Ann Surg Oncol (2015) 22:460–466 DOI 10.1245/s10434-014-4058-y
ORIGINAL ARTICLE – ENDOCRINE TUMORS
Rare Metastases of Well-Differentiated Thyroid Cancers: A Systematic Review Amin Madani, MD1, Yelda Jozaghi, MD2, Roger Tabah, MD1, Jacques How, MBChB3, and Elliot Mitmaker, MD MSc FRCS(C)1 Division of General Surgery, McGill University, Montreal, QC, Canada; 2Faculty of Medicine, McGill University, Montreal, QC, Canada; 3Division of Endocrinology, McGill University, Montreal, QC, Canada
1
ABSTRACT Background. A minority of metastatic well-differentiated thyroid cancer (WDTC) patients present with end-organ disease other than in the lung, bone or lymph nodes. These metastases tend to be overlooked because of their low incidence, and this results in delayed diagnosis. The purpose of this study was to perform a systematic review of the clinical and histologic features of unusual WDTC metastases. Methods. A systematic literature search of bibliographic databases, reference lists of articles, and conference proceedings was performed up to 2013. Studies were included if they reported on adult patients with WDTC and pathology-proven metastases to end-organs other than lung, bone, or lymph nodes. A total of 238 studies were included in a qualitative analysis. Data is expressed as N (%) and median [interquartile range]. Results. A total of 492 patients (median age, 62 years [50–70 years]) were identified in 197 case reports and 42 case series. There were 22 different end-organ metastatic sites documented with either papillary [255 (57 %)], follicular [172 (39 %)], or Hu¨rthle-cell [18 (4 %)] histology. A total of 181 (41 %) patients presented with solitary metastasis and 54 (93 %) with elevated serum thyroglobulin. Positron emission tomography and whole-body radioactive iodine scans revealed hypermetabolic foci in 28
Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-4058-y) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 14 July 2014; Published Online: 6 September 2014 E. Mitmaker, MD MSc FRCS(C) e-mail: [email protected]
(97 %) and 50 (81 %) cases, respectively. Disease-free interval following the initial diagnosis of the primary thyroid cancer was highly variable, ranging from synchronous presentation [66 (33 %)] to metachronous disease after 516 months [mean 86 months (SD 90)]. Conclusions. WDTC can manifest with highly variable and unusual clinical features. Rare sites of metastases should be considered in the absence of the more common extra-cervical disease recurrence locations.
Well-differentiated thyroid cancers (WDTC), including papillary, follicular, and Hu¨rthle-cell subtypes, are characterized by a slow progressive course and usually remain localized to the thyroid, with a 10-year survival rate of 80–95 %.1 Fortunately, only a minority (4–15 %) develop distant metastases that commonly involve lung, bone, and lymph nodes.2,3 Rare sites of end-organ distant metastases have been reported anecdotally in the literature. However, because of their low incidence, they tend to be overlooked, resulting in delayed diagnosis and management. There is a need for the histopathologic features, clinical manifestations, and outcomes of these unusual metastases to be analyzed in order to develop enhanced surveillance protocols. Song et al. published a pictorial review of rare metastases from WDTCs and provided insight into the clinical presentation of such patients.4 Since this review, there have been a number of reports in the literature documenting new and unconventional sites of metastasis from WDTC. The objective of this study was to perform a systematic review of the literature to determine the histopathologic characteristics and clinical presentation of WDTC patients with metastases to unusual locations excluding lung, bone, and lymph nodes.
Rare Metastases of Thyroid Cancer
METHODS
461
studies were included in the qualitative analysis (Online Appendix).
Search Strategy Quality Control A systematic literature search was performed for all articles published up to 2013. All aspects of the Preferred Reporting Items for Systematic Review and Meta-Analysis statement were followed.5 We searched bibliographic databases (MEDLINE, EMBASE, Cochrane Collaboration, PubMed), as well as conference proceedings, using electronic search terms focused on two main themes: thyroid neoplasm and metastasis using a combination of medical subject headings and keywords. Details of the search syntax are listed in ‘‘Appendix’’ section. The authors of relevant abstracts were contacted if their data was not published. In addition, the journal Thyroid was handsearched for relevant articles from 1990 (Volume 1, Issue 1) until June 2013 (Volume 23, Issue 6), including all online first articles up to June 10, 2013. The reference and citation lists from relevant reviews that were identified using the above search strategy, as well as the studies retained for full-text review, were also searched. Searches were limited to adult subjects (18? years) with no language or date restrictions. Studies were initially screened for relevance based on title and abstract and subsequently retained if they met the inclusion criteria: if the study population included adult (18?) patients with WDTC and pathology-proven metastasis to end-organs other than lung, bone, or lymph nodes. WDTC was defined as papillary, follicular, or Hu¨rthle-cell histologic subtypes. Pediatric patients, autopsy studies, patients with medullary thyroid carcinoma, thyroid lymphoma, and poorly or undifferentiated thyroid cancers were excluded. Two authors (A.M. and Y.J.) independently assessed each record for eligibility, extracted the data, and assessed study quality. Disagreement between reviewers was resolved by consensus from a third reviewer (E.M.). Agreement between reviewers was assessed using kappa statistic. Data Extraction and Synthesis A total of 737 studies were screened for eligibility (Fig. 1). All required data from each study included were extracted using a standardized form that covered: study characteristics (study design and publication year), sample size, patient demographics, histological subtype, metastatic sites, serum thyroglobulin (Tg) levels, diagnostic radioactive iodine whole-body (WBS), and [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) scan results, patient management, disease-free interval, and overall survival. The primary outcomes of this systematic review were histological subtype and metastatic sites. A total of 238
