- Email: [email protected]
Medullary thyroid cancer: The controversy continues
c. CA 27.29 d. CA 15-3 e. a and b
8. Yamauchi H, Stearns V, Hayes DF. When is a tumor
marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer. J Clin Oncol. 2001;19: 2334-2356. 9. Yamauchi H, O’Neill A, Gelman R, Carney W, Hosch S,
Hayes D F. Prediction of response to antiestrogen therapy in advanced breast cancer patients by pretreatment circulating levels of extracellular domain of the HER-2/c-neu protein. J Clin Oncol. 1997;15:2518-2525.
2. Mab-based sandwich assays detect elevated levels of ECD of the HER-2 proto-oncogene in approximately what percentage of patients with metastatic breast cancer? a. b. c. d. e.
10. Molina R, Jo J, Filella X, et al. C-erbB-2, CEA and CA
15.3 serum levels in the early diagnosis of recurrence of breast cancer patients. Anticancer Res. 1999;19:25512555.
3. ASCO has recommended: a. Breast cancer patients should be tested with a panel of tumor markers at time of diagnosis only. b. Breast cancer patients should be tested with a panel of tumor markers at time of recurrence only. c. Breast cancer patients should be followed with tumor markers during chemotherapy only. d. All breast cancer patients should be routinely followed with a panel of tumor markers. e. None of the above.
11. Edgerton SM, Moore D, Merkel D, Thor AD. ErbB-2
(HER-2) and breast cancer progression. Appl Immunohistochem Mol Morphol. 2003;3:214-221. 12. Hayes D, Sekine H, Ohao T, Abe M, Keefe K, Kufe DW.
Use of murine monoclonal antibodies for detection of circulating plasma DF3 antigen levels in breast cancer patients. J Clin Invest. 1985;75:1671-1678. 13. Bast RC, Ravdin P, Hayes D, et al. 2000 Update of Rec-
ommendations for the Use of Tumor Markers in Breast and Colorectal Cancer: Clinical Practice Guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001;19:1865-1878.
QUESTIONS AND ANSWERS Questions 1. Which tumor marker does not involve a monoclonal antibody against the MUC-1 mucin? a. CEA b. AFP
5% to 10% 10% to 20% 20% to 40% 40% to 50% 50% to 70%
4. CEA a. Is the “gold standard” for following breast cancer patients. b. Is far more sensitive that any of the MUC-1 associated glycoproteins. c. Is cost effective. d. Is significantly less sensitive than CA 15.3. e. Can be used to screen the general population to establish the diagnosis of breast cancer. Answers 1. 2. 3. 4.
e c e d
Endocrine Medullary Thyroid Cancer: The Controversy Continues Guest Reviewers: Brandon Helbling, MD,*† Kurt Wharton, MS IV, and Michael K. McLeod, MD,*† *Kalamazoo Center for Medical Studies, Michigan State University and †Michigan State University College of Human Medicine, Lansing, Michigan IMPACT OF ROUTINE MEASUREMENT OF SERUM CALCITONIN ON THE DIAGNOSIS AND OUTCOME OF MEDULLARY THYROID CANCER: EXPERIENCE IN 10,864 PATIENTS WITH NODULAR THYROID.
Objective: To determine the prevalence of medullary thyroid
Elisei R, Bottici V, Luchetti F, et al. J Clin Endocrinol Metab.
Setting: Tertiary-Departments of Endocrinology and Metabolism, Oncology, and Surgery at the University of Pisa, Italy;
2004;89:163-168.
cancer (MTC) in thyroid nodular disease and the role of routine measurement of serum calcitonin (CT) on outcome. Design: This is a retrospective cohort study.
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and the Departments of Internal Medicine, Endocrinology and Metabolism and Biochemistry, University of Siena, Italy. Participants: The study included 44 of 10,864 patients seen
in the respective departments between 1991 and 1998 for nodular thyroid disease who were screened for and diagnosed with MTC by serum CT measurement (Group 1), and a historical group of 45 patients with MTC diagnosed from 1970 to 1990 by fine-needle aspirate cytology (FNAC) when screening for MCT was not performed (Group 2). Results: The clinical features of patients with MTC diagnosed after (Group 1) and before (Group 2) the routine use of CT screening were different only by median age. Group 1 patients had a median age of 55 years compared with Group 2 patients who had a median age of 47 years (p ⬍ 0.0001). There were no significant differences with respect to sex, distribution of types of MCT (hereditary versus sporadic disease), or incidence of C-cell hyperplasia (2/44 [4.5%] in group 1 compared with 0/45 in group 2, p ⫽ NS).
MTC in CT-screened Patients (Group 1) Forty-seven of 10,864 patients had elevated basal serum CT levels that ranged from 20 to 6200 pg/ml. In 2 cases, the increased basal CT was caused by chronic renal failure. These 2 patients underwent FNAC, which suggested benign nodular disease and did not undergo surgery. A third patient with a basal CT level of 30 pg/ml (normal ⬍ 20 pg/ml) and a FNAC demonstrating benign nodular disease refused pentagastrin stimulated testing and surgery and was lost to follow-up. The resulting cohort of 44 patients in Group 1 had abnormal peak CT levels after pentagastrin stimulation tests. The clinical diagnosis in these patients was multinodular goiter in 26 (59%), uninodular goiter in 15 (34%), toxic multinodular goiter in 1, an autonomously functioning thyroid nodule in 1, and autoimmune thyroid disease with a dominant nodule in 1 (2.3%). Fine-needle aspirate cytology was suspicious for MTC in 20 of 44 cases (46%), suspicious for undefined malignancy in 9 (20%), suggestive of benign disease in 11 (25%), and inadequate in 4 (9%). These 44 patients underwent total thyroidectomy and central neck compartment dissection. All patients in Group 1 were found to have MTC. The incidence of MTC was 44 of 10,864 (0.40%). There was no case of MTC detected among patients who had normal basal serum CT levels and underwent a thyroidectomy for other reasons. The authors stated that 8 patients (18%) had stage 1, 22 (50%) had stage II, 13 (30%) had stage III, and 1 (2.3%) had stage IV disease. However, the reader should note that this study used an earlier TNM staging classification than the American Joint Committee on Cancer TNM staging of 2002. MTC in Historical Patients Diagnosed and Treated Before Routine CT Screening (Group 2) Fine-needle aspirate cytology was performed on 13 of 45 (29%) patients in Group 2, which suggested MTC in 2 of 13 (15%) and suspicious for an unspecified malignancy in 11 of 13 (85%). In the other 32 patients, the diagnosis was made on final 538
surgical pathology. According to an older TNM classification, no patient in this group had stage 1 disease, 20 patients (45%) had stage II disease, 18 patients (40%) had stage III disease, and 7 (16%) had stage IV disease. This staging was significantly more advanced than the staging observed in group 1 (p ⫽ 0.0004, by 2analysis). Outcome Among MTC patients in Group 1 versus Group 2 Basal serum CT levels became undetectable in 29 of 44 (66%) patients in Group 1, with no response to pentagastrin stimulation in 26 of 29 (90%) and a mild increase in 3 (10%) of these patients after surgical treatment. Basal serum CT was still detectable in 15 patients (34%), although reduced when compared to presurgical levels (Group 1). In Group 2, serum CT values after surgical treatment were available in 36 of 45 (80%) patients and were detectable in all but 1 (97%). The difference between the 2 groups was significant (p ⬍ 0.0001, by Fisher exact test). The mean follow-up was 6.2 ⫾ 2.5 years (range 3-10) in Group 1 and 18.7 ⫾ 5.4 years (range 10-39) in Group 2. Deaths occurred in 2 of 44 (5%) patients in Group 1 and in 25 of 36 (70%) in Group 2. Among the 42 of 44 (96%) patients in Group 1 still alive, 26 (59%) were free of disease with undetectable basal and pentagastrin stimulated serum CT, 6 (14%) had evidence of local or distant disease and elevated serum CT levels, and 10 (23%) had no evidence of disease but detectable basal and pentagastrin-stimulated serum CT levels. Among the 11 of 36 (31%) patients in Group 2 still alive, 1 (3%) was free of disease, 6 (17%) had evidence of local or distant disease and elevated serum CT levels, and 4 (11%) had no evidence of disease, but detectable basal and/or pentagastrin-stimulated serum CT levels. There was a significant difference between the 2 groups (p ⬍ 0.0001, by 2analysis). To correct for the longer follow-up in the historical group, the same analysis was performed considering only the first 6 years of follow-up of Group 2. After 6 years, 14 of 42 (33%) patients in Group 2 were dead of MTC. Among the 28 of 42 patients in Group 2 still alive after 6 years, only 1 (2%) was free of disease and 27 (64%) had evidence of persistent disease. The patients in Group 1 had a significantly better outcome (p ⬍ 0.0001, by 2analysis) after 6 years of follow-up. The survival curves shown in the manuscript demonstrated that, using Kaplan-Mayer analysis of the 2 groups, there was a better survival among Group 1 patients (5-year survival, 98%; 10-year survival, 87%) compared with Group 2 patients (5-year survival, 82%; 10-year survival, 44%) with a p value ⫽ 0.0005, by log-rank test. Conclusions: The routine measurement of basal serum CT levels in patients evaluated for nodular thyroid disease should be considered an important step in the diagnostic algorithm. Calcitonin measurement is specific and may be more sensitive than fine-needle aspiration biopsy (FNAB) of palpable thyroid nodules for MTC. It may prove to be more sensitive than ultrasound-guided FNAB of thyroid nodules for the diagnosis of unsuspected and/or early MTC. The incidence of MTC in this study is 0.40%, and this may underestimate the prevalence of MTC in patients with nodular thyroid disease.
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REVIEWER COMMENTS
This article suffers from limitations that are inherent to all retrospective studies. However, it represents a unique dataset with sufficient power to identify significant differences in study cohorts that typically have too few patients to be confidently analyzed. There are some methodological problems with the study. The authors do not give the actual sizes of the MTCs nor do they describe the extent of involvement for each case so that it is not possible to reclassify these cases using the updated TNM classification. They state that, in Group 1, no case of MTC was detected among patients with normal serum CT levels who underwent surgery for other reasons, but we do not know why those patients underwent surgery and to what extent of surgery they were treated. The institutions involved used a reliable CT assay, but there is no way to evaluate the quality of their cytopathology. No blinded review of all cytology by an unbiased expert in cy-
topathology was performed to confirm the initial cytologic diagnoses upon which much of the comparisons on outcome are based. The possibility of bias still remains despite the author’s attempt to answer some questions that arise from comparing 2 treatment groups from different decades. The much longer period of follow-up in the patients in Group 2 remains a possible source of bias in this study, notwithstanding the normalization of the 2 groups by analyzing the data for similar follow-up periods of 6 years in both groups. Nevertheless, routine screening with basal serum CT measurements appears to identify earlier stage disease in patients with unsuspected MTC. This results in more cases of MTC being identified at earlier stages of disease having a higher likelihood of cure after total thyroidectomy and central compartment nodal dissection combined with unilateral nodal dissection when lymph nodes are involved.
