study was to determine the intrathoracic volume changes during OLT and to test whether there were any relationships between intra- and extravascular volume shifts and pulmonary function, as determined by the calculation of venous admixture (QS/QT) and alveolar-arterial oxygen gradient (AaDO2). METHODS: Twenty-five patients undergoing OLT were studied. Using the transpulmonary double indicator dilution method, ITBV, PBV, and EVLW were determined from the mean transit times and exponential decay times of the indocyanine green and the thermal indicator curves recorded simultaneously with a fiberoptic catheter in the descending aorta. Recordings were made after induction of anesthesia, at the end of the anhepatic stage, immediately after reperfusion, and 1 and 4 h postoperatively. RESULTS: Significant increases in QS/QT related to changes of ITBV were observed after reperfusion. Only a minor impact on AaDO2 was perceived. EVLW remained constant during the study period. CONCLUSIONS: Postreperfusion increases of ITBV influence pulmonary function, as demonstrated by the increase in QS/QT. However, they need not be associated with greater EVLW levels, and impact on oxygenation is less severe than assumed. Hence, sufficient mechanisms protecting oxygenation and stalling increased EVLW seem to be present during uncomplicated human OLT.

Primary small bowel malignancies: single-center results of three decades.

We highlight one medical center's experiences with primary malignancies of the small bowel. During a 27-year period, 79 patients were treated for small bowel tumors. Of these, 15 (20%) were lost to follow-up; thus, 64 patients were reviewed retrospectively with emphasis on histological distribution and their topography, perioperative complications, overall survival, and prognostic factors. In our 64-patient series, 33 (51.6%) presented with adenocarcinoma; 10 (15.5%), lymphoma; 8 (12.1%), leiomyosarcoma; 5 (7.6%), neurogenic tumor; 2 (3%), unclassified carcinoma; 5 (7.6%), other types of sarcoma; and 1 patient presented with synchronous adenocarcinoma and lymphoma. Of all patients, 30 (46.9%) were curatively treated, whereas 34 (53.1%) underwent palliative procedures. Hospital lethality was 9.4% and mainly occurred in patients operated on under emergency circumstances. Reoperation rate was 29.7%. The observation period lasted at least five years or until death; three patients were alive less than five years postoperatively. Cumulative five-year survival rate was 22.5% in the adenocarcinoma group, 33.3% in the lymphoma group, 33.3% in the leiomyosarcoma group, and 22.2% in patients with other tumors. The uncharacteristic symptoms presented by patients suffering from small intestinal malignancies make early diagnosis difficult. Therefore, especially in patients with long-standing bowel diseases, malignancy should be considered. Early diagnosis and surgical treatment lead to a good prognosis as shown by our study.

Long-term results after laparoscopic unroofing of solitary symptomatic congenital liver cysts.

BACKGROUND: Reports about laparoscopic management of symptomatic nonparasitic liver cysts are increasing, proving the procedure feasible and safe. However, late results of endoscopic unroofing currently are not available. The primary aim of the study was to offer long-term results with a follow-up of more than 5 years. Two diagnostic pitfalls are presented. METHODS: Preoperatively, diagnosis was established by sonography, computed tomography (CT) scan, echinococcus serology, and tumor-marker measurement. The outcome of 12 laparoscopic fenestrations in 11 patients with symptomatic solitary liver cysts is presented. Nine patients were reexamined after a median observation time of 3.1 years (range, 0.6-6.4 years) by clinical investigation and ultrasonography, CT scan, or magnetic resonance imaging (MRI), respectively. RESULTS: All operations could be finished laparoscopically, and no death occurred. Simultaneous cholecystectomy was performed in six cases. All patients experienced immediate relief of symptoms. Postoperatively, no complications were observed except one patient with unilateral brachial vein thrombosis. Histologically, we discovered one hydatide cyst and one cystadenoma underlying the cystic disorder leading to further therapy. At follow-up, one of the remaining seven patients (14.3%) suffered symptomatic recurrence and successfully underwent reoperation endoscopically. CONCLUSIONS: The results of this study confirm the outcome reported previously after short- and intermediate-term follow-up showing that laparoscopic management of symptomatic solitary nonparasitic liver cysts is permanently successful in a large majority of cases when diagnosis is correct.