Nelson Wohllk

Recommendations of the Latin American Thyroid Society on diagnosis and management of differentiated thyroid cancer.

The aims of these recommendations were to develop clinical guidelines for evaluation and management of patients with differentiated thyroid cancer applicable to Latin American countries. The panel was composed by 13 members of the Latin American Thyroid Society (LATS) involved with research and management of thyroid cancer from different medical centers in Latin America. The recommendations were produced on the basis of the expert opinion of the panel with use of principles of Evidence-Based Medicine. Following a group meeting, a first draft based on evidences and the expert opinions of the panel was elaborated and, later, circulated among panel members, for further revision. After, this document was submitted to the LATS members, for commentaries and considerations, and, finally, revised and refined by the authors. The final recommendations presented in this paper represent the state of the art on management of differentiated thyroid cancer applied to all Latin American countries.

Risk Profiles and Penetrance Estimations in Multiple Endocrine Neoplasia Type 2A Caused by Germline RET Mutations Located in Exon 10

Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical‐risk profiles. Presentation, age‐dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4–86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon‐associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609→620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected. Hum Mutat 31:1–8, 2010.

Multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant cancer syndrome with major components of medullary thyroid carcinoma (MTC), pheochromocytoma and hyperparathyroidism. The disease is caused by germline mutations of the RET proto-oncogene. Subtypes of MEN 2 include MEN 2A, MEN 2B and familial MTC (FMTC) which differ in pattern of additional lesions or--in FMTC--lack of pheochromocytoma. In 2009, after extensive review of the literature, the guidelines of the American Thyroid Association made several recommendations regarding clinical and genetic diagnostic testing and treatment options. In this article, the recently published literature is reviewed and concerns regarding future perspectives are added. In particular, a critical handling of rare DNA variants and double mutations is necessary. Up to now, mutation-specific risk profiles and mutation-associated treatment recommendations are unavailable. We emphasise the need for approved centres for treatment of patients affected by MEN 2, not only adults but young children as well. As a high level of skill is required for endoscopic adrenal-sparing surgery, surgeons should declare their expertise before operating such patients. Registry-based follow-up should be mandatory including documentation of short- and long-term outcome in order to provide valid data for future counselling of patients with MEN 2.

Head and neck paragangliomas: clinical and molecular genetic classification

Head and neck paragangliomas are tumors arising from specialized neural crest cells. Prominent locations are the carotid body along with the vagal, jugular, and tympanic glomus. Head and neck paragangliomas are slowly growing tumors, with some carotid body tumors being reported to exist for many years as a painless lateral mass on the neck. Symptoms depend on the specific locations. In contrast to paraganglial tumors of the adrenals, abdomen and thorax, head and neck paragangliomas seldom release catecholamines and are hence rarely vasoactive. Petrous bone, jugular, and tympanic head and neck paragangliomas may cause hearing loss. The internationally accepted clinical classifications for carotid body tumors are based on the Shamblin Class I–III stages, which correspond to postoperative permanent side effects. For petrous-bone paragangliomas in the head and neck, the Fisch classification is used. Regarding the molecular genetics, head and neck paragangliomas have been associated with nine susceptibility genes: NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2 (SDH5), and TMEM127. Hereditary HNPs are mostly caused by mutations of the SDHD gene, but SDHB and SDHC mutations are not uncommon in such patients. Head and neck paragangliomas are rarely associated with mutations of VHL, RET, or NF1. The research on SDHA, SDHAF2 and TMEM127 is ongoing. Multiple head and neck paragangliomas are common in patients with SDHD mutations, while malignant head and neck paraganglioma is mostly seen in patients with SDHB mutations. The treatment of choice is surgical resection. Good postoperative results can be expected in carotid body tumors of Shamblin Class I and II, whereas operations on other carotid body tumors and other head and neck paragangliomas frequently result in deficits of the cranial nerves adjacent to the tumors. Slow growth and the tendency of hereditary head and neck paragangliomas to be multifocal may justify less aggressive treatment strategies.

Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation.

