The incidence of thyroid cancer diagnoses has tripled over the past 30 years [
In light of recent important changes in thyroid pathological classification, we sought to retrospectively evaluate our community endocrine surgical experience with noninvasive EFVPTCs over the past 45 months. Based on our clinical, ultrasound, and fine needle aspiration biopsy cytology data, we propose an algorithm for surgical management in suspected noninvasive EFVPTC patients.
We queried the Memorial Center for Endocrine Surgery Registry for fully encapsulated follicular variant of papillary cancer diagnoses from January 2012 through September 2016. All these tumors were removed by a single surgeon, DNB, and had pathologic diagnoses rendered by a single pathology group serving our six-hospital consortium with a patient referral base encompassing South Florida and the Caribbean (Memorial Health Systems). Neck ultrasound evaluation was performed by AG or RMH for 36 out of 37 patients (97% of patients). Thyroid fine needle aspiration (FNA) biopsies were performed by AG or RMH in 15 thyroid nodules (40.5%) with 15 nodule FNAs (40.5%) performed by outside physicians. Seven nodules (19%) were not biopsied prior to removal. Cytology was read by Thyroid Cytopathology Partners of Austin, Texas, in 51% of cases and a combination of CBL and other community reference laboratory cytopathologists in 49%.
Tumors in which the pathologist identified any vascular invasion or any capsular discontinuity or invasion were excluded from consideration in this report. Isolated subcentimeter encapsulated follicular variant of papillary tumors (EFVPTC) that were incidentally noted by the pathologist following surgery for another indication (symptomatic goiter, other larger non-EFVPTC tumors) were excluded. In addition, tumors without ultrasound data were excluded (one patient).
We systematically reviewed electronic medical records on each of the subjects to confirm that ultrasound, cytology, and pathology reports were concordant on a nodule-by-nodule basis.
Twelve hundred and ten unique patients underwent thyroid surgery at the Memorial Center for Integrative Endocrine Surgery from January 2013 through September of 2016, of which 796 demonstrated nonincidental thyroid malignancies. Of these, 413 (52%) were follicular variant of papillary cancers (FVPTC). Eighty-eight (21%) of the FVPTC tumors were fully encapsulated (EFVPTC) and 50 (12%) were fully encapsulated with no evidence of capsular or vascular invasion and were considered noninvasive EFVPTC. In these fifty patients, neither capsular invasion, vascular invasion, nor papillary architectural features were identified in the primary tumor pathology report. Twelve of these tumors were excluded because they were subcentimeter incidental lesions discovered by our pathologists in thyroid glands removed for other reasons (symptomatic goiter or larger non-EFVPTC tumors). One tumor was excluded due to the absence of ultrasound data. Thus 37 out of 796 (4.6%) of our resected thyroid malignancies were found to meet our inclusion criteria as noninvasive encapsulated follicular variant of papillary thyroid cancers removed by our surgeon from 1/2013 to 9/2016. Thirty-seven tumors of interest were found in 37 patients.
In our practice, the typical noninvasive EFVPTC tumor patient had an average age of 44 years. Twenty-nine of the 37 patients were female (78%).
On neck ultrasound, noninvasive EFVPTC nodules had a mean diameter of 3.1 cm in greatest dimension (range 0.8 cm–6.9 cm with a median size of 3 cm). Nodules were evenly distributed throughout the thyroid with 18 (49%) in the right lobe, 17 (46%) in the left lobe, and 2 (5%) in the isthmus. Echogenicity was variable, with 9 (24%) read as hypoechoic, 21 (57%) read as isoechoic, and 7 (19%) described as heteroechoic on ultrasound. Thirty-three nodules (89%) were solid and 4 (11%) were described as partially cystic. Borders were sharp and well defined in 34 nodules (92%). Three nodules had hypoechoic halos (8%). Thirty-six nodules (97%) lacked intranodular calcifications, whereas intranodular arcuate calcification was described in one nodule. Twelve nodules (32%) demonstrated grade 1 vascularity as assessed by Power Doppler, 11 nodules had grade 2 vascularity (30%), and 14 nodules had grade 3 vascularity (38%). No nodules had grade 4 vascularity. The mean vascularity grade was 2.1.
Thirty patients out of 37 (81%) underwent fine needle aspiration biopsy prior to surgery. Seven patients were referred directly to surgery based on sonographic findings alone. Eight nodules (27%) yielded benign cytological results (Bethesda 2), 14 (47%) nodules demonstrated atypia of uncertain significance (Bethesda 3), and 8 (27%) nodules were read as follicular neoplasm/suspicious for follicular neoplasm (Bethesda 4). Nondiagnostic, suspicious for malignancy, or frankly malignant cytological results (Bethesda 1, Bethesda 5, and Bethesda 6) were not encountered (Table
Demographics, US, surgery and pathology results in 37 noninvasive EFVPTC patients.
