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Nuclear Medicine (C.S., E.B., S.L., M.S.), Surgery (J.-P.T.), Biostatistics and Epidemiology (N.B.), and Pathology (B.C.), Institut Gustave-Roussy, 94805 Villejuif cedex, France
Address all correspondence and requests for reprints to: Dr. Martin Schlumberger, Service de Médecine Nucléaire et de Cancérologie Endocrinienne, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France. E-mail: schlumbg{at}igr.fr.
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Abstract |
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In conclusion: 1) lymph node metastases occur early in the course of MTC; 2) the pattern of lymph node metastatic distribution in neck areas varied between patients and was not related to the thyroid tumor size; 3) contralateral lymph node metastases were observed even in patients with small thyroid tumor; 4) total thyroidectomy with central and complete bilateral neck dissection should be performed routinely in all patients with sporadic and hereditary MTC, even in those with small thyroid tumors—a contralateral neck dissection may be avoided only in sporadic MTC patients with unilateral involvement of the thyroid gland in the absence of central and ipsilateral neck involvement; and 5) the number of lymph node metastases was predictive of biological cure after surgery.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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MTC readily invades the intraglandular lymphatics and the regional lymph nodes. Distant metastases to the lungs, bones, and liver occur early during the course of the disease. The hereditary form is characterized by an early onset of multifocal and bilateral C cell disease and can be treated at an early stage. The sporadic form often presents clinically as a palpable thyroid tumor, with palpable neck lymph nodes in 30–60% of cases (1, 2, 3). At histology, lymph node involvement is found in more than 80% of cases. Lymph node involvement is present in 10–30% of tumors smaller than 1 cm (4, 5, 6) and is more frequently found in patients with larger tumors. Furthermore, contralateral lymph node metastases were found at histology in 44% of patients with an unilateral palpable MTC, and in 25% of patients with a tumor less than 1 cm (6).
Surgery is the only curative treatment for MTC and should remove all neoplastic foci present in the neck with an acceptable morbidity (7, 8, 9). After surgery, persisting elevated CT levels are found in more than half of MTC patients who present with clinical disease. Also, high recurrence rates have been reported in neck lymph nodes (3, 9, 10, 11). Meticulous lymph node dissection has been reported to result in a higher biochemical cure rate (6, 12). Further surgery eventually based on venous sampling catheterization with CT measurements permits CT normalization in only 8–35% of cases (9, 10, 11, 13). This may decrease the risk of neck recurrence, but benefits on long-term survival are still not demonstrated. Several studies have suggested that recurrence and survival rates depend upon the adequacy of initial surgery (7, 9, 13). These data underline the need for a well-defined protocol for initial surgery.
Total thyroidectomy and central neck dissection is recommended for all MTC patients, but the indication for lateral neck dissection is still controversial. According to the guidelines of the Society of Surgical Oncology (14, 15), an ipsilateral neck dissection is advocated only in sporadic MTC with palpable lateral neck lymph nodes or in patients with involvement of the central neck compartment. According to National Comprehensive Cancer Network guidelines, an ipsilateral modified radical neck dissection is advocated only for sporadic MTC more than 1 cm in size and contralateral dissection is to be considered in patients with bilateral thyroid disease; in patients with a sporadic MTC less than 1 cm in size, a central neck dissection only is advocated (16). According to German guidelines (9, 17), routine bilateral neck dissection is recommended for hereditary MTC and ipsilateral neck dissection for sporadic forms, with contralateral dissection only when the ipsilateral lymph nodes are involved. Other surgeons advocate routine bilateral neck dissection, even in sporadic forms, with unilateral palpable tumors (6, 12, 18). Thus, there is considerable confusion regarding standard surgical treatment of MTC. This is mainly related to the scarcity of available data, due to the fact that a complete bilateral and central neck dissection has seldom been performed. A better knowledge of the natural history of lymph node involvement may help to delineate the indication of lateral neck dissection. Furthermore, the incidence of complications related to neck dissection, including hypoparathyroidism, recurrent laryngeal nerve palsy, injury of the trachea or esophagus, has not been routinely evaluated.
In the present retrospective study, we assessed lymph node involvement in 101 MTC patients who underwent total thyroidectomy and central and bilateral neck dissection at Institut Gustave-Roussy (IGR), to identify the frequency and the pattern of cervical lymph node involvement, and to evaluate complication risks and therapeutic results.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Records of the 465 MTC patients treated and/or followed at IGR from 1964–2001 were reviewed. Among them, 220 patients underwent at least one surgical procedure at IGR. Of these 220 patients, 119 were excluded: 99 underwent surgery for recurrent or persistent MTC after inadequate primary surgery at another medical center, 18 underwent total thyroidectomy with only central neck dissection, including patients with rearranged during transfection (RET) germline mutation with no evidence of C cell disease who were operated at a young age, and 2 patients with a microcarcinoma underwent a total thyroidectomy with no lymph node dissection. The remaining 101 consecutive patients underwent a total thyroidectomy and central and bilateral neck dissection and form the basis of this report.
