Impact of Transoral Endoscopic Vestibular Approach Thyroidectomy on Pathologic Assessment

Institutional review board approval was obtained for this analysis that included prospective pathologic examination of cases followed by a retrospective review of clinical data. The department of pathology laboratory information system and the hospital electronic medical record system were queried for transoral thyroidectomy specimens received since the start of this technique in March 2016 through December 2019. Clinical information, including age, sex, and follow-up data, where available, was retrieved from the electronic medical record.

At our institution, 2 experienced endocrine surgeons performed TOETVA following a period of specialized training in early 2016. Patients were selected for the TOETVA procedure at the surgeons' discretion based on preoperative assessment. Factors such as morbid obesity, large substernal goiters, prior neck operation, sonographic findings suggestive of extrathyroidal extension (ETE), and/or lateral neck disease represented relative or absolute contraindications. Lesion size was incorporated as part of this assessment, but hard cutoff sizes were not used. The added complexity of specimen retrieval was discussed with patients and detailed discussions about the effect on pathologic analysis were limited.

After the specimens were removed, gross and microscopic examinations were performed prospectively on all cases as part of ongoing patient care. All specimens were photographed upon receipt in pathology, and specimen integrity was assessed as intact when the specimen was received as a single piece with a smooth surface without evidence of disruption of the thyroid pseudocapsule and disrupted when the specimen was received in multiple fragments or with evidence of disrupted pseudocapsule revealing the underlying parenchyma. Fragments (the number of separate pieces) in disrupted cases were enumerated except when the specimens were clearly morcellated into more than 20 pieces, in which case “>20 fragments” was recorded. In cases where malignancy was identified, microscopic assessment of the following tumor parameters was recorded: tumor size, margin status, and presence of microscopic ETE. The presence of lymph nodes and parathyroid tissue was also recorded in all cases. Gross examination and sampling were performed in accordance with the College of American Pathologists protocol for examination of thyroid specimens.²²  Malignant cases were assessed using the College of American Pathologists and American Joint Committee on Cancer 8th edition guidelines.¹¹  Level sections and ancillary stains were performed as needed for assessment. The findings, including preoperative fine-needle aspiration cytology diagnosis, any molecular testing, and accompanying ultrasound findings, were reviewed for the purpose of the study. Thyroid fine-needle aspiration cytology results were rendered based on the Bethesda System for Reporting Thyroid Cytopathology²³  by using a standard template that documents cytologic features at the time of pathology review.

Fifty thyroid resections via TOETVA were received in pathology from 48 women and 2 men, ranging in age from 28 to 74 years (mean, 47 years) (Table 1). Forty-seven patients had preoperative fine-needle aspiration cytology. In the remaining 3 cases, a clinical diagnosis of “toxic adenoma” or “nodule” was the indication for surgery. Preoperative nodule sizes, taken from ultrasonographic reports, ranged from 0.6 to 6.3 cm (mean, 2.6 cm). The TOETVA resections included 41 thyroid lobectomies or hemithyroidectomies, 7 total thyroidectomies, 1 isthmusectomy, and 1 cyst excision. The specimens weighed 2 to 44.9 g (mean, 16.3 g ± 13.4). The thyroid tissue was disrupted in 34 cases (68%) and intact in 16 (32%) (Figure 1, A through D). Twenty-three specimens (46%) showed fragmentation, with a mean of 4 fragments (range, 2–8 fragments) per case. Fragment sizes ranged from 0.1 to more than 4 cm. The median nodule size in disrupted cases was 3 cm (range, 0.4–6.3 cm; mean, 3.3 cm). The median nodule size in intact cases was 1.9 cm (range, 0.8–5 cm; mean, 2.4 cm). Microscopically, parathyroid tissue was found in 14 cases (28%), ranging in size from 0.1 to 0.7 cm (mean, 0.4 cm). Lymph nodes were identified in 10 cases (20%; average 2 nodes/case), all of which were peri-thyroidal (level VI).

