Ann Surg Oncol DOI 10.1245/s10434-013-3448-x

ORIGINAL ARTICLE – ENDOCRINE TUMORS

Fine-Needle Aspiration of the Thyroid: Correlating Suspicious Cytology Results with Histological Outcomes Andrea L. Baynes, MBBS1, Andres Del Rio, MBBS1, Catriona McLean, BSc, MBBS, FRCPA, MD2, Simon Grodski, MBBS, FRACS1, Meei J. Yeung, MBBS, FRACS1, William R. Johnson, MBBS, MD, FRACS, FRCS, FACS1, and Jonathan W. Serpell, MBBS, MD, MEd, FRACS, FACS3 1

Monash University Endocrine Surgery Unit, Department of Surgery, The Alfred Hospital, Prahran, VIC, Australia; Department of Pathology, The Alfred Hospital, Prahran, VIC, Australia; 3Department of General Surgery, The Alfred Hospital, Prahran, VIC, Australia

2

ABSTRACT Purpose. Fine-needle aspiration cytology (FNAC) assists the diagnosis of thyroid malignancy. A ‘suspicious for malignancy’ on FNAC creates a management dilemma. The aims of this study were to investigate the malignancy rate for patients with suspicious cytology, and to describe a management approach for those with a suspicious result. Methodology. A retrospective review of prospectively collected data in an endocrine surgery database was undertaken. Patients undergoing thyroidectomy with preoperative FNAC from 1992 to 2012 were analysed. Results. Preoperative FNAC was undertaken in 2,692 patients, and the FNAC result was ‘suspicious for malignancy’ in 94 (3.5 %) patients. Of these, 53 (56.4 %) were malignant, with the majority 44 (83.0 %) being papillary thyroid cancer. 48 patients went straight to total thyroidectomy, 40 patients had an initial diagnostic hemithyroidectomy, and 1 patient had a diagnostic isthmusectomy. 5 patients required reoperative total thyroidectomy as an initial procedure. Of the 94 suspicious cases, 55 were reported by an unknown, presumably non-expert, thyroid cytopathologist. 38 of these cases were available for review and re-reporting by an experienced cytopathologist. On review, 28 (73.7 %) were reclassified as cytologically malignant, and all of these were confirmed as malignant on subsequent histopathology. Conclusions. Suspicious cytology has a high risk of malignancy. Expert thyroid cytopathology can improve diagnostic

Ó Society of Surgical Oncology 2014 First Received: 15 August 2013 J. W. Serpell, MBBS, MD, MEd, FRACS, FACS e-mail: [email protected]

accuracy and a preoperative malignant diagnosis should be pursued to enable one-stage surgery where possible. Keywords Thyroid  Cytology  Suspicious  Thyroid cancer  Fine-needle aspiration INTRODUCTION Fine-needle aspiration cytology (FNAC) is a well-established diagnostic adjunct in the assessment of a thyroid nodule. The overall sensitivity of FNAC is up to 98 %,1 with a specificity up to 99 %.2,3 There is a false negative rate for malignancy of 0.7–5 %.4–6 This technique has resulted in improved assessment of preoperative likelihood of malignancy, reduces the number of diagnostic thyroidectomies for thyroid nodules, increases the proportion of cancers in resected specimens, and guides operative management if a definitive diagnosis is made.7 It is cost effective, has a low morbidity, and is well tolerated by patients.8 Since 2007, the Monash University Endocrine Surgery Unit (MUESU) has used a five-tiered classification system9 for thyroid cytology, based on the guidelines of the Papanicolaou Society.10 The five categories are C1—non-diagnostic; C2—benign; C3—indeterminate follicular lesion; C4—suspicious for malignancy; and C5—malignant. The Bethesda System (National Cancer Institute 2008) and the British Thyroid Association synoptic cytology systems are similar, encompassing these five categories.11–13 The utility of this cytological classification is that it guides subsequent management of the nodule.14 A non-diagnostic result on a thyroid nodule should be repeated, benign nodules may be observed, indeterminate follicular lesions in most cases will be removed, and suspicious or malignant nodules are removed.12,15

