Peter E. Goretzki

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.

German Association of Endocrine Surgeons practice guidelines for the surgical treatment of benign thyroid disease

IntroductionBenign thyroid disorders are among the most common diseases in Germany, affecting around 15 million people and leading to more than 100,000 thyroid surgeries per year. Since the first German guidelines for the surgical treatment of benign goiter were published in 1998, abundant new information has become available, significantly shifting surgical strategy towards more radical interventions. Additionally, minimally invasive techniques have been developed and gained wide usage. These circumstances demanded a revision of the guidelines.MethodsBased on a review of relevant recent guidelines from other groups and additional literature, unpublished data, and clinical experience, the German Association of Endocrine Surgeons formulated new recommendations on the surgical treatment of benign thyroid diseases. These guidelines were developed through a formal expert consensus process and in collaboration with the German societies of Nuclear Medicine, Endocrinology, Pathology, and Phoniatrics & Pedaudiology as well as two patient organizations. Consensus was achieved through several moderated conferences of surgical experts and representatives of the collaborating medical societies and patient organizations.ResultsThe revised guidelines for the surgical treatment of benign thyroid diseases include recommendations regarding the preoperative assessment necessary to determine when surgery is indicated. Recommendations regarding the extent of resection, surgical techniques, and perioperative management are also given in order to optimize patient outcomes.ConclusionsEvidence-based recommendations for the surgical treatment of benign thyroid diseases have been created to aid the surgeon and to support optimal patient care, based on current knowledge. These recommendations comply with the Association of the Scientific Medical Societies in Germany requirements for S2k guidelines.

Adrenal involvement in multiple endocrine neoplasia type 1

Adrenal lesions belong to the spectrum of multiple endocrine neoplasia type 1 (MEN-1) syndrome. However, the prevalence of adrenal involvement, the characteristics, and the clinical management of adrenal lesions have not yet been clearly defined. A total of 66 patients with confirmed MEN1 germline mutations and 1 additional patient with typical manifestations in three organ systems were monitored in a regular screening program that included evaluation of the adrenals (median follow-up 96 months; range 12 to 300 months). Age at the diagnosis of MEN-1 and of adrenal tumors and the clinical characteristics, genotype, treatment, and follow-up of adrenal disease were analyzed. Adrenal lesions were identified in 18 of 67 (26.8%) MEN-1 patients and were diagnosed 5 years later than MEN-1. The median tumor diameter at diagnosis was 3.0 cm (range 1.2–15.0 cm), with most tumors being 3 cm or smaller. Eight patients had bilateral tumors. Ten patients had nonfunctional benign tumors, three had benign adrenal Cushing syndrome, and one patient had a pheochromocytoma. Four patients developed adrenocortical carcinomas (ACCs), three of which were functional. Nine adrenalectomies and one subtotal adrenalectomy were performed in six patients. Three patients with ACC died owing to the tumor. Patients with mutations in exons 2 and 10 developed adrenal tumors significantly more often than patients with other mutations (p <0.01). Adrenal tumors are a common feature of MEN-1 but occur later in the course of the disease. The lesions are often small and nonfunctional and can therefore be managed by close surveillance; others have significant malignant potential and should be considered for surgery when they are 3 cm or larger.

German Association of Endocrine Surgeons practice guideline for the surgical management of malignant thyroid tumors

IntroductionOver the past years, the incidence of thyroid cancer has surged not only in Germany but also in other countries of the Western hemisphere. This surge was first and foremost due to an increase of prognostically favorable (“low risk”) papillary thyroid microcarcinomas, for which limited surgical procedures are often sufficient without loss of oncological benefit. These developments called for an update of the previous practice guideline to detail the surgical treatment options that are available for the various disease entities and tumor stages.MethodsThe present German Association of Endocrine Surgeons practice guideline was developed on the basis of clinical evidence considering current national and international treatment recommendations through a formal expert consensus process in collaboration with the German Societies of General and Visceral Surgery, Endocrinology, Nuclear Medicine, Pathology, Radiooncology, Oncological Hematology, and a German thyroid cancer patient support organization.ResultsThe practice guideline for the surgical management of malignant thyroid tumors includes recommendations regarding preoperative workup; classification of locoregional nodes and terminology of surgical procedures; frequency, clinical, and histopathological features of occult and clinically apparent papillary, follicular, poorly differentiated, undifferentiated, and sporadic and hereditary medullary thyroid cancers, thyroid lymphoma and thyroid metastases from primaries outside the thyroid gland; extent of thyroidectomy; extent of lymph node dissection; aerodigestive tract resection; postoperative follow-up and surgery for recurrence and distant metastases.ConclusionThese evidence-based recommendations for surgical therapy reflect various “treatment corridors” that are best discussed within multidisciplinary teams and the patient considering tumor type, stage, progression, and inherent surgical risk.

