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Positron emission tomography-positive thyroid nodules: rate of malignancy and histological features Stephanie Flukes,* Nat Lenzo,† Girolamo Moschilla† and Chady Sader* *Department of Otolaryngology, Fremantle Hospital, Fremantle, Western Australia, Australia and †Department of Nuclear Medicine, Fremantle Hospital, Fremantle, Western Australia, Australia
Key words biopsy, fine-needle, histology, positron emission tomography, thyroid carcinoma, thyroid nodule. Correspondence Dr Stephanie Flukes, Department of Otolaryngology, Fremantle Hospital, 2 Alma Street, Fremantle, WA 6160, Australia. Email: stephanie.fl[email protected] S. Flukes BMedSc, MBBS (Hons); N. Lenzo MBBS, FRACP; G. Moschilla MBBS, FRACP; C. Sader MBBS, FRACS. This paper was presented at the Australian Society of Head and Neck Surgery (ASOHNS) Annual Scientific Meeting 2013 in Perth, Western Australia. Accepted for publication 28 July 2014. doi: 10.1111/ans.12834
Abstract Background: Thyroid nodules may be incidentally detected on 18F-FDG-positron emission tomography (PET) scans. Previous reports suggest a high incidence of malignancy in FDG-avid nodules. The aims of this study were to examine the incidence of malignancy in a large cohort and to report on the histological features. The findings suggest that poor prognostic histologic features are often associated with FDG-avid thyroid nodules and this may have clinical implications. Methods: A retrospective review of prospectively collected data was conducted. A database containing all patients who underwent PET scanning at a single tertiary referral centre from January 2006 to January 2013 was searched to identify those with incidental PET-positive thyroid nodules. Patients with known preexisting thyroid disease were excluded from analysis. The demographics, fine-needle aspiration (FNA) biopsy result and operative histopathology were analysed. Results: A total of 27 851 FDG-PET scans were performed of which 221 found incidental PET-positive thyroid nodules (incidence 0.8%). Fifty-three patients went on to have further investigation and 21 of these were found to have malignant disease (incidence 39.6%). Histopathological examination of 12 malignant nodules revealed an expected rate of poor prognostic features, including poorly differentiated subtype (8.3%), lymphovascular invasion (16.7%), perineural invasion (8.3%) and extrathyroid extension (33.3%). Conclusion: Our data indicate that PET-positive thyroid nodules are associated with a high incidence of malignancy. This finding provides strong support for further investigation including FNA biopsy in all surgically suitable patients.
Introduction Thyroid anomalies are common and their incidence increases with age.1 The prevalence of palpable nodules in an otherwise healthy population is reported as 3–5%,1–3 and the prevalence on dedicated ultrasound examination is 27–35%.4–6 Nodules may also be detected incidentally on positron emission tomography (PET) scanning, which is now routinely performed for investigation of various malignancies. Nodules detected by PET scan are different entities in that they represent not only structural abnormalities but also functional changes. The presence of FDG-avid (‘PETpositive’) thyroid nodules poses a clinical dilemma: what do these incidental finings represent and how aggressively should they be managed? © Australasian College College of of Surgeons Surgeons © 2014 2014 Royal Australasian
A number of authors have reported small series of patients with incidental PET-positive thyroid nodules.7–17 It has been suggested that these nodules are associated with a high rate of primary thyroid malignancy. Because of the small sample sizes, the reported rates of malignancy vary widely. There is very little data regarding the histological type and aggressiveness of these neoplasms. The behaviour of thyroid cancer varies widely between slow-growing papillary thyroid tumours and anaplastic carcinoma. Differentiating between these growth patterns is of critical importance in predicting clinical outcome. The aim of the study was to identify the rate of malignancy in patients with incidental PET-positive thyroid nodules. The study also examined the histological subtype of identified malignancies. Increased understanding of the typical behaviour of these incidental tumours will assist in developing a clinical management algorithm. ANZ J Surg (2014) ••–•• ANZ J Surg 86•• (2016) 487–491
2488
Methods A retrospective analysis of prospectively collected data was performed using a database from a single tertiary referral centre in Western Australia servicing a population of 2.1 million people. The database contained details of all 18F-FDG-PET scans obtained at the centre over a 7-year period from January 2006 to January 2013. All patients who had undergone PET scans at this institution had provided written consent for the use of their results for clinical research purposes. The database was searched for the term ‘thyroid nodule’ and all reports containing this term were manually examined by the authors. Reports of FDG-negative thyroid nodules were excluded. Patients with known thyroid disease (both past and current) were also excluded. In some cases, a single patient had undergone multiple PET scans, and in this instance only the initial scan was included in data analysis. The demographics, primary pathology and details of the thyroid abnormality were collated for all included patients. Pathology on the subjects was sought via the major state pathology providers. Reports of further investigations were obtained; including imaging studies, fine-needle aspiration (FNA) biopsy and operative intervention. FNA cytology results were classified as ‘benign’, ‘indeterminate’, ‘malignant’ or ‘non-diagnostic’ by the reporting pathologist according to a modified Bethesda criteria.18 Operative histopathology reports were reviewed to obtain details of the histopathological diagnosis and the presence of any aggressive features including subtype and extent of tumour.