A. L. Baynes et al.

However, there are limitations with FNAC for thyroid nodules. The literature reports a 3.7–11 %1,7 rate of suspicious cytological findings (C4) on FNAC.16 The presence of suspicious cytological results lowers specificity and can create a management dilemma. Suspicious cytology has a risk of malignancy on histology of between 29 and 75 %.1,11,17,18 It is therefore current practice to perform surgical excision by diagnostic hemithyroidectomy of all cytological suspicious thyroid nodules. If the final histology is malignant, the patient usually undergoes completion thyroidectomy. In this instance the opportunity for central lymph node clearance is lost given the risk to the parathyroid glands and recurrent laryngeal nerve of reoperating on the recently operated side. However, an initial malignant cytological diagnosis of a thyroid nodule allows for definitive one-stage surgery, usually a total thyroidectomy and ipsilateral central lymph node clearance. We reviewed the experience of the MUESU with a suspicious FNAC result on a thyroid nodule. The primary aim of this study was to establish the malignancy rate for patients with suspicious cytology. A further aim was to describe and evaluate a management approach for the patient with a suspicious FNAC result, including reviewing the cytology.

suspicious FNAC (C4). These 94 cases form the study cohort and were analysed for subsequent management and histopathology diagnosis. Cases with Reviewed Fine-Needle Aspiration Cytology Of the 94 suspicious cases, 39 patients were worked up by one of the authors, and cytology was referred to an experienced thyroid cytopathologist. On the other hand, 55 patients had been worked up in the community and cytology had been performed by an unfamiliar pathologist of uncertain expertise. In more recent years, we had concerns about the quality of outside cytology reporting and had 13 cases reviewed by one of our expert thyroid cytopathologists prior to surgery. For the purposes of this study we aimed to retrospectively review the remaining 42 cases; of these we were able to obtain the original slides of 25 patients and have these reviewed by one

TABLE 1 Cytological results for initial fine-needle aspiration correlated with final histology Cytology

n

Percentage (%)

Malignancy rate

4.7

11.8 % (15)

PATIENTS AND METHODS A retrospective review of prospectively collected data in a dedicated endocrine surgery database was undertaken. All patients who underwent thyroid surgery in the MUESU from 1992 to June 2012 were included. Data analysed included age, sex, FNAC result, reviewed FNAC result (where applicable), indication for surgery, type of surgery, completion surgery for cancer, and final histology. The database was designed using FileMaker Pro (FileMaker, Santa Clara, CA, USA) and has institutional ethics approval. The study group comprised a mixed patient population reflecting the varied nature of the authors’ practice. Some patients were referred in having been worked up in the community; cytology was performed by an outside pathologist of uncertain expertise in thyroid cytopathology. Other patients were evaluated by the surgeon, and cytology sent to one of several expert pathologists. Although these expert pathologists have no specific expert training or qualification, they all have a keen interest in thyroid cytopathology and this represents a significant part of their practice. FNAC was performed under ultrasound guidance and since 2007 was synoptically reported according to our five-tiered classification system described above.9

C1

Non-diagnostic

C2

Benign

C3 C4

Indeterminate follicular Suspicious

C5

Malignant Total

127 1509

56.1

2.9 % (44)

756 94

28.1 3.5

14.9 % (113) 56.4 % (53)

206

7.7

99.5% (205)

2692

100

TABLE 2 Histology results from the first operation for 94 patients with suspicious cytology on initial fine-needle aspiration cytology Histology

n = 94

%

Benign

41

43.6

MNG

17

18.1

Follicular adenoma

16

17.0

Colloid/hyperplastic

4

4.3

Hashimoto’s thyroiditis

4

4.3

53

56.4

PTC [10 mm

35

37.2

PTC \10 mm

a

9.6

Malignant

Patients

9

Follicular carcinoma

3

3.2

Medullary

3

3.2

Hurthle cell carcinoma

1

1.1

Lymphoma

1

1.1

Metastases

1

1.1

MNG multinodular goitre, PTC papillary thyroid carcinoma

A total of 2,692 operative cases had FNAC and definitive histopathology and of these, 94 were reported as

a

All nine cases represent the index lesion; there were no incidental microcarcinomas

Suspicious FNA Cytology in Thyroid Nodules

of our expert thyroid cytopathologists. The reviewing pathologist was blinded to the final histology result.