MEDULLARY THYROID CARCINOMA: RESULTS OF A STANDARDIZED SURGICAL APPROACH IN A CONTEMPORARY SERIES OF 80 CONSECUTIVE PATIENTS.
hereditary MTC. Four patients had their initial operation, and 6 were reoperated for persistent (n ⫽ 1) and recurrent (n ⫽ 5) disease at the study institution. Five of the 10 patients subsequently received systemic therapy, and at last follow-up, none of the 10 had developed a cervical recurrence; 6 were alive with disease (AWD), 3 were dead of disease (DOD), and 1 was lost to follow-up. Among the 70 patients without distant metastatic disease (M0), the median age at diagnosis was 41 years (range, 5-78 years), and the median age at the time of operation at M.D. Anderson was 45 years (range, 5-78 years). Forty-five of 70 (64%) had sporadic and 25 (36%) had hereditary MTC. In the patients with sporadic MTC, 37 (82%) had evidence of cervical node involvement, 32 of whom had N1b disease (metastases to unilateral, bilateral, or contralateral cervical, superior or mediastinal lymph nodes) involving levels IIA, III, IV, or V (suggest referring to AJCC 2002 publication or Eng et al1). Disease recurred in 16 of 45 (36%) patients with sporadic MTC 23 months after surgery at study institution. Six patients had isolated cervical recurrences, and all had presented initially with lymph node involvement (N1b ⫽ 5, N1a ⫽ 1). N1a represents metastasis to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian) lymph nodes. All 6 underwent reoperation and are currently alive with no evidence of disease (NED). Isolated distant metastases developed in 7 patients (liver ⫽ 4, bone ⫽ 4, lung ⫽ 2, some patients had isolated distant metastases in more than 1 site), and both cervical and distant recurrences developed in 3 patients (liver ⫽ 3, lung ⫽ 2, and bone ⫽ 2). Of these 10 patients, 2 (20%) presented with T4a disease (tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve) and 9 (90%) presented with N1b (stage IVA) disease. Seven of the 10 patients with distant metastases were AWD, and 3 were DOD at last follow-up.
Yen TW, Shapiro SE, Gagel RF, Sherman SI, Lee JE, Evans DB. Surgery. 2003;134:890-901. Objective: To obtain data on the natural history and pattern of disease progression of MTC after a standardized compartment-oriented approach to surgical management. Design: A retrospective cohort study. Setting: Tertiary-Departments of Surgical Oncology and En-
docrine Neoplasia and Hormonal Disorders, University of Texas M.D. Anderson Cancer Center, Houston, Texas. Participants: A consecutive series of all patients who under-
went a cervical operation for MTC from May 1991 to December 2002. Results: During the period of study, 92 patients underwent
either therapeutic (n ⫽ 75) or prophylactic (n ⫽ 17) cervical operations for either sporadic or hereditary MTC. Five of the 17 patients who underwent prophylactic thyroidectomy had invasive MTC, and 12 had C-cell hyperplasia. Of the 80 patients with invasive MTC, 10 presented with distant metastatic disease (M1) and 70 had disease confined to the neck (M0). The median follow-up was 35 months. Ten patients presented with distant metastases (5 to liver, 3 to lung, 1 to bone, and 1 to an extracervical lymph node) and required a cervical operation for local-regional disease control. The median age of these patients at diagnosis was 33 years (range, 10-60 years), and the median age at time of surgery at M.D. Anderson was 40 years (range, 12-70 years). Four of the 10 had sporadic disease, and 6 had
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The 25 patients with hereditary MTC all had (M0) early stage disease at presentation (21 (84%) had T1, 2 of 25 (8%) had T2, and 1 (4%) had T3, and 1 had Tx disease). Fourteen (56%) patients had N0, 3 (12%) patients had N1a, 4 (16%) patients had N1b, and 4 had Nx disease. The RET protooncogene mutations (RET) were known in 23 of 25 patients and consisted of 10 (43%) mutations at codon 634, 3 (13%) at codon 891, 3 at codon 918, 2 (9%) at codon 609, 2 at codon 620, and 1 (4.5%) each at codons 611, 618, and 804. Only 2 (8%) of the 25 patients had recurrent disease develop at last follow-up. One patient developed a cervical recurrence 8 years after initial operation at the study institution and was treated with a repeated central neck dissection and is NED 24 months after this reoperation. A second patient developed bone metastases 16 months after the initial operation at the study institution, and the patient is currently alive with stable metastatic disease 52 months after the initial operation. Preoperative serum CT levels were available for 66 of the 70 patients (median was 585 pg/ml, and the range was 5 to 39,348 pg/ml). The recurrence rate was higher in the patients with preoperative CT levels equal to or above the median than in those with preoperative CT levels below the median. There were 18 recurrences in the 70 patients; 12 occurred in patients with preoperative CT levels equal to or above the median, and 2 occurred in patients with preoperative CT levels below the median. The remaining 4 recurrences were in patients without available preoperative CT levels. The estimated 5-year recurrence-free survival (RFS) rates were 0.54 and 0.89 for patients with CT levels equal to or above and below the median, respectively (p ⬍ 0.01). Postoperative CT levels were available for 63 of 70 (90%) patients with no distant metastasis (M0 disease). The median was 46 pg/ml, and the range was undetectable to 3410 pg/ml. The recurrence rate was higher in the patients with postoperative CT levels equal to or above the median than in those with postoperative CT levels below the median. The estimated 5-year RFS rates were 0.54 and 0.90 for patients with CT levels equal to or above and below the median, respectively (p ⬍ 0.01). Calcitonin levels were available for 17 of the 18 patients who developed recurrence. The median was 804 pg/ml, and the range was 32 to 36,000 pg/ml. Recurrence was associated with a CT level greater than 250 pg/ml in all but 4 patients, 2 of which had isolated cervical disease and 2 had distant metastases with evidence of tumor dedifferentiation and clinical evidence of rapid tumor progression. Carcinoembryonic antigen (CEA) levels in these 4 patients were normal at the time of recurrence. In contrast, only 5 (11%) patients had CT levels greater than 250 pg/ml among the 46 patients without recurrence, at last follow-up. Prophylactic thyroidectomy was performed in 17 patients (4 with familial MTC, 13 with MEN2) at a median age of 7 years (range, 4 to 30 years) on the basis of DNA analysis for RET mutations in all but 1 patient. Stage 1 invasive MTC was found
540
in 5 (29%) of these 17 patients at a median age of 12 years (range, 5 to 30 years). The median preoperative CT level for these 5 patients was 32 pg/ml (range, 21 to 204 pg/ml). The median preoperative CT level for the patients with normal histology or C-cell hyperplasia was 21 pg/ml (range, 4 to 26 pg/ ml). There was no correlation between preoperative CT levels and finding invasive MTC in patients who underwent prophylactic thyroidectomy. Fifteen patients with elevated CT levels but no clinical evidence of disease underwent a reoperative cervical dissection. The median age of diagnosis was 44 years (range, 9 to 66 years). The median age at time of first operation was 45 years (range, 11 to 66 years). Medullary thryroid cancer was found on histopathology in 12 of 15 (80%). No patient received adjuvant external-beam radiation therapy (EBRT). Four patients developed recurrent disease in the follow-up period, and all were among sporadic MTC. Three of the 4 had stage IVA disease, and cervical recurrences developed in all 3. The fourth patient had stage II disease and developed isolated bone metastases. Twelve of 15 (80%) patients had NED, 2 were AWD, and 1 was DOD at last follow-up. External-beam radiation therapy was delivered to 20 (25%) of the 80 patients with invasive MTC at presentation (13 with M0 disease and 7 with M1 disease) either because they had bulky cervical disease with evidence of extrathyroidal or extranodal soft tissue extension, or because of concern over a microscopically positive margin of resection. External-beam radiation therapy doses ranged from 42 to 76 Gy. External-beam radiation therapy was given after the first operation in 14 patients and after the second operation in the remaining 6 patients. Only 1 of the 14 patients treated with EBRT after 1 operation developed recurrence (cervical) diagnosed 14 months after completing EBRT. This patient who underwent repeat central neck dissection had NED at the completion of the study period. Among the 6 patients who received EBRT after their second operation, none developed a subsequent cervical recurrence. In contrast, cervical recurrence developed in 9 (14%) of the 66 patients who did not receive EBRT after their first operation. Surgical morbidity for this series included resection of the ipsilateral recurrent laryngeal nerve (n ⫽ 3), permanent hypoparathyroidism (n ⫽ 4; which was defined as the need for both calcium and Vitamin D after 6 months postoperatively), postoperative hemorrhage requiring reoperation (n ⫽ 2), chylous fistula (n ⫽ 2), chylothorax (n ⫽ 1), transient palsy of the spinal accessory nerve (n ⫽ 2), and Horner’s syndrome (n ⫽ 1). Conclusions: Complete compartment-oriented surgery can
minimize cervical recurrence. The radiographic evidence of recurrent MTC is unlikely when the serum CT level is less than 250 pg/ml. There is no reliable correlation between preoperative CT levels and finding invasive MTC in a patient undergoing prophylactic thyroidectomy for hereditary MTC.
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REVIEWER COMMENTS
This retrospective study of 92 patients referred to a tertiary care center for the surgical management of biopsy-proven or presumed MTC suggests the following: 1. That death from MTC is uncommon in the absence of clinically evident distant metastases at the time of surgery and that stage of disease at the time of diagnosis is one of the most important prognostic factors for MTC. 2. The likelihood of cervical recurrence can be minimized (13% found in this study) with timely compartment-oriented surgery emphasizing careful nodal dissection. However, the morbidity associated with such dissection, particularly for reoperative surgery is high. For example, the frequency of permanent hypoparathyroidism was 8 of 92 (9%) in this series. 3. The preoperative levels of basal CT cannot be relied on to direct the timing of prophylactic thyroidectomy in at-risk patients with familial MTC, although the postoperative levels of basal CT can be used to guide management of patients with MTC in general. 4. External-beam radiation therapy should be considered in high-risk patients who have undergone compartment-ori-
ented dissections for regionally advanced MTC (stage IVA or greater). This is a controversial matter in the management of MTC, but these authors cite an experience that supports its use in advanced disease. 5. Patients can exhibit rapidly progressive, clinically apparent metastatic disease in the absence of an elevation in serum levels of either the CT or CEA secondary to the dedifferentiation of the MTC tumor. 6. Finally, the approach one takes to surgically manage MTC must be directed by the extent of clinical disease at the time of diagnosis. The authors recommend in patients with sporadic MTC and no clinical evidence of cervical nodal disease that we perform a total thyroidectomy, central compartment dissection, and an ipsilateral modified neck dissection. In patients with sporadic MTC and positive imaging or clinical evidence of cervical disease, the authors recommend total thyroidectomy and central and bilateral neck dissection. In patients with familial MTC and grossly evident cervical nodal disease, they recommend total thyroidectomy, central and bilateral neck dissection.