Results A total of 27 851 FDG-PET scans were performed during the study period. A search of the database for the term ‘thyroid nodule’ returned 262 results. Two hundred and twenty-one of these met the inclusion criteria. The incidence of PET-positive thyroid nodules in the study population was therefore 0.8%. Some patients had undergone multiple scans and in these cases the repeat scans were excluded, resulting in a total of 154 individual patient scans. This included 86 males and 68 females. The mean age was 65.9 years (range 35–92). For all patients, the primary pathology for which they were undergoing PET scan was related to investigation of malignancy (Table 1).
Rate of malignancy Of the 154 patients with PET-positive thyroid nodules, 53 went on to have FNA biopsy to establish a cytological diagnosis (Fig. 1). The remainder did not proceed to biopsy because of significant co-morbidities (as determined by the referring physician). The 53 patients included 21 males and 32 females with a mean age of 66.2 years (range 41–88). FNA results were classed as ‘benign’, ‘indeterminate’, ‘malignant’ or ‘non-diagnostic’. For example, all follicular cell neoplasms were classified as ‘indeterminate’, as it was not possible to comment on tumour architecture based on cytology alone. A proportion of those patients classed as ‘indeterminate’ went on to have definitive surgical management leading to histological diagnosis. Following this investigation and reclassification, a total of
Flukes et al.
Table 1 The primary pathology under investigation in patients with incidental PET-positive thyroid nodules. Numbers represent the number of patients with each of the listed primary pathologies Primary pathology
Number
Lymphoma Malignant melanoma Colorectal carcinoma Lung carcinoma Head and neck carcinoma Pancreatic adenocarcinoma Gastric adenocarcinoma Ovarian carcinoma Cervical adenocarcinoma Breast adenocarcinoma Prostate carcinoma Sarcoma Other malignancy Suspected malignancy, unknown site† Total
36 22 17 16 12 9 6 4 4 3 3 3 11 8 154
†Suspected malignancy, unknown site includes positron emission tomography (PET) scans performed to investigate paraneoplastic syndrome of unknown origin.
21 patients were found to have malignant disease (12 confirmed by histopathology and nine who had malignant cytology but did not proceed to surgery). The most commonly identified malignancy was papillary thyroid carcinoma (PTC). Other malignant neoplasms included follicular thyroid carcinoma, medullary thyroid carcinoma, lymphoma and metastatic squamous cell carcinoma (Fig. 2). When considered in the context of the 53 who underwent FNA biopsy, this represents a malignancy rate of 39.6%. The prevalence of malignancy was correlated to age and sex. The mean age of those patients found to have malignant disease was 63.5 years (Student’s t-test, P = 0.55) and the male to female ratio was 12:11 (Chi-squared test, P = 0.64). Neither variable was found to be significant. One hundred and one patients with PET-positive nodules did not undergo FNA biopsy and therefore had insufficient data to be included in further analysis.
Histological features A total of 19 patients underwent operative intervention (either hemior total thyroidectomy). Seven patients had benign disease and 12 had malignant disease. Benign disease included four patients with follicular adenomas, one with Hashimoto’s thyroiditis and one with a multinodular goitre. Of those with malignancy, all had a variant of PTC. Seven of these were microcarcinomas. One patient had both a papillary microcarcinoma and a medullary carcinoma, and was classified as medullary as this was the predominant tumour type. Microscopic examination of tumour showed capsular breach in 11 patients (91.7%), lymphovascular invasion in two (16.7%), perineural invasion in one (8.3%) and extrathyroid extension (ETE) in four (33.3%) (Table 2).
Discussion This study examined over 27 000 PET scans and to our knowledge represents the largest study of its kind. The incidence of PETpositive thyroid nodules was 0.8%. Other authors have previously ©©2014 2014 Royal Royal Australasian Australasian College of Surgeons
PET-positive thyroid thyroid nodules nodules
3 489
Fig. 1. Investigation of patients with positron emission tomography (PET)-positive thyroid nodules. A total of 154 patients were identified, of which 101 had no further investigation and 53 underwent fine-needle aspiration (FNA) biopsy to obtain cytological diagnosis. Biopsy results were classified as benign, indeterminate, malignant or non-diagnostic. Of those with indeterminate FNA, four had no further investigation and 10 underwent surgery to obtain histopathological diagnosis. Histopathology results were classified as benign or malignant. A total of 21 patients were found to have malignant disease based on a combination of cytology and histology.
