Excellent Prognosis of Patients with Nonhereditary Medullary Thyroid Carcinoma with Ultrasonographic Findings of Follicular Tumor or Benign Nodule
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- Fukushima, M., Ito, Y., Hirokawa, M. et al. World J Surg (2009) 33: 963. doi:10.1007/s00268-009-9939-z
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Medullary thyroid carcinoma (MTC) accounts for only 1.4% of all thyroid malignancies in Japan. Generally, MTC shows ultrasonographic findings typical of thyroid carcinoma. However, in our experience, some MTC may be diagnosed as a follicular tumor or a benign nodule on ultrasonography because ultrasonographic findings of malignancy are lacking. In this study we investigated differences in biological behavior between these two types of MTC.
Seventy-seven patients with nonhereditary MTC who underwent surgery in our department between 1988 and 2007 were enrolled in this study. Of these patients, 54 were diagnosed as having thyroid carcinoma (malignant, or M-type) but the remaining 23 were diagnosed as having follicular tumor or benign nodule (benign, or B-type) on ultrasonography.
Clinically apparent lateral node metastasis, extrathyroid extension, and extranodal tumor extension were observed in 37%, 17%, and 11% of M-type patients, respectively, but none of the B-type patients showed any of these features. All B-type patients but only 59% of M-type patients were biochemically cured. Lymph node metastasis was pathologically confirmed in 38 and 65% of B-type and M-type patients, respectively. Eight patients showed recurrence and three have died of carcinoma to date; all of these patients were M-type patients.
B-type MTC is highly indolent and shows an excellent prognosis. However, thyroidectomy and lymph node dissection for B-type MTC should be the same as for M-type MTC because 38% of B-type MTC showed pathologic node metastasis.
Medullary thyroid carcinoma (MTC) is a comparably rare malignancy originating from calcitonin-producing cells (C cells) of the thyroid. It accounts for only 1.4% of all thyroid malignancies in Japan and 3-10 % of those in Western countries [1–5]. Approximately 75% of MTC patients do not have any family history of the disease, while the remaining expressed a hereditary autosomal dominant trait based on the germline RET gene mutation . Hereditary forms of medullary carcinoma consist of three types [7–9]: (1) multiple endocrine neoplasia type 2A (MEN 2A), medullary carcinoma with pheochromocytoma and hyperparathyroidism; (2) MEN 2B, medullary carcinoma with pheochromocytoma, ganglioneuromas, and marfanoid habitus; and (3) familial medullary carcinoma (FMTC) in the absence of other endocrinopathy or neural abnormality. Previous reports demonstrated that nonhereditary MTC had a worse prognosis than hereditary MTC except MEN 2B [10–15].
Recently, the resolution of ultrasonographic images has drastically improved, facilitating not only detection but also qualitative diagnosis of thyroid nodules. In our department we have evaluated nodules subject to our classification system for stratifying nodules into classes 1–5 [16, 17]: class 1, round or oval anechoic lesion; class 2, regular-shaped nodule with cystic change (the echo level of a solid lesion is similar to that of a normal thyroid); class 3, solid and regular-shaped nodule (internal echo is homogeneous or may have strong echoes internally or at the capsule); class 4, solid and regular-shaped nodule (internal echo is usually low and may have fine strong echoes internally); class 5, solid and irregular-shaped nodule with extrathyroid extension. Intermediate steps of 0.5, e.g., class 3.5, are permitted for nodules with indeterminant features. Typically, classes 1–3 indicate cyst, adenomatous nodule or nodular goiter, and follicular tumor, respectively. Nodules classified as 3.5 or greater were ultrasonographically diagnosed as malignant, i.e., papillary, medullary, or anaplastic carcinoma. As previously described, the positive predictive value of ultrasonographic diagnosis of thyroid carcinoma was 97% [16, 17].
After ultrasonography, fine-needle aspiration biopsy (FNAB) was routinely performed, and when the nodule was cytologically suspected of MTC, serum calcitonin and carcinoembryonic antigen (CEA) were measured to confirm the diagnosis. If the nodule was diagnosed as MTC using these diagnostic techniques, ret gene mutation analysis was routinely performed.
However, in our experience, some MTC showed ultrasonographic findings similar to those of follicular tumor or benign nodule that were classified as class 3 or lower in our classification system. Furthermore, cytologic diagnosis of MTC is not always easy, although there are some specific cytologic findings such as dispersed cell pattern of polygonal or triangular cells, azurophilic cytoplasmic granules, and amyloid [18, 19], and calcitonin measurement in FNAB specimens was recently reported to be useful for diagnosis of MTC . Therefore, it is possible that patients with MTC will be diagnosed as having benign nodule and undergo a limited thyroidectomy only without lymph node dissection if neither ultrasonography nor cytologic examination can demonstrate the malignant potential of their tumor. In this study we investigated differences in biological characteristics, including prognosis, between nonhereditary MTC with ultrasonographic findings typical of thyroid carcinoma and that with findings of follicular tumor or benign nodule.
