Surgical therapy of rncdullary thyroid carcinoma

GIOVANNI STURNIOLO, LORETTA BONANNO, ETTORE GAGLIANO, AGATA TONANTE, FILIPPO TARANTO, MARCELLO MAMO, GIOVANNI D E SALVO, GIACOMO STURNIOLO3

Chair of General Surgery - Department of General and Specialist Surgical Disciplines - University of Messina - General Endocrine Surgical Unit ' Department of Clinical and Experimental Medicine and Pharmacology, Endocrinology Section - University of Messina

Correspondence to: Dr. Ettore Gagliano - Via Siligato 8 / C - 98124 Messina

Riassunto Gli Autori riportano i risultati di uno studio retrospettivo su 57 casi di carcinoma mi­dollare della tiroide (CMT), osservati nei maggiori Centri siciliani, di cui 6 di osser­vazione personale. Dopo avere effettuato una revisione della letteratura riguardo alle forme sporadi­che di CMT e alle sindromi cancerose ereditarie, viene presentata la propria casi­st ica, sottol ineando i protocoll i diagnostici adottat i , la terapia chirurgica e gli aspetti anatomopatologici. In particolare gli Autori si soffermano sulle modalità di metastatizzazione del CMT e sulle differenti linee di pensiero riguardo all'estensione della linfadenectomia e al comportamento in caso di recidiva. Infine, viene riportato il proprio orientamento personale, che vede nella t iroidecto-mia totale extracapsulare allargata associata allo svuotamento delle stazioni linfo-ghiandolari del collo il gold standard nel trattamento di tale patologia.

Parole chiave: carcinoma midollare tiroideo, tìroidectomia totale

Summary Surgical therapy of medullary thyroid carcinoma. G. Sturniolo, L. Bonanno, E Gagliano, A Tonante, F. Taranto, M. Mamo. G. De Salvo, G. Sturniolo This study describes the findings of a retrospective study of 57 medullary thyroid cancer patients observed at the main Sicilian centres for endocrine surgery. Six of these patients were observed locally in order to add a further dimension to the dis-cussion of surgical therapies for medullary thyroid carcinoma. A review of the literature on sporadic forms of medullary thyroid carc inoma and hereditary neoplastic syndromes is fol lowed by presentation of the authors ' se-ries.

Introduction This study presents the outcomes of a r e t rospec t ive s tudy of 57 medullary thyroid cancer (MTC) pa t ien t s obse rved at the main Sicilian Centres for endocrine sur­gery. The study was based on data from 13 Sicilian hospitals with general and endocr ine surgery units (4 university and 9 hospital centres).The data were compiled from questionnaires designed by us and distributed to the surgery units of interest. Six of the 57 cases were obse rved personally. The questionnaire was returned by 13 of 28 centres contacted (46.4%). Only 5 of centres fully answered ali questions,which related to epi-demiologydiagnosis, clinical char-acteristics, therapy, pathological anatomy and therapeutic results. Data collected from the Sicilian register of thyroid tumours, insti-

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tuted in 2002 and housed at the Endoc r ino logy Depa r tmen t of Messina University, were funda-men ta l for the s u c c e s s of this study. Our own 6 cases also con-tributed to drawing conclusions regarding the efficacy of MTC ther­apy MTC is known to be a rather un-common tumour arising from thy­roid C cells, which, in addition to calcitonin (CT), sometimes also p roduce histamine, ACTH, sero-tonin and prostaglandins.lt had al-ways been considered an anaplas-tic cancer until properly defined by Hazar in 1959. Its degree of malignancy places it b e t w e e n d i f ferent ia ted a n d anaplastic tumours.accounting for 5-10% of ali thyroid cancers.lt is al-most always associated with MEN 2 (multiple endocr ine neoplas ia) syndromes as it is present in both type A and type B, which account for90-100% of these syndromes1. The sporadic form of this cancer is present in 75% of cases (not asso­c i a t ed with o the r e n d o c r i n e pathologies), while in the remain-ing 25% we observe 3 different hereditary neoplastic syndromes, known as"multiple endocrine neo­plasia type 2 "(MEN 2); these are: multiple endocrine neoplasia type 2A (MEN 2A); multiple endocrine neoplasia type 2B (MEN 2B); and familial medullary thyroid carcino­