The methodologic quality of the included studies was also assessed independently using standardized criteria for the presence of specific methodologic components known to be related to bias in observational studies.5 This included study-level assessment of risk of bias including study design and patient selection, as well as outcome-level assessment of risk of bias including method of diagnosis, management and length of follow-up.5 Statistical Analysis Weighted averages based on study size are calculated as pooled summary statistics. Proportions for categorical data are based on the total number of reported cases. Data is expressed as (N, %), median [interquartile range] and mean (standard deviation, SD). RESULTS The initial search yielded 737 studies for potential inclusion. Figure 1 demonstrates the study inclusion algorithm. A total of 630 studies were identified for full-text review, with a further 96 studies from reference lists. Also included were 35 abstracts from conference proceedings. Only 238 studies satisfied all inclusion criteria and formed the basis of our analysis. The most common reason for study exclusion was metastasis to either lung, bone, or lymph nodes with no rare end-organ metastasis mentioned (N = 452). Agreement between reviewers for inclusion of identified studies after screening was 100 % (kappa 1.0). A total of 197 case reports and 42 case series satisfied all inclusion criteria. Overall, the results are presented for 492 patients, with a median age of 62 years [50–70] and female-to-male ratio of 1.6. Most patients had papillary thyroid cancer (N = 255; 57 %), outnumbering follicular and Hu¨rthle-cell cancers 1.5-fold (N = 172; 39 %) and 12-fold (N = 18; 4 %), respectively. The most common sites of metastases were the brain (N = 217; 44 %), skin (N = 86; 17 %), and liver (N = 40; 8 %) (Fig. 1). Despite the predominance of papillary histology in the overall cohort, subgroup analysis shows a follicular prominence in the meninges (6 of 7, 86 %) and eyes (10 of 14, 71 %). End-organ sites with a disproportionate proportion of follicular carcinoma of at least 40 % included skin (36 of 86, 42 %), liver (17 of 40, 43 %), kidney (10 of 23, 43 %), soft tissue, including skeletal muscle or subcutaneous tissue (9 of 22, 41 %), breast (3 of 7, 43 %), and endobronchus (3 of
A. Madani et al.
Identification
462
630 studies identified through database searches
96 studies identified from reference lists
35 abstracts identified from conference proceedings
Screening
24 studies excluded as duplicate 737 screened and assessed for eligibility 498 studies excluded during screening
Eligibility
Reasons for exclusion: No rare metastatic site (N = 452) Medullary carcinoma, thyroid lymphoma, poorly/non-differentiated neoplasm (N = 38) Autopsy studies (N = 7)
Included
Pediatric population (N = 1)
239 studies included in qualitative analysis
FIG. 1 Study selection flow diagram. Kappa = 1.0 TABLE 1 Clinical presentation of the entire cohort
TABLE 2 Management of patients for the entire cohort
Solitary metastasis, % (N)
41 % (181)
Multiple metastasis, % (N)
59 % (264)
Proportion with [1 rare metastatic sites, % (N)
36 % (160)
Positron emission tomography
Management
Total reported (N)
Proportion, % (N)
Surgical metastasectomy
150
60 % (90)
97 % (28)
Radioiodine ablation therapy Proportion of 131-iodine scan positive patients that underwent RAI therapy
113 48
81 % (92) 96 % (46)
62
External beam radiation
98
53 % (52)
81 % (50)
Chemotherapy
88
15 % (13)
Total studies reported, N
58
Proportions are calculated based on the total number of studies that reported patient management
Elevated, % (N)
93 % (54)
RAI radioactive iodine
Total studies reported, N
29
Hypermetabolic foci, % (N) 131-iodine scan Total studies reported, N Hypermetabolic foci, % (N) Serum thyroglobulin
Proportion of positive test findings are calculated based on the total number of studies that reported each test result
8, 43 %). The majority of the other sites showed a strong papillary predominance (Fig. 1). The least common site among these rare metastases was the penis; only a single patient harboring a follicular thyroid carcinoma has so far been documented in the literature.6 Most patients (N = 264, 59 %) had multiple metastases to both conventional and uncommon sites, while 160 patients (36 %) had multiple uncommon end-organs
involved. A total of 181 (41 %) presented with a solitary metastasis (Table 1). FDG-PET and 131-iodine scan results were documented in 29 and 62 individuals and showed avidity in 97 % (27 of 28) and 81 % (50 of 62) of cases, respectively, while serum Tg levels were elevated in 93 % of cases (54 of 58). A total of 92 patients (81 %) received radioactive iodine therapy, including 46 (96 %) of those who had a positive 131-iodine scans. The majority also underwent surgical metastasectomy (N = 90, 60 %) and/or external beam
Rare Metastases of Thyroid Cancer
radiation (N = 52, 53 %) (Table 2). Only 13 patients (15 %) received either chemotherapy or targeted therapy. There were 66 patients (33 %) who presented with metastasis at the time of initial diagnosis of thyroid cancer. The other two-thirds presented with a known history of thyroid cancer at a mean disease-free interval of 86 months (SD 90; range 1–516 months). Survival data only was reported in 94 patients from 77 studies, with a mean overall survival after diagnosis of end-organ metastasis of 60 months (SD 57; range 1–360 months).