Indeterminate, no further invesgaon, 8%
Papillary thyroid carcinoma, 26%
Follicular thyroid carcinoma, 6% Benign thyroid nodule, 53%
Medullary thyroid carcinoma, 2% Lymphoma, 4% Metastac squamous cell carcinoma, 2%
Fig. 2. Final diagnosis of 53 patients with positron emission tomographypositive thyroid nodules based on fine-needle aspiration (FNA) biopsy and operative histopathology where FNA was indeterminate.
reported incidences of 1.1–2.5%.7,10,13,15,17 However, many of these studies included patients with both diffuse and focal FDG uptake in the thyroid, and this is likely to account for the higher rates they found when compared with our results. Are et al. reviewed 16 300 PET scans and found 101 patients to have focal uptake, representing an incidence of 0.6% which is more consistent with our results.13 © Australasian College College of of Surgeons Surgeons © 2014 2014 Royal Australasian
The rate of malignancy based on a combination of cytology and histology was found to be 39.6%. It should be noted that this conclusion relies on the assumption that malignant cytology is an accurate predictor of malignant histology, given the reported positive predictive value of malignant FNA of 97–99%.18 Previously reported rates of malignancy in PET-positive nodules vary widely from 14 to 71%, and our results are comparable with those obtained in the larger and more recent series7–13 (Table 3). In contrast, only 5–25% of all thyroid nodules are found to be malignant based on surgical and autopsy findings.19–21 The results of this study therefore support the conclusion of other authors that PET-positive nodules are associated with a higher rate of malignancy than those detected by conventional techniques. It is important to consider not only the rate of malignancy in this setting but also the likely disease course. This requires an understanding of the histological aggressiveness of the tumour. It has been suggested by some authors that a significant proportion of incidentally detected thyroid cancers will follow a clinically indolent course.22 The histological factors associated with more aggressive tumour behaviour include poorly differentiated carcinoma; capsular, lymphovascular and perineural invasion; and ETE of disease. These features are associated with higher rates of nodal and distant metastases, corresponding to an increased mortality rate.23 In this series, we examined the results of 12 patients who were found to have thyroid carcinoma on operative histopathology. One patient had a poorly differentiated tumour type (8.3%) which is associated with a
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Flukes et al.
Table 2 Histopathological characteristics of patients found to have malignant diagnosis on surgical resection of PET-positive thyroid nodules Sex
1 2 3 4 5 6 7 8 9 10 11 12†
Age
Tumour type
Maximum tumour dimension (mm)
Capsular breach
Lymphovascular invasion
Perineural invasion
Extrathyroid extension
70 66 60 41 45 48 61 42 72 49 69 82
PTC, follicular PTC PTC PTC PTC PTC, follicular PTC PTC, oncocytic PTC PTC PTC Medullary PTC
1.8 5 7 7 9 10 11 12 13 23 24 9 0.8
Y Y Y Y N Y Y Y Y Y Y Y N
N N N N N N Y Y N N N N N
N N N N N N Y N N N N N N
N Y Y N N N Y Y N N N N N
M F M M F F F F M F M F
†Patient 12 had both medullary carcinoma (9 mm maximum diameter) and papillary microcarcinoma (0.8 mm maximum diameter) of the thyroid. F, female; M, male; N, no; PET, positron emission tomography; PTC, papillary thyroid carcinoma; Y, yes.
Table 3 Results of previous studies examining PET-positive thyroid nodules Author (date)
Cytology available
Histopathology available
Percentage malignancy (%)
Type of malignancy
4525
15
—
47
—
8
7
71
1330 4136
— 32
15 —
27 50
4803 6241 16 300
50 14 57
7 — 27
14 29 42
7347
22
11
35
King et al. (2007)15
11 623
21
15
23
Pagano et al. (2011)16
10 881
36
17
39
Yang et al. (2012)17
15 948
53
40
29
3 PTC 2 FTC, oncocytic variant 2 poorly differentiated 3 PTC 2 MTC 4 PTC 14 PTC 2 metastatic disease 7 PTC 4 PTC 19 PTC 1 primary thyroid lymphoma 12 PTC 2 lymphoma 1 metastatic disease 2 PTC 4 micro-PTC 1 MTC 13 PTC 1 FTC 26 PTC 11 metastatic disease 5 MTC 1 anaplastic carcinoma
Cohen et al. (2001)7
Van den Bruel et al. (2002)8 Kang et al. (2003)9 Kim et al. (2005)10 Chen et al. (2005)11 Chu et al. (2006)12 Are et al. (2007)13 Bogsrud et al. (2007)14
PET scans analysed
FTC, follicular thyroid carcinoma; MTC, medullary thyroid carcinoma; PET, positron emission tomography; PTC, papillary thyroid carcinoma.
