© Springer International Publishing Switzerland 2016
David S. Cooper and Cosimo Durante (eds.)Thyroid Cancer10.1007/978-3-319-22401-5_44. Incidentally Discovered Micropapillary Thyroid Cancer
(1)
Thyroid Unit WAC 730 S, Massachusetts General Hospital, Boston, MA 02114, USA
Keywords
Thyroid cancerPapillary thyroid cancerMicropapillary thyroid cancerBRAFThyroidectomyRadioiodineThyroid hormone suppressionThyrotropinTSHCase Presentation
A 49-year-old woman presented to her primary care physician with a chronic nonproductive cough of 3-month duration. A chest CT scan showed a 12 mm right thyroid nodule. Thyroid ultrasound showed a right 15 × 8 × 7 mm hypoechoic nodule with mild central vascularity but no microcalcifications. Several other 3–5 mm nodules were noted in both lobes, none with suspicious ultrasonographic characteristics. Fine-needle aspiration cytology of the dominant nodule was read as follicular lesion of uncertain significance. The sample was composed of approximately equal numbers of micro- and macrofollicles. There was no nuclear atypia. Three months later, the nodule measured 16 × 7 × 7 mm. Repeat fine-needle aspiration cytology was again read as a follicular lesion of uncertain significance. The sample was assessed by a gene expression classifier and was felt to be suspicious. The patient had a right hemithyroidectomy . The pathology revealed a 12 mm follicular adenoma composed of mixed micro- and macrofollicular tissue. There was an incidental 5 mm intrathyroidal micropapillary thyroid cancer. Six weeks after her surgery, the patient had a serum TSH of 1.6 mIU/L.
Assessment and Literature Review
Micropapillary thyroid cancer is an extremely common neoplasm associated with an excellent prognosis. Our knowledge of this tumor comes from both retrospective clinical series and prospective observational trials. Both argue for conservative management.
Definition
Thyroid micropapillary cancers are defined by the World Health Organization as papillary cancers that measure 10 mm or less in their largest diameter. The increasing incidence of thyroid cancers of all sizes has been attributed in part to both the increased use and increased sensitivity of imaging used for assessing non-thyroid-related problems. The incidental findings of a thyroid nodule on chest CT, carotid Doppler study, or neck MRI are common examples of the incidental detection of thyroid nodules. Since microcarcinomas are rarely palpable, they are usually discovered in this manner or on a neck ultrasound ordered to assess a palpable nodule or goiter. The term “incidental,” when applied to micropapillary cancer, refers to cancers that were not identified preoperatively and are found unexpectedly in the postsurgical pathology specimen.
Prevalence
Prevalence data for micropapillary cancer come from autopsy data. In the United States 6–13 % of the population are found to have micropapillary cancers [1], while percentages as high as 36 % have been reported in Finland [2]. In a series from Sweden, the prevalence was 7 % for patients under age 50 or over age 80 [3]. In a series from Wisconsin, 3 % of young adults had micropapillary cancers [4]. It is therefore not surprising that incidental micropapillary cancers are found in 2–24 % of surgical pathology specimens [5].
Retrospective Studies
There are many institutional as well as registry-based reports regarding outcome in patients with micropapillary cancer. A series from the Mayo Clinic of 900 patients has an average follow-up of 17.2 years (range 6–89 years) [6]. At presentation, 23 % were multifocal, 30 % had cervical lymph node involvement, 2 % had extrathyroidal extension, and only 0.3 % had distant metastases. The 40-year cause-specific mortality was 0.7 %. The recurrence rate was 8 %—1.5 % in the thyroid bed and the remainder in cervical nodes. Recurrences were more common in patients with nodes at presentation: 16 vs. 0.8 %. Recurrences were also more common in patients with multifocal disease: 11 vs. 4 %. The recurrence rates were not diminished with postoperative radioiodine therapy.
Similar data have been reported from Japan. The Noguchi Thyroid Clinic series of 2070 patients has an average follow-up of 15 years [7]. The authors report recurrences in only 3.5 % of patients and distant metastases in only 0.2 % of patients.