Thirty-nine resection specimens were negative for carcinoma, comprising 35 cases of nodular hyperplasia, 2 Hürthle cell adenomas (HCAs), 1 follicular adenoma, and 1 noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFT-P). An additional HCA and NIFT-P each were also diagnosed in 2 of the cases of PTC (described further below). For all 4 follicular adenomas/HCAs and both NIFT-Ps, microscopic examination of the tumor capsule was possible, as it was largely intact. These tumors ranged in size from 0.5 to 2.2 cm. The preoperative ultrasound sizes for these lesions ranged from 1 to 2.8 cm. A total of 11 patients had carcinoma at final diagnosis, all of which were PTC (Figure 2, A through D). This included all 4 cases with a preoperative diagnosis of suspicious or positive for PTC (Bethesda V/VI), 2 follicular lesion of undetermined significance (FLUSs) with nuclear atypia, and 1 follicular neoplasm (Bethesda III/IV); 4 carcinomas were incidentally detected (Tables 2 and 3). There were 8 microcarcinomas, 2 follicular variant carcinomas, and 1 classic variant carcinoma. The mean PTC size was 0.8 cm (range, 0.2–2.6 cm); this includes the size of 1 lesion that was estimated (at least 2.6 cm) and excludes the size of 1 lesion that could not be determined on surgical pathology (see below). One case showed metastatic disease to lymph nodes (4 of 4 lymph nodes) with the size of the largest lymph node measuring 0.6 cm with a 0.6-cm lymph node tumor deposit and no extranodal extension. Six of these 11 thyroids (55%) were grossly disrupted, with a mean of 3 pieces (range, 2–4 pieces). In 2 cases—both with indeterminate cytology (Bethesda III) —tumor size, microscopic ETE, and margin status could not be determined because of specimen fragmentation. However, one of these tumors was estimated to be at least 2.6 cm based on the surgical pathology findings and had a preoperative ultrasound size of 4.5 cm, and the other had a preoperative ultrasound size of 3 cm. In each case, the tumor displayed follicular architecture and the capsule could not be well visualized. In one case, there were scattered papillae estimated to be more than 1% of the lesion, and in the other case, areas of solid and trabecular growth were present; these findings led to diagnoses of carcinoma. In 2 cases of PTC, immunohistochemical stains were used as part of the diagnostic workup. These stains included TTF1, thyroglobulin, calcitonin, estrogen receptor, β-catenin, and CD10. Additional diagnoses that were noted, but not recorded in detail for the purposes of this study, were chronic lymphocytic thyroiditis and a background of nodular hyperplasia in cases where tumors were present.

With respect to molecular analysis, 12 cases had molecular testing performed on the preoperative fine-needle aspiration, including 8 cases of FLUS (Bethesda III), 2 cases suspicious for PTC (Bethesda V) and 2 cases positive for PTC (Bethesda VI). Methods included BRAF status by polymerase chain reaction single-strand conformation polymorphism analysis (10 cases) and next-generation sequence analysis (ThyroSeq v2, Pittsburgh, Pennsylvania; 2 cases). BRAF V600E mutation was detected in 2 cases of PTC (both on cytology and confirmed histologically); the remaining BRAF mutation analyses were negative. ThyroSeq v2 detected an NRAS (p.Q61R, c.182A>G) in 1 case of a Bethesda III lesion that had a final diagnosis of follicular variant PTC (one of the cases that was disrupted and unable to have tumor parameters assessed). The other ThyroSeq v2 analysis was negative, and the final diagnosis was a nodular hyperplasia. No molecular analyses were performed on resection specimens.

The mean clinical follow-up time for all cases was 101 days (range, 4–460 days; SD = 117 days). The mean clinical follow-up time for malignant cases was 185 days (range, 30–460 days). Four patients reported temporary postoperative vocal cord paralysis that resolved within several weeks following the surgery. In 1 case, vocal cord paralysis remained for at least 1 year postoperation. Four patients reported chin/neck numbness and/or paresthesias. No instances of recurrent carcinoma were identified. Only one patient with PTC was offered postoperative radioactive iodine because of metastatic disease involving 4 of 4 level VI lymph nodes, as well as carcinoma extending to a single cauterized edge in a disrupted specimen.