significantly worse prognosis.23 Four patients were found to have ETE of tumour (33.3%). This is similar to the ETE rates reported in the literature of 25–40%,23–25 in contrast to the high prevalence reported by Are et al. of 63%.26 Are et al. also reported high prevalence of the aggressive tall-cell variant PTC; however, there was no such trend found in this current study.26 The high rate of malignancy found in this study has significant clinical implications. Although the detection of these nodules is a relatively rare occurrence, the use of PET-scanning technology is rapidly increasing. An increased number of incidental findings are therefore expected. A sound investigative algorithm to guide clinical management for these patients is indicated. The authors suggest aggressive investigation is appropriate in all surgically suitable
patients, including obtaining a cytological diagnosis whenever possible. Given the 33% incidence of ETE of tumour, it may be appropriate to obtain additional preoperative imaging to assist with surgical planning. This study did not find the high rate of aggressive histological subtypes reported by Are et al.;26 however, the number of cases in which histopathology was available was limited. It would be beneficial to focus further research on the histological features in order to improve prognostic accuracy and guide management paradigms. The retrospective nature of this study resulted in some limitations. The decision as to how to investigate the PET-positive nodules was made by the original referring physician, often in the setting of severe co-morbidities, and a large proportion of patients did not ©©2014 2014 Royal Royal Australasian Australasian College of Surgeons
PET-positive thyroid thyroid nodules nodules
undergo biopsy. It is not known how the referring physicians decided on whether to conduct further investigation. Current guidelines suggest the use of ultrasound imaging as an important diagnostic tool;27 however, data regarding its use in this population was not available. Only one-third of patients underwent FNA biopsy and this low investigation rate may represent a source of selection bias. A further limitation is that the histopathology slides were not available for re-examination by the authors and the data were collected from reports only. The reports were prepared by multiple pathologists and hence there may be variability in the interpretation of the histology. In conclusion, the incidental detection of an FDG-avid thyroid nodule on PET scanning is associated with a high likelihood of thyroid malignancy. These patients should therefore be investigated and managed aggressively in order to achieve the best clinical outcome.
5 491
11.
12.
13.
14.
15.
Acknowledgement The authors wish to acknowledge the assistance of Jan Boucek, nuclear medicine physicist at Fremantle Hospital in Western Australia, for his assistance in accessing the PET database. This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
References 1. Vander JB, Gaston EA, Dawber TR. The significance of nontoxic thyroid nodules. Final report of a 15-year study of the incidence of thyroid malignancy. Ann. Intern. Med. 1968; 69: 537–40. 2. Tunbridge WM, Evered DC, Hall R et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin. Endocrinol. (Oxf) 1977; 7: 481–93. 3. Wang C, Crapo LM. The epidemiology of thyroid disease and implications for screening. Endocrinol. Metab. Clin. North Am. 1997; 26: 189–218. 4. Carroll BA. Asymptomatic thyroid nodules: incidental sonographic detection. AJR Am. J. Roentgenol. 1982; 138: 499–501. 5. Brander A, Viikinkoski P, Nickels J, Kivisaari L. Thyroid gland: US screening in a random adult population. Radiology 1991; 181: 683–7. 6. Bruneton JN, Balu-Maestro C, Marcy PY, Melia P, Mourou MY. Very high frequency (13 MHz) ultrasonographic examination of the normal neck: detection of normal lymph nodes and thyroid nodules. J. Ultrasound Med. 1994; 13: 87–90. 7. Cohen MS, Arslan N, Dehdashti F et al. Risk of malignancy in thyroid incidentalomas identified by fluorodeoxyglucose-positron emission tomography. Surgery 2001; 130: 941–6. 8. Van den Bruel A, Maes A, De Potter T et al. Clinical relevance of thyroid fluorodeoxyglucose-whole body positron emission tomography incidentaloma. J. Clin. Endocrinol. Metab. 2002; 87: 1517–20. 9. Kang KW, Kim SK, Kang HS et al. Prevalence and risk of cancer of focal thyroid incidentaloma identified by 18F-fluorodeoxyglucose positron emission tomography for metastasis evaluation and cancer screening in healthy subjects. J. Clin. Endocrinol. Metab. 2003; 88: 4100–4. 10. Kim TY, Kim WB, Ryu JS, Gong G, Hong SJ, Shong YK. 18Ffluorodeoxyglucose uptake in thyroid from positron emission tomo-