RATIONALE FOR CENTRAL AND BILATERAL LYMPH NODE DISSECTION IN SPORADIC AND HEREDITARY MEDULLARY THYROID CANCER.
observed in 8 of 12 (67%) of patients with sporadic MTC who had tumors smaller than 1 cm, and in 6 of 27 (22%) of patients with hereditary MTC with tumors smaller than 1 cm. After exclusion of 6 tumors revealed by the presence of palpable lymph node metastases, only 2 of 6 (33%) patients with sporadic MTCs less than 1 cm had unilateral lymph node metastases and 1 of 6 (17%) had contralateral lymph node metastases. Contralateral metastases were observed in 2 of 27 (7%) patients with hereditary MTC and lesions less than 1 cm. An undetectable basal CT level was obtained in 59 of 96 (61%) of patients with MTC, in 41 of 43 (95%) patients with no lymph node involvement (N0 disease), and in 18 of 56 (32%) of patients with lymph node involvement (N1 disease). The ipsilateral, contralateral and the central compartments were involved with the same frequency in patients with either sporadic or hereditary MTC, even in patients with unilateral thyroid lesions. Further, these investigators observed that even with extensive lymph node dissection (total thyroidectomy, central and bilateral lymph node dissections), only 32% of the patients with lymph node metastases in any compartment subsequently demonstrated normal serum calcitonin (CT) levels postoperatively. The postoperative CT level was normal in 95% of patients without lymph node metastases at the initial surgical procedure performed as described (vide ante). A strong correlation was observed between tumor size and the presence of lymph node metastases for both sporadic and hereditary MTC. Permanent hypoparathyroidism occurred in 4% of patients and laryngeal nerve palsy in 5% in this series.
Scollo C, Baudin E, Travagli JP, et al. J Clin Endocrinol Metab. 2003;88:2070-2075. Objective: To clarify the role of lateral lymph node dissection
and further define a protocol for initial surgery in the management of patients with MTC. Design: A retrospective cohort study. Setting: Referral Institution-Institut Gustave-Roussy (IGR),
France. Participants: Patients with medullary thyroid cancer treated and followed from 1964 to 2001. Results: These investigators conducted a retrospective study of
101 patients with MTC in an attempt to identify the frequency and the pattern of cervical lymph node involvement, and to evaluate the complication risks and therapeutic results associated with their current algorithm. The 101 patients all underwent a total thyroidectomy and central and bilateral neck dissection from 1964 to 2001. They observed that 55% of the patients had lymph node metastases. These metastases were found in the central neck compartment (50%), ipsilateral jugulocarotid chain (57%), and contralateral jugulocarotid chain (28%) of patients with sporadic MTC, and 45%, 36%, and 19% of the respective compartments in patients with hereditary MTC. Lymph node involvement was
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Conclusions: These investigators concluded that in patients with MTC, lymph node metastases occur early and that the pattern of lymph node involvement was variable and did not correlate with the size of the tumor. Contralateral lymph node metastases occurred even in patients with small thyroid tumors. These investigators recommend that a total thyroidectomy and central and bilateral neck dissection should be performed in all
patients with sporadic and hereditary MTC even for unilateral tumors smaller than 1 cm in diameter. A contralateral neck dissection may be avoided only in patients with sporadic MTC with a unilateral tumor and no central and ipsilateral lymph node involvement. The number of lymph nodes involved was predictive of a biological cure after surgery.
REVIEWER COMMENTS
These investigators provide reasonable retrospective data that supports the conclusion that an aggressive approach to the management of MTC does not necessarily result in better outcomes. Their experience suggests that MTC with lymph node metastases cannot be cured by surgery alone and
that other therapies, yet defined, may be needed. It appears that the stage of disease at the time of diagnosis is the most critical prognostic factor for the likelihood of cure in a patient with either sporadic or hereditary MTC.
REVIEWER SUMMARY
Medullary thyroid cancer is a rare, neuroendocrine carcinoma that originates from parafollicular C cells within the thyroid gland. The parafollicular C cells are derived from ultimobranchial bodies and are positioned within the middle and upper portions of the lateral thyroid lobes.2 These cells secrete calcitonin, a 32 amino acid polypeptide hormone, which is considered to play a minor role in decreasing serum calcium levels and maintaining bone structure through the inhibition of osteoclastic activity and the augmentation of renal calcium excretion.3 In addition to calcitonin, medullary thyroid cancer cells also secrete several other polypetide hormones and neuroendocrine markers such as CEA, corticotropin, serotonin, vasoactive intestional peptide (VIP), and somatostatin.2-4 Medullary thyroid cancers on gross appearance are typically firm, unencapsulated masses with a gray to tan color on cross section.4 Familial cases of medullary thyroid cancer are characteristically bilateral and multicentric, whereas sporadic neoplasms typically originate in a single thyroid lobe. Microscopically, medullary carcinomas are classically composed of polygonal to round cells in nests or trabeculae with a vascular stroma.4 Eighty percent contain acellular amyloid deposits that are believed to be produced from altered calcitonin gene products.3 Familial cancers also have multiple foci of C-cell hyperplasia in the surrounding thyroid parenchyma. Immunohistochemical staining demonstrates calcitonin (along with CEA and other substances) within the medullary carcinoma cells.2 Although medullary thyroid cancer accounts for less than 10% of all thyroid cancers, it results in 13.4% of all deaths because of thyroid cancer.2 A recent pooled analysis of 67 cases of MTC found a significant association with several risk factors, which included a history of thyroid nodules, hypertension, gallbladder disease, allergies, and women who had a first birth after age 25.5 Medullary thyroid cancer is sporadic (an isolated neoplasm) in 75% to 80% of cases with a mean age at presentation of 49 years, and it is familial in the remaining 20% to 25% of cases with a mean age at presentation of 30 years.2,3 Familial 542
cases are inherited as an autosomal dominant trait with variable, age-related, penetrance linked to chromosome 10. Inherited MTC occurs in 3 distinct clinical subtypes: multiple endocrine neoplasia (MEN) 2A, MEN 2B, and familial medullary thyroid cancer (FMTC). Germline gain-of-function mutations in RET are responsible for at least 92% of cases of MEN 2.6 Multiple endocrine neoplasia 2A (Sipple syndrome) is characterized by pheochromocytomas, parathyroid hyperplasia, MTC, and occasionally, cutaneous lichen amyloidosis and Hirschsprung’s disease.4 In MEN 2A, MTC has a high phenotypic penetrance as it occurs in almost 100% of cases and usually occurs at a younger age than pheochromocytomas (which is present in roughly half of cases) and hyperparathyroidism (which is present in 10% to 20%).2,3 Multiple endocrine neoplasia 2B is a generally a more aggressive condition and usually presents at a younger age (first or second decade) than MEN 2A. In addition to MTC and pheochromocytomas, MEN 2B is associated with a marfanoid habitus and mucocutaneous ganglioneuromas of the conjuctiva, lips, tongue, skin, and intestines.3 Familial medullary thyroid cancer is associated with isolated MTC without other endocrinopathies. Familial medullary thyroid cancer generally presents at a later age (fourth decade) and is the least aggressive of all types of MTC.3 Germline mutations in the RET (rearranged during transfection) proto-oncogene in the pericentromeric region of chromosome 10(10q11.2) have been implicated in the carcinogenesis of inherited MTC.2,3,6 In addition, somatic mutations of the RET proto-oncogene have been found in sporadic MTC.1,4,6 The RET proto-oncogene encodes a cell surface tyrosine kinase receptor for glial-derived neurotrophic factor and is normally expressed in neuroendocrine cells such as the thyroid C cells, parathyroid cells, and chromaffin cells in the adrenal medulla.4 The precise physiological role of the RET expression is unclear; however, it is believed to influence neural crest tissue migration and development.3 The RET mutations implicated in inherited MTC involve a gain of function mutation that ultimately re-
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sults in impaired disulfide bonding between RET molecules and increased activation of the tyrosine kinase receptor.7 These mutations are associated with the development of multifocal C cell hyperplasia. It is not known whether these RET mutations alone are sufficient for the progression to MTC, and it is postulated that a second somatic mutation is required for the progression to carcinoma.3 The RET mutations can be broadly classified into those involving codons of the extracellular/cystein-rich, domain of the receptor and those involving the intracellular/catalytic domain.3,7 However, the association of the type of RET mutation to the expression of a MEN phenotype and the rate of progression from C cell hyperplasia to MTC must be considered separately for each codon mutation.7 Clinical Presentation Medullary thyroid carcinoma occurs in 1 sporadic and 3 hereditary autosomal-dominant forms (familial MTC, MEN 2A and 2B). Sporadic MTC commonly presents as a painless lump in the thyroid. This lump is associated with cervical lympadenopathy that is not always palpable in up to 75% of pa-
tients with MTC.2 The familial MTC, MEN 2A and 2B forms are usually diagnosed while undergoing screening tests after being diagnosed with a neoplasm or having a family member with components of these 3 forms of MTC (see Fig. 1). Diagnosis Ultrasonography is a well established imaging technique in the evaluation of the thyroid gland.2 Tumor size and multiplicity, neck adenopathy, and disruption of adjacent structures can all be evaluated by ultrasound. The ultrasound patterns of MTC and non-medullary thyroid cancer are very similar and cannot distinguish between the different entities.8 Fine needleaspiration cytology has also been an established standard diagnostic tool for thyroid cancer, and MTC is not an exception to the rule. This can be combined with ultrasonography for greater accuracy and diagnosis of MTC. Finally, as MTC is a biochemically active neoplasm that secretes calcitonin, this can be used in the screening, diagnosis, and follow-up of MTC. Serum calcitonin is the most specific and sensitive marker of MTC for both the primary diagnosis and the postsurgical follow-up. Se-
MEDULLARY THYROID CARCINOMA DIAGNOSIS
1. 2. 3. 4. 5.
+ RET
ȣ TT + CeND + ILND (If there is no evidence of CCCLN involvement.) ȣ BND If there is evidence of CCCLN involvement and/or CoLN involvement.
- RET
ȣ Lobectomy + Isthmusectomy (or TT)
Sporadic MTC (75 – 80% of cases)
Elevated Basal Serum Calcitonin (EBSC) {In a patient with normal renal function} Fine – Needle Aspiration Biopsy (FNAB) RET Proto-Oncogene Mutation in Chromosome 10. Nodular Thyroid Disease and EBSC. Family History and any of 1-4.