Patients and methods
Between 1988 and 2007, 122 patients with MTC underwent initial surgery in Kuma Hospital. The ret gene mutation analysis was performed preoperatively for all but five patients who were not diagnosed as having MTC preoperatively. Patients who were treated after November 1995 underwent the analysis preoperatively, whereas the analysis was performed postoperatively for patients who underwent surgery before that date. The five patients who were not diagnosed as having MTC preoperatively and had not undergone ret mutation analysis underwent the analysis after surgery and were confirmed as having sporadic MTC at last. Finally, of these patients, 78 were diagnosed with nonhereditary MTC because they did not demonstrate any ret gene mutations. One patient who was transferred to another hospital due to cerebral hemorrhage 3 days after surgery was excluded, and the remaining 77 were enrolled in this study. They consisted of 20 males and 57 females with an average age of 55.8 ± 14.0 years.
Classification of 77 patients based on ultrasonographic findings
All patients underwent ultrasonography preoperatively. Those images were re-reviewed. Fifty-four of these patients were diagnosed as having malignancy on ultrasonography and their lesions were classified as the M-type, based on a score of 3.5 or more in our classification system . Two of these patients were misdiagnosed as having malignant lymphoma and papillary or follicular carcinoma on FNAB, but the remaining 52 were diagnosed as having MTC on FNAB and high levels of serum CEA and calcitonin. Twenty-three patients showing a regular-shaped solid nodule with homogeneous internal echo were diagnosed as having follicular tumor or benign nodule on ultrasonography; the lesions were classified as B-type. Eighteen of these patients were diagnosed as having MTC on FNAB followed by measurement of serum CEA and calcitonin levels, but the remaining five were diagnosed as having benign nodules also on FNAB and underwent surgery with a preoperative diagnosis of follicular tumor or benign nodule.
Therapeutic strategy for MTC in our department
Extent of resection of 77 patients
B-type (23 patients) (%)
M-type (54 patients) (%)
Total or near total
Lobectomy with isthmectomy
Lymph node dissection
Postoperative evaluation of recurrence
Postoperative follow-up and evaluation of recurrence in our department were described previously . Briefly, about 1 week after surgery, we routinely measured calcitonin levels before and after stimulation by calcium gluconate with or without tetragastrin [22, 23]. We classified patients as being biochemically cured when basal calcitonin was within the normal range and the peak calcitonin level was less than threefold greater than basal calcitonin, as described previously [22, 23]. One patient showed clinically apparent distant metastasis at surgery. Of the remaining 76 patients, 55 (70%) were diagnosed as biochemically cured.
Serum CEA and calcitonin levels were measured 2–4 times per year. Systematic imaging studies were not performed for patients who were diagnosed as biochemically cured and without postoperative elevation of serum CEA and calcitonin. In patients with elevated serum CEA and calcitonin levels, imaging studies such as ultrasonography and CT scan were also performed. Postoperative follow-up periods averaged 83 months (range = 6–234 months). In this study we regarded patients as having carcinoma recurrence when carcinoma recurrences were observed on imaging studies. If carcinoma recurrence was clinically detected either in the cervical or mediastinal lymph nodes, reoperation was recommended. For metastasis in the distant organs or in the lymph nodes that could not be surgically dissected, external beam radiation therapy was considered. To date, three patients underwent radiation therapy for metastases to the bone and mediastinal lymph nodes. Chemotherapy was not performed in principle.
To date, eight patients have shown carcinoma recurrence and all of these patients showed elevation of serum CEA and calcitonin levels. The organs in which carcinoma recurred were the lymph node in six patients, bone in two patients, lung in three patients, and liver in one patient. Three patients showed recurrence in two or more organs. To date, three patients, including one with distant metastasis at diagnosis, have died of carcinoma.
Fisher’s exact test was used to compare variables. The Kaplan-Meier method and log rank test were adopted to analyze time-dependent variables. These analyses were performed using StatView-J 5.0. A p value less than 0.05 was regarded as significant.
