Dietmar Simon

Prophylactic Thyroidectomy in 75 Children and Adolescents with Hereditary Medullary Thyroid Carcinoma: German and Austrian Experience

Abstract. When mutations of theRETproto-oncogene were found in 1993 to account for hereditary medullary thyroid carcinoma (MTC), surgeons obtained the opportunity to operate on patients prophylactically (i.e., at a clinically asymptomatic stage). Whether this approach is justified, and, if so, when and to which extent surgery should be performed remained to be clarified. A questionnaire was sent to all surgical departments in Germany and Austria. All of the patients who fulfilled the following criteria were enrolled: (1) preoperatively proved RET mutation; (2) age ≤ 20 years, (3) clinically asymptomatic thyroid C cell disease; and (4) TNM classification pT0–1/pNX/pN0–1/M0. Seventy-five patients were identified, and fifteen mutations were detected in six codons. Two adolescents had unilateral pheochromocytomas as part of the multiple endocrine neoplasia II (MEN-II) syndrome. No hyperparathyroidism was noted. All patients underwent total thyroidectomy, and 57 patients went on to have lymph node dissection. Parathyroid glands were removed in 34 patients and autografted in 11. Histopathology revealed MTC in 46 patients (61%, youngest 4 years); C cell hyperplasia (CCH) only was detected in the other 29 patients. Three patients had lymph node metastases (LNMs) the youngest being age 14 years. Calcitonin levels were not useful for differentiating between CCH and MTC, but in all patients with LNMs at least the stimulated calcitonin levels were assayed. After surgery, five patients (6.7%) sustained permanent hypoparathyroidism, and one patient (1.3%) had a permanent unilateral recurrent nerve palsy. All but three patients (96%) were biochemically cured. In conclusion, prophylactic total thyroidectomy can be performed safely in experienced centers. We recommend prophylactic total thyroidectomy at age 6. Cervicocentral lymph node dissection should be included when calcitonin levels are elevated or if patients are older than 10 years. Bilateral lymph node dissection should be performed if LNMs are suspected or when patients with elevated calcitonin are older than 15 years.

Incidence of Regional Recurrence Guiding Radicality in Differentiated Thyroid Carcinoma

Abstract. Total thyroidectomy has become the routine procedure for treatment of differentiated thyroid carcinoma. However, the necessity of unilateral or bilateral neck dissection is far less standardized. Our usual procedure has been to perform a routine neck dissection in T4 tumors and in all other tumor stages only in the presence of positive diagnostic or intraoperative findings. The results concerning regional tumor recurrence in cervical lymph nodes subsequent to thyroidectomy are studied and discussed. Between April 1986 and December 1992 a group of 252 patients were operated on for differentiated thyroid carcinoma (DTC) (176 papillary, 76 follicular). Postoperative treatment included radioiodine therapy as a rule in all patients more than stage T1, and follow-up encompassed thyroglobulin measurements, cervical ultrasonography, and radioiodine scintigraphy. After a mean follow-up of 6.9 years, 77 (31%) of the patients underwent reoperation because of regional tumor recurrence [46 of 176 (26%) papillary, 31 of 76 (41%) follicular]. In papillary thyroid cancer a significant difference could be demonstrated between patients with thyroidectomy only versus thyroidectomy plus neck dissection in all tumor stages (T2, 13 of 29 (45%) versus 1 of 34 (3%); T3, 10 of 13 (77%) versus 4 of 11 (36%); T4, 6 of 8 (75%) versus 6 of 18 (33%) (p < 0.0001). Similar results could be achieved for follicular thyroid cancer, showing statistical significance with regard to operative procedure (p < 0.009). Our experience demonstrates a positive correlation of regional tumor recurrence with increasing tumor stage for both histologic tumor types. The high rate of regional recurrence justifies a more radical approach, including neck dissection at the initial operation. The impact on survival, however, must be proved by further evaluation.

Redifferentiation Therapy with Retinoids: Therapeutic Option for Advanced Follicular and Papillary Thyroid Carcinoma

Abstract. During the course of tumor progression the differentiated morphologic and functional characteristics of differentiated thyroid carcinomas (DTC) disappear. This corresponds to more aggressive growth, metastatic spread, and loss of iodine uptake. Experimental data give strong evidence that differentiated functions of iodine metabolism can be reinduced by retinoic acids. Results of a study performed in patients with advanced DTC are presented. Twenty patients with DTC (eight follicular, seven papillary, five oxyphilic) were selected for treatment with retinoic acid 1.5 mg/kg body weight/day over 5 weeks. All patients had advanced tumor stages with prior operative and radioiodine treatment. Extensive tumor invasion, distant metastatic spread, or insufficient or no radioiodine uptake precluded any conventional therapeutic option. The aim was to assess the changes under retinoid treatment. Iodine uptake increased in eight patients (three follicular, three papillary, two oxyphilic). Thyroglobulin (TG) as parameter for tumor mass and differentiation increased in 12 (63%) patients, decreased in 6 (32%), and did not change in 1 (5%). Retinoids do have an effect on differentiation status of DTC, reinducing iodine uptake in 50% of patients. TG levels do not always parallel a response in iodine uptake.