+ Central Node Dissection (CeND) + Ipsilateral Lymph Node Dissection.
Inherited MTC (20 – 25% of cases) ȣ TT + CeND + BND
CONFIRM DIAGNOSIS OF MTC
or
Familial
ȣ Cervical Lymph Node Dissection
(NON-MEN)
only on side of lymph node involvement (ILND).
MEN II b MEN II a
No gross evidence of disease, surveillance basal serum calcitonin at 4, 12, and 24 weeks. Checked annually in the absence of physical findings/new symptoms.
POSTOPERATIVE MANAGEMENT
Extensive Nodal Involvement and/or Extensive Involvement of Soft Tissues.
+Imaging New Physical Findings or New/Persistent EBSC
IMAGING CAT/MRI/PET/Octreotide Scan/Scinitigraphy
Recommend External Beam Radiation Therapy.
Repeat Neck Dissection to Remove all Gross/Nodal Disease.
EBSC 250
Follow-up Expectantly
Follow-up Expectantly
Follow-up Expectantly
Follow-up Expectantly
-Imaging
EBSC > 250
LEGEND:
BND = Bilateral Cervical Lymph Node Dissection CCCLN = Central Compartment Cervical Lymph Nodes CeND = Central Compartment Cervical Lymph Node Dissection CoLN = Contralateral Cervical Lymph Node(s)
EBSC = Elevated Basal Serum Calcitonin FNAB = Fine-Needle Aspiration Biopsy ILND = Ipsilateral Lymph Node Dissection MTC = Medullary Thyroid Cancer
RET = RET, Proto-Oncogene Mutation, Chromosome 10 (+) RET = Yes RET, Proto-Oncogene Mutation, Chromosome 10 (-) RET = No RET, Proto-Oncogene Mutation, Chromosome 10 TT = Total Thyroidectomy
FIGURE 1. Algorithm. CURRENT SURGERY • Volume 61/Number 6 • November/December 2004
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rum calcitonin is even more sensitive then FNAC in the diagnosis of MTC (see the reviewed article by Elisei et al). Patients whose conditions are diagnosed with MTC should receive computed tomography of the neck and mediastinum. After the diagnosis of MTC, patients should then be screened for RET mutations, and if positive, relatives of the patient can then be screened for MTC and prophylactically treated. Treatment Total thyroidectomy and central neck dissection is recommended for all MTC patients, but the indication for lateral neck dissection is still controversial. The extent of neck dissection varies from the dissection of a clinically and or radiographically positive neck to routine bilateral comprehensive neck dissections.2 This controversy is demonstrated by differing recommendations as follows: (1) Society of Surgical Oncology advocates an ipsilateral neck dissection in sporadic MTC with palpable lateral neck lymph nodes or in patients with involvement of the central neck compartment; (2) National Comprehensive Cancer Network guidelines advocates an ipsilateral modified radical neck for sporadic MTC more than 1 cm in size; (3) German guidelines advocate routine bilateral neck dissection for hereditary MTC and ipsilateral neck dissection for sporadic forms; (4) Other surgeons advocate routine bilateral neck dissection, even in unilateral palpable tumors (see the reviewed articles by Scollo et al and Yen et al). The high incidence of multifocality, the lack of effective adjuvant therapies, and the observation that patients with completely resected disease do better than those with residual disease or with disease that cannot be resected are justifications for aggressive surgical treatment (see the reviewed article by Scollo et al). Patients with positive nodes after complete resection or extensive involvement of the surrounding soft tissues structures should receive adjuvant radiation therapy although this remains controversial. Calcitonin should be measured preoperatively, approximately 4 weeks postoperatively, and at regular intervals thereafter to assess recurrence. Miyauchi et al reported on 72 patients with MTC whose retrospective data were analyzed, and the genetic nature and clinical features of their MTCs were established. Fifteen patients with nonhereditary MTC were then treated with a unilateral surgery policy. This study group was found to have an 80% biochemical cure rate postoperatively. This outcome was compared with that of a control group of 22 patients who were retrospectively analyzed and found to have a 68% biochemical cure rate. There were no significant demographic differences between the 2 groups. The results of this study indicated that in patients with sporadic or nonhereditary MTC with no detectable RET mutations, hemithyroidectomy with systematic central and ipsilateral neck dissection is appropriate.9 In conclusion, medullary thyroid carcinoma of the thyroid is a rare form of thyroid malignancy that kills on rare occasion irregardless of whether it is sporadic or hereditary in nature. It may be that all forms of this thyroid neoplasm have an identifiable genetic mechanism, even sporadic disease, which eventu544
ally may prove to be a useful device for treatment or gene therapy. The most important predictor of cure, recurrence, and poor outcome is the stage (TNM) of disease at the time of the initial diagnosis. The extent of surgery that is optimal remains controversial, but it is well established that the removal of all gross disease and lymph node involvement at the initial operation is the best chance to achieve a curative resection. Adjuvant forms of therapy that are the most useful and efficacious have yet to be identified. doi:10.1016/j.cursur.2004.07.001
REFERENCES 1. Eng C, Clayton D, Schuffenecker I, et al. The relationship
between specific RET proto-oncogene mutations and disease phenotype in multiple enocrine Neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996;276:1575-1579. 2. Clayman GL, El-Baradie TS. Medullary thyroid cancer.
Otolaryngol Clin N Am. 2003;36(1):91-105. 3. Randolph GW, Maniar D. Medullary carcinoma of the
thyroid. Cancer Control. 2000;7:253-261. 4. Cotran RS, Kumar V, Collins T, editors. The endocrine
system. In: Robbins Pathologic Basis of Disease. 6th ed. New York: W.B. Saunders Company; 1999:1121-1169. 5. Negri E, Ron E, Franceschi S, et al. Risk factors for medul-
lary thyroid carcinoma: a pooled analysis. Cancer Causes Control. 2002;13:365-372. 6. Fernández RM, Robledo M, Antinolo G, et al. The RET
IVS1-126G⬎T variant is strongly associated with the development of sporadic medullary thyroid cancer. Thyroid. 2004;14:329-331. 7. Machens A, Niccoli-Sire P, et al. Early malignant progres-
sion of hereditary medullary thyroid cancer. N Engl J Med. 2003;346:1517-1525. 8. Saller B, Moeller L, Gorges R, et al. Ultrasonography of
medullary thyroid carcinoma. Exp Clin Endocrinol Diabetes. 2002;110:403-407. 9. Miyauchi A, Matsuzuka F, Hirai K, et al. Prospective trial of
unilateral surgery for nonhereditary medullary thyroid carcinoma in patients with out germline RET mutations. World J Surg. 2002;26:1023-1028.
QUESTIONS AND ANSWERS Questions 1. T or F: A contralateral neck dissection may be avoided only in patients with sporadic MTC with a unilateral tumor and no central and ipsilateral lymph node involvement.
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2. T or F: A total thyroidectomy and central and bilateral neck dissection should be performed in all patients with sporadic and hereditary MTC even for unilateral tumors smaller than 1 cm in diameter. 3. The radiographic evidence of recurrent MTC is unlikely when the serum CT level is: a. b. c. d. e.
ⱕ150 pg/ml. ⱕ 250 pg/mL ⱖ250 pg/ml ⱖ500 pg/ml ⱖ1000 pg/ml
4. What is the correlation between preoperative CT levels and finding invasive MTC in a patient undergoing prophylactic thyroidectomy for hereditary MTC? a. No correlation b. CT levels ⬍50 pg/ml indicate no invasion
c. CT levels ⬎50 pg/ml but ⬍100 pg/ml indicate invasive MTC d. CT levels ⬎250 pg/ml indicate invasive MTC 5. The clinical features of patients with MTC diagnosed after (Group 1) and before (Group 2) the routine use of CT screening were different only by ______________. 6. The incidence of MTC in this study is ________and this may ___________the prevalence of MTC in patients with nodular thyroid disease. Answers 1. 2. 3. 4. 5. 6.
T T b a median age 0.40% and underestimate
Endocrine Thyroid Incidentalomas: A New Epidemic Guest Reviewers: Jamie C. Mitchell, MD, and Sareh Parangi, MD, Department of Surgery, Harvard University, Beth Israel Deaconess Medical Center, Boston, Massachusetts RISK OF MALIGNANCY IN NONPALPABLE THYROID NODULES: PREDICTIVE VALUE OF ULTRASOUND AND COLOR DOPPLER FEATURES. Papini E, Guglielmi R, Bianchini A, et al. J Clin Endocrinol Metab. 2002;87:1941-1946. Objective: To correlate the sonographic [ultrasound (US)] and color-flow-Doppler (CFD) findings with the results of fineneedle aspiration biopsy (FNAB) and pathologic staging of resected thyroid carcinomas. To establish the relative importance of US features as risk factors of thyroid malignancy and develop a cost-effective management strategy for nonpalpable thyroid nodules. Design: Prospective study. Setting: Universita La Sapienza, Rome, Italy. Participants: Four hundred ninety-four consecutive patients (1995 to 2000) with nonpalpable thyroid nodules between 8and 15-mm maximal diameter, either solitary or within a multinodular goiter, chosen from 3500 patients referred to the thyroid clinic at Universita La Sapienza, Rome, Italy. All patients had normal serum levels of TSH and free thyroid hormone (FT3 and FT4). Of the 494 patients included in the study, 64 were males and 430 were females ranging in age from 16 to 84
years (mean, 47.8 ⫾ 13.3). Ninety-two of the 492 patients were dropped from the study after FNAB because of inadequacy of the specimen, leaving 402 patients for statistical analysis. Results: Incidentally detected thyroid nodules were diagnosed by US performed for various reasons, including evaluation of diffuse or multinodular goiter, cervical constriction or pain, doubtful palpation of the thyroid gland on clinical examination, routine follow-up after resection for benign thyroid nodules, hoarseness, carotid artery evaluation, and cervical adenopathy. There was a fairly equal distribution between solitary nodules and nodules contained within a multinodular goiter in the study population, with 195 (48.5%) and 207 (51.5%) respectively. Cytological evaluation after US-guided FNA revealed 306 benign lesions (76.3%), 73 suspicious lesions (18.1%), and 23 malignant lesions (5.7%). The 96 nodules that were either suspicious or malignant by cytological evaluation underwent surgical resection. An additional 11 cases that were initially benign by cytology underwent surgical resection because of increase in nodule size or increased local discomfort at 6-month follow-up, for a total of 107 patients undergoing surgery (26.6%). Of these 107 surgical specimens, histological examination revealed 31 carcinomas (28.9%), 24 follicular adenomas (22.4%), and 52 cases of benign disease (48.6%). When combining histological and cytological diagnoses, the distribution
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8. Yamauchi H, Stearns V, Hayes DF. When is a tumor
marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer. J Clin Oncol. 2001;19: 2334-2356. 9. Yamauchi H, O’Neill A, Gelman R, Carney W, Hosch S,
Hayes D F. Prediction of response to antiestrogen therapy in advanced breast cancer patients by pretreatment circulating levels of extracellular domain of the HER-2/c-neu protein. J Clin Oncol. 1997;15:2518-2525.