Relationship between ultrasonographic type of MTC and clinicopathologic features
53.6 ± 27.4
56.7 ± 12.8
3 (13)/20 (87)
17 (31)/37 (69)
N status (N1b/N0, N1a)a
20 (37)/34 (63)
Tumor size (cm)
3.2 ± 1.3
2.2 ± 1.4
Extrathyroid extension (+/−)
9 (17)/45 (83)
Extranodal tumor extension (+/−)
6 (11)/48 (89)
pN status (pN1/pN0)a
5 (38)/13 (62)
35 (65)/19 (35)
(5 cases unknown)
Biochemical cure (−/+)
22 (41)/32 (59)
All B-type MTC patients, including five who did not undergo lymph node dissection, and 32 (59%) M-type MTC patients were biochemically cured. To date, eight patients had carcinoma recurrence on imaging studies and three patients, including one with distant metastasis at surgery, have died of carcinoma, but all of these patients were M-type.
We previously demonstrated the prognosis for and prognostic factors of 122 MTC patients who were treated in our department between 1975 and 2005 . The prognosis for MTC patients in our series was better than in Western countries [3, 4, 10–14, 25–30]; 10-year and 20-year disease-free survival rates were 89.0% and 82.5%, respectively, and 10-year and 20-year cause-specific survival rates were 96.6% and 91.7%, respectively. This may be partially because of our routine MND together with central node dissection regardless of whether clinically apparent node metastasis is detected. To date, in Western countries several prognostic factors such as age, gender, and extrathyroid extension have been identified [3, 4, 10–14, 25–30]. We have also shown that clinically apparent and pathologically confirmed lymph node metastases, tumor size larger than 4 cm, extrathyroid extension, extranodal tumor extension, and biochemical cure significantly affected the prognosis of MTC patients in Japan .
Recent advances in the resolution of ultrasonography has facilitated the qualitative diagnosis of thyroid nodules, and we previously demonstrated that the positive predictive value of ultrasonographic diagnosis of thyroid carcinoma, including MTC, was very high at 97% . In this study, however, 23 of 77 nonhereditary MTC patients (30%) lacked ultrasonographic findings typical for thyroid carcinoma and were diagnosed with having follicular tumor or benign nodule on ultrasonography (classified as the B-type in this study). Furthermore, five of these patients (22%) were also diagnosed with benign nodule or follicular tumor on FNAB, while 52 of 54 patients (96%) with M-type MTC were diagnosed with MTC on FNAB. It is therefore suggested that B-type MTC is difficult to diagnose not only on imaging studies but also on cytologic examination.
Interestingly, the biological characteristics of B-type MTC significantly differed from those of M-type MTC. Although the tumor of B-type was larger than that of M-type, none of the B-type patients showed clinically apparent node metastasis or extrathyroid and extranodal tumor extensions, which were significant prognostic factors of MTC . Furthermore, all of the B-type patients were biochemically cured, including five who did not undergo lymph node dissection. Regarding patient prognosis, none of the B-type patients had recurrence or died of carcinoma, while eight patients with M-type MTC had carcinoma recurrence and three died of carcinoma. These findings strongly suggest that although the follow-up periods were shorter than those of our previous study , B-type MTC has a more indolent character than M-type MTC. Because five patients with B-type MTC who underwent thyroidectomy without lymph node dissection based on the preoperative diagnosis of benign nodule or follicular tumor were biochemically cured and did not show recurrence, additional surgery such as total thyroidectomy and lymph node dissection may not be mandatory for B-type patients misdiagnosed as having benign nodule, if their MTC are nonhereditary and they are biochemically cured.
Although clinically apparent node metastasis was not observed in B-type patients, 5 of 13 patients (38%) demonstrated lymph node metastasis on pathologic examination. Furthermore, of the five patients with B-type MTC who were positive for lymph node metastasis, three had metastasis in the lateral compartment. We previously demonstrated that MTC metastasizes independently to the central and lateral compartments because the incidence of lateral-positive and central-negative patients did not differ from that of lateral-negative and central-positive patients . Complete surgical resection for MTC patients is more important than for patients with papillary or follicular carcinoma, because radioiodine ablation therapy and thyroid stimulating hormone (TSH) suppression are not effective for MTC patients. Therefore, lymph node dissection of not only the central compartment but also the lateral compartment together with thyroidectomy would also be recommended for B-type patients, when their nodules are preoperatively diagnosed as MTC.
In summary, we demonstrated the difference in biological characteristics between patients with MTC who have typical findings of thyroid carcinoma and those diagnosed with follicular tumor or benign nodule on ultrasonography. The latter is a highly indolent disease and has an excellent prognosis, although thyroidectomy with central node dissection and MND is still recommended for surgical treatment. Further studies, including those using molecular biological methods, are needed to find the reason for the difference in biological behavior between these two types of MTC.