ma (FMTC). Each hereditary syn-drome is produced by a RET proto­oncogene mutation. Ali three forms of MEN 2 have the presence of medullary thyroid can­cer in common.In the MEN 2A and MEN 2B syndromes , bes ides the medullary thyroid cancer, there is a high risk of pheochromocytoma and related pathologies such as hy-perparathyroidism (MEN 2A), dif­fuse ganglioneuromas of the gas-trointestinal tract, mucosal neuro-mas and Marfanoid habitus (MEN 2B).MEN 2A is 3 times as frequent as MEN 2B,while the isolated famil­ial carcinoma is the rarest form1. Unlike the standard biochemical teste (determination of calcitonin, serum and urinary catecholami-nes.serum calcium and parathor-mone levels) used for monitoring patients with a familial history of MEN 2 and FMTC, DNA analysis makes it possible to identify pa­tients at real risk. Furthermore, this test obviates the need to screen ali the members of a family at repeated clinical examinations2.

Patients and methods The records of 57 MTC patients, t reated at a number of Sicilian centres for endocrine surgery (in-

cluding 6 treated at Messina) over a period of 30 years were reviewed and each case of MTC was classi-fied as hereditary or sporadic. Cases were classified as sporadic if associated with an absence of RET mutation or, in those cases ob­served before the introduction of RET analysis, with no family histo­ry of MTC and with family mem­bers testing negative at pentagas-trin stimulation screening.

Clinical characteristics Of the 57 MTC patients 41 were fe-males and 16 males (M/F ratio of over 2 to l).Mean age at diagnosis was 38.4 years (range: 9-69 years). Forty-four cases (77.2%) were spo­radic and 13 (22.8%) hereditary. The hereditary MTC patients pre-sented: FMTC, as a single entity, in 2 cases (15.4%); MEN 2A in 8 cases (61.5%); and MEN 2B in 3 cases (23.1%). The diagnosis of MTC was made in 29 patients (51%) preoperativelyin 6 (10.5%) intraoperatively and in 22 (38.5%) postoperatively. In 3 pa­tients the diagnosis was made by family screening. The relatives of 2 patients tested positive for the presence of MEN 2B syndrome at DNA analysis. Two members of one family and 1 of another, ali young, aged 9,13 and 21,presented high basai CT levels. At preventive thyroidectomy ali 3 cases p r e s e n t e d e v i d e n c e of macroscopic MTC, and CT levels returned to normal postoperatively A palpable thyroid nodule was ob­served in 12 pat ients , pa lpable lymph nodes in 3 and both in 7 pa­tients. In 4 of our cases the cancer lesion was associated with diffuse

Diagnostic protocols, surgical therapies and pathological observations are dis­cusseci. Particular attention is paid to patterns of metastases of medullary thyroid carcinoma and to the differing opinions regarding the extent of lymph-node dis-section required and the treatment of recurrent disease. Total extracapsular thy­roidectomy with lymph-node dissection is identified as the gold standard of surgi­cal therapies for this form of cancer.

Key words: medullary thyroid carcinoma, total thyroidectomy

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Surgical therapy of medullary thyroid carcinoma

multinodular goiter with MTC oc-casionally apparent at postopera-tive pathological examina t ion . One of our patients, with preopera-tively diagnosed papillary thyroid carcinoma, underwent total thy­roidectomy and centrai and later-al neck dissection on the left side. Postoperative pathological exami­nation indicated the coexistence of an undifferentiated sclerotic papi l lary c a r c i n o m a and MTC within the same lobe. The pres­ence of 2 carc inomas was con-firmed by examination of 6 lymph nodes in the ipsilateral jugulo-carotid compartment: 3 presented papillary carcinoma metastases and 1 massive MTC metastasis.At 1 year of follow-up, the patient was disease-free and presented nor-mal basai CT levels even after pen-tagastrin stimulation. Another patient, presenting a volu-minous palpable and visible neck mass associated with dysphonia and dysphagia , was d iagnosed preoperatively as having an undif­ferentiated papillary carcinoma. Histological examination revealed this to be a sporadic MTC, which had infiltrated the trachea with metastatic involvement of the cen­trai and ipsilateral jugulocarotid compartments. Postoperative per-sistence of high CT levels was due to hepatic metastases. Of our 13 hereditary MTC cases, 8 were diagnosed following total thyroidectomy and prompted us to screen family members, identi-fying a further 3 cases in apparent-ly healthy individuals who,as men-tioned before.displayed increased CT levels following pentagastrin stimulation. High basai or post-pentagastrin stimulation CT levels were found in ali patients with pre­operatively or postoperatively di­agnosed MTC.