We presented detailed pathologic examination of 50 consecutive thyroid specimens resected using TOETVA and its impact in the assessment of 17 tumors, including 11 PTCs, 4 adenomas, and 2 NIFT-Ps. We showed that tissue disruption and/or fragmentation is frequent, seen in approximately two-thirds of all cases. Although this did not affect the final pathologic diagnosis in any of the 50 cases, in 2 cases of PTC, the tumor size, margin status, and microscopic ETE could not be determined because of fragmentation. These cases had indeterminate cytology (Bethesda III) and accounted for the largest lesions on preoperative ultrasound (3 and 4.5 cm) of the cases with a neoplastic final diagnosis. Both cases showed predominantly follicular architecture. In both, invasion of the capsule could not be assessed, but fortunately other histologic findings led to a diagnosis of carcinoma. Given that invasion into the surrounding thyroid parenchyma is critical in the assessment of HCA versus Hürthle cell carcinoma, follicular adenoma versus follicular thyroid carcinoma, and follicular variant PTC versus NIFT-P, the inability to evaluate the capsule in such cases may lead to ambiguity in distinguishing between benign and malignant entities. Cases classified as HCA, follicular adenoma, or NIFT-P in this series showed preoperative ultrasound sizes less than or equal to 2.8 cm. Ten of the carcinomas in our series were classified as low risk based on the American Thyroid Association risk stratification.¹²  One case with lymph node metastasis was classified as intermediate risk.

The clinical impact of reported pathologic findings in TOETVA specimens may be significant, leading to overtreatment or undertreatment. Pathologists traditionally take cautery effect on tumor as evidence of positive margin; multiple cauterized fragments assessed in TOETVA specimens may lead to erroneous margin reporting. Undetermined margin status might lead to unnecessary radioactive iodine therapy. Determining tumor size and focality can be challenging when tumors are present in more than one fragment. Adding the size of tumor in different fragments or its determination by preoperative imaging may lead to overestimation of pT stage and unnecessary therapy.¹³  Additionally, a false impression of microscopic ETE or suspicion for ETE may be created through this fragmentation, further impacting management decisions.¹⁴  Per the American Joint Committee on Cancer 8th edition guidelines,¹¹  staging is based on gross ETE, which necessitates correlation of macroscopic findings along with operative and imaging findings. Fragmented or disrupted specimens may pose a challenge in accurate evaluation of macroscopic ETE.

Fragmentation may not be limited to the thyroid gland, but indeed may involve lymph nodes or other structures of the neck. The size and the location of involved lymph nodes in the neck are factors informing further therapy, including administration of radioactive iodine and/or external-beam therapy (in some cases).¹¹ 

The American Thyroid Association has not established uniform indications and contraindications for TOETVA, but has issued a general statement on remote-access thyroidectomy.¹⁵  Many tumors identified incidentally or even known preoperatively—including the 11 in our study—are low-risk tumors by morphology and size criteria.¹⁶  Fernandez-Ranvier et al¹  proposed several eligibility criteria, with favorable features including the patient's own motivation to avoid a cervical scar, symptomatic benign nodules 6 cm or smaller, cytologically indeterminate nodules (Bethesda III or IV lesions) smaller than 6 cm, estimated thyroid diameter 10 cm or smaller on ultrasound, estimated gland volume 45 mL or smaller on ultrasound, symptomatic Hashimoto thyroiditis, Graves disease (euthyroid, if possible), and differentiated thyroid cancer smaller than 3 cm without ETE or lymph node metastasis on preoperative ultrasonography. Unfavorable features (substernal goiters, previous surgical intervention, previous cervical radiotherapy) are provided with recommendation against TOETVA. Importantly, as Fernandez-Ranvier et al¹  noted, “more important than cosmetics is the correct management of the patient's thyroid pathology… guidelines set forth by the American Thyroid Association should coincide with [these] recommendations… when deciding to utilize the TOETVA.” With these eligibility criteria in mind, preoperative cytopathologic diagnoses including indeterminate, suspicious, or malignant results are not necessarily a contraindication for TOETVA.