MTC was classified as hereditary or sporadic. Sporadic MTC was defined by the absence of RET mutation, or before the introduction of RET analysis, by a negative familial history of MTC and by a negative familial screening with pentagastrin stimulation test. The diagnosis of hereditary MTC was assessed by the finding of a RET proto-oncogene mutation in 46 of 47 patients (19, 20) and by a positive familial history of MTC in the remaining patient who was screened before the availability of RET analysis.
Surgical treatment
Total thyroidectomy and central and bilateral lymph node dissection were performed during the first surgical procedure in 69 patients and after a median period of 8 months after the total thyroidectomy in the other 32 patients.
The surgical procedure was performed with a curative intent for all sporadic MTC patients. Preoperative diagnosis of MTC was performed in 45 of 47 hereditary MTC patients for elevated preoperative basal CT levels in 41 and only elevated pentagastrin stimulated CT levels in 4 patients; thyroid nodules were detected by palpation in 23 and by ultrasonography in 30. In the remaining 2 hereditary MTC patients who had no preoperative CT determination, the MTC was diagnosed intraoperatively.
The central neck dissection consisted in the removal of all soft tissue containing lymph nodes from the hyoid bone superiorly, to the innominate vessels inferiorly, and the jugular veins laterally (level VI). In 12% of patients with a macroscopic central node involvement an upper mediastinal dissection was performed by the cervical incision in 10 and by sternotomy in 2. Two patients with apparent surgical invasion of the trachea were treated by shaving the tumor off the trachea; and resection of an invaded recurrent laryngeal nerve was performed in another patient.
In patients with a clinical thyroid tumor, a bilateral dissection of the jugulocarotid chains including the removal of the nodes around the spinal accessory nerve was performed (levels III, IV, and Va as described for modified radical neck dissection; Ref. 12). In hereditary MTC patients with no detectable thyroid tumor and before 1980 in sporadic MTC patients, a dissection of only the lower two thirds of the jugular chains was performed; in these patients, the dissection was extended to the upper third of the jugulocarotid chain when frozen section revealed metastatic involvement of the lower two thirds, or when palpable lymph nodes were present. The lateral neck dissection preserved the internal jugular vein, the sternocleidomastoid muscle and the spinal accessory nerve.
Parathyroid glands were identified and this was simplified with methylene blue staining. If a parathyroid gland was removed, a frozen section analysis confirmed that it was indeed parathyroid tissue and not a metastatic lymph node. The parathyroid gland was then sliced into few mm3 pieces and auto-transplanted into individual pockets in the sternocleidomastoid muscle, or in a muscle of the nondominant forearm.
These treatment procedures were performed according to the ethical rules of our institution.
Surgical complications
Laryngeal examination was performed in the postoperative period and thereafter regularly if a laryngeal nerve palsy was observed; serum calcium, phosphorus and PTH 1–84 were periodically measured until normalization. Laryngeal nerve palsy and hypoparathyroidism were considered definitive when persisting for more than 1 yr after surgery.
Pathological diagnosis
The diagnosis of MTC was confirmed by a positive immunostaining for CT and carcino-embryonic antigen in all patients. The characteristics of the tumor, including the location (upper, central-upper, or lower part of the thyroid lobe), the size, uni- or multifocality, uni- or bilaterality were assessed by an experienced pathologist (B.C.). Two millimeter sections of each lymph node without apparent metastases were routinely performed. In case of macroscopic metastases, fewer sections were performed. In case of doubtful diagnosis of micrometastases, CT and carcino-embryonic antigen immunostaining was performed on the lymph node sections. No attempt was made to categorize central lymph nodes as right or left because this compartment was removed en bloc. The latero-cervical lymph nodes were categorized as right or left. In cases of bilateral thyroid involvement, the contralateral lymph nodes were defined as contralateral to the largest tumor.
Therapeutic results
Between 6 wk and 3 months after surgery, assessment of the completeness of surgical resection included determination of basal CT (using a polyclonal antibody RIA before 1986 and since 1986 using the ELSA-CT, CIS-Bio International, Gif-sur-Yvette, France; normal < 10 pg/ml). When the basal CT was undetectable, a pentagastrin stimulation test was performed (slow iv injection of 0.5 µg/kg pentagastrin-Peptavlon, and peak CT measured at 2 and 5 min).