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gram (PET) for evaluation in cancer patients: high prevalence of malignancy in thyroid PET incidentaloma. Laryngoscope 2005; 115: 1074–8. Chen YK, Ding HJ, Chen KT et al. Prevalence and risk of cancer of focal thyroid incidentaloma identified by 18F-fluorodeoxyglucose positron emission tomography for cancer screening in healthy subjects. Anticancer Res. 2005; 25 (2B): 1421–6. Chu QD, Connor MS, Lilien DL, Johnson LW, Turnage RH, Li BD. Positron emission tomography (PET) positive thyroid incidentaloma: the risk of malignancy observed in a tertiary referral center. Am. Surg. 2006; 72: 272–5. Are C, Hsu JF, Schoder H, Shah JP, Larson SM, Shaha AR. FDG-PET detected thyroid incidentalomas: need for further investigation? Ann. Surg. Oncol. 2007; 14: 239–47. Bogsrud TV, Karantanis D, Nathan MA et al. The value of quantifying 18F-FDG uptake in thyroid nodules found incidentally on whole-body PET-CT. Nucl. Med. Commun. 2007; 28: 373–81. King DL, Stack BC Jr, Spring PM, Walker R, Bodenner DL. Incidence of thyroid carcinoma in fluorodeoxyglucose positron emission tomography-positive thyroid incidentalomas. Otolaryngol. Head Neck Surg. 2007; 137: 400–4. Pagano L, Samà MT, Morani F et al. Thyroid incidentaloma identified by 18F-fluorodeoxyglucose positron emission tomography with CT (FDG-PET/CT): clinical and pathological relevance. Clin. Endocrinol. (Oxf) 2011; 75: 528–34. Yang Z, Shi W, Zhu B et al. Prevalence and risk of cancer of thyroid incidentaloma identified by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography. J. Otolaryngol. Head Neck Surg. 2012; 41: 327–33. Cibas ES, Ali SZ. The Bethesda system for reporting thyroid cytopathology. Thyroid 2009; 19: 1159–65. Yeung MJ, Serpell JW. Management of the solitary thyroid nodule. Oncologist 2008; 13: 105–12. Mazzaferri EL. Thyroid cancer in thyroid nodules: finding a needle in the haystack. Am. J. Med. 1992; 93: 359–62. Brooks JR. The solitary thyroid nodule. Am. J. Surg. 1973; 125: 477–81. Franceschi S, La Vecchia C. Thyroid cancer. Cancer Surv. 1994; 19–20: 393–422. Jukkola A, Bloigu R, Ebeling T, Salmela P, Blanco G. Prognostic factors in differentiated thyroid carcinomas and their implications for current staging classifications. Endocr. Relat. Cancer 2004; 11: 571–9. Gulcelik MA, Gulcelik NE, Kuru B, Camlibel M, Alagol H. Prognostic factors determining survival in differentiated thyroid cancer. J. Surg. Oncol. 2007; 96: 598–604. Shin JH, Ha TK, Park HK et al. Implication of minimal extrathyroidal extension as a prognostic factor in papillary thyroid carcinoma. Int. J. Surg. 2013; 11: 944–7. Are C, Hsu JF, Ghossein RA, Schoder H, Shah JP, Shaha AR. Histological aggressiveness of fluorodeoxyglucose positron-emission tomogram (FDG-PET)-detected incidental thyroid carcinomas. Ann. Surg. Oncol. 2007; 14: 3210–5. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper D, Doherty G et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009; 19: 1167–214.
Positron emission tomography-positive thyroid nodules: rate of malignancy and histological features Stephanie Flukes,* Nat Lenzo,† Girolamo Moschilla† and Chady Sader* *Department of Otolaryngology, Fremantle Hospital, Fremantle, Western Australia, Australia and †Department of Nuclear Medicine, Fremantle Hospital, Fremantle, Western Australia, Australia
Key words biopsy, fine-needle, histology, positron emission tomography, thyroid carcinoma, thyroid nodule. Correspondence Dr Stephanie Flukes, Department of Otolaryngology, Fremantle Hospital, 2 Alma Street, Fremantle, WA 6160, Australia. Email: stephanie.fl[email protected] S. Flukes BMedSc, MBBS (Hons); N. Lenzo MBBS, FRACP; G. Moschilla MBBS, FRACP; C. Sader MBBS, FRACS. This paper was presented at the Australian Society of Head and Neck Surgery (ASOHNS) Annual Scientific Meeting 2013 in Perth, Western Australia. Accepted for publication 28 July 2014. doi: 10.1111/ans.12834
Abstract Background: Thyroid nodules may be incidentally detected on 18F-FDG-positron emission tomography (PET) scans. Previous reports suggest a high incidence of malignancy in FDG-avid nodules. The aims of this study were to examine the incidence of malignancy in a large cohort and to report on the histological features. The findings suggest that poor prognostic histologic features are often associated with FDG-avid thyroid nodules and this may have clinical implications. Methods: A retrospective review of prospectively collected data was conducted. A database containing all patients who underwent PET scanning at a single tertiary referral centre from January 2006 to January 2013 was searched to identify those with incidental PET-positive thyroid nodules. Patients with known preexisting thyroid disease were excluded from analysis. The demographics, fine-needle aspiration (FNA) biopsy result and operative histopathology were analysed. Results: A total of 27 851 FDG-PET scans were performed of which 221 found incidental PET-positive thyroid nodules (incidence 0.8%). Fifty-three patients went on to have further investigation and 21 of these were found to have malignant disease (incidence 39.6%). Histopathological examination of 12 malignant nodules revealed an expected rate of poor prognostic features, including poorly differentiated subtype (8.3%), lymphovascular invasion (16.7%), perineural invasion (8.3%) and extrathyroid extension (33.3%). Conclusion: Our data indicate that PET-positive thyroid nodules are associated with a high incidence of malignancy. This finding provides strong support for further investigation including FNA biopsy in all surgically suitable patients.