2. Mab-based sandwich assays detect elevated levels of ECD of the HER-2 proto-oncogene in approximately what percentage of patients with metastatic breast cancer? a. b. c. d. e.
10. Molina R, Jo J, Filella X, et al. C-erbB-2, CEA and CA
15.3 serum levels in the early diagnosis of recurrence of breast cancer patients. Anticancer Res. 1999;19:25512555.
3. ASCO has recommended: a. Breast cancer patients should be tested with a panel of tumor markers at time of diagnosis only. b. Breast cancer patients should be tested with a panel of tumor markers at time of recurrence only. c. Breast cancer patients should be followed with tumor markers during chemotherapy only. d. All breast cancer patients should be routinely followed with a panel of tumor markers. e. None of the above.
11. Edgerton SM, Moore D, Merkel D, Thor AD. ErbB-2
(HER-2) and breast cancer progression. Appl Immunohistochem Mol Morphol. 2003;3:214-221. 12. Hayes D, Sekine H, Ohao T, Abe M, Keefe K, Kufe DW.
Use of murine monoclonal antibodies for detection of circulating plasma DF3 antigen levels in breast cancer patients. J Clin Invest. 1985;75:1671-1678. 13. Bast RC, Ravdin P, Hayes D, et al. 2000 Update of Rec-
ommendations for the Use of Tumor Markers in Breast and Colorectal Cancer: Clinical Practice Guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001;19:1865-1878.
QUESTIONS AND ANSWERS Questions 1. Which tumor marker does not involve a monoclonal antibody against the MUC-1 mucin? a. CEA b. AFP
5% to 10% 10% to 20% 20% to 40% 40% to 50% 50% to 70%
4. CEA a. Is the “gold standard” for following breast cancer patients. b. Is far more sensitive that any of the MUC-1 associated glycoproteins. c. Is cost effective. d. Is significantly less sensitive than CA 15.3. e. Can be used to screen the general population to establish the diagnosis of breast cancer. Answers 1. 2. 3. 4.
e c e d
Endocrine Medullary Thyroid Cancer: The Controversy Continues Guest Reviewers: Brandon Helbling, MD,*† Kurt Wharton, MS IV, and Michael K. McLeod, MD,*† *Kalamazoo Center for Medical Studies, Michigan State University and †Michigan State University College of Human Medicine, Lansing, Michigan IMPACT OF ROUTINE MEASUREMENT OF SERUM CALCITONIN ON THE DIAGNOSIS AND OUTCOME OF MEDULLARY THYROID CANCER: EXPERIENCE IN 10,864 PATIENTS WITH NODULAR THYROID.
Objective: To determine the prevalence of medullary thyroid
Elisei R, Bottici V, Luchetti F, et al. J Clin Endocrinol Metab.
Setting: Tertiary-Departments of Endocrinology and Metabolism, Oncology, and Surgery at the University of Pisa, Italy;
2004;89:163-168.
cancer (MTC) in thyroid nodular disease and the role of routine measurement of serum calcitonin (CT) on outcome. Design: This is a retrospective cohort study.
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and the Departments of Internal Medicine, Endocrinology and Metabolism and Biochemistry, University of Siena, Italy. Participants: The study included 44 of 10,864 patients seen
in the respective departments between 1991 and 1998 for nodular thyroid disease who were screened for and diagnosed with MTC by serum CT measurement (Group 1), and a historical group of 45 patients with MTC diagnosed from 1970 to 1990 by fine-needle aspirate cytology (FNAC) when screening for MCT was not performed (Group 2). Results: The clinical features of patients with MTC diagnosed after (Group 1) and before (Group 2) the routine use of CT screening were different only by median age. Group 1 patients had a median age of 55 years compared with Group 2 patients who had a median age of 47 years (p ⬍ 0.0001). There were no significant differences with respect to sex, distribution of types of MCT (hereditary versus sporadic disease), or incidence of C-cell hyperplasia (2/44 [4.5%] in group 1 compared with 0/45 in group 2, p ⫽ NS).
MTC in CT-screened Patients (Group 1) Forty-seven of 10,864 patients had elevated basal serum CT levels that ranged from 20 to 6200 pg/ml. In 2 cases, the increased basal CT was caused by chronic renal failure. These 2 patients underwent FNAC, which suggested benign nodular disease and did not undergo surgery. A third patient with a basal CT level of 30 pg/ml (normal ⬍ 20 pg/ml) and a FNAC demonstrating benign nodular disease refused pentagastrin stimulated testing and surgery and was lost to follow-up. The resulting cohort of 44 patients in Group 1 had abnormal peak CT levels after pentagastrin stimulation tests. The clinical diagnosis in these patients was multinodular goiter in 26 (59%), uninodular goiter in 15 (34%), toxic multinodular goiter in 1, an autonomously functioning thyroid nodule in 1, and autoimmune thyroid disease with a dominant nodule in 1 (2.3%). Fine-needle aspirate cytology was suspicious for MTC in 20 of 44 cases (46%), suspicious for undefined malignancy in 9 (20%), suggestive of benign disease in 11 (25%), and inadequate in 4 (9%). These 44 patients underwent total thyroidectomy and central neck compartment dissection. All patients in Group 1 were found to have MTC. The incidence of MTC was 44 of 10,864 (0.40%). There was no case of MTC detected among patients who had normal basal serum CT levels and underwent a thyroidectomy for other reasons. The authors stated that 8 patients (18%) had stage 1, 22 (50%) had stage II, 13 (30%) had stage III, and 1 (2.3%) had stage IV disease. However, the reader should note that this study used an earlier TNM staging classification than the American Joint Committee on Cancer TNM staging of 2002. MTC in Historical Patients Diagnosed and Treated Before Routine CT Screening (Group 2) Fine-needle aspirate cytology was performed on 13 of 45 (29%) patients in Group 2, which suggested MTC in 2 of 13 (15%) and suspicious for an unspecified malignancy in 11 of 13 (85%). In the other 32 patients, the diagnosis was made on final 538
surgical pathology. According to an older TNM classification, no patient in this group had stage 1 disease, 20 patients (45%) had stage II disease, 18 patients (40%) had stage III disease, and 7 (16%) had stage IV disease. This staging was significantly more advanced than the staging observed in group 1 (p ⫽ 0.0004, by 2analysis). Outcome Among MTC patients in Group 1 versus Group 2 Basal serum CT levels became undetectable in 29 of 44 (66%) patients in Group 1, with no response to pentagastrin stimulation in 26 of 29 (90%) and a mild increase in 3 (10%) of these patients after surgical treatment. Basal serum CT was still detectable in 15 patients (34%), although reduced when compared to presurgical levels (Group 1). In Group 2, serum CT values after surgical treatment were available in 36 of 45 (80%) patients and were detectable in all but 1 (97%). The difference between the 2 groups was significant (p ⬍ 0.0001, by Fisher exact test). The mean follow-up was 6.2 ⫾ 2.5 years (range 3-10) in Group 1 and 18.7 ⫾ 5.4 years (range 10-39) in Group 2. Deaths occurred in 2 of 44 (5%) patients in Group 1 and in 25 of 36 (70%) in Group 2. Among the 42 of 44 (96%) patients in Group 1 still alive, 26 (59%) were free of disease with undetectable basal and pentagastrin stimulated serum CT, 6 (14%) had evidence of local or distant disease and elevated serum CT levels, and 10 (23%) had no evidence of disease but detectable basal and pentagastrin-stimulated serum CT levels. Among the 11 of 36 (31%) patients in Group 2 still alive, 1 (3%) was free of disease, 6 (17%) had evidence of local or distant disease and elevated serum CT levels, and 4 (11%) had no evidence of disease, but detectable basal and/or pentagastrin-stimulated serum CT levels. There was a significant difference between the 2 groups (p ⬍ 0.0001, by 2analysis). To correct for the longer follow-up in the historical group, the same analysis was performed considering only the first 6 years of follow-up of Group 2. After 6 years, 14 of 42 (33%) patients in Group 2 were dead of MTC. Among the 28 of 42 patients in Group 2 still alive after 6 years, only 1 (2%) was free of disease and 27 (64%) had evidence of persistent disease. The patients in Group 1 had a significantly better outcome (p ⬍ 0.0001, by 2analysis) after 6 years of follow-up. The survival curves shown in the manuscript demonstrated that, using Kaplan-Mayer analysis of the 2 groups, there was a better survival among Group 1 patients (5-year survival, 98%; 10-year survival, 87%) compared with Group 2 patients (5-year survival, 82%; 10-year survival, 44%) with a p value ⫽ 0.0005, by log-rank test. Conclusions: The routine measurement of basal serum CT levels in patients evaluated for nodular thyroid disease should be considered an important step in the diagnostic algorithm. Calcitonin measurement is specific and may be more sensitive than fine-needle aspiration biopsy (FNAB) of palpable thyroid nodules for MTC. It may prove to be more sensitive than ultrasound-guided FNAB of thyroid nodules for the diagnosis of unsuspected and/or early MTC. The incidence of MTC in this study is 0.40%, and this may underestimate the prevalence of MTC in patients with nodular thyroid disease.
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REVIEWER COMMENTS
This article suffers from limitations that are inherent to all retrospective studies. However, it represents a unique dataset with sufficient power to identify significant differences in study cohorts that typically have too few patients to be confidently analyzed. There are some methodological problems with the study. The authors do not give the actual sizes of the MTCs nor do they describe the extent of involvement for each case so that it is not possible to reclassify these cases using the updated TNM classification. They state that, in Group 1, no case of MTC was detected among patients with normal serum CT levels who underwent surgery for other reasons, but we do not know why those patients underwent surgery and to what extent of surgery they were treated. The institutions involved used a reliable CT assay, but there is no way to evaluate the quality of their cytopathology. No blinded review of all cytology by an unbiased expert in cy-
topathology was performed to confirm the initial cytologic diagnoses upon which much of the comparisons on outcome are based. The possibility of bias still remains despite the author’s attempt to answer some questions that arise from comparing 2 treatment groups from different decades. The much longer period of follow-up in the patients in Group 2 remains a possible source of bias in this study, notwithstanding the normalization of the 2 groups by analyzing the data for similar follow-up periods of 6 years in both groups. Nevertheless, routine screening with basal serum CT measurements appears to identify earlier stage disease in patients with unsuspected MTC. This results in more cases of MTC being identified at earlier stages of disease having a higher likelihood of cure after total thyroidectomy and central compartment nodal dissection combined with unilateral nodal dissection when lymph nodes are involved.