Statistics
Data are described as mean ± SD. An ANOVA was used to compare percentages of lymph node metastases in the central, ipsilateral, and contralateral compartments and in patients with either sporadic or hereditary MTC. Associations between lymph node involvement and tumor size were tested using 
2 test. 2 test was also used to evaluate the relationship between normalization of postoperative CT levels and the number of involved lymph node. P < 0.05 was considered significant.
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Results |
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The clinical characteristics of the 101 patients are reported in Table 1
. They were 41 males and 60 females. MTC was sporadic in 54 patients and hereditary in 47, being part of a MEN 2A syndrome in 23, of a MEN 2B in 10, and being an FMTC in 14. The mean age at diagnosis was 37.4 yr (range 1–69 yr). Forty-seven patients presented with a palpable thyroid nodule, 8 with palpable lymph nodes only, and 19 with both palpable lymph nodes and palpable nodules. The diagnosis of MTC was performed preoperatively in 77 patients and intraoperatively on frozen section in 24 patients. Among the 47 patients with hereditary MTC, 16 were index cases (and only two were diagnosed intraoperatively) and the other 31 (66%) were picked up preoperatively by routine family screening, basal or pentagastrin-stimulated CT levels being elevated in all and thyroid nodules being detected by palpation in 10 and by ultrasonography in 17.
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Pathological thyroid involvement was bilateral in 42 of 47 (89%) hereditary MTC, and in 7 of 54 (13%) sporadic MTC. The tumor-node-metastasis staging is reported in Table 1
(21).
The total number of resected lymph nodes ranged from 7–142 and was similar in cases of hereditary or sporadic MTC (median, 43 and 39, respectively). No difference was observed in the number of resected lymph nodes from the various compartments. Lymph node metastases were found in 56 of the 101 patients (55%): in 34 of 54 (63%) patients with a sporadic MTC and in 22 of 47 (47%) patients with a hereditary MTC (Table 2). Among the 54 patients with sporadic MTC, lymph node metastases were observed in 27 (50%) in the central neck compartment, in 31 (57%) in the ipsilateral jugulocarotid chain and in 15 (28%) in the contralateral jugulocarotid chain. Among the 47 patients with hereditary MTC, lymph node metastases were identified in 21 (45%) in the central neck compartment, in 17 (36%) in the ipsilateral jugulocarotid chain and in 9 (19%) in the contralateral jugulocarotid chain. The frequency of involvement of the central neck, the ipsilateral and contralateral jugulocarotid areas was similar for sporadic and familial MTC. When present, lymphatic spread was found in both the central and ipsilateral compartments in 73% of patients with either a sporadic or a hereditary MTC (Table 3). However, eight patients had ispsilateral metastases without central involvement and seven had central metastases without ipsilateral involvement. The variability of anatomic distribution was not related to tumor size or primary tumor localization.
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). Only 1 of the 46 patients without lymph node metastases in the central and ipsilateral neck compartments had contralateral lymph node involvement; this patient had a bilateral sporadic thyroid tumor. No other factor (uni- or bilaterality, tumor size, tumor localization) was predictive of contralateral involvement and in particular the presence of contralateral lymph node metastases was not related to tumor size.
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Among patients with tumor less than 1 cm, lymph node involvement was observed in 8 of 12 (67%) patients with sporadic MTC and in 6 of 27 (22%) patients with hereditary MTC. Of note, as indicated in Table 2, after exclusion of the six tumors revealed by palpable lymph node metastases, only two of six (33%) patients with sporadic MTC less than 1 cm had lymph node metastases. Contralateral metastases were also observed in patients with tumors less than 1 cm, respectively, in 2 of 27 hereditary MTC (7%) and one of six sporadic unilateral MTC (after exclusion of the sporadic MTC revealed by lymph node metastases). In hereditary MTC, lymph node involvement was more frequently observed in patients with larger tumors (P < 0.01); this was also the case for sporadic MTC after exclusion of tumors revealed by palpable lymph node metastases (P < 0.02).
Therapeutic results
Therapeutic results were analyzed after exclusion of the five patients with distant metastases at diagnosis. An undetectable basal CT level was obtained in 59 of 96 MTC patients (61%), in 41 of 43 (95%) patients without lymph node metastases at histology (N0) and in 18 of 56 (32%) patients with lymph node metastases (N1). A pentagastrin stimulation test performed in 45 patients with undetectable basal CT level, disclosed no CT response in 32. When the total number of lymph node metastases was considered, undetectable basal CT level was observed in 17 of 30 (57%) patients with less than or with 10 lymph node metastases and in only 1 of 26 (4%) patients with more than 10 (P < 0.01). The biological cure was not related to the location of lymph node metastases; in particular, this was observed in 9 of 26 patients with unilateral lymph node involvement and in 6 of 23 with bilateral lymph node involvement and in 3 of 7 with only central metastases.