Patient | Gender | Age | EFVPTC size (cm) | Echo type | Cytology | Afirma GEC | Operation | Nodes | Other cancer |
---|---|---|---|---|---|---|---|---|---|
|
F | 34 | 6.1 | Iso | FN/SFN | TT | 0/1 | No | |
2 | M | 52 | 5.6 | Hetero | Benign | LHT, RHT | 0/1 | No | |
3 | F | 31 | 4.7 | Iso | Benign | TT |
|
MicroPTC-c | |
4 | F | 69 | 6.9 | Hypo | FN/SFN | Benign | TT | 0/0 | No |
5 | F | 36 | 4.5 | Hypo | TT | 0/0 | MicroPTC-c | ||
|
F | 27 | 4.2 | Hetero | FLUS/AUS | LHT | 0/1 | No | |
7 | F | 55 | 5.8 | Iso | LHT | 0/0 | No | ||
8 | M | 30 | 4.1 | Iso | FLUS/AUS | Suspicious | RHT | 0/0 | No |
9 | F | 51 | 3.9 | Hetero | FLUS/AUS | Suspicious | TT | 0/1 | MicroFvPTC |
10 | M | 56 | 3.6 | Hetero | FLUS/AUS | Suspicious | LHT | 0/3 | MicroPTC |
11 | F | 41 | 4.4 | Iso | FN/SFN | Suspicious | RHT | 0/0 | No |
12 | F | 50 | 3.1 | Iso | LHT | 0/2 | No | ||
13 | F | 38 | 3.8 | Iso | LHT | 0/1 | No | ||
14 | F | 30 | 2.8 | Iso | FN/SFN | LHT | 0/1 | No | |
15 | F | 35 | 2.6 | Hetero | Benign | TT | 0/1 | No | |
16 | F | 21 | 3.15 | Hetero | FN/SFN | RHT | 0/1 | No | |
17 | F | 50 | 2.4 | Hypo | Benign | TT | 0/3 | MicroPTC | |
18 | F | 60 | 3 | Iso | FLUS/AUS | Suspicious | TT | 0/0 | MicroFvPTC |
19 | F | 46 | 1.4 | Hypo | FLUS/AUS | Suspicious | RHT | 0/1 | No |
20 | M | 38 | 3 | Iso | FLUS/AUS | Suspicious | TT | 0/2 | MicroPTC |
21 | F | 32 | 3.3 | Iso | FN/SFN | Suspicious | TT | 0/0 | No |
22 | M | 53 | 2.5 | Iso | FN/SFN | RHT | 0/0 | No | |
23 | F | 16 | 2.7 | Iso | Benign | LHT, RHT | 0/1 | MicroFvPTC-c | |
24 | F | 37 | 2.63 | Hypo | FLUS/AUS | TT | 0/3 | No | |
25 | F | 53 | 1.9 | Hypo | LHT, RHT | 0/1 | 2.1 cm FVPTC and microFVPTC-c | ||
26 | F | 56 | 2.53 | Hetero | Benign | RHT, LHT | 0/1 | MicroPTC | |
27 | F | 55 | 1.6 | Hypo | FLUS/AUS | TT | 0/1 | No | |
28 | M | 39 | 2.1 | Iso | FLUS/AUS | Suspicious | LHT | 0/1 | No |
29 | F | 40 | 1.3 | Hypo | FLUS/AUS | Suspicious | TT | 0/0 | No |
30 | M | 64 | 1.6 | Hypo | Benign | TT | 0/0 | No | |
31 | F | 58 | 1.3 | Iso | FLUS/AUS | Suspicious | LHT | 0/1 | MicroPTCs |
32 | F | 55 | 1.1 | Iso | FLUS/AUS | Suspicious | TT | 0/0 | No |
33 | F | 37 | 0.8 | Iso | TT | 0/4 | No | ||
|
F | 37 | 1.3 | Iso | TT + CND |
|
1.5 cm PTC-c | ||
35 | F | 45 | 0.9 | Iso | FLUS/AUS | Suspicious | TT | 0/0 | 2 cm FvPTC |
36 | F | 32 | 4 | Iso | FN/SFN | TT | 0/0 | No | |
37 | M | 56 | 4.3 | Iso | Benign | TT | 0/0 | No |
The Afirma GEC® gene expression classifier was requested in eleven nodules with Bethesda 3 and three nodules with Bethesda 4 cytology. The GEC result was “suspicious” in all eleven Bethesda 3 nodules and in two of the three Bethesda 4 nodules. The Afirma GEC “benign” Bethesda 4 nodule was removed due to its size (6.9 cm) and suspicious sonographic features (Patient 4 in Table
Twenty patients were treated with total thyroidectomy (one with central compartment lymphadenectomy) and 17 patients underwent lobectomy. Four patients who had an initial lobectomy underwent a completion thyroidectomy and 2 of these 4 patients had microscopic follicular variant of papillary cancer in the lobe opposite to the previously removed noninvasive EFVPTC tumor. Permanent postsurgical hypoparathyroidism and vocal cord dysfunction were not encountered in any of the 37 patients.