RESULTS A total of 2,692 patients underwent FNAC for investigation of a thyroid nodule. Table 1 details the five cytological categories for the total study and their relative proportions. 94 (3.5 %) patients had cytology suspicious for malignancy (C4), with a mean age of 55 (range 20–98) years. Of the 94 patients with suspicious for malignancy cytology, 53 (56.4 %) were malignant on definitive histopathology, the majority being papillary thyroid cancer 44 (83.0 %). The malignancy rates for benign (C2) and indeterminate follicular (C3) nodules were 2.9 and 14.9 %. respectively. Table 2 lists the definitive histology of the 94 patients with suspicious cytology. Table 3 highlights the varied initial operation undertaken in cases with suspicious cytology, as opposed to total thyroidectomy for patients with initial malignant cytology (C5). Forty patients underwent a diagnostic hemithyroidectomy and one patient had a diagnostic isthmusectomy. In 48 cases, initial total thyroidectomy was undertaken, and in another five patients, reoperative (total) thyroidectomy was performed, having previously had a partial thyroidectomy for an alternative indication. Of the 48 patients undergoing initial total thyroidectomy (rather than a diagnostic procedure) malignancy was confirmed preoperatively by review of the cytology in 12 patients. In addition, five patients had malignancy confirmed intraoperatively by frozen section (FS), one patient had raised calcitonin confirming malignancy, and one patient had malignant features on imaging. Some of the additional indications for total thyroidectomy as the initial procedure included a combined decision by patient and surgeon (12), large goitre/pressure symptoms (12), already thyroxinedependent (3), and Graves’ disease/thyroiditis (2). Of the 53 patients with malignancy, 35 underwent initial total thyroidectomy, and 15 underwent initial diagnostic hemithyroidectomy or isthmusectomy, of which 14 (93 %) then underwent completion thyroidectomy. 3 patients had reoperative total thyroidectomy after previous partial thyroidectomy. Cytology previously reported by an unknown/non-expert pathologist was reviewed by an expert thyroid cytopathologist. Of 55 cases, 13 were reviewed prospectively prior to initial surgery, 25 retrospectively, and 17 cases were unavailable. 12 of 13 cases reviewed prospectively were reclassified as malignant and one remained suspicious. An additional 16 cases were retrospectively reclassified as malignant. Of the remaining 9 cases, 2 were reclassified nondiagnostic, 5 benign, and 1 follicular/indeterminate. Only 1

case remained classified as suspicious for malignancy. Table 4 demonstrates the results of expert review of suspicious cytology. Of the 38 reviews, 28 (73.7 %) were reclassified following review as malignant cytology rather than suspicious. All these patients subsequently demonstrated TABLE 3 Histological diagnosis in 94 patients with suspicious preoperative cytology (C4) after initial operation Operation

n

Histology

Hemithyroidectomy

40 Benign

n

%

26

65.0

14

35.0a

Follicular adenoma (12) MNG (8) Other (6) Malignant PTC (9) Follicular carcinoma (3) Other (2) Isthmusectomy

1

Benign

0

Malignant

1

100.0b

0.0

13

27.1

35

72.9

2

40.0

3

60.0

PTC (1) Total thyroidectomy 48 Benign MNG (8) Follicular adenoma (3) Hashimoto’s thyroiditis (2) Malignant PTC (31) Other (4) Redo thyroidectomy 5