DISCUSSION Uncommon sites of end-organ distant metastases in WDTC have been reported in many case reports and case series. Yet, due to their rarity and uncommon clinical presentation, they are prone to being overlooked, resulting in delayed diagnosis and management. This is the first systematic review to catalog metastases of WDTCs to rare end-organ locations and to characterize their histopathologic features, clinical manifestations, imaging, and nuclear medicine findings, management, and outcomes. Several factors have been identified that predict outcomes in patients with WDTC, including the presence of distant metastasis, age, and gender. WDTC patients with distant metastases have a poorer prognosis with a 10-year survival of 50 %.7 The vast majority of patients with metastatic disease will develop end-organ disease in the lymph nodes, lungs, or bones, while a smaller minority (\5 %) will metastasize to other locations.8,9 Tumor histopathology has also been shown to affect the prognosis of WDTC, with follicular and Hu¨rthle-cell thyroid cancers having 10-year survival rates of 85 and 76 %, respectively, while that of papillary thyroid cancer is greater than 90 %.10 The majority of WDTC are papillary and its subtypes, outnumbering follicular and Hu¨rthle-cell cancers by a factor of 7- and 25-fold, respectively.10 Similarly, in this study, papillary subtypes were dominant (57 %), but the proportions decreased to 1.5-fold (from 7-fold) and 12-fold (from 25-fold) with respect to follicular and Hu¨rthle-cell cancers, respectively. Interestingly, despite papillary dominance in the overall cohort, several sites had a high proportion of metastatic follicular carcinoma, including meninges (86 %), eyes (71 %), skin (42 %), liver (43 %), kidney (43 %), soft tissue (41 %), breast (43 %), and endobronchus (43 %) (Fig. 2). One possible explanation is that follicular thyroid cancers tend to spread hematogenously, as opposed to papillary subtypes, which are more likely to spread via the lymphatics. The fact that most of the organs with follicular predominance tend to be vascularized may explain the discrepancy. However, the concept of colonization of thyroid
463
cancer cells to organ-specific sites (organ tropism) is complex and requires a deeper understanding of the various models of oncogenesis. Although several models invoking a variety of signaling pathways have been proposed to help understand patterns of thyroid cancer progression (e.g., MAPK and PI3K-Akt pathways), they still fall short of explaining or predicting the phenomena of rare organ metastatic deposits in thyroid cancer. By using other important factors such as tumor immunology as well as the molecular mediators of organ tropism, the clinical course of an individual with WDTC may well be predicted, thus allowing clinicians to individualize patient management and surveillance, even in the face of rare organ metastases. Identifying the metastatic mediators of the various types and subtypes of thyroid cancer may prove to be a critical factor in determining the biological behavior of organ tropism. A current theory has emerged that posits the concept of genetic heterogeneity within a primary tumor due to the presence of a subpopulation of cancer stem cells (CSCs), which can give rise to all morphological and biochemical cell types found within a given cancer. CSCs are considered a distinct type of somatic cells known as tumor-initiating cells and are capable of self-renewal along with the genesis of daughter cancer cells, some of which will be capable of metastasizing. Although there is controversy concerning CSCs, the concept of their existence is gaining traction as they have been demonstrated in a variety of blood-borne and solid organ malignancies.11–13 The importance of cellular heterogeneity and tumor cell predisposition based on genetic and epigenetic events in the life cycle of a given thyroid cancer cell stresses the need for lifelong surveillance in WDTC, with the intent of diagnosing and treating both the usual and rare sites of metastases. Thyroglobulin (Tg), high-resolution ultrasonography, diagnostic WBS, and FDG-PET are used routinely to detect and localize metastases. In the absence of antithyroglobulin antibodies, an elevated Tg during follow-up is suspicious for recurrent or metastatic disease. In patients with a suppressed TSH, the sensitivity of Tg testing is reported to be 80–100 %. Conversely, a single serum Tg level less than 0.5 ng/mL in the absence of TSH suppressive therapy has a reported negative predictive value of 98 %.14–16 In the current study, Tg levels were elevated in 93 % of reported cases (54 of 58), reflecting its high sensitivity. Patients with elevated Tg, or signs and symptoms related to both conventional and unconventional end-organ metastatic sites, should therefore be thoroughly evaluated in order to identify occult metastatic disease. According to the American Thyroid Association’s (ATA) 2009 revised guidelines, WBS should be offered to patients with poor prognostic features, while FDG-PET is recommended for initial staging and follow-up of high-risk patients with poorly differentiated thyroid cancers, invasive
464 FIG. 2 Histogram of the total number of patients with rare thyroid cancer metastasis according to anatomic location. Histological subtypes are also shown for each metastatic site