MEDULLARY THYROID CARCINOMA: RESULTS OF A STANDARDIZED SURGICAL APPROACH IN A CONTEMPORARY SERIES OF 80 CONSECUTIVE PATIENTS.
hereditary MTC. Four patients had their initial operation, and 6 were reoperated for persistent (n ⫽ 1) and recurrent (n ⫽ 5) disease at the study institution. Five of the 10 patients subsequently received systemic therapy, and at last follow-up, none of the 10 had developed a cervical recurrence; 6 were alive with disease (AWD), 3 were dead of disease (DOD), and 1 was lost to follow-up. Among the 70 patients without distant metastatic disease (M0), the median age at diagnosis was 41 years (range, 5-78 years), and the median age at the time of operation at M.D. Anderson was 45 years (range, 5-78 years). Forty-five of 70 (64%) had sporadic and 25 (36%) had hereditary MTC. In the patients with sporadic MTC, 37 (82%) had evidence of cervical node involvement, 32 of whom had N1b disease (metastases to unilateral, bilateral, or contralateral cervical, superior or mediastinal lymph nodes) involving levels IIA, III, IV, or V (suggest referring to AJCC 2002 publication or Eng et al1). Disease recurred in 16 of 45 (36%) patients with sporadic MTC 23 months after surgery at study institution. Six patients had isolated cervical recurrences, and all had presented initially with lymph node involvement (N1b ⫽ 5, N1a ⫽ 1). N1a represents metastasis to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian) lymph nodes. All 6 underwent reoperation and are currently alive with no evidence of disease (NED). Isolated distant metastases developed in 7 patients (liver ⫽ 4, bone ⫽ 4, lung ⫽ 2, some patients had isolated distant metastases in more than 1 site), and both cervical and distant recurrences developed in 3 patients (liver ⫽ 3, lung ⫽ 2, and bone ⫽ 2). Of these 10 patients, 2 (20%) presented with T4a disease (tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve) and 9 (90%) presented with N1b (stage IVA) disease. Seven of the 10 patients with distant metastases were AWD, and 3 were DOD at last follow-up.
Yen TW, Shapiro SE, Gagel RF, Sherman SI, Lee JE, Evans DB. Surgery. 2003;134:890-901. Objective: To obtain data on the natural history and pattern of disease progression of MTC after a standardized compartment-oriented approach to surgical management. Design: A retrospective cohort study. Setting: Tertiary-Departments of Surgical Oncology and En-
docrine Neoplasia and Hormonal Disorders, University of Texas M.D. Anderson Cancer Center, Houston, Texas. Participants: A consecutive series of all patients who under-
went a cervical operation for MTC from May 1991 to December 2002. Results: During the period of study, 92 patients underwent
either therapeutic (n ⫽ 75) or prophylactic (n ⫽ 17) cervical operations for either sporadic or hereditary MTC. Five of the 17 patients who underwent prophylactic thyroidectomy had invasive MTC, and 12 had C-cell hyperplasia. Of the 80 patients with invasive MTC, 10 presented with distant metastatic disease (M1) and 70 had disease confined to the neck (M0). The median follow-up was 35 months. Ten patients presented with distant metastases (5 to liver, 3 to lung, 1 to bone, and 1 to an extracervical lymph node) and required a cervical operation for local-regional disease control. The median age of these patients at diagnosis was 33 years (range, 10-60 years), and the median age at time of surgery at M.D. Anderson was 40 years (range, 12-70 years). Four of the 10 had sporadic disease, and 6 had
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The 25 patients with hereditary MTC all had (M0) early stage disease at presentation (21 (84%) had T1, 2 of 25 (8%) had T2, and 1 (4%) had T3, and 1 had Tx disease). Fourteen (56%) patients had N0, 3 (12%) patients had N1a, 4 (16%) patients had N1b, and 4 had Nx disease. The RET protooncogene mutations (RET) were known in 23 of 25 patients and consisted of 10 (43%) mutations at codon 634, 3 (13%) at codon 891, 3 at codon 918, 2 (9%) at codon 609, 2 at codon 620, and 1 (4.5%) each at codons 611, 618, and 804. Only 2 (8%) of the 25 patients had recurrent disease develop at last follow-up. One patient developed a cervical recurrence 8 years after initial operation at the study institution and was treated with a repeated central neck dissection and is NED 24 months after this reoperation. A second patient developed bone metastases 16 months after the initial operation at the study institution, and the patient is currently alive with stable metastatic disease 52 months after the initial operation. Preoperative serum CT levels were available for 66 of the 70 patients (median was 585 pg/ml, and the range was 5 to 39,348 pg/ml). The recurrence rate was higher in the patients with preoperative CT levels equal to or above the median than in those with preoperative CT levels below the median. There were 18 recurrences in the 70 patients; 12 occurred in patients with preoperative CT levels equal to or above the median, and 2 occurred in patients with preoperative CT levels below the median. The remaining 4 recurrences were in patients without available preoperative CT levels. The estimated 5-year recurrence-free survival (RFS) rates were 0.54 and 0.89 for patients with CT levels equal to or above and below the median, respectively (p ⬍ 0.01). Postoperative CT levels were available for 63 of 70 (90%) patients with no distant metastasis (M0 disease). The median was 46 pg/ml, and the range was undetectable to 3410 pg/ml. The recurrence rate was higher in the patients with postoperative CT levels equal to or above the median than in those with postoperative CT levels below the median. The estimated 5-year RFS rates were 0.54 and 0.90 for patients with CT levels equal to or above and below the median, respectively (p ⬍ 0.01). Calcitonin levels were available for 17 of the 18 patients who developed recurrence. The median was 804 pg/ml, and the range was 32 to 36,000 pg/ml. Recurrence was associated with a CT level greater than 250 pg/ml in all but 4 patients, 2 of which had isolated cervical disease and 2 had distant metastases with evidence of tumor dedifferentiation and clinical evidence of rapid tumor progression. Carcinoembryonic antigen (CEA) levels in these 4 patients were normal at the time of recurrence. In contrast, only 5 (11%) patients had CT levels greater than 250 pg/ml among the 46 patients without recurrence, at last follow-up. Prophylactic thyroidectomy was performed in 17 patients (4 with familial MTC, 13 with MEN2) at a median age of 7 years (range, 4 to 30 years) on the basis of DNA analysis for RET mutations in all but 1 patient. Stage 1 invasive MTC was found
540
in 5 (29%) of these 17 patients at a median age of 12 years (range, 5 to 30 years). The median preoperative CT level for these 5 patients was 32 pg/ml (range, 21 to 204 pg/ml). The median preoperative CT level for the patients with normal histology or C-cell hyperplasia was 21 pg/ml (range, 4 to 26 pg/ ml). There was no correlation between preoperative CT levels and finding invasive MTC in patients who underwent prophylactic thyroidectomy. Fifteen patients with elevated CT levels but no clinical evidence of disease underwent a reoperative cervical dissection. The median age of diagnosis was 44 years (range, 9 to 66 years). The median age at time of first operation was 45 years (range, 11 to 66 years). Medullary thryroid cancer was found on histopathology in 12 of 15 (80%). No patient received adjuvant external-beam radiation therapy (EBRT). Four patients developed recurrent disease in the follow-up period, and all were among sporadic MTC. Three of the 4 had stage IVA disease, and cervical recurrences developed in all 3. The fourth patient had stage II disease and developed isolated bone metastases. Twelve of 15 (80%) patients had NED, 2 were AWD, and 1 was DOD at last follow-up. External-beam radiation therapy was delivered to 20 (25%) of the 80 patients with invasive MTC at presentation (13 with M0 disease and 7 with M1 disease) either because they had bulky cervical disease with evidence of extrathyroidal or extranodal soft tissue extension, or because of concern over a microscopically positive margin of resection. External-beam radiation therapy doses ranged from 42 to 76 Gy. External-beam radiation therapy was given after the first operation in 14 patients and after the second operation in the remaining 6 patients. Only 1 of the 14 patients treated with EBRT after 1 operation developed recurrence (cervical) diagnosed 14 months after completing EBRT. This patient who underwent repeat central neck dissection had NED at the completion of the study period. Among the 6 patients who received EBRT after their second operation, none developed a subsequent cervical recurrence. In contrast, cervical recurrence developed in 9 (14%) of the 66 patients who did not receive EBRT after their first operation. Surgical morbidity for this series included resection of the ipsilateral recurrent laryngeal nerve (n ⫽ 3), permanent hypoparathyroidism (n ⫽ 4; which was defined as the need for both calcium and Vitamin D after 6 months postoperatively), postoperative hemorrhage requiring reoperation (n ⫽ 2), chylous fistula (n ⫽ 2), chylothorax (n ⫽ 1), transient palsy of the spinal accessory nerve (n ⫽ 2), and Horner’s syndrome (n ⫽ 1). Conclusions: Complete compartment-oriented surgery can
minimize cervical recurrence. The radiographic evidence of recurrent MTC is unlikely when the serum CT level is less than 250 pg/ml. There is no reliable correlation between preoperative CT levels and finding invasive MTC in a patient undergoing prophylactic thyroidectomy for hereditary MTC.
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REVIEWER COMMENTS
This retrospective study of 92 patients referred to a tertiary care center for the surgical management of biopsy-proven or presumed MTC suggests the following: 1. That death from MTC is uncommon in the absence of clinically evident distant metastases at the time of surgery and that stage of disease at the time of diagnosis is one of the most important prognostic factors for MTC. 2. The likelihood of cervical recurrence can be minimized (13% found in this study) with timely compartment-oriented surgery emphasizing careful nodal dissection. However, the morbidity associated with such dissection, particularly for reoperative surgery is high. For example, the frequency of permanent hypoparathyroidism was 8 of 92 (9%) in this series. 3. The preoperative levels of basal CT cannot be relied on to direct the timing of prophylactic thyroidectomy in at-risk patients with familial MTC, although the postoperative levels of basal CT can be used to guide management of patients with MTC in general. 4. External-beam radiation therapy should be considered in high-risk patients who have undergone compartment-ori-
ented dissections for regionally advanced MTC (stage IVA or greater). This is a controversial matter in the management of MTC, but these authors cite an experience that supports its use in advanced disease. 5. Patients can exhibit rapidly progressive, clinically apparent metastatic disease in the absence of an elevation in serum levels of either the CT or CEA secondary to the dedifferentiation of the MTC tumor. 6. Finally, the approach one takes to surgically manage MTC must be directed by the extent of clinical disease at the time of diagnosis. The authors recommend in patients with sporadic MTC and no clinical evidence of cervical nodal disease that we perform a total thyroidectomy, central compartment dissection, and an ipsilateral modified neck dissection. In patients with sporadic MTC and positive imaging or clinical evidence of cervical disease, the authors recommend total thyroidectomy and central and bilateral neck dissection. In patients with familial MTC and grossly evident cervical nodal disease, they recommend total thyroidectomy, central and bilateral neck dissection.