Introduction Thyroid anomalies are common and their incidence increases with age.1 The prevalence of palpable nodules in an otherwise healthy population is reported as 3–5%,1–3 and the prevalence on dedicated ultrasound examination is 27–35%.4–6 Nodules may also be detected incidentally on positron emission tomography (PET) scanning, which is now routinely performed for investigation of various malignancies. Nodules detected by PET scan are different entities in that they represent not only structural abnormalities but also functional changes. The presence of FDG-avid (‘PETpositive’) thyroid nodules poses a clinical dilemma: what do these incidental finings represent and how aggressively should they be managed? © Australasian College College of of Surgeons Surgeons © 2014 2014 Royal Australasian
A number of authors have reported small series of patients with incidental PET-positive thyroid nodules.7–17 It has been suggested that these nodules are associated with a high rate of primary thyroid malignancy. Because of the small sample sizes, the reported rates of malignancy vary widely. There is very little data regarding the histological type and aggressiveness of these neoplasms. The behaviour of thyroid cancer varies widely between slow-growing papillary thyroid tumours and anaplastic carcinoma. Differentiating between these growth patterns is of critical importance in predicting clinical outcome. The aim of the study was to identify the rate of malignancy in patients with incidental PET-positive thyroid nodules. The study also examined the histological subtype of identified malignancies. Increased understanding of the typical behaviour of these incidental tumours will assist in developing a clinical management algorithm. ANZ J Surg (2014) ••–•• ANZ J Surg 86•• (2016) 487–491
2488
Methods A retrospective analysis of prospectively collected data was performed using a database from a single tertiary referral centre in Western Australia servicing a population of 2.1 million people. The database contained details of all 18F-FDG-PET scans obtained at the centre over a 7-year period from January 2006 to January 2013. All patients who had undergone PET scans at this institution had provided written consent for the use of their results for clinical research purposes. The database was searched for the term ‘thyroid nodule’ and all reports containing this term were manually examined by the authors. Reports of FDG-negative thyroid nodules were excluded. Patients with known thyroid disease (both past and current) were also excluded. In some cases, a single patient had undergone multiple PET scans, and in this instance only the initial scan was included in data analysis. The demographics, primary pathology and details of the thyroid abnormality were collated for all included patients. Pathology on the subjects was sought via the major state pathology providers. Reports of further investigations were obtained; including imaging studies, fine-needle aspiration (FNA) biopsy and operative intervention. FNA cytology results were classified as ‘benign’, ‘indeterminate’, ‘malignant’ or ‘non-diagnostic’ by the reporting pathologist according to a modified Bethesda criteria.18 Operative histopathology reports were reviewed to obtain details of the histopathological diagnosis and the presence of any aggressive features including subtype and extent of tumour.
Results A total of 27 851 FDG-PET scans were performed during the study period. A search of the database for the term ‘thyroid nodule’ returned 262 results. Two hundred and twenty-one of these met the inclusion criteria. The incidence of PET-positive thyroid nodules in the study population was therefore 0.8%. Some patients had undergone multiple scans and in these cases the repeat scans were excluded, resulting in a total of 154 individual patient scans. This included 86 males and 68 females. The mean age was 65.9 years (range 35–92). For all patients, the primary pathology for which they were undergoing PET scan was related to investigation of malignancy (Table 1).
Rate of malignancy Of the 154 patients with PET-positive thyroid nodules, 53 went on to have FNA biopsy to establish a cytological diagnosis (Fig. 1). The remainder did not proceed to biopsy because of significant co-morbidities (as determined by the referring physician). The 53 patients included 21 males and 32 females with a mean age of 66.2 years (range 41–88). FNA results were classed as ‘benign’, ‘indeterminate’, ‘malignant’ or ‘non-diagnostic’. For example, all follicular cell neoplasms were classified as ‘indeterminate’, as it was not possible to comment on tumour architecture based on cytology alone. A proportion of those patients classed as ‘indeterminate’ went on to have definitive surgical management leading to histological diagnosis. Following this investigation and reclassification, a total of
Flukes et al.
Table 1 The primary pathology under investigation in patients with incidental PET-positive thyroid nodules. Numbers represent the number of patients with each of the listed primary pathologies Primary pathology
Number
Lymphoma Malignant melanoma Colorectal carcinoma Lung carcinoma Head and neck carcinoma Pancreatic adenocarcinoma Gastric adenocarcinoma Ovarian carcinoma Cervical adenocarcinoma Breast adenocarcinoma Prostate carcinoma Sarcoma Other malignancy Suspected malignancy, unknown site† Total
36 22 17 16 12 9 6 4 4 3 3 3 11 8 154
†Suspected malignancy, unknown site includes positron emission tomography (PET) scans performed to investigate paraneoplastic syndrome of unknown origin.