A. Madani et al.
Brain Skin Liver 0
50
100
150
200
250
20
25
Total Number (N) Kidney Soft Tissue Adrenal Eye Pancreas Spinal Cord Endobronchus Papillary Breast
Follicular Hürthle
Dura Gastrointestinal Ovary Vascular Thymus Parotid Submandibular Pleura Spleen Oral Cavity Penis 0
5
10
15
Total Number (N)
or metastatic Hu¨rthle-cell carcinomas, determining prognosis, identifying patients unlikely to respond to additional RAI therapy, and assessing therapeutic response.17 FDGPET has shown to be useful in detecting active disease in WDTC patients with serum Tg levels greater than 10 ng/ml and negative iodine WBS.18 The reported sensitivity, specificity, and accuracy of FDG-PET to detect recurrent or metastatic WDTC are between 70 and 100, 70 and 80, and 75 %, respectively.19–21 Diagnostic iodine scanning is reported to have a sensitivity of 75 %.14 In the current study, FDG-PET and WBS scans showed activity in 97 % (28 of 29) and 81 % (50 of 62) of reported cases, respectively, making them an invaluable tool for detecting occult and rare metastases in WDTC patients. Overall, the cases analyzed in this series of unusual metastases have similar
rates of positive FDG-PET, WBS, and elevated Tg levels compared with all patients with WDTC. Thus, tumors that metastasize to unusual sites seem to maintain similar biological behavior to those that do not. Despite the indolent nature of WDTCs, they can also behave aggressively. Overall survival [60 months (SD 57; range 1–360 months)] and disease-free interval [86 months (SD 90; range 1–516 months)] were highly variable as onethird of rare thyroid cancer metastases present synchronously with the primary tumor, while metachronous lesions can sometimes manifest a decade or more following the initial diagnosis and treatment of the primary. The latter survives for long periods of time with occult disease, with or without elevated Tg, before manifesting itself systemically. This period of ‘‘dormancy’’ varies from 1 patient to
Rare Metastases of Thyroid Cancer
another, and clinicians should be cognizant of this heterogeneity, especially when following patients with high-risk WDTC. Studies are needed to explain and predict which tumors are more indolent and therefore more amenable to more aggressive and potentially curative surgical metastasectomy. In order to assess the quality of studies in this systematic review, we divided our analysis into 2 parts: study-level and outcome-level risk of bias. At the study level, the lack of high-quality data represents a significant weakness and a high risk of bias due to case reports and case series without controls. Nevertheless, the nature of this study and the rarity of end-organ metastases other than lymph node, lung, or bone make it unlikely for prospective studies to be done. Furthermore, the lack of high-quality studies emphasizes the need for additional studies to characterize the clinical behavior and outcomes of these patients. Another source of bias was the lack of follow-up for the majority of patients, including survival data, which likely is the biggest contributor to outcome-level risk of bias. Length of follow-up was highly variable and in some studies, undocumented. Several other weaknesses are associated with the current study. First, proportions were calculated based on the total number of patients with reported test results and outcomes only. This is a source of reporting bias since it is possible that some authors did not report findings because they were negative, thus confounding the interpretation of data. Second, 4 of 58 (7 %) patients in this cohort with proven metastases had no elevation in Tg. It was unclear what proportion of these patients were on TSH-suppressive therapy, had thyrogen-stimulated Tg, or had elevated serum anti-Tg antibodies that can lead to false negative values by interfering with Tg immunometric assays.22 Lastly, the vast majority of studies failed to include important tumor characteristics such as the degree of differentiation and size. In conclusion, WDTC ordinarily manifests an indolent behavior, but can also have highly variable and unusual clinical features. Clinicians should be cognizant of rare sites of metastases in the absence of the more common extracervical disease-recurrence locations, while maintaining a low threshold for performing investigations during surveillance of patients with WDTCs who are at high risk of developing systemic disease. DISCLOSURE
There are no competing interests declared.
APPENDIX: SEARCH STRATEGY Medline OvidSP 1. exp Thyroid Neoplasms/ (18886) 2. exp Adenocarcinoma, Follicular/ (2572)
465
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33.
follicular.tw. (25603) Carcinoma, Papillary/ (7254) papillary.tw. (20358) 2 or 3 or 4 or 5 (45277) well differentiated.tw. (8563) differentiated.tw. (68308) 7 or 8 (68308) 6 or 9 (110398) 1 and 10 (10497) exp Carcinoma/sc [Secondary] (26502) exp Neoplasm Metastasis/ (69902) metasta$3.tw. (170857) 12 or 13 or 14 (197273) unusual.tw. (74000) rare.tw. (218902) uncommon.tw. (47903) infrequent.tw. (13765) 16 or 17 or 18 or 19 (328804) 15 and 20 (22103) 11 and 21 (677) *Carcinoma, Medullary/ (1705) thyroid lymphoma.tw. (184) undifferentiated.tw. (13800) non differentiated.tw. (234) poorly differentiated.tw. (7955) 23 or 24 or 25 or 26 or 27 (23308) 22 not 28 (588) limit 29 to humans (584) limit 30 to ‘‘all child (0 to 18 years)’’ (89) 30 not 31 (495) limit 32 to year=‘‘2001–Current’’ (396)
REFERENCES 1. Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med. 1998;338:297–306. 2. Clark JR, Lai P, Hall F, Borglund A, Eski S, Freeman JL. Variables predicting distant metastases in thyroid cancer. Laryngoscope. 2005;115:661–7. 3. Aggarwal V, Bhargav PR, Mishra A, Agarwal G. Clinico-pathological characteristics and long-term outcome in patients with distant metastases from differentiated thyroid carcinoma. World J Surg. 2007;31:246–7; author reply 247–8. 4. Song HJ, Xue YL, Xu YH, Qiu ZL, Luo QY. Rare metastases of differentiated thyroid carcinoma: pictorial review. Endocr Relat Cancer. 2011;18:R165–74. 5. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62:1006–12. 6. Grimm MO, Spiegelhalder P, Heep H, Gerharz CD, Roher HD, Ackermann R. Penile metastasis secondary to follicular thyroid carcinoma. Scand J Urol Nephrol. 2004;38:253–5. 7. Elisei R, Molinaro E, Agate L, Bottici V, Masserini L, Ceccarelli C, et al. Are the clinical and pathological features of differentiated thyroid carcinoma really changed over the last 35 years? Study on 4187 patients from a single Italian institution to answer this question. J Clin Endocrinol Metab. 2010;95:1516–27.