Importance of lymph node metastases in follicular thyroid cancer.

There are many concepts of risk and prognostic factor analysis for differentiated thyroid cancer. The prognostic role of lymph node metastases in follicular thyroid cancer (FTC), however, is still controversial. We performed a retrospective trial in 186 patients with FTC (124 women, 62 men; mean follow-up 5.5 years) questioning whether lymph node metastases and radical thyroid surgery with neck dissection contribute to the prognosis of FTC. Univariate analysis demonstrated that lymph node metastasesp <0.005), tumor size (p <0.005), tumor stage (p <0.005), distant metastases p = 0.0063), and gender (p = 0.003) are significant prognostic factors for recurrence (Kaplan-Meier). Tumor size (p = 0.004), lymph node metastases p = 0.0478), and distant metastases p = 0.0064) influenced mortality. Age and extent of surgery were not significant for recurrence nor was gender for mortality. Multivariate analysis (Cox regression test) characterized tumor size (p <0.005) and lymph node metastases p = 0.004) as prognostic factors for recurrence of FTC. No significant difference was detected between patients being treated by thyroidectomy when compared to patients treated by thyroidectomy plus neck dissection in relation to recurrence. Our data demonstrate lymph node metastases to be a significant prognostic factor for recurrence of FTC and the patient’s survival. We advocate thyroidectomy plus central lymph node dissection as the basic surgical strategy. For T3 and T4 tumors, unilateral modified neck dissection is an all but optional procedure. Whether radical surgery with thyroidectomy plus neck dissection has an impact on survival remains questionable.

Involvement of Soluble CD95 in Churg-Strauss Syndrome

Deficiency of CD95 (Apo-1/Fas)-mediated apoptosis has recently been found in some autoimmune lymphoproliferative disorders due to inherited mutations of the CD95 gene. In this study, impairment of CD95 ligand-mediated killing of lymphocytes and eosinophils in Churg-Strauss Syndrome (CSS), which was a result of variation of CD95 receptor isoform expression, is demonstrated. Compared to those from healthy individuals, peripheral blood lymphocytes from eight CSS patients exhibit a switch from the membrane-bound CD95 receptor expression to its soluble splice variant, which protects from CD95L-mediated apoptosis. In five out of seven CSS patients recurrent oligoclonal T cell expansions were found, all using a Vbeta-gene from the Vbeta21 family associated with similar CDR3 motifs, indicating the predominance of T cell clones of a similar specificity in the CSS patients. In two of them, the effect of immunosuppressive therapy was studied. In both cases aberrant overexpression of the soluble CD95 receptor isoform and deviations from normal TCR Vbeta-gene usage normalized in parallel with the clinical improvement. Furthermore, soluble CD95 was identified as a survival factor for eosinophils rescuing eosinophils from apoptosis in the absence of growth factors in vitro. Given the role of eosinophils as effector cells in CSS, these findings suggest that soluble CD95 may be mechanistically involved in the disease.

Long-term Biochemical Results after Operative Treatment of Primary Hyperparathyroidism Associated with Multiple Endocrine Neoplasia Types I and IIa: Is a More or Less Extended Operation Essential?

OBJECTIVE To analyse our long term results in patients operated on for primary hyperparathyroidism associated with multiple endocrine neoplasia types I and IIa. DESIGN Retrospective (data collection) and prospective (follow-up) analysis. SETTING University hospital, Germany. SUBJECTS 39 patients with MEN type I-associated and 7 patients with MEN-type-IIa-associated primary hyperparathyroidism. INTERVENTIONS Subtotal parathyroidectomy (n = 25 with MEN I and 1 with MEN IIa), total parathyroidectomy and autotransplantation (one in each group) and removal of only enlarged glands (13 with MEN type I and 5 with MEN type IIa). MAIN OUTCOME MEASUREMENTS Recurrence rate of hyperparathyroidism and permanent hypocalcaemia postoperatively. RESULTS Subtotal parathyroidectomy in patients with MEN type I gave a significantly lower recurrence rate than removal of only enlarged glands (3/25 compared with 3/13, log rank, p = 0.04). Permanent hypocalcaemia developed in 3/25 compared with 3/13, respectively. 2/5 patients with MEN type IIa developed recurrences after removal of only enlarged glands and the rate was higher than expected. CONCLUSIONS A more extensive operation is essential for patients with MEN type I; the rate of permanent hypocalcaemia is not increased, but the recurrence rate is reduced. Patients with MEN type IIa should be treated by excision of enlarged glands alone, but this may be extended to subtotal parathyroidectomy in patients with severe symptoms.