Benign MNG (1) Follicular adenoma (1) Malignant PTC (3)

MNG multinodular goitre, PTC papillary thyroid carcinoma a

Thirteen of 14 patients underwent completion thyroidectomy

b

This patient underwent completion thyroidectomy

TABLE 4 Thirty-eight of 55 cases with suspicious (C4) cytology reported by a non-expert pathologist were reviewed by an expert thyroid cytopathologist Cytology after review

n

%

Final histology

C1: Non diagnostic

2

5.3

Benign (2)

C2: Benign

5

13.2

Benign (5)

1

2.6

Benign (1)

2a

5.3

Benign (2)

73.7

Malignant (28)

C3: Indeterminate follicular lesion C4: Suspicious for malignancy C5: Malignant Total

b

28

38

100

Cytology after review and final histology by classification a

One case was reviewed preoperatively and remained classified as suspicious for malignancy

b

Twelve cases were reviewed and reclassified preoperatively

A. L. Baynes et al.

malignant histology (although there remains debate on one case, with some pathologists favouring a benign lesion and others a malignant lesion). Of the remaining 10 cases, including 2 remaining suspicious for malignancy, all were benign on final histology.

DISCUSSION FNAC is widely recognized to be the most accurate method for assessing thyroid nodules.19 The overall sensitivity of FNAC is up to 98 %,1 with a specificity of up to 99 %.2 FNAC stratifies patients with thyroid nodules into diagnostic categories. This aids the clinician in determining the preoperative malignancy risk in conjunction with clinical and radiological features. Of the five categories of cytology used by our group,14 the fourth or suspicious for malignancy (C4), corresponding to Bethesda V, may include results described as suspicious for papillary carcinoma, suspicious for medullary carcinoma, suspicious for other primary and secondary malignancies, and suspicious for neoplasms because of total necrosis of the lesional cells (anaplastic carcinoma).20 Suspicious cytology findings account for 3.7–11 % all aspirates.1,7 Our incidence of suspicious cytology was 3.5 %, therefore at the lower range of this reported incidence. After review and reclassification, we are left with an incidence of suspicious cytology in only 2.2 % of cases, which is lower than previously reported incidences. Suspicious cytology carries a risk of malignancy of between 29 and 75 %.1,11,17,18 Of our suspicious FNAC results, 53 of 94 (56.4 %) were malignant on subsequent histology. Of these, the diagnosis of papillary thyroid cancer was the most common in 44 cases (83.0 %), and this is consistent with the literature and cytopathological reporting criteria. If we reclassify the 36 cases as per the expert review then we are left with only 58 cases of suspicious cytology and a malignancy rate of 43 % (25 of 58 cases). This is slightly less than the expected 50–75 % reported in the Bethesda guidelines. This is possibly due to our group’s pursuit of a malignant diagnosis in patients with suspicious cytology. We will not uncommonly repeat the cytology in patients with suspicious cytology in the hope of obtaining a more definitive sample for our cytopathologists to make the diagnosis of malignancy and hence allow us to definitively manage the patients with one operation. Although we have no way of identifying patients managed in this way, it has certainly been a trend in our group to try and minimize the number of patients undergoing diagnostic hemithyroidectomy in this circumstance. In 2007, the National Cancer Institute (NCI) hosted the NCI ‘Thyroid Fine-Needle Aspiration State of the Science Conference’ in Bethesda, and subsequently published ‘The Bethesda System for Reporting Thyroid Cytopathology’ in