466 8. Lee J, Soh EY. Differentiated thyroid carcinoma presenting with distant metastasis at initial diagnosis clinical outcomes and prognostic factors. Ann Surg. 2010;251:114–9. 9. Sampson E, Brierley JD, Le LW, Rotstein L, Tsang RW. Clinical management and outcome of papillary and follicular (differentiated) thyroid cancer presenting with distant metastasis at diagnosis. Cancer. 2007;110:1451–6. 10. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995 [see comments]. Cancer. 1998;83:2638–48. 11. Zhang P, Zuo H, Ozaki T, Nakagomi N, Kakudo K. Cancer stem cell hypothesis in thyroid cancer. Pathol Int. 2006;56:485–9. 12. Hardin H, Montemayor-Garcia C, Lloyd RV. Thyroid cancer stem-like cells and epithelial-mesenchymal transition in thyroid cancers. Hum Pathol. 2013;44:1707–13. 13. Derwahl M. Linking stem cells to thyroid cancer. J Clin Endocrinol Metab. 2011;96:610–3. 14. de Geus-Oei LF, Oei HY, Hennemann G, Krenning EP. Sensitivity of 123I whole-body scan and thyroglobulin in the detection of metastases or recurrent differentiated thyroid cancer. Eur J Nucl Med Mol Imaging. 2002;29:768–74. 15. Kloos RT, Mazzaferri EL. A single recombinant human thyrotropin-stimulated serum thyroglobulin measurement predicts differentiated thyroid carcinoma metastases three to five years later. J Clin Endocrinol Metab. 2005;90:5047–57. 16. Castagna MG, Brilli L, Pilli T, Montanaro A, Cipri C, Fioravanti C, et al. Limited value of repeat recombinant human thyrotropin (rhTSH)-stimulated thyroglobulin testing in differentiated thyroid
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carcinoma patients with previous negative rhTSH-stimulated thyroglobulin and undetectable basal serum thyroglobulin levels. J Clin Endocrinol Metab. 2008;93:76–81. American Thyroid Association Guidelines Taskforce on Thyroid N, Differentiated Thyroid C, Cooper DS, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19:1167–214. Palaniswamy SS, Subramanyam P. Diagnostic utility of PETCT in thyroid malignancies: an update. Ann Nucl Med. 2013;27: 681–93. Shammas A, Degirmenci B, Mountz JM, McCook BM, Branstetter B, Bencherif B, et al. 18F-FDG PET/CT in patients with suspected recurrent or metastatic well-differentiated thyroid cancer. J Nucl Med. 2007;48:221–6. Kingpetch K, Pipatrattana R, Tepmongkol S, Sirisalipoch S, Chaiwatanarat T. Utility of 8F-FDG PET/CT in well differentiated thyroid carcinoma with high serum antithyroglobulin antibody. J Med Assoc Thai. 2011;94:1238–44. Finkelstein SE, Grigsby PW, Siegel BA, Dehdashti F, Moley JF, Hall BL. Combined [18F]Fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) for detection of recurrent, 131I-negative thyroid cancer. Ann Surg Oncol. 2008;15:286–92. Verburg FA, Luster M, Cupini C, Chiovato L, Duntas L, Elisei R, et al. Implications of thyroglobulin antibody positivity in patients with differentiated thyroid cancer: a clinical position statement. Thyroid. 2013;23:1211–25.
ORIGINAL ARTICLE – ENDOCRINE TUMORS
Rare Metastases of Well-Differentiated Thyroid Cancers: A Systematic Review Amin Madani, MD1, Yelda Jozaghi, MD2, Roger Tabah, MD1, Jacques How, MBChB3, and Elliot Mitmaker, MD MSc FRCS(C)1 Division of General Surgery, McGill University, Montreal, QC, Canada; 2Faculty of Medicine, McGill University, Montreal, QC, Canada; 3Division of Endocrinology, McGill University, Montreal, QC, Canada
1
ABSTRACT Background. A minority of metastatic well-differentiated thyroid cancer (WDTC) patients present with end-organ disease other than in the lung, bone or lymph nodes. These metastases tend to be overlooked because of their low incidence, and this results in delayed diagnosis. The purpose of this study was to perform a systematic review of the clinical and histologic features of unusual WDTC metastases. Methods. A systematic literature search of bibliographic databases, reference lists of articles, and conference proceedings was performed up to 2013. Studies were included if they reported on adult patients with WDTC and pathology-proven metastases to end-organs other than lung, bone, or lymph nodes. A total of 238 studies were included in a qualitative analysis. Data is expressed as N (%) and median [interquartile range]. Results. A total of 492 patients (median age, 62 years [50–70 years]) were identified in 197 case reports and 42 case series. There were 22 different end-organ metastatic sites documented with either papillary [255 (57 %)], follicular [172 (39 %)], or Hu¨rthle-cell [18 (4 %)] histology. A total of 181 (41 %) patients presented with solitary metastasis and 54 (93 %) with elevated serum thyroglobulin. Positron emission tomography and whole-body radioactive iodine scans revealed hypermetabolic foci in 28
Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-4058-y) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 14 July 2014; Published Online: 6 September 2014 E. Mitmaker, MD MSc FRCS(C) e-mail: [email protected]
(97 %) and 50 (81 %) cases, respectively. Disease-free interval following the initial diagnosis of the primary thyroid cancer was highly variable, ranging from synchronous presentation [66 (33 %)] to metachronous disease after 516 months [mean 86 months (SD 90)]. Conclusions. WDTC can manifest with highly variable and unusual clinical features. Rare sites of metastases should be considered in the absence of the more common extra-cervical disease recurrence locations.
Well-differentiated thyroid cancers (WDTC), including papillary, follicular, and Hu¨rthle-cell subtypes, are characterized by a slow progressive course and usually remain localized to the thyroid, with a 10-year survival rate of 80–95 %.1 Fortunately, only a minority (4–15 %) develop distant metastases that commonly involve lung, bone, and lymph nodes.2,3 Rare sites of end-organ distant metastases have been reported anecdotally in the literature. However, because of their low incidence, they tend to be overlooked, resulting in delayed diagnosis and management. There is a need for the histopathologic features, clinical manifestations, and outcomes of these unusual metastases to be analyzed in order to develop enhanced surveillance protocols. Song et al. published a pictorial review of rare metastases from WDTCs and provided insight into the clinical presentation of such patients.4 Since this review, there have been a number of reports in the literature documenting new and unconventional sites of metastasis from WDTC. The objective of this study was to perform a systematic review of the literature to determine the histopathologic characteristics and clinical presentation of WDTC patients with metastases to unusual locations excluding lung, bone, and lymph nodes.