21 patients were found to have malignant disease (12 confirmed by histopathology and nine who had malignant cytology but did not proceed to surgery). The most commonly identified malignancy was papillary thyroid carcinoma (PTC). Other malignant neoplasms included follicular thyroid carcinoma, medullary thyroid carcinoma, lymphoma and metastatic squamous cell carcinoma (Fig. 2). When considered in the context of the 53 who underwent FNA biopsy, this represents a malignancy rate of 39.6%. The prevalence of malignancy was correlated to age and sex. The mean age of those patients found to have malignant disease was 63.5 years (Student’s t-test, P = 0.55) and the male to female ratio was 12:11 (Chi-squared test, P = 0.64). Neither variable was found to be significant. One hundred and one patients with PET-positive nodules did not undergo FNA biopsy and therefore had insufficient data to be included in further analysis.
Histological features A total of 19 patients underwent operative intervention (either hemior total thyroidectomy). Seven patients had benign disease and 12 had malignant disease. Benign disease included four patients with follicular adenomas, one with Hashimoto’s thyroiditis and one with a multinodular goitre. Of those with malignancy, all had a variant of PTC. Seven of these were microcarcinomas. One patient had both a papillary microcarcinoma and a medullary carcinoma, and was classified as medullary as this was the predominant tumour type. Microscopic examination of tumour showed capsular breach in 11 patients (91.7%), lymphovascular invasion in two (16.7%), perineural invasion in one (8.3%) and extrathyroid extension (ETE) in four (33.3%) (Table 2).
Discussion This study examined over 27 000 PET scans and to our knowledge represents the largest study of its kind. The incidence of PETpositive thyroid nodules was 0.8%. Other authors have previously ©©2014 2014 Royal Royal Australasian Australasian College of Surgeons
PET-positive thyroid thyroid nodules nodules
3 489
Fig. 1. Investigation of patients with positron emission tomography (PET)-positive thyroid nodules. A total of 154 patients were identified, of which 101 had no further investigation and 53 underwent fine-needle aspiration (FNA) biopsy to obtain cytological diagnosis. Biopsy results were classified as benign, indeterminate, malignant or non-diagnostic. Of those with indeterminate FNA, four had no further investigation and 10 underwent surgery to obtain histopathological diagnosis. Histopathology results were classified as benign or malignant. A total of 21 patients were found to have malignant disease based on a combination of cytology and histology.
Indeterminate, no further invesgaon, 8%
Papillary thyroid carcinoma, 26%
Follicular thyroid carcinoma, 6% Benign thyroid nodule, 53%
Medullary thyroid carcinoma, 2% Lymphoma, 4% Metastac squamous cell carcinoma, 2%
Fig. 2. Final diagnosis of 53 patients with positron emission tomographypositive thyroid nodules based on fine-needle aspiration (FNA) biopsy and operative histopathology where FNA was indeterminate.
reported incidences of 1.1–2.5%.7,10,13,15,17 However, many of these studies included patients with both diffuse and focal FDG uptake in the thyroid, and this is likely to account for the higher rates they found when compared with our results. Are et al. reviewed 16 300 PET scans and found 101 patients to have focal uptake, representing an incidence of 0.6% which is more consistent with our results.13 © Australasian College College of of Surgeons Surgeons © 2014 2014 Royal Australasian
The rate of malignancy based on a combination of cytology and histology was found to be 39.6%. It should be noted that this conclusion relies on the assumption that malignant cytology is an accurate predictor of malignant histology, given the reported positive predictive value of malignant FNA of 97–99%.18 Previously reported rates of malignancy in PET-positive nodules vary widely from 14 to 71%, and our results are comparable with those obtained in the larger and more recent series7–13 (Table 3). In contrast, only 5–25% of all thyroid nodules are found to be malignant based on surgical and autopsy findings.19–21 The results of this study therefore support the conclusion of other authors that PET-positive nodules are associated with a higher rate of malignancy than those detected by conventional techniques. It is important to consider not only the rate of malignancy in this setting but also the likely disease course. This requires an understanding of the histological aggressiveness of the tumour. It has been suggested by some authors that a significant proportion of incidentally detected thyroid cancers will follow a clinically indolent course.22 The histological factors associated with more aggressive tumour behaviour include poorly differentiated carcinoma; capsular, lymphovascular and perineural invasion; and ETE of disease. These features are associated with higher rates of nodal and distant metastases, corresponding to an increased mortality rate.23 In this series, we examined the results of 12 patients who were found to have thyroid carcinoma on operative histopathology. One patient had a poorly differentiated tumour type (8.3%) which is associated with a
4490
Flukes et al.