RET testing in multiple endocrine neoplasia type 2 for molecular diagnosis is the paradigm for the practice of clinical cancer genetics. However, precise data for distinct mutation-based risk profiles are not available. Here, we survey the clinical profile for one specific genotype as a model, TGC to TGG in codon 634 (C634W). By international efforts, we ascertained all available carriers of the RET C634W mutation. Age at diagnosis, penetrance, and clinical complications were analyzed for medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT), as well as overall survival. Our series comprises 92 carriers from 20 unrelated families worldwide. Sixty-eight subjects had MTC diagnosed at age 3-72 years (mean 29). Lymph node metastases were observed in 16 subjects aged 20-72 and distant metastases in 4 subjects aged 28-69. Forty-one subjects had pheochromocytoma detected at age 18-67 (mean 36). Amongst the 28 subjects with MTC and pheochromocytoma, six developed pheochromocytoma before MTC. Six subjects had HPT diagnosed at age 26-52 (mean 39). Eighteen subjects died; of the 16 with known causes of death, 8 died of pheochromocytoma and 4 of MTC. Penetrance for MTC is 52% by age 30 and 83% by age 50, for pheochromocytoma penetrance is 20% by age 30 and 67% by age 50, and for HPT penetrance is 3% by age 30 and 21% by age 50. These data provide, for the first time, RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling.

Latin American Thyroid Society recommendations for the management of thyroid nodules

Several guidelines on diagnosis and treatment of thyroid nodules and cancer have recently been published. However, recommended practices are not always appropriate to different settings or countries. The aim of this consensus was to develop Clinical Guidelines for evaluation and management of patients with thyroid nodules applicable to Latin American countries. The panel was composed by 13 members of the Latin American Thyroid Society involved with research and management of thyroid nodules and cancer from different medical centers in Latin America. The consensus was produced based on the expert opinion of the panel with use of principles of evidence-based medicine. Following a group meeting, a first draft based on the expert opinion of the panel was elaborated and later circulated among panel members for further revision. After revision, this document was submitted to all LATS members for commentaries and considerations and finally revised and refined by the authors. The final recommendations represent state of the art on management of thyroid nodules applied to all Latin American countries.

MELANOTIC NONPSAMMOMATOUS TRIGEMINAL SCHWANNOMA AS THE FIRST MANIFESTATION OF CARNEY COMPLEX: CASE REPORT

OBJECTIVEMelanotic schwannoma is a rare neoplasm, classifiable as a peripheral nerve sheath tumor, and differentiated from a typical schwannoma by heavy pigmentation. Psammoma bodies can be visualized in more than 50% of melanotic schwannomas. Half of patients with such “psammomatous melanotic schwannomas” have Carney complex, a dominantly transmitted autosomal disorder. Most recently, the tumor suppressor gene, PRKAR1A, coding for the Type 1α regulatory subunit of protein kinase A was found to be mutated in approximately half of the known Carney complex families. Although cranial schwannomas have been described in patients with Carney complex, their numbers are too small to be considered a definite part of the syndrome. Furthermore, only melanotic schwannomas with psammoma bodies are included as diagnostic criteria for Carney complex. The objective of this report is to communicate a case of trigeminal nonpsammomatous melanotic schwannoma as the first manifestation of Carney complex. CLINICAL PRESENTATIONA 34-year-old woman presented with odontalgia, right V3 hypoesthesia, V2 paresthesia, and diplopia. Magnetic resonance imaging scans of the brain revealed a small tumor with homogenous contrast in the right trigeminal pathway. INTERVENTIONWe performed an extradural approach to the right cavernous sinus by a middle fossa approach. The lateral wall was opened between the cranial nerves, and a soft and black tumor was resected in a piecemeal fashion. Histology and immunohistochemical analysis of the tumor were compatible with melanotic schwannoma, but no psammomatous bodies were identified. Endocrine evaluation showed that this patients symptoms fulfilled the diagnostic criteria of Carney complex, with lentiginosis, multiple breast ductal adenomas, multiple hypoechoic nodules on thyroid ultrasonography, and a 4 × 5-cm asymptomatic atrial cardiac myxoma, which was removed 15 days after the neurosurgery. Three months later, a recurrence of melanotic schwannoma was identified. Molecular analyses of genomic and somatic deoxyribonucleic acid from the patient found a 578 to 579delTG mutation of PRKAR1A. CONCLUSIONWe present the unusual case of a nonpsammomatous trigeminal melanotic schwannoma associated with Carney complex, with confirmed PRKAR1A gene mutation. Our case highlights that neurosurgeons, in the presence of a melanotic schwannoma, should be aware of the features of the Carney complex because, in such cases, pre- and postoperative management is significantly affected. We also postulate that the absence of psammoma bodies or cranial localization do not exclude this diagnosis.