Rare Metastases of Thyroid Cancer
METHODS
461
studies were included in the qualitative analysis (Online Appendix).
Search Strategy Quality Control A systematic literature search was performed for all articles published up to 2013. All aspects of the Preferred Reporting Items for Systematic Review and Meta-Analysis statement were followed.5 We searched bibliographic databases (MEDLINE, EMBASE, Cochrane Collaboration, PubMed), as well as conference proceedings, using electronic search terms focused on two main themes: thyroid neoplasm and metastasis using a combination of medical subject headings and keywords. Details of the search syntax are listed in ‘‘Appendix’’ section. The authors of relevant abstracts were contacted if their data was not published. In addition, the journal Thyroid was handsearched for relevant articles from 1990 (Volume 1, Issue 1) until June 2013 (Volume 23, Issue 6), including all online first articles up to June 10, 2013. The reference and citation lists from relevant reviews that were identified using the above search strategy, as well as the studies retained for full-text review, were also searched. Searches were limited to adult subjects (18? years) with no language or date restrictions. Studies were initially screened for relevance based on title and abstract and subsequently retained if they met the inclusion criteria: if the study population included adult (18?) patients with WDTC and pathology-proven metastasis to end-organs other than lung, bone, or lymph nodes. WDTC was defined as papillary, follicular, or Hu¨rthle-cell histologic subtypes. Pediatric patients, autopsy studies, patients with medullary thyroid carcinoma, thyroid lymphoma, and poorly or undifferentiated thyroid cancers were excluded. Two authors (A.M. and Y.J.) independently assessed each record for eligibility, extracted the data, and assessed study quality. Disagreement between reviewers was resolved by consensus from a third reviewer (E.M.). Agreement between reviewers was assessed using kappa statistic. Data Extraction and Synthesis A total of 737 studies were screened for eligibility (Fig. 1). All required data from each study included were extracted using a standardized form that covered: study characteristics (study design and publication year), sample size, patient demographics, histological subtype, metastatic sites, serum thyroglobulin (Tg) levels, diagnostic radioactive iodine whole-body (WBS), and [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) scan results, patient management, disease-free interval, and overall survival. The primary outcomes of this systematic review were histological subtype and metastatic sites. A total of 238
The methodologic quality of the included studies was also assessed independently using standardized criteria for the presence of specific methodologic components known to be related to bias in observational studies.5 This included study-level assessment of risk of bias including study design and patient selection, as well as outcome-level assessment of risk of bias including method of diagnosis, management and length of follow-up.5 Statistical Analysis Weighted averages based on study size are calculated as pooled summary statistics. Proportions for categorical data are based on the total number of reported cases. Data is expressed as (N, %), median [interquartile range] and mean (standard deviation, SD). RESULTS The initial search yielded 737 studies for potential inclusion. Figure 1 demonstrates the study inclusion algorithm. A total of 630 studies were identified for full-text review, with a further 96 studies from reference lists. Also included were 35 abstracts from conference proceedings. Only 238 studies satisfied all inclusion criteria and formed the basis of our analysis. The most common reason for study exclusion was metastasis to either lung, bone, or lymph nodes with no rare end-organ metastasis mentioned (N = 452). Agreement between reviewers for inclusion of identified studies after screening was 100 % (kappa 1.0). A total of 197 case reports and 42 case series satisfied all inclusion criteria. Overall, the results are presented for 492 patients, with a median age of 62 years [50–70] and female-to-male ratio of 1.6. Most patients had papillary thyroid cancer (N = 255; 57 %), outnumbering follicular and Hu¨rthle-cell cancers 1.5-fold (N = 172; 39 %) and 12-fold (N = 18; 4 %), respectively. The most common sites of metastases were the brain (N = 217; 44 %), skin (N = 86; 17 %), and liver (N = 40; 8 %) (Fig. 1). Despite the predominance of papillary histology in the overall cohort, subgroup analysis shows a follicular prominence in the meninges (6 of 7, 86 %) and eyes (10 of 14, 71 %). End-organ sites with a disproportionate proportion of follicular carcinoma of at least 40 % included skin (36 of 86, 42 %), liver (17 of 40, 43 %), kidney (10 of 23, 43 %), soft tissue, including skeletal muscle or subcutaneous tissue (9 of 22, 41 %), breast (3 of 7, 43 %), and endobronchus (3 of