Table 2 Histopathological characteristics of patients found to have malignant diagnosis on surgical resection of PET-positive thyroid nodules Sex
1 2 3 4 5 6 7 8 9 10 11 12†
Age
Tumour type
Maximum tumour dimension (mm)
Capsular breach
Lymphovascular invasion
Perineural invasion
Extrathyroid extension
70 66 60 41 45 48 61 42 72 49 69 82
PTC, follicular PTC PTC PTC PTC PTC, follicular PTC PTC, oncocytic PTC PTC PTC Medullary PTC
1.8 5 7 7 9 10 11 12 13 23 24 9 0.8
Y Y Y Y N Y Y Y Y Y Y Y N
N N N N N N Y Y N N N N N
N N N N N N Y N N N N N N
N Y Y N N N Y Y N N N N N
M F M M F F F F M F M F
†Patient 12 had both medullary carcinoma (9 mm maximum diameter) and papillary microcarcinoma (0.8 mm maximum diameter) of the thyroid. F, female; M, male; N, no; PET, positron emission tomography; PTC, papillary thyroid carcinoma; Y, yes.
Table 3 Results of previous studies examining PET-positive thyroid nodules Author (date)
Cytology available
Histopathology available
Percentage malignancy (%)
Type of malignancy
4525
15
—
47
—
8
7
71
1330 4136
— 32
15 —
27 50
4803 6241 16 300
50 14 57
7 — 27
14 29 42
7347
22
11
35
King et al. (2007)15
11 623
21
15
23
Pagano et al. (2011)16
10 881
36
17
39
Yang et al. (2012)17
15 948
53
40
29
3 PTC 2 FTC, oncocytic variant 2 poorly differentiated 3 PTC 2 MTC 4 PTC 14 PTC 2 metastatic disease 7 PTC 4 PTC 19 PTC 1 primary thyroid lymphoma 12 PTC 2 lymphoma 1 metastatic disease 2 PTC 4 micro-PTC 1 MTC 13 PTC 1 FTC 26 PTC 11 metastatic disease 5 MTC 1 anaplastic carcinoma
Cohen et al. (2001)7
Van den Bruel et al. (2002)8 Kang et al. (2003)9 Kim et al. (2005)10 Chen et al. (2005)11 Chu et al. (2006)12 Are et al. (2007)13 Bogsrud et al. (2007)14
PET scans analysed
FTC, follicular thyroid carcinoma; MTC, medullary thyroid carcinoma; PET, positron emission tomography; PTC, papillary thyroid carcinoma.
significantly worse prognosis.23 Four patients were found to have ETE of tumour (33.3%). This is similar to the ETE rates reported in the literature of 25–40%,23–25 in contrast to the high prevalence reported by Are et al. of 63%.26 Are et al. also reported high prevalence of the aggressive tall-cell variant PTC; however, there was no such trend found in this current study.26 The high rate of malignancy found in this study has significant clinical implications. Although the detection of these nodules is a relatively rare occurrence, the use of PET-scanning technology is rapidly increasing. An increased number of incidental findings are therefore expected. A sound investigative algorithm to guide clinical management for these patients is indicated. The authors suggest aggressive investigation is appropriate in all surgically suitable
patients, including obtaining a cytological diagnosis whenever possible. Given the 33% incidence of ETE of tumour, it may be appropriate to obtain additional preoperative imaging to assist with surgical planning. This study did not find the high rate of aggressive histological subtypes reported by Are et al.;26 however, the number of cases in which histopathology was available was limited. It would be beneficial to focus further research on the histological features in order to improve prognostic accuracy and guide management paradigms. The retrospective nature of this study resulted in some limitations. The decision as to how to investigate the PET-positive nodules was made by the original referring physician, often in the setting of severe co-morbidities, and a large proportion of patients did not ©©2014 2014 Royal Royal Australasian Australasian College of Surgeons
PET-positive thyroid thyroid nodules nodules
undergo biopsy. It is not known how the referring physicians decided on whether to conduct further investigation. Current guidelines suggest the use of ultrasound imaging as an important diagnostic tool;27 however, data regarding its use in this population was not available. Only one-third of patients underwent FNA biopsy and this low investigation rate may represent a source of selection bias. A further limitation is that the histopathology slides were not available for re-examination by the authors and the data were collected from reports only. The reports were prepared by multiple pathologists and hence there may be variability in the interpretation of the histology. In conclusion, the incidental detection of an FDG-avid thyroid nodule on PET scanning is associated with a high likelihood of thyroid malignancy. These patients should therefore be investigated and managed aggressively in order to achieve the best clinical outcome.
5 491
11.
12.
13.
14.
15.
Acknowledgement The authors wish to acknowledge the assistance of Jan Boucek, nuclear medicine physicist at Fremantle Hospital in Western Australia, for his assistance in accessing the PET database. This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
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