Surgical therapy Total thyroidectomy (TT) a lone was performed in 24 of 44 patients with sporadic MTC.TT plus centrai neck dissection was performed in 9 cases. TT plus centrai neck dis­section plus jugulocarotid dissec­tion was performed in 15 patients (in a single operation in 4 cases; in 2 in the o t h e r l l ) . Total thyroidectomy plus centrai neck dissection extended to the upper mediastinum and thymus plus lateral neck dissection were performed in 2 procedures on 3 patients treated in our surgical unit. Another of our patients, with ad-vanced stage carcinoma, was treat­ed by palliative extended TT, with ipsilateral and centrai neck dissec­tion. Resection of the left recurrent laryngeal nerve and shaving of the tumour off the t rachea were re-quired b e c a u s e of widespread lymph-node metastases. Four cases diagnosed preopera­tively by isthmus lobectomy un­derwent TT plus centrai and ipsi­lateral jugulocarotid dissection (2 cases) and bilateral dissection (2 cases) some days after diagnosis. Only a few surgeons identified parathyroid glands (6 out of 13) intraoperatively and only 4 centres (including ours) performed an au-totransplantation of parathyroid glands removed accidentally or in-tentionally. Routine laryngoscopy was per­formed preopera t ive ly in only 7/13 and postoperatively in only 3/13 centres. Laryngoscopy was performed without exception in ali patients with laryngeal nerve palsy Serum calcium, phosphorous and PTH were determined in ali pa­t ien ts . Transient hypopara thy-

roidism was observed in 15% and definitive hypoparathyroidism in 5% of cases. Definitive laryngeal nerve palsy was observed in 7 pa­tients and transient palsy in 5; la­ryngeal nerve resection was inten-tional in 2 cases, 1 of which was ours. In ali centres, laryngeal nerve palsy and hypopara thyroid ism were considered definitive when they persisted for a period of 6 months to 1 year after surgery. Diagnosis of MTC was confirmed by positive CT immunostaining and carcino-embryonic antigen tests in only 60% of patients. In al-most ali patients, assessment of the completeness of surgical resec­tion was determined by basai CT measurements between 2 weeks and 3 m o n t h s after surgery. In some patients, when basai CT was undetectable, a pentagastrin stim­ulation test was performed. In 5 of our cases analysis of RET proto­o n c o g e n e m u t a t i o n s was per­formed by means of a direct auto-matic sequent ia l test. Our sixth case is stili under study. The opin­ion of centres as regards follow-up was unanimous: they ali consid­ered familial and sporadic MTC to be different forms of the disease. Familial MTC pat ients were as-sessed every 4-6 months by clini-cai examination and determina-tion of basai and post-stimulation CT, total and ionised serum calci­um, phosphorous , phosphaturia and urinary catecholamines and catabolites. Patients with persistent or recur­rent hypercalcitoninaemia at fol­low-up and with no evidence of neck recurrence underwent fur­ther assessment by computed to-mography or MR imaging of the neck , ches t and a b d o m e n , posi t ron emission tomography (PET) and thyroid scintigraphy

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with I131 MIBC (only for patients susceptible to metabol ic radio-therapy). Sporadic MTC patients underwent r o u t i n e e x a m i n a t i o n s every 6 months and those with persistent or residuai hypercalcitoninaemia underwen t a diagnost ic proce­dure like the sporadic MTC pa­tients.

Pathological diagnosis None of our 5 cases (1 is stili un­der study) presented RET proto­o n c o g e n e muta t ions ; ali were therefore classified as non-MEN sporadic MTCs. Tumour location was specified only by certain cen­tres and was, for the most part, in the centrai upper portion of the thyroid lobe, where thyroid C cells are known to be located. Tumours were bilateral and multi-focal in almost ali cases of heredi­tary MTC (92%) and only in 30% of sporadic cases. Monolateral multi­p le thyroid t u m o u r s were ob­served in 8% of hereditary MTC c a s e s . Regiona l l y m p h - n o d e metastases were observed in both sporadic and hereditary MTC. In MEN syndromes, distant metas­tases are identified early (26% of c a s e s ) and in bo th MEN syn­dromes the centrai compartment is affected first and generally be-fore the jugulocarotid compart­ment. Only 3 patients, 1 observed by us, presented involvement of the ipsilateral compartment, with-out involvement of the centrai compar tmen t . One patient pre­sented involvement of the centrai and contralateral compartments. No re la t ionship was found be-tween tumour size and lymph-node involvement. Lymph-node metastases were found in tumours