A. Madani et al.
Identification
462
630 studies identified through database searches
96 studies identified from reference lists
35 abstracts identified from conference proceedings
Screening
24 studies excluded as duplicate 737 screened and assessed for eligibility 498 studies excluded during screening
Eligibility
Reasons for exclusion: No rare metastatic site (N = 452) Medullary carcinoma, thyroid lymphoma, poorly/non-differentiated neoplasm (N = 38) Autopsy studies (N = 7)
Included
Pediatric population (N = 1)
239 studies included in qualitative analysis
FIG. 1 Study selection flow diagram. Kappa = 1.0 TABLE 1 Clinical presentation of the entire cohort
TABLE 2 Management of patients for the entire cohort
Solitary metastasis, % (N)
41 % (181)
Multiple metastasis, % (N)
59 % (264)
Proportion with [1 rare metastatic sites, % (N)
36 % (160)
Positron emission tomography
Management
Total reported (N)
Proportion, % (N)
Surgical metastasectomy
150
60 % (90)
97 % (28)
Radioiodine ablation therapy Proportion of 131-iodine scan positive patients that underwent RAI therapy
113 48
81 % (92) 96 % (46)
62
External beam radiation
98
53 % (52)
81 % (50)
Chemotherapy
88
15 % (13)
Total studies reported, N
58
Proportions are calculated based on the total number of studies that reported patient management
Elevated, % (N)
93 % (54)
RAI radioactive iodine
Total studies reported, N
29
Hypermetabolic foci, % (N) 131-iodine scan Total studies reported, N Hypermetabolic foci, % (N) Serum thyroglobulin
Proportion of positive test findings are calculated based on the total number of studies that reported each test result
8, 43 %). The majority of the other sites showed a strong papillary predominance (Fig. 1). The least common site among these rare metastases was the penis; only a single patient harboring a follicular thyroid carcinoma has so far been documented in the literature.6 Most patients (N = 264, 59 %) had multiple metastases to both conventional and uncommon sites, while 160 patients (36 %) had multiple uncommon end-organs
involved. A total of 181 (41 %) presented with a solitary metastasis (Table 1). FDG-PET and 131-iodine scan results were documented in 29 and 62 individuals and showed avidity in 97 % (27 of 28) and 81 % (50 of 62) of cases, respectively, while serum Tg levels were elevated in 93 % of cases (54 of 58). A total of 92 patients (81 %) received radioactive iodine therapy, including 46 (96 %) of those who had a positive 131-iodine scans. The majority also underwent surgical metastasectomy (N = 90, 60 %) and/or external beam
Rare Metastases of Thyroid Cancer
radiation (N = 52, 53 %) (Table 2). Only 13 patients (15 %) received either chemotherapy or targeted therapy. There were 66 patients (33 %) who presented with metastasis at the time of initial diagnosis of thyroid cancer. The other two-thirds presented with a known history of thyroid cancer at a mean disease-free interval of 86 months (SD 90; range 1–516 months). Survival data only was reported in 94 patients from 77 studies, with a mean overall survival after diagnosis of end-organ metastasis of 60 months (SD 57; range 1–360 months).
DISCUSSION Uncommon sites of end-organ distant metastases in WDTC have been reported in many case reports and case series. Yet, due to their rarity and uncommon clinical presentation, they are prone to being overlooked, resulting in delayed diagnosis and management. This is the first systematic review to catalog metastases of WDTCs to rare end-organ locations and to characterize their histopathologic features, clinical manifestations, imaging, and nuclear medicine findings, management, and outcomes. Several factors have been identified that predict outcomes in patients with WDTC, including the presence of distant metastasis, age, and gender. WDTC patients with distant metastases have a poorer prognosis with a 10-year survival of 50 %.7 The vast majority of patients with metastatic disease will develop end-organ disease in the lymph nodes, lungs, or bones, while a smaller minority (\5 %) will metastasize to other locations.8,9 Tumor histopathology has also been shown to affect the prognosis of WDTC, with follicular and Hu¨rthle-cell thyroid cancers having 10-year survival rates of 85 and 76 %, respectively, while that of papillary thyroid cancer is greater than 90 %.10 The majority of WDTC are papillary and its subtypes, outnumbering follicular and Hu¨rthle-cell cancers by a factor of 7- and 25-fold, respectively.10 Similarly, in this study, papillary subtypes were dominant (57 %), but the proportions decreased to 1.5-fold (from 7-fold) and 12-fold (from 25-fold) with respect to follicular and Hu¨rthle-cell cancers, respectively. Interestingly, despite papillary dominance in the overall cohort, several sites had a high proportion of metastatic follicular carcinoma, including meninges (86 %), eyes (71 %), skin (42 %), liver (43 %), kidney (43 %), soft tissue (41 %), breast (43 %), and endobronchus (43 %) (Fig. 2). One possible explanation is that follicular thyroid cancers tend to spread hematogenously, as opposed to papillary subtypes, which are more likely to spread via the lymphatics. The fact that most of the organs with follicular predominance tend to be vascularized may explain the discrepancy. However, the concept of colonization of thyroid
463
cancer cells to organ-specific sites (organ tropism) is complex and requires a deeper understanding of the various models of oncogenesis. Although several models invoking a variety of signaling pathways have been proposed to help understand patterns of thyroid cancer progression (e.g., MAPK and PI3K-Akt pathways), they still fall short of explaining or predicting the phenomena of rare organ metastatic deposits in thyroid cancer. By using other important factors such as tumor immunology as well as the molecular mediators of organ tropism, the clinical course of an individual with WDTC may well be predicted, thus allowing clinicians to individualize patient management and surveillance, even in the face of rare organ metastases. Identifying the metastatic mediators of the various types and subtypes of thyroid cancer may prove to be a critical factor in determining the biological behavior of organ tropism. A current theory has emerged that posits the concept of genetic heterogeneity within a primary tumor due to the presence of a subpopulation of cancer stem cells (CSCs), which can give rise to all morphological and biochemical cell types found within a given cancer. CSCs are considered a distinct type of somatic cells known as tumor-initiating cells and are capable of self-renewal along with the genesis of daughter cancer cells, some of which will be capable of metastasizing. Although there is controversy concerning CSCs, the concept of their existence is gaining traction as they have been demonstrated in a variety of blood-borne and solid organ malignancies.11–13 The importance of cellular heterogeneity and tumor cell predisposition based on genetic and epigenetic events in the life cycle of a given thyroid cancer cell stresses the need for lifelong surveillance in WDTC, with the intent of diagnosing and treating both the usual and rare sites of metastases. Thyroglobulin (Tg), high-resolution ultrasonography, diagnostic WBS, and FDG-PET are used routinely to detect and localize metastases. In the absence of antithyroglobulin antibodies, an elevated Tg during follow-up is suspicious for recurrent or metastatic disease. In patients with a suppressed TSH, the sensitivity of Tg testing is reported to be 80–100 %. Conversely, a single serum Tg level less than 0.5 ng/mL in the absence of TSH suppressive therapy has a reported negative predictive value of 98 %.14–16 In the current study, Tg levels were elevated in 93 % of reported cases (54 of 58), reflecting its high sensitivity. Patients with elevated Tg, or signs and symptoms related to both conventional and unconventional end-organ metastatic sites, should therefore be thoroughly evaluated in order to identify occult metastatic disease. According to the American Thyroid Association’s (ATA) 2009 revised guidelines, WBS should be offered to patients with poor prognostic features, while FDG-PET is recommended for initial staging and follow-up of high-risk patients with poorly differentiated thyroid cancers, invasive
464 FIG. 2 Histogram of the total number of patients with rare thyroid cancer metastasis according to anatomic location. Histological subtypes are also shown for each metastatic site