2008.11,20 Its aim was to establish comprehensive guidelines regarding terminology and morphological criteria in reporting thyroid FNAC. It delineates the reporting of ‘suspicious for malignancy’ as an aspirate containing some features of malignancy, but lacking definitive diagnostic changes. Papillary thyroid carcinoma (PTC) is most often considered in this diagnostic category as the nuclear and architectural changes can be subtle and focal.20 This pattern is often true in the follicular variant of PTC, which can be difficult to distinguish from a benign follicular neoplasm. The report states that if only one or two characteristic features of PTC are present, and they are not widespread throughout the follicular cell population, a malignant diagnosis cannot be made with certainty.20 The same principle applies with other thyroid malignancies, although they do not occur as frequently. In our series, this group made up 9.7 % of all suspicious cytology results and included follicular carcinoma, medullary carcinoma, Hurthle cell carcinoma, lymphoma and metastases. Given that a ‘suspicious’ FNAC result significantly increases the probability of a thyroid malignancy, it is an indication for surgical excision.14,15 Our practice, in agreement with others1,14 is to perform a diagnostic hemithyroidectomy. Following a malignant histological diagnosis, a completion thyroidectomy is usually performed. Of our suspicious FNAC results, 14 patients underwent two-stage surgical management: a hemithyroidectomy or isthmusectomy followed by a completion total thyroidectomy ± lymph node dissection based on confirmed malignant histology for the primary operation. In these patients, a malignant diagnosis preoperatively would have avoided a second operation. The best outcome for the patient is a single operation for definitive treatment of their thyroid cancer. The advantages include preventing the increased risk of a re-exploration operation, as well as the ability to appropriately stage the disease, and avoiding the emotional cost to the patient of a second surgery. Importantly it allows a central lymph node clearance on the ipsilateral side of the cancer at surgery, if this is considered appropriate. A two-stage procedure loses this opportunity because of the difficulties of reoperating on the operated side, and the risk to the recurrent laryngeal nerve and parathyroid glands. At the same time, avoidance of unnecessary extensive surgery and lifelong thyroxine for benign disease should be considered. Of our suspicious FNAC results, 48 patients underwent an initial total thyroidectomy, rather than a diagnostic hemithyroidectomy. In over a third of cases (19) this was due to subsequent confirmation of malignancy, the majority of which (12) were determined by reviewing the cytology. Other means included FS, radiological appearance, positive lymph node biopsy, or high calcitonin levels indicating a medullary thyroid carcinoma.

Suspicious FNA Cytology in Thyroid Nodules

For the remaining 29 patients, a decision to proceed to total thyroidectomy was made in the absence of a confirmed malignancy. Of these, 12 were a joint decision between patient and surgeon that the risk of malignancy was sufficient to warrant total thyroidectomy, avoiding the potential need for a two-stage procedure. The other major contributing factor in this group was large multinodular goitre or pressure symptoms (12 patients). 3 patients were already thyroxine-dependent and thus this disadvantage of total thyroidectomy was of less relevance. Prior to the advent of FNAC, preoperative clinical information and FS were the only methods available to assist operative decision making. FS has largely since been abandoned due to cost, difficulty in interpretation, time involved, and the sensitivity of FNAC preoperatively.21 However, its utilization in ‘suspicious’ FNAC cases to assist intraoperative diagnosis at the time of hemithyroidectomy has been debated. Cheng et al.22 reviewed seven cases where the preoperative FNAC was suspicious for malignancy. FS identified two cancers allowing intraoperative conversion and facilitating one-stage surgery. Hamming et al.2 reported that of 18 thyroid malignancies with an ‘uncertain’ FNAC, FS detected six as malignant, 11 non-diagnostic, and 1 as benign. Boyd et al.18 included 5 cases of malignant thyroid cancer, with initial ‘suspicious’ FNAC. FS detected 3 as cancer, 1 as follicular, and 1 as suspicious. While FS has assisted in a proportion of cases, its false negative result coupled with time and cost involved, make it unappealing. FS does not completely avoid reoperation and it does not allow for preoperative staging or planning. For these reasons an alternative option should be sought. A recent trial reported by Alexander et al.23 investigated the use of a gene expression classifier (GEC) in patients with indeterminate cytology to identify a subpopulation of patients with a low likelihood of malignancy. The GEC demonstrated a stronger negative predictive value for C3 nodules (94–95 %) compared with that for C4 nodules (85 %). The false negative rate of 15 % for C4 nodules is concerning and limits the use of GEC in these patients. B-RafV600E mutation detection by PCR has been demonstrated to be useful in assessing preoperative risk of PTC in the setting of suspicious cytology (C4) and for prognostic evaluation in proven PTC, given that it is the most commonly targeted gene in the development of PTC.24 A higher prevalence of B-RafV600E has been demonstrated in nodules suspicious for PTC compared with follicular lesions.25–27 At this stage the GEC and B-RafV600E are not readily available in the Australian market. We do not feel that the GEC would be helpful in the management of suspicious cytology as the high false negative rate is of concern. B-RafV600E does show some promise in guiding the management of suspicious cytology but as yet is not part of our routine practice.