Multiple endocrine neoplasia: the Chilean experience

Multiple endocrine neoplasia (MEN) types 1 and 2 are genetic diseases that are inherited as autosomal traits. The major clinical manifestations of multiple endocrine neoplasia type 1 include the so-called “3 Ps”: parathyroid, pituitary, and pancreatic tumors, including gastroenteroneuroendocrine tumors. Genetic testing can be performed on patients and the potential carriers of the menin gene mutation, but the genotype-phenotype correlation in multiple endocrine neoplasia type 1 is less straightforward than multiple endocrine neoplasia type 2. Most likely, the main advantage of genetic testing in MEN1 is to exclude from further studies those who are negative for the genetic mutation if they belong to a family with a known history of MEN1. In Chile, we started with rearranged during transfection proto-oncogene genetic testing (MEN2) 15 years ago. We carried out a prophylactic total thyroidectomy to prevent medullary thyroid carcinoma in a three-year-old girl who presented with microscopic medullary thyroid carcinoma. More than 90% of the individuals who tested positive using a genetic test achieved a biochemical cure compared with only 27% of patients who receive a clinical diagnosis. Mutations are mainly located in exon 11; the most common is C634W, rather than C634R. Hypertensive crisis was the cause of death in three patients, and extensive distant metastases occurred in nine (including two patients with multiple endocrine neoplasia type 2B) of 14 patients. Earlier recognition of medullary thyroid carcinoma and the other features of the disease, especially pheochromocytoma, will improve the survival rate of patients with multiple endocrine neoplasia.

Utilidad de la detección de tiroglobulina en el aspirado de punción ganglionar cervical en el seguimiento de pacientes con cancer papilar de tiroides

Background: During the detection of neck recurrence in patients with Papillary Thyroid Carcinoma (PTC), sometimes it is difficult to distinguish metastatic from inflammatory neck lymph nodes. The measurement of serum thyroglobulin (sTg) under thyroid hormone suppression therapy, the presence of serum thyroglobulin antibodies (sAbTg), the diagnostic whole body scan and cytology can give false negative results. Measurement of thyroglobulin in the washout fluid from fine-needle aspiration biopsy (FNAB) of suspicious neck lymph nodes could improve the diagnostic accuracy. Aim: To evaluate the usefulness of detecting Tg in lymph nodes (LTg) suspicious by ultrasonography (US) and compare it to cytology. Patients and Methods: Between the years 2004 and 2007 we prospectively studied 30 patients with PTC and cervical US findings of suspicious recurrence. LTg was assayed in US guided FNAB used for cytology. Results: Sixteen out of 30 patients underwent surgery using as selective criteria an LTg higher than sTg or a positive cytology. Surgery confirmed the presence of metastasis in all 15 patients with positive LTg (8 with positive cytology) and in 1 patient with negative LTg and positive cytology (a case with undifferentiated thyroid cancer). The sensitivity was 93.7% for LTg and 56.2% for cytology. We identified by LTg 3 of 6 patients with undetectable sTg and positive sAbTg. Conclusions: The presence of LTg showed a higher sensitivity than cytology for the detection of cervical lymph node metastasis. This method is useful even in the presence of sAbTg (Rev Med Chile 2008; 136: 1107-12). (Key words: Biopsy, fine-needle; Neoplasm metastasis; Thyroid neoplasms)

Preventive medicine for von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.