A. Madani et al.
Brain Skin Liver 0
50
100
150
200
250
20
25
Total Number (N) Kidney Soft Tissue Adrenal Eye Pancreas Spinal Cord Endobronchus Papillary Breast
Follicular Hürthle
Dura Gastrointestinal Ovary Vascular Thymus Parotid Submandibular Pleura Spleen Oral Cavity Penis 0
5
10
15
Total Number (N)
or metastatic Hu¨rthle-cell carcinomas, determining prognosis, identifying patients unlikely to respond to additional RAI therapy, and assessing therapeutic response.17 FDGPET has shown to be useful in detecting active disease in WDTC patients with serum Tg levels greater than 10 ng/ml and negative iodine WBS.18 The reported sensitivity, specificity, and accuracy of FDG-PET to detect recurrent or metastatic WDTC are between 70 and 100, 70 and 80, and 75 %, respectively.19–21 Diagnostic iodine scanning is reported to have a sensitivity of 75 %.14 In the current study, FDG-PET and WBS scans showed activity in 97 % (28 of 29) and 81 % (50 of 62) of reported cases, respectively, making them an invaluable tool for detecting occult and rare metastases in WDTC patients. Overall, the cases analyzed in this series of unusual metastases have similar
rates of positive FDG-PET, WBS, and elevated Tg levels compared with all patients with WDTC. Thus, tumors that metastasize to unusual sites seem to maintain similar biological behavior to those that do not. Despite the indolent nature of WDTCs, they can also behave aggressively. Overall survival [60 months (SD 57; range 1–360 months)] and disease-free interval [86 months (SD 90; range 1–516 months)] were highly variable as onethird of rare thyroid cancer metastases present synchronously with the primary tumor, while metachronous lesions can sometimes manifest a decade or more following the initial diagnosis and treatment of the primary. The latter survives for long periods of time with occult disease, with or without elevated Tg, before manifesting itself systemically. This period of ‘‘dormancy’’ varies from 1 patient to
Rare Metastases of Thyroid Cancer
another, and clinicians should be cognizant of this heterogeneity, especially when following patients with high-risk WDTC. Studies are needed to explain and predict which tumors are more indolent and therefore more amenable to more aggressive and potentially curative surgical metastasectomy. In order to assess the quality of studies in this systematic review, we divided our analysis into 2 parts: study-level and outcome-level risk of bias. At the study level, the lack of high-quality data represents a significant weakness and a high risk of bias due to case reports and case series without controls. Nevertheless, the nature of this study and the rarity of end-organ metastases other than lymph node, lung, or bone make it unlikely for prospective studies to be done. Furthermore, the lack of high-quality studies emphasizes the need for additional studies to characterize the clinical behavior and outcomes of these patients. Another source of bias was the lack of follow-up for the majority of patients, including survival data, which likely is the biggest contributor to outcome-level risk of bias. Length of follow-up was highly variable and in some studies, undocumented. Several other weaknesses are associated with the current study. First, proportions were calculated based on the total number of patients with reported test results and outcomes only. This is a source of reporting bias since it is possible that some authors did not report findings because they were negative, thus confounding the interpretation of data. Second, 4 of 58 (7 %) patients in this cohort with proven metastases had no elevation in Tg. It was unclear what proportion of these patients were on TSH-suppressive therapy, had thyrogen-stimulated Tg, or had elevated serum anti-Tg antibodies that can lead to false negative values by interfering with Tg immunometric assays.22 Lastly, the vast majority of studies failed to include important tumor characteristics such as the degree of differentiation and size. In conclusion, WDTC ordinarily manifests an indolent behavior, but can also have highly variable and unusual clinical features. Clinicians should be cognizant of rare sites of metastases in the absence of the more common extracervical disease-recurrence locations, while maintaining a low threshold for performing investigations during surveillance of patients with WDTCs who are at high risk of developing systemic disease. DISCLOSURE
There are no competing interests declared.
APPENDIX: SEARCH STRATEGY Medline OvidSP 1. exp Thyroid Neoplasms/ (18886) 2. exp Adenocarcinoma, Follicular/ (2572)
465
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33.
follicular.tw. (25603) Carcinoma, Papillary/ (7254) papillary.tw. (20358) 2 or 3 or 4 or 5 (45277) well differentiated.tw. (8563) differentiated.tw. (68308) 7 or 8 (68308) 6 or 9 (110398) 1 and 10 (10497) exp Carcinoma/sc [Secondary] (26502) exp Neoplasm Metastasis/ (69902) metasta$3.tw. (170857) 12 or 13 or 14 (197273) unusual.tw. (74000) rare.tw. (218902) uncommon.tw. (47903) infrequent.tw. (13765) 16 or 17 or 18 or 19 (328804) 15 and 20 (22103) 11 and 21 (677) *Carcinoma, Medullary/ (1705) thyroid lymphoma.tw. (184) undifferentiated.tw. (13800) non differentiated.tw. (234) poorly differentiated.tw. (7955) 23 or 24 or 25 or 26 or 27 (23308) 22 not 28 (588) limit 29 to humans (584) limit 30 to ‘‘all child (0 to 18 years)’’ (89) 30 not 31 (495) limit 32 to year=‘‘2001–Current’’ (396)
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