We reviewed a subgroup of patients with suspicious FNAC findings, where their cytology was not initially reported by an experienced thyroid cytopathologist. The majority (94.7 %) of reports were reclassified after review; 28 of 38 (73.7 %) were reclassified to be malignant on cytology and this was accurate 100 % of the time. Twelve of these cases were preoperative reviews, allowing these patients to proceed directly to one-stage total thyroidectomy. We know that FNA specificity ranges widely from 56.8 to 99 % depending on the experience of cytopathologists.22,28,29 We know that the diagnosis of follicular variant of papillary carcinoma is not always reproducible.30 Different institutions may have different outcomes for the same cytological information due to a bias towards diagnosing a follicular variant of PTC. In a recent publication, Olson et al.31 described their experience of reviewing 3,885 thyroid cytological samples, the largest series to date documenting a second review of thyroid cytology specimens. They describe a change in classification occurring 32 % of the time after second review. For suspicious cytology, the rate changed from 6.7 to 5.8 % after second review. Second review decreased the indeterminate rate from 38 to 28 % in their series (p \ 0.000001). It is stated ‘‘second review occasionally uncovers more findings than had previously been appreciated and, as a consequence, decreases the false negative rate’’. The authors conclude that second review changes the diagnosis in a significant number and may significantly alter the management of the patient. The accuracy of FNAC can be maximized by ensuring a dedicated team, expert radiologist, pathologist in attendance to assess the adequacy of the specimen, two passes into nodule, each at least six groups of follicular cells (each group of 10–15 cells), avoiding blood and drying, and Papanicolou staining for greater detail.8,20 Based on our experience, it has become common practice for the surgeons in our unit to obtain further opinions from experienced pathologists for all suspicious cytological results, with the aim that it may provide a definitive malignant diagnosis, allowing one-stage surgery. In addition, we will often repeat the FNA if the expert cytopathology suggests ‘suspicious for malignancy’ in the hope that another sample may provide more material, allowing for definitive management and minimizing the number of diagnostic hemithyroidectomy procedures. Therefore, our suggested approach to a suspicious cytological result is to ensure appropriate efforts have been made to maximize the accuracy of the cytology (detailed above), read the body text of the cytological report carefully, have the slides reviewed by an expert pathologist, and consider a repeat aspirate of the nodule in cases that are truly suspicious for malignancy. In the future, B-RafV600E testing may help further guide the management

A. L. Baynes et al.

of patients with truly suspicious cytology after expert cytology is unable to be more definitive. It is important to recognize that a cytological report is an opinion, and places a nodule into a synoptic category, and hence becomes a guide to management. The clinician must consider this opinion in the overall context of the patient, the clinical picture and radiological features of the nodule, in order to make a judgement as to whether to proceed to diagnostic hemithyroidectomy or total thyroidectomy. ACKNOWLEDGMENT The authors wish to thank Melissa Vereker for her assistance in the collection and extraction of data used in this study.

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Fine-needle aspiration of the thyroid: correlating suspicious cytology results with histological outcomes.

Fine-needle aspiration cytology (FNAC) assists the diagnosis of thyroid malignancy. A 'suspicious for malignancy' on FNAC creates a management dilemma...
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