During follow up (range, 1–35 yr; median, 10 yr), 21 recurrences occurred, 15 at distant sites, 2 at distant sites and in the neck (in dissected areas), and 4 in the neck only, including 2 in lymph nodes (1 in dissected areas and 1 in nondissected areas) and 2 in the thyroid bed.
Surgical treatment and complications. Neck surgery was considered macroscopically complete in 99 patients, and incomplete in the remaining 2 patients for tumor infiltration of the trachea and esophagus. Postoperative complications included permanent hypoparathyroidism in 4% of cases (3 cases after initial thyroidectomy performed at another medical center, before referral at IGR and in one patient after neck surgery performed at IGR). Recurrent laryngeal nerve palsy was observed in 5 patients (5%), recurrent nerve resection being intentionally performed in 3 patients to achieve complete tumor resection. One patient presented a Claude Bernard Horner syndrome and one patient presented a spinal nerve palsy.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Indeed, a contralateral involvement was found in 20% of unilateral sporadic thyroid tumors, being also present in 1 of 6 sporadic tumors less than 1 cm. It was found mostly in patients with involvement of the ipsilateral and/or the central neck compartments and only in 1 of 46 (2%) patient without lymph node metastases in the central and ipsilateral neck compartments. No other factor (uni- or bilaterality, tumor size, genotype) was predictive for contralateral involvement. The metastatic pathway (22) may involve retro-pharyngeal lymph nodes or anastomoses between the central and lateral neck lymph nodes.
The upper third of the jugulocarotid compartment was involved in 18% of the cases without metastases in the lower two thirds, and this was observed in patients with thyroid tumor located in the central or upper part of the lobe. Thus, a complete bilateral neck dissection should be performed in patients when the thyroid tumor arises in the central or upper part of the lobe, and this is frequently the case for MTC, its embryonic cells of origin being located at this level.
In accordance with previous data, a strong relationship was found between lymph node involvement and tumor size, in the two groups of MTC (4, 5, 6). In our series, lymph node metastases were found even in tumors less than 1 cm, in 22% of hereditary MTC and in 33% of sporadic MTC after exclusion of tumors with palpable lymph nodes at presentation. This clearly demonstrates that the same surgical protocol should be applied also to patients with small thyroid tumors. However, these recommendations do not apply to subjects who undergo prophylactic surgery on the basis of a RET gene mutation and who have no evidence of disease. In fact, these subjects were not included in the present study.
In accordance with previous reports (16, 23), CT normalization was obtained in 95% of patients without lymph node metastases and in 32% of patients with lymph node metastases. Furthermore, CT normalization was significantly related to the total number of lymph node metastases, being obtained in 57% of patients with less than or with 10 lymph node metastases and in only 4% with more than 10 lymph node metastases. This clearly shows that among patients with lymph node involvement, those with the most extended disease could not be cured by surgery alone, and this may indicate other treatment modalities such as external radiation therapy to the neck when CT level remains elevated after apparently complete surgery, and in the absence of distant metastases.
In our study, surgical complications resulted in permanent hypoparathyroidism in 4% and in laryngeal palsy in 5%. Hypocalcemia following thyroidectomy was more frequently observed after central neck dissection than after lateral neck dissection (24). Complication rates after further surgery for residual MTC were higher, ranging from 5–14% (10, 12, 13, 25) and complete neck dissection at initial treatment will reduce surgical morbidity.
In conclusion, our data provide support for a standard approach to neck surgery, similar for sporadic and hereditary MTC patients, and whatever the size of the thyroid tumor. The high incidence of lymph node metastases both in the central and lateral neck compartments, including in the contralateral neck compartment, supports the indication of a central and bilateral lymph node dissection, even for unilateral tumor smaller than 1 cm in diameter. Contralateral lymph node dissection may be avoided only in patients with unilateral tumor with no central and ipsilateral lymph node involvement. Finally, the total number of lymph node metastases was found to be predictive for biological remission after surgery.
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Acknowledgments |
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Footnotes |
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Abbreviations: CT, Calcitonin; FMTC, familial MTC; IGR, Institut Gustave-Roussy; MEN, multiple endocrine neoplasia; MTC, medullary thyroid cancer; RET, rearranged during transfection.
Received November 6, 2002.
Accepted February 11, 2003.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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