measuring less than 1 cm, in 57 % of sporadic and in 28% of heredi­tary cases of MTC. Contralateral (as well as centrai and ipsilateral) involvement was obse rved even in s p o r a d i c tu­mours measuring less than 1 cm. At diagnosis, in addition to region­al m e t a s t a s e s ( l imi ted to the neck), 4 patients (ali with heredi­tary MTC) p r e s e n t e d d i s t an t m e t a s t a s e s (in the liver a n d lungs): obviouslyin these patients, the CT level remained high even after the operation (> 10 000 pg/1). Around 50% of patients presented undetectable CT levels after the operation and ali tested negative at pentagastrin stimulation.

Discussion We were able to draw a number of conclusions from our analysis of the histories of 47 MTC patients, 6 of whom were treated locally Firstly MTC is an uncommon thy­roid tumour, accounting for only 2% of ali thyroid tumours, and is more frequent in females than in m a l e s with a rat io of 2 to 1. Sporadic MTC is more frequent than hereditary MTC and MEN 2A is 3 times as frequent as MEN 2B3. Diagnosis of MTC, once based on increased basai CT levels follow­ing pentagastrin stimulation (the method used to identify family members at risk of developing the disease),is today confirmed by ge-netic screening for MEN4. Genetic screening starts at birth and is in-creasingly employed in paediatric d e p a r t m e n t s , w h e r e it is per­formed on ali members of MEN-positive families5. We observed there was a broad consensus among doctors as re-gards diagnostic protocols, thera-

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peutic techniques and timing, pro-phylaxis and postoperative follow-up of MTC patients, and early in-tervention is unanimously held to be the key to a positive prognosis6. Total thyroidectomy is considered to be the standard cure for MTC and its efficacy is deemed to be enhanced when it is performed prophylactically7. Opinions as to the usefulness of lymph node dissection, however, vary considerably8. In line with re-ports from the literature, in a ma­jority of cases both sporadic and hereditary MTC patients (except-ing those diagnosed by genetic s c r een ing ) p resen t a pa lpab le neck mass at diagnosis (82% of our cases)9. Furthermore, almost 60% of patients also present palpable metastatic lymph nodes10.The inci-dence of metastases in these pa­tients at the time of diagnosis is re-ported in two different studies: one by the G. Roussy Institute in Paris (55% metastatic patients), the oth-er by the Endocrine Surgery and Oncology Department of St Louis in the USA (over 63% metastatic patients)11. The centrai compar tment is the first lymph-node compartment to harbour metastases and in most patients this, along with the me-diastinal compartments, is affect­ed bilaterally1 2 . Consequent ly , many authors are persuaded that the surgical therapy of sporadic and heredi tary MTC should be similar11. In most patients with metastases in the jugulocarot id chain , the metastases are located in the up­per third of this chain, where the C cells reside, and into which the lymphatic vessels of the uppe r third of the lobe drain. This is al­most invariably the primary site of MTC,although the supraclavicular

Surgical therapy of medullary thyroid carcinoma

compartment and posterior trian-gle are sometimes involved13. The adjacent structures most com-monly affected by advanced MTC are the trachea, the recurrent la­ryngeal nerve, the iugular veins and the carotid arteries, while dis­tant metastases are observed in the liver,lungs,and bone.mainly in the MEN 2 syndromes14. In our series, we noticed that both sporadic and hereditary MTC pa­tients with tumours measur ing less than 1 cm p resen ted con­t ra la te ra l m e t a s t a s e s w i thou t metastasis in the centrai compart­ment. The literature reports cases with distant metastases, but with­out regional metas tases 1 5 . The presence of micrometastases, on the other hand, is the cause of per-sistently high CT levels even after TT and regional neck dissection. Consequently as many authors be-lieve,a similar surgical approach is appropriate for both sporadic and hereditary patients, whatever the site and size of the tumour. The high incidence of metastases in different lymph-node compart­ments, often with no pathological rationale, confirms the expedien-cy of centrai and bilateral dissec­tion regardless of t u m o u r size while contralateral neck dissec­tion may be avoided in the rare patients with unilateral tumours and no contralateral involvement. Most authors suggest prophylactic TT only be performed in MEN 2 syndromes because of the early metastatic spread that characteris-es this type. A c c o r d i n g to the g u i d e l i n e s of the Soc ie ty of Surgical Oncology an ipsilateral neck dissection is advocated only in sporadic MTC with palpable lat-eral neck lymph nodes or for pa­tients with centrai compartment involvement7.