RATIONALE FOR CENTRAL AND BILATERAL LYMPH NODE DISSECTION IN SPORADIC AND HEREDITARY MEDULLARY THYROID CANCER.
observed in 8 of 12 (67%) of patients with sporadic MTC who had tumors smaller than 1 cm, and in 6 of 27 (22%) of patients with hereditary MTC with tumors smaller than 1 cm. After exclusion of 6 tumors revealed by the presence of palpable lymph node metastases, only 2 of 6 (33%) patients with sporadic MTCs less than 1 cm had unilateral lymph node metastases and 1 of 6 (17%) had contralateral lymph node metastases. Contralateral metastases were observed in 2 of 27 (7%) patients with hereditary MTC and lesions less than 1 cm. An undetectable basal CT level was obtained in 59 of 96 (61%) of patients with MTC, in 41 of 43 (95%) patients with no lymph node involvement (N0 disease), and in 18 of 56 (32%) of patients with lymph node involvement (N1 disease). The ipsilateral, contralateral and the central compartments were involved with the same frequency in patients with either sporadic or hereditary MTC, even in patients with unilateral thyroid lesions. Further, these investigators observed that even with extensive lymph node dissection (total thyroidectomy, central and bilateral lymph node dissections), only 32% of the patients with lymph node metastases in any compartment subsequently demonstrated normal serum calcitonin (CT) levels postoperatively. The postoperative CT level was normal in 95% of patients without lymph node metastases at the initial surgical procedure performed as described (vide ante). A strong correlation was observed between tumor size and the presence of lymph node metastases for both sporadic and hereditary MTC. Permanent hypoparathyroidism occurred in 4% of patients and laryngeal nerve palsy in 5% in this series.
Scollo C, Baudin E, Travagli JP, et al. J Clin Endocrinol Metab. 2003;88:2070-2075. Objective: To clarify the role of lateral lymph node dissection
and further define a protocol for initial surgery in the management of patients with MTC. Design: A retrospective cohort study. Setting: Referral Institution-Institut Gustave-Roussy (IGR),
France. Participants: Patients with medullary thyroid cancer treated and followed from 1964 to 2001. Results: These investigators conducted a retrospective study of
101 patients with MTC in an attempt to identify the frequency and the pattern of cervical lymph node involvement, and to evaluate the complication risks and therapeutic results associated with their current algorithm. The 101 patients all underwent a total thyroidectomy and central and bilateral neck dissection from 1964 to 2001. They observed that 55% of the patients had lymph node metastases. These metastases were found in the central neck compartment (50%), ipsilateral jugulocarotid chain (57%), and contralateral jugulocarotid chain (28%) of patients with sporadic MTC, and 45%, 36%, and 19% of the respective compartments in patients with hereditary MTC. Lymph node involvement was
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Conclusions: These investigators concluded that in patients with MTC, lymph node metastases occur early and that the pattern of lymph node involvement was variable and did not correlate with the size of the tumor. Contralateral lymph node metastases occurred even in patients with small thyroid tumors. These investigators recommend that a total thyroidectomy and central and bilateral neck dissection should be performed in all
patients with sporadic and hereditary MTC even for unilateral tumors smaller than 1 cm in diameter. A contralateral neck dissection may be avoided only in patients with sporadic MTC with a unilateral tumor and no central and ipsilateral lymph node involvement. The number of lymph nodes involved was predictive of a biological cure after surgery.
REVIEWER COMMENTS
These investigators provide reasonable retrospective data that supports the conclusion that an aggressive approach to the management of MTC does not necessarily result in better outcomes. Their experience suggests that MTC with lymph node metastases cannot be cured by surgery alone and
that other therapies, yet defined, may be needed. It appears that the stage of disease at the time of diagnosis is the most critical prognostic factor for the likelihood of cure in a patient with either sporadic or hereditary MTC.
REVIEWER SUMMARY
Medullary thyroid cancer is a rare, neuroendocrine carcinoma that originates from parafollicular C cells within the thyroid gland. The parafollicular C cells are derived from ultimobranchial bodies and are positioned within the middle and upper portions of the lateral thyroid lobes.2 These cells secrete calcitonin, a 32 amino acid polypeptide hormone, which is considered to play a minor role in decreasing serum calcium levels and maintaining bone structure through the inhibition of osteoclastic activity and the augmentation of renal calcium excretion.3 In addition to calcitonin, medullary thyroid cancer cells also secrete several other polypetide hormones and neuroendocrine markers such as CEA, corticotropin, serotonin, vasoactive intestional peptide (VIP), and somatostatin.2-4 Medullary thyroid cancers on gross appearance are typically firm, unencapsulated masses with a gray to tan color on cross section.4 Familial cases of medullary thyroid cancer are characteristically bilateral and multicentric, whereas sporadic neoplasms typically originate in a single thyroid lobe. Microscopically, medullary carcinomas are classically composed of polygonal to round cells in nests or trabeculae with a vascular stroma.4 Eighty percent contain acellular amyloid deposits that are believed to be produced from altered calcitonin gene products.3 Familial cancers also have multiple foci of C-cell hyperplasia in the surrounding thyroid parenchyma. Immunohistochemical staining demonstrates calcitonin (along with CEA and other substances) within the medullary carcinoma cells.2 Although medullary thyroid cancer accounts for less than 10% of all thyroid cancers, it results in 13.4% of all deaths because of thyroid cancer.2 A recent pooled analysis of 67 cases of MTC found a significant association with several risk factors, which included a history of thyroid nodules, hypertension, gallbladder disease, allergies, and women who had a first birth after age 25.5 Medullary thyroid cancer is sporadic (an isolated neoplasm) in 75% to 80% of cases with a mean age at presentation of 49 years, and it is familial in the remaining 20% to 25% of cases with a mean age at presentation of 30 years.2,3 Familial 542
cases are inherited as an autosomal dominant trait with variable, age-related, penetrance linked to chromosome 10. Inherited MTC occurs in 3 distinct clinical subtypes: multiple endocrine neoplasia (MEN) 2A, MEN 2B, and familial medullary thyroid cancer (FMTC). Germline gain-of-function mutations in RET are responsible for at least 92% of cases of MEN 2.6 Multiple endocrine neoplasia 2A (Sipple syndrome) is characterized by pheochromocytomas, parathyroid hyperplasia, MTC, and occasionally, cutaneous lichen amyloidosis and Hirschsprung’s disease.4 In MEN 2A, MTC has a high phenotypic penetrance as it occurs in almost 100% of cases and usually occurs at a younger age than pheochromocytomas (which is present in roughly half of cases) and hyperparathyroidism (which is present in 10% to 20%).2,3 Multiple endocrine neoplasia 2B is a generally a more aggressive condition and usually presents at a younger age (first or second decade) than MEN 2A. In addition to MTC and pheochromocytomas, MEN 2B is associated with a marfanoid habitus and mucocutaneous ganglioneuromas of the conjuctiva, lips, tongue, skin, and intestines.3 Familial medullary thyroid cancer is associated with isolated MTC without other endocrinopathies. Familial medullary thyroid cancer generally presents at a later age (fourth decade) and is the least aggressive of all types of MTC.3 Germline mutations in the RET (rearranged during transfection) proto-oncogene in the pericentromeric region of chromosome 10(10q11.2) have been implicated in the carcinogenesis of inherited MTC.2,3,6 In addition, somatic mutations of the RET proto-oncogene have been found in sporadic MTC.1,4,6 The RET proto-oncogene encodes a cell surface tyrosine kinase receptor for glial-derived neurotrophic factor and is normally expressed in neuroendocrine cells such as the thyroid C cells, parathyroid cells, and chromaffin cells in the adrenal medulla.4 The precise physiological role of the RET expression is unclear; however, it is believed to influence neural crest tissue migration and development.3 The RET mutations implicated in inherited MTC involve a gain of function mutation that ultimately re-
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sults in impaired disulfide bonding between RET molecules and increased activation of the tyrosine kinase receptor.7 These mutations are associated with the development of multifocal C cell hyperplasia. It is not known whether these RET mutations alone are sufficient for the progression to MTC, and it is postulated that a second somatic mutation is required for the progression to carcinoma.3 The RET mutations can be broadly classified into those involving codons of the extracellular/cystein-rich, domain of the receptor and those involving the intracellular/catalytic domain.3,7 However, the association of the type of RET mutation to the expression of a MEN phenotype and the rate of progression from C cell hyperplasia to MTC must be considered separately for each codon mutation.7 Clinical Presentation Medullary thyroid carcinoma occurs in 1 sporadic and 3 hereditary autosomal-dominant forms (familial MTC, MEN 2A and 2B). Sporadic MTC commonly presents as a painless lump in the thyroid. This lump is associated with cervical lympadenopathy that is not always palpable in up to 75% of pa-
tients with MTC.2 The familial MTC, MEN 2A and 2B forms are usually diagnosed while undergoing screening tests after being diagnosed with a neoplasm or having a family member with components of these 3 forms of MTC (see Fig. 1). Diagnosis Ultrasonography is a well established imaging technique in the evaluation of the thyroid gland.2 Tumor size and multiplicity, neck adenopathy, and disruption of adjacent structures can all be evaluated by ultrasound. The ultrasound patterns of MTC and non-medullary thyroid cancer are very similar and cannot distinguish between the different entities.8 Fine needleaspiration cytology has also been an established standard diagnostic tool for thyroid cancer, and MTC is not an exception to the rule. This can be combined with ultrasonography for greater accuracy and diagnosis of MTC. Finally, as MTC is a biochemically active neoplasm that secretes calcitonin, this can be used in the screening, diagnosis, and follow-up of MTC. Serum calcitonin is the most specific and sensitive marker of MTC for both the primary diagnosis and the postsurgical follow-up. Se-
MEDULLARY THYROID CARCINOMA DIAGNOSIS
1. 2. 3. 4. 5.
+ RET
ȣ TT + CeND + ILND (If there is no evidence of CCCLN involvement.) ȣ BND If there is evidence of CCCLN involvement and/or CoLN involvement.
- RET
ȣ Lobectomy + Isthmusectomy (or TT)
Sporadic MTC (75 – 80% of cases)
Elevated Basal Serum Calcitonin (EBSC) {In a patient with normal renal function} Fine – Needle Aspiration Biopsy (FNAB) RET Proto-Oncogene Mutation in Chromosome 10. Nodular Thyroid Disease and EBSC. Family History and any of 1-4.