FUNCTIONAL RETINOID AND THYROID HORMONE RECEPTORS IN HUMAN THYROID-CARCINOMA CELL LINES AND TISSUES

Thyroid carcinomas no longer accessible to radio‐iodide or TSH‐suppressive T4 therapy, due to loss of thyroid‐specific functions, might be sufficiently re‐differentiated by retinoic acid (RA) to be treated by conventional methods again. To help evaluate the feasibility of RA re‐differentiation therapy in thyroid carcinomas, we examined the functionality of RA receptors (RARs/RXRs), central RA signal mediators, in human thyroid‐carcinoma cell lines as model systems. [3H]‐RA binding assays with nuclear extracts from follicular thyroid‐carcinoma cell lines FTC‐133 and ‐238 revealed high‐affinity binding sites for RA. Electrophoretic mobility shift and supershift assays using a DR2 (“direct repeat” 2) RA response element demonstrated DNA‐binding of RARα, RARγ, RXRα and RXRβ in nuclear extracts of FTC‐133 and anaplastic HTh74 cells. Use of a DR5 RA response element revealed no difference in DNA binding. In supershift assays with a DR4 T3 response element, we found DNA‐binding by TRα1, TRα2, and TRβ. Northern‐blot analysis showed low expression of RXRβ mRNA in FTC‐133 and of TRα1 mRNA in FTC‐133 and FTC‐238 cells. Using RT‐PCR, we detected mRNA for RARα, RARβ, RARγ, RXRα, and RXRβ in the 4 cell lines and in human thyroid‐carcinoma samples. RARβ mRNA was reduced in FTC‐238 cells and RXRβ mRNA was decreased in anaplastic C643 cells and 9 of 12 tumor samples. Differential RA regulation of RA‐receptor‐mRNA expression was observed in the various cell lines. Thus, RA and T3 nuclear receptors are present in thyroid‐carcinoma cell lines or tissues, albeit with cell‐line and tumor‐dependent variations; in the cell lines, they were shown to be functional with respect to DNA and/or ligand binding. Int. J. Cancer 76:368–376, 1998.© 1998 Wiley‐Liss, Inc.

Therapy of suspected intrathoracic parathyroid adenomas

Background and aims: Ectopic mediastinal parathyroid adenoma as a cause of primary hyperparathyroidism (pHPT) can normally be resected from conventional collar incision. In rare cases with adenomas deeper in the chest, a transthoracic approach is necessary. Patients/methods: We report our experience of 19 patients with suspected mediastinal parathyroid adenomas from a total of 1035 patients with pHPT who were operated on between 1986 and 2000 using an open approach (sternotomy or thoracotomy) or video-assisted mediastinal or thoracoscopic surgery (VAMS/VATS). Results: Fourteen patients underwent an open approach with a success rate of 71% (10 of 14). Four patients remained hypercalcaemic. There were four complications in three patients: three permanent recurrent nerve palsies and one chylus fistula, requiring further surgery. VATS was successful in three of four patients with conversion to sternal splitting because of a false-negative frozen section in one patient. Another patient had parathyroid adenoma retrosternally which could not be resected by means of VAMS and had to be excised using a transsternal approach. There were no complications of minimal invasive procedures. All five patients were normocalcaemic after the operation. Conclusion: Ectopic parathyroid adenomas not resectable by means of a collar incision are rare causes of pHPT and comprise 1.25% of all patients with pHPT in our series. For these patients, VATS revealed an alternative to conventional open procedures. In questionable cases, however, the collar incision should precede the VATS procedure.

Dendritic cell immunotherapy in a neuroendocrine pancreas carcinoma

OBJECTIVE Metastatic neuroendocrine carcinomas of the pancreas frequently fail to respond to conventional therapies, including radiation and chemotherapy. We therefore tested a dendritic cell‐based immunotherapy in an attempt to eradicate residual tumour masses in a patient suffering from a metastatic insulin‐producing pancreatic carcinoma.

Genetic and Biochemical Screening for Endocrine Disease

AbstractThe development of biochemical and genetic screening tests for inherited endocrine diseases has dramatically changed our approach to surgical patients with endocrine tumors. Among more than 1800 patients with endocrine tumors and a possible inherited disease operated on between 1986 and 1997, there were 6.1% to 7.3% who were found to have a familial disease associated with familial medullary thyroid cancer, (MTC), multiple endocrine neoplasia type IIa (MEN-IIa), MEN-IIb, or MEN-I. Genetic testing for the RET proto-oncogene is therefore recommended for all patients with MTC, and testing for the MEN-I gene is recommended in patients with suspected MEN-I and in specific clinical subgroups with an increased probability of endocrine tumor heredity. Early treatment based on early diagnosis by genetic testing appears to improve survival and to decrease morbidity in these patients.