Age-related penetrance of endocrine tumours in multiple endocrine neoplasia type 1 (MEN1): a multicentre study of 258 gene carriers

Objective  In multiple endocrine neoplasia type 1 (MEN1), age‐related tumour penetrance according to the type of MEN1 germline mutation has not been investigated in‐depth. This study was conducted to examine whether carriers of out‐of‐frame/truncating and in‐frame MEN1 mutations differ in age‐related tumour penetrance.

Clinical management of malignant adrenal tumors.

Abstract Malignant primary adrenal tumors are rare forms of cancer with an estimated incidence of two to ten new cases per one million inhabitants per year. The 5-year survival rate for adrenocortical carcinoma is approximately 35%, whereas the 10-year survival rate of malignant pheochromocytoma reaches 40%. Clinical studies support repeated surgery as the mainstay of treatment, either with curative or palliative intention. For adrenocortical carcinoma, adjunctive treatment with oral mitotane leads to well-documented improvement of survival. Rare malignant pheochromocytomas with distant metastases are preferably treated by 131I-MIBG. Chemotherapy is reserved for unresectable tumors without sufficient response to mitotane or 131I-MIBG, respectively. Cisplatin and etoposide as single therapy, or in combination with doxorubicine or etoposide, appear to be effective in adrenocortical carcinoma. Malignant pheochromocytoma may be treated with vincristine, dacarbazine, and cyclophosphamide. Treatment with octreotide is currently being evaluated. Radiotherapy is indicated if unresectable tumor masses cause local symptoms. If symptoms of endocrine activity are not sufficiently controlled by measures aiming at tumor mass reduction, specific inhibitors of hormone synthesis or action are available. Ketoconazole is widely used for adrenocortical carcinoma, and phenoxybenzamine and metyrosine are available for malignant pheochromocytoma. This review provides guidelines for rational disease management based on still scanty clinical evidence.

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.

Differential loss of heterozygosity in familial, sporadic, and uremic hyperparathyroidism

Abstract Various genetic loci harboring oncogenes, tumor suppressor genes, and genes for calcium receptors have been implicated in the development of parathyroid tumors. We have carried out loss of heterozygosity (LOH) studies in chromosomes 1p, 1q, 3q, 6q, 11q, 13q, 15q, and X in a total of 89 benign parathyroid tumors. Of these, 28 were sporadic parathyroid adenomas from patients with no family history of the disease, 41 were secondary parathyroid tumors, 5 were from patients with a history of previous irradiation to the neck, 12 were from patients with a family history of hyperparathyroidism, and 3 were parathyroid tumors related to multiple endocrine neoplasia type 1 (MEN1). In addition, we determined the chromosomal localization of a second putative calcium-sensing receptor, CaS, for inclusion in the LOH studies. Based on analysis of somatic cell hybrids and fluorescent in situ hybridization to metaphase chromsomes, the gene for CaS was mapped to chromosomal region 2q21-q22. The following results were obtained from the LOH studies: (1) out of the 24 tumors that showed LOH, only 4 had more than one chromosomal region involved, (2) in the tumours from uremic patients, LOH of chromosome 3q was detected in a subset of the tumors, (3) LOH of the MEN1 region at 11q13 was the most common abnormality found in both MEN1-related and sporadic parathyroid tumours but was not a feature of the other forms of parathyroid tumors, (4) LOH in 1p and 6q was not as frequent as previously reported, and (5) tumor suppressor genes in 1q and X might have played a role, particularly on the X chromosome, in the case of familial parathyroid adenomas. We therefore conclude that the tumorigenesis of familial, sporadic, and uremic hyperparathyroidism involves different genetic triggers in a non-progressive pattern.

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.