+ Central Node Dissection (CeND) + Ipsilateral Lymph Node Dissection.
Inherited MTC (20 – 25% of cases) ȣ TT + CeND + BND
CONFIRM DIAGNOSIS OF MTC
or
Familial
ȣ Cervical Lymph Node Dissection
(NON-MEN)
only on side of lymph node involvement (ILND).
MEN II b MEN II a
No gross evidence of disease, surveillance basal serum calcitonin at 4, 12, and 24 weeks. Checked annually in the absence of physical findings/new symptoms.
POSTOPERATIVE MANAGEMENT
Extensive Nodal Involvement and/or Extensive Involvement of Soft Tissues.
+Imaging New Physical Findings or New/Persistent EBSC
IMAGING CAT/MRI/PET/Octreotide Scan/Scinitigraphy
Recommend External Beam Radiation Therapy.
Repeat Neck Dissection to Remove all Gross/Nodal Disease.
EBSC 250
Follow-up Expectantly
Follow-up Expectantly
Follow-up Expectantly
Follow-up Expectantly
-Imaging
EBSC > 250
LEGEND:
BND = Bilateral Cervical Lymph Node Dissection CCCLN = Central Compartment Cervical Lymph Nodes CeND = Central Compartment Cervical Lymph Node Dissection CoLN = Contralateral Cervical Lymph Node(s)
EBSC = Elevated Basal Serum Calcitonin FNAB = Fine-Needle Aspiration Biopsy ILND = Ipsilateral Lymph Node Dissection MTC = Medullary Thyroid Cancer
RET = RET, Proto-Oncogene Mutation, Chromosome 10 (+) RET = Yes RET, Proto-Oncogene Mutation, Chromosome 10 (-) RET = No RET, Proto-Oncogene Mutation, Chromosome 10 TT = Total Thyroidectomy
FIGURE 1. Algorithm. CURRENT SURGERY • Volume 61/Number 6 • November/December 2004
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rum calcitonin is even more sensitive then FNAC in the diagnosis of MTC (see the reviewed article by Elisei et al). Patients whose conditions are diagnosed with MTC should receive computed tomography of the neck and mediastinum. After the diagnosis of MTC, patients should then be screened for RET mutations, and if positive, relatives of the patient can then be screened for MTC and prophylactically treated. Treatment Total thyroidectomy and central neck dissection is recommended for all MTC patients, but the indication for lateral neck dissection is still controversial. The extent of neck dissection varies from the dissection of a clinically and or radiographically positive neck to routine bilateral comprehensive neck dissections.2 This controversy is demonstrated by differing recommendations as follows: (1) Society of Surgical Oncology advocates an ipsilateral neck dissection in sporadic MTC with palpable lateral neck lymph nodes or in patients with involvement of the central neck compartment; (2) National Comprehensive Cancer Network guidelines advocates an ipsilateral modified radical neck for sporadic MTC more than 1 cm in size; (3) German guidelines advocate routine bilateral neck dissection for hereditary MTC and ipsilateral neck dissection for sporadic forms; (4) Other surgeons advocate routine bilateral neck dissection, even in unilateral palpable tumors (see the reviewed articles by Scollo et al and Yen et al). The high incidence of multifocality, the lack of effective adjuvant therapies, and the observation that patients with completely resected disease do better than those with residual disease or with disease that cannot be resected are justifications for aggressive surgical treatment (see the reviewed article by Scollo et al). Patients with positive nodes after complete resection or extensive involvement of the surrounding soft tissues structures should receive adjuvant radiation therapy although this remains controversial. Calcitonin should be measured preoperatively, approximately 4 weeks postoperatively, and at regular intervals thereafter to assess recurrence. Miyauchi et al reported on 72 patients with MTC whose retrospective data were analyzed, and the genetic nature and clinical features of their MTCs were established. Fifteen patients with nonhereditary MTC were then treated with a unilateral surgery policy. This study group was found to have an 80% biochemical cure rate postoperatively. This outcome was compared with that of a control group of 22 patients who were retrospectively analyzed and found to have a 68% biochemical cure rate. There were no significant demographic differences between the 2 groups. The results of this study indicated that in patients with sporadic or nonhereditary MTC with no detectable RET mutations, hemithyroidectomy with systematic central and ipsilateral neck dissection is appropriate.9 In conclusion, medullary thyroid carcinoma of the thyroid is a rare form of thyroid malignancy that kills on rare occasion irregardless of whether it is sporadic or hereditary in nature. It may be that all forms of this thyroid neoplasm have an identifiable genetic mechanism, even sporadic disease, which eventu544
ally may prove to be a useful device for treatment or gene therapy. The most important predictor of cure, recurrence, and poor outcome is the stage (TNM) of disease at the time of the initial diagnosis. The extent of surgery that is optimal remains controversial, but it is well established that the removal of all gross disease and lymph node involvement at the initial operation is the best chance to achieve a curative resection. Adjuvant forms of therapy that are the most useful and efficacious have yet to be identified. doi:10.1016/j.cursur.2004.07.001
REFERENCES 1. Eng C, Clayton D, Schuffenecker I, et al. The relationship
between specific RET proto-oncogene mutations and disease phenotype in multiple enocrine Neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996;276:1575-1579. 2. Clayman GL, El-Baradie TS. Medullary thyroid cancer.
Otolaryngol Clin N Am. 2003;36(1):91-105. 3. Randolph GW, Maniar D. Medullary carcinoma of the
thyroid. Cancer Control. 2000;7:253-261. 4. Cotran RS, Kumar V, Collins T, editors. The endocrine
system. In: Robbins Pathologic Basis of Disease. 6th ed. New York: W.B. Saunders Company; 1999:1121-1169. 5. Negri E, Ron E, Franceschi S, et al. Risk factors for medul-
lary thyroid carcinoma: a pooled analysis. Cancer Causes Control. 2002;13:365-372. 6. Fernández RM, Robledo M, Antinolo G, et al. The RET
IVS1-126G⬎T variant is strongly associated with the development of sporadic medullary thyroid cancer. Thyroid. 2004;14:329-331. 7. Machens A, Niccoli-Sire P, et al. Early malignant progres-
sion of hereditary medullary thyroid cancer. N Engl J Med. 2003;346:1517-1525. 8. Saller B, Moeller L, Gorges R, et al. Ultrasonography of
medullary thyroid carcinoma. Exp Clin Endocrinol Diabetes. 2002;110:403-407. 9. Miyauchi A, Matsuzuka F, Hirai K, et al. Prospective trial of
unilateral surgery for nonhereditary medullary thyroid carcinoma in patients with out germline RET mutations. World J Surg. 2002;26:1023-1028.
QUESTIONS AND ANSWERS Questions 1. T or F: A contralateral neck dissection may be avoided only in patients with sporadic MTC with a unilateral tumor and no central and ipsilateral lymph node involvement.
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2. T or F: A total thyroidectomy and central and bilateral neck dissection should be performed in all patients with sporadic and hereditary MTC even for unilateral tumors smaller than 1 cm in diameter. 3. The radiographic evidence of recurrent MTC is unlikely when the serum CT level is: a. b. c. d. e.
ⱕ150 pg/ml. ⱕ 250 pg/mL ⱖ250 pg/ml ⱖ500 pg/ml ⱖ1000 pg/ml
4. What is the correlation between preoperative CT levels and finding invasive MTC in a patient undergoing prophylactic thyroidectomy for hereditary MTC? a. No correlation b. CT levels ⬍50 pg/ml indicate no invasion
c. CT levels ⬎50 pg/ml but ⬍100 pg/ml indicate invasive MTC d. CT levels ⬎250 pg/ml indicate invasive MTC 5. The clinical features of patients with MTC diagnosed after (Group 1) and before (Group 2) the routine use of CT screening were different only by ______________. 6. The incidence of MTC in this study is ________and this may ___________the prevalence of MTC in patients with nodular thyroid disease. Answers 1. 2. 3. 4. 5. 6.
T T b a median age 0.40% and underestimate
Endocrine Thyroid Incidentalomas: A New Epidemic Guest Reviewers: Jamie C. Mitchell, MD, and Sareh Parangi, MD, Department of Surgery, Harvard University, Beth Israel Deaconess Medical Center, Boston, Massachusetts RISK OF MALIGNANCY IN NONPALPABLE THYROID NODULES: PREDICTIVE VALUE OF ULTRASOUND AND COLOR DOPPLER FEATURES. Papini E, Guglielmi R, Bianchini A, et al. J Clin Endocrinol Metab. 2002;87:1941-1946. Objective: To correlate the sonographic [ultrasound (US)] and color-flow-Doppler (CFD) findings with the results of fineneedle aspiration biopsy (FNAB) and pathologic staging of resected thyroid carcinomas. To establish the relative importance of US features as risk factors of thyroid malignancy and develop a cost-effective management strategy for nonpalpable thyroid nodules. Design: Prospective study. Setting: Universita La Sapienza, Rome, Italy. Participants: Four hundred ninety-four consecutive patients (1995 to 2000) with nonpalpable thyroid nodules between 8and 15-mm maximal diameter, either solitary or within a multinodular goiter, chosen from 3500 patients referred to the thyroid clinic at Universita La Sapienza, Rome, Italy. All patients had normal serum levels of TSH and free thyroid hormone (FT3 and FT4). Of the 494 patients included in the study, 64 were males and 430 were females ranging in age from 16 to 84
years (mean, 47.8 ⫾ 13.3). Ninety-two of the 492 patients were dropped from the study after FNAB because of inadequacy of the specimen, leaving 402 patients for statistical analysis. Results: Incidentally detected thyroid nodules were diagnosed by US performed for various reasons, including evaluation of diffuse or multinodular goiter, cervical constriction or pain, doubtful palpation of the thyroid gland on clinical examination, routine follow-up after resection for benign thyroid nodules, hoarseness, carotid artery evaluation, and cervical adenopathy. There was a fairly equal distribution between solitary nodules and nodules contained within a multinodular goiter in the study population, with 195 (48.5%) and 207 (51.5%) respectively. Cytological evaluation after US-guided FNA revealed 306 benign lesions (76.3%), 73 suspicious lesions (18.1%), and 23 malignant lesions (5.7%). The 96 nodules that were either suspicious or malignant by cytological evaluation underwent surgical resection. An additional 11 cases that were initially benign by cytology underwent surgical resection because of increase in nodule size or increased local discomfort at 6-month follow-up, for a total of 107 patients undergoing surgery (26.6%). Of these 107 surgical specimens, histological examination revealed 31 carcinomas (28.9%), 24 follicular adenomas (22.4%), and 52 cases of benign disease (48.6%). When combining histological and cytological diagnoses, the distribution
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