On histologic examination, 13 out of 37 (35%) thyroidectomy specimens were found to contain additional incidental malignancies. These included 10 patients with incidental subcentimeter papillary thyroid cancers (PTCs) or follicular variant of papillary cancers (FVPTCs) (one with a single positive central compartment LN, Patient 3, Table
Two of the 37 patient specimens (5%) contained one or more malignant lymph nodes with subcentimeter, noninvasive tumor deposits. In the first patient (Patient 3, Table
Two of the 37 patients received adjuvant radioactive iodine therapy postoperatively. Patient 34 received adjuvant radioactive iodine for her 1.5 cm classical papillary cancer with 4 left paratracheal metastatic lymph nodes. Another patient (Patient 1, Table
We describe the clinical characteristics of 37 tumors from 37 patients with noninvasive encapsulated follicular variant of papillary thyroid cancer (EFVPTC) culled from a community-based endocrine surgery registry from January 2013 through September 2016.
Our noninvasive EFVPTC patients were relatively young (mean age 44) and predominately female with nodules that, on ultrasound, were large (3.1 cm on average), hypo- to isoechoic, and mildly hypervascular with crisp boundaries in all 37 cases. Highly suspicious sonographic features such as microscopic calcifications or infiltrative borders were not seen in any of these lesions. Noninvasive EFVPTC nodules typically yielded indeterminate cytology results on fine needle aspiration biopsy (73% Bethesda Classification 3 or 4) with 12 of the 13 (92%) who underwent Afirma GEC testing classified as “suspicious.” Although we did not routinely perform mutational testing at our center from 1/2013 to 9/2016, two of our patients were found at outside institutions to have DNA alterations including a PAX8/PPAR gamma translocation and a low level NRAS mutation affecting 8% of thyrocytes, corresponding to an allelic frequency of 4%. Although we did not recut surgical specimens, our noninvasive EFVPTC patients’ clinical, ultrasound, cytology, and molecular characteristics appear to resemble those of the NIFTP tumor patients described by Nikiforov et al. [
Interestingly, in our patient group, molecular markers influenced surgical decision-making in 16 of the 17 patients in whom molecular testing was performed, while the other twenty patients had surgical decision-making driven by other factors such as family history, clinical symptoms, and, most importantly, ultrasound findings. Cytology evaluation was less helpful as all our patients who underwent fine needle aspiration biopsy (FNA) fell into Bethesda categories 2 (Benign), 3 (AUS/FLUS), or 4 (FN/SFN).
Twenty out of 37 of our noninvasive EFVPTC patients (54%) underwent total thyroidectomy due to primary tumor size, tumor appearance, or ultrasound demonstrable contralateral disease. One of these twenty patients underwent a total thyroidectomy and a central lymph node dissection due to suspected central lymph involvement and subsequently received postoperative radioiodine therapy for remnant ablation when 4 central lymph nodes were found to contain microscopic cancer on pathologic examination with the largest nodal deposit measuring 0.4 cm (Patient 34, Table
At the time of this writing, we have not seen a clinical recurrence in any of our 37 noninvasive EFVPTC patients, but our average length of follow-up of 18 months is far too short to allow a definitive conclusion of benign clinical behavior.
Thirteen of our 37 noninvasive EFVPTC patients (35%) had synchronous thyroid cancers elsewhere in the thyroid gland. This is a higher than expected rate of thyroidectomy-detected occult microscopic carcinoma with the typical reported rate approximating 10% [
In the current endocrine surgical practice environment we lack prospective studies that provide guidance for the surgical management of patients with suspected noninvasive EFVPTCs and/or NIFTP tumors (collectively referred to as “encapsulated follicular tumors”). Our current approach is to assess all patients referred for thyroid nodule evaluation for characteristic ultrasound and fine needle aspiration features of encapsulated follicular tumors which include (1) nonhyperechoic lesion on ultrasound, (2) smooth, uniform, and uninterrupted margins, (3) no microscopic calcifications, (4) Bethesda 3 or 4 cytology, and (5) either a suspicious Afirma GEC or a mutation panel demonstrating a follicular tumor mutation, rearrangement, or fusion (specifically, no BRAF V600, RET/PTC, RET, TERT, TP53, or PTEN mutations, rearrangements, or fusions, all associated with other more aggressive thyroid cancer subtypes) (Figure
Algorithm for surgical decision-making with suspected encapsulated follicular tumors.
In conclusion, because of a high risk of tumor multifocality, careful preoperative neck ultrasound and appropriate use of fine needle aspiration biopsy are essential in the management of suspected noninvasive EFVPTC tumors. The extent of surgery should be guided by ultrasound findings, biopsy results and clinical judgement. Molecular testing with Afirma GEC is often “suspicious” in noninvasive encapsulated follicular variant of papillary thyroid cancers and should lead to ipsilateral lobectomy and isthmusectomy in the absence of historical, clinical, neck ultrasound or fine needle aspiration biopsy findings elsewhere suggesting metastatic lymph node involvement or synchronous thyroid malignancy [
The authors declare that there are no conflicts of interest regarding the publication of this paper.