The Nat ional C o m p r e h e n s i v e Cancer Network guidelines rec-ommend ipsilateral neck dissec­tion only for sporadic MTCs meas­uring more than 1 cm in size; bilat­eral neck dissection is advocated for patients with bilateral neopla­sia; for the patients with a sporadic MTC measuring less than 1 cm in size, centrai neck dissection alone is advocated16. German guidelines recommend bilateral neck dissec­tion for hereditary MTC and ipsi­lateral neck dissection for spo­radic forms17. In fact, data are few and most sur-geons do not perform lymph-node neck dissection because of the dif-ficulties it presents and the risk of complications it entails. It is there-fore impossible to r ecommend any standard surgical treatment. In MEN 2 syndrome several authors do not per form p r o p h y l a c t i c lymph-node neck d issec t ion in children because of the high relat-ed risk of hypoparathyroidism and d y s p h o n i a ; c h i l d h o o d hy­poparathyroidism is known to be difficult to manage18.Hypoparathy-roidism following TT and lymph-node neck dissection is a serious condition even in adults and the in-traoperative treatment of parathy­roid glands is a matter of some con-troversy Other authors perform parathy-roidectomy and autotransplanta-tion.We would tend to agree with those authors who recommend that total extended thyroidectomy with centrai compar tment neck dissection be performed in con-junction with parathyroidectomy and parathyroid autotransplanta-tion in order to achieve surgical radicalisation. Following ablation, the glands are sliced into 1 x 3 mm fragments and preserved in cold saline solution19.

In patients with MEN 2A, who may develop parathyroid a d e n o m a s and hyperparathyroidism, auto-transplantation is performed in the muscle of the forearm to allow easier removal. In patients with sporadic MTC and MEN 2B it is pe r fo rmed on the s tern-ocleiodomastoid muscle. In t raopera t ive a s s e s s m e n t of nodal status and extent by palpa-tion and inspection proved an un-reliable means of establishing the expediency or otherwise of pro-ceeding with lymph-node dissec­tion since intraoperative palpation of nodes is not an accurate predic-tor of the presence or absence of metas tases , as a specific study demonstrated. In this study an "experienced sur-geon"was able to assess nodal sta­tus with only 64% sensitivity and 71% specificity; reliance on intra­operative assessment alone, there-fore, would cause affected nodes to b e ove r looked 20% of the time20. More than 50% of patients with sporadic or hereditary MTC develop persistent or recurrent disease after primary surgical re­section; this is evident from the reappearance of a palpable and visible neck mass, high postopera­tive calcitonin levels or the results of pentagastrin stimulation tests. Pat ients , with high CT levels , should undergo a postoperative metastatic work-up to rule out the presence of distant metastases or to confirm the need for prompt re-peat surgery21. Although ultrasonographycompu-terd tomography, magnetic reso-nance and positron emission to­mography imaging are useful for initial patient evaluation, a specif­ic study has shown the limitations of imaging t echn iques . Almost 93% of liver metastases were iden-

(OD

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tified by laparoscopy or laparo-tomy22. Once recurrence of disease in the neck has been confirmed and no distant metastases have been iden-tified, repeat neck surgery should p r o c e e d promptly. A tho rough search for parathyroid glands must be ca r r i ed out and no n o d e s s h o u l d b e r emoved unti l the parathyroid glands are identified. Currently there is no chemothera-py protocol capable of effectively treating recurrent MTC.

These tumours do not respond to radioiodine treatment and there is a high i n c i d e n c e of compl ica-tions.such as radiation-induced fi-brosis of the neck23. It was not possible to draw conclu-s ions abou t long-term survival through lack of data, although the literature confirms that survival rates for both forms of MTC are similar. Eighty-five p e r c e n t of patients without metastases sur-vive for 5 years following treat­ment, while the survival rate for pa­

tients with distant metastases is 55%24. In conclusion.we can confirm that early, radicai thyroidectomy re-mains the gold standard of treat­ment for MTC patients. Extended TT and lymph-node neck dissec­tion ensure a good prognosis, es-pecially for the forms of limited extent. Finally the surgical man­agement of MTC always requires an adequate understanding of tu­mour biology and appropriate sur­gical expertise.

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