Some authors have attempted to define indications for TOETVA in the context of suspicious or malignant thyroid nodules while avoiding any significant impact to critical pathologic staging and prognostic parameters.¹⁴  One selection criterion studied was the appropriate nodule diameter that would obviate the need to disrupt the specimen and protect the mental nerve from injury. Strict preoperative size criteria would greatly decrease the likelihood of specimen disruption, but would also narrow the pool of patients who would be eligible for this surgery, particularly those who have large malignant nodules and still desire to avoid a cutaneous scar. Wu et al⁸  concluded that the safest diameter to remove a suspicious or malignant nodule is 20 mm. Razavi et al¹⁶  also outlined certain indications and contraindications for TOETVA, including a cutoff of 20 mm or smaller for malignant cases. For nodules larger than 20 mm, other techniques have been proposed to remove larger specimens without injury to the mental nerve or fragmentation of the specimen.^9,17–19  Tai et al⁶  assessed 269 patients retrospectively who had a preoperative diagnosis of PTC via cytopathology; most tumors identified were pT1a lesions (<1 cm in size). Despite positive lymph nodes being identified and 2 documented cases of ETE (pT3b disease as defined by the American Joint Committee on Cancer 7th edition,²⁰  which included microscopic ETE), the authors of this study do not comment on any challenges in determining pathologic staging. The authors conclude that TOETVA may be feasible for PTCs larger than 1 cm.⁶ 

As noted above, some neoplasms in our series that required complete examination of the lesion/capsule for classification were amenable to diagnosis. These lesions were 2.8 cm or less in greatest dimension. However, it is of concern, from a surgical pathologist's viewpoint, that an ambiguous diagnosis (eg, “follicular thyroid neoplasm, cannot exclude malignancy”) may need to be rendered on lesions of this nature appearing in multiple fragments. Moreover, given that subcentimeter PTC is often undetected preoperatively (“incidental”), there exists an inherent risk in every TOETVA procedure that fragmentation may lead to diagnosis of an incidental malignancy that may not be adequately pathologically assessed.

Of note, a preoperative pathologically confirmed diagnosis of poorly differentiated thyroid carcinoma and preoperative radiographic evidence of ETE have been regarded as contraindications for TOETVA.²¹  We can find no mention in the literature of whether adverse histology as diagnosed on cytopathology (eg, hobnail variant, tall cell variant, or dedifferentiation) has an impact on the indication for TOETVA. Given the aggressive nature of these lesions, we urge caution in considering these preoperative diagnoses—if rendered—for TOETVA.

A limitation of this study is the sample size of 50 cases, and we suspect that in larger series examining the pathologic assessment of TOETVA specimens, instances of fragmentation leading to diagnostic ambiguity between benign and malignant entities is likely to occur. Additionally, the long-term follow-up on patients is limited. A final limitation is that these 50 cases were among the first performed in the United States, and may not represent improvements in technique and refinement of indications over time.

To date, nearly 700 or more cases of TOETVA have been reported,²¹  including 7 cases described previously by our institution.¹⁰  Notably, these studies have not included pathologists, and our series is the first to our knowledge to report detailed pathologic findings in such cases. We showed that TOETVA can be performed without compromising the pathologic assessment of neoplastic lesions in the majority of cases (15 of 17). We also showed that in a subset of cases tumor parameter evaluation is compromised in the setting of PTC because of specimen fragmentation and disruption. This appears to be the case as the lesions increase in size (>3 cm), and this should be taken into consideration when selecting patients for TOETVA with indeterminate, suspicious, or malignant lesions on cytology. Guideline development should also consider these potential pathology limitations, and additional studies regarding the pathology of these cases is needed to further inform such guidelines.