The National Thyroid Cancer Treatment Cooperative Study Group maintains a registry of thyroid cancer patients from 11 centers in North America. A report of 611 patients with intrathyroidal micropapillary cancer who were disease-free after initial therapy found a recurrence rate of 6.2 %, almost all in the neck [8]. Distant metastases occurred in one patient (0.2 %) and mediastinal nodes in two patients (0.3 %). Half of the recurrences occurred in the first 2.8 years. Recurrence was more common in patients with multifocal disease who had only a hemithyroidectomy (18 vs. 6 %), but as in the Mayo Clinic experience, recurrence was not reduced by adjunctive radioiodine treatment.
Observational Studies
Because micropapillary thyroid cancer has a near-negligible mortality rate and low recurrence rate, and because cervical node recurrences are not life-threatening, two groups of investigators from Japan have published observational data on micropapillary thyroid cancer. Ito et al. have reported on 1235 patients, after excluding those with tumors adjacent to the trachea, those possibly invading the recurrent laryngeal nerve, and those associated with high-grade histology or central or lateral compartment lymph nodes [9, 10]. Twenty eight percent had multifocal tumors. These patients have been observed for an average of 5 years, but some as long as 19 years. After 10 years of observation, only 8 % of the tumors grew by 3 mm or more, and only 3.8 % have developed lateral compartment nodes. Among the 191 patients who had surgery after a period of observation because of tumor growth, the development of lateral nodes, or patient preference, no one has died, no one has developed distant metastases, and one patient has had a recurrence in a thyroid remnant, which is being observed.
In another Japanese study of 230 patients, 7 % of the tumors grew by 3 mm or more, and only 1 % of tumors were associated with new nodal metastases during a mean observation period of 5 years [11].
Incidental Versus Non-incidental Tumors
A meta-analysis of 17 studies that identified tumors as incidental or non-incidental included 854 incidental and 2669 non-incidental micropapillary cancers with an average follow-up of 70 months [12]. At presentation, the non-incidental tumors were larger (6.9 vs. 4.6 mm), were more likely to be multifocal (30 vs. 19 %), and have lymph node metastases (30 vs. 2.6 %). The patients with non-incidental tumors were more likely to have had a total thyroidectomy (59 vs. 51 %) and to have received radioiodine (47 vs. 33 %).
Overall recurrence was 7.9 % in the non-incidental group and 0.45 % in the incidental group. However, a disproportionate number of recurrences were recorded in two small studies (including 129 patients); exclusion of these reduced the recurrence rate in the non-incidental group to 4 %. All four recurrences in the incidental group were in cervical lymph nodes. Mortality was 0.1 % in the non-incidental group; no one died in the incidental group. Thus, incidentally discovered micropapillary cancer has an even better prognosis than that of non-incidental tumors.
BRAF
BRAF mutations have recently been associated with increased aggressiveness in papillary thyroid cancers. The V600E mutation was found in 53 % of papillary cancers in a South Korean study [13]. Cancers that had the mutation were more likely to have extracapsular invasion, cervical nodes, or advanced stage. In an Italian study of 134 patients with micropapillary cancers, disease persistence was found in 12 % of patients who had the BRAF mutation vs. 2 % with wild-type BRAF [14]. In a multicenter study, the BRAF mutation was associated with increased mortality, but after adjusting for extracapsular invasion, and nodal and distant metastases, the BRAF mutation did not add any additional risk [15]. In that study, 435 patients had micropapillary cancers, and while their presenting characteristics are not separately reported, overall mortality for patients with micropapillary cancer was 0.9 %, but all patients who died had the BRAF mutation (2.4 % of those with the mutation).
Management of the Case
It should be evident from the forgoing discussion that micropapillary thyroid cancer is associated with an excellent prognosis. While rare patients do present with or develop distant metastases, or die, these unusual patients can frequently be identified as high-risk at presentation, and this information is hard to extract from published series. For example, in the Mayo Clinic series [6], of the three patients who died, all had lymphadenopathy at presentation (massive in one patient), and one had pulmonary metastases at presentation. In the National Thyroid Cancer Treatment Cooperative Study Group report [8], one death occurred in a patient who had anaplastic transformation of the tumor.
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