Accepted 18 December 2009 Published online 25 May 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: /hed.21373

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1 ORIGINAL ARTICLE DIMINISHING DIAGNOSIS OF FOLLICULAR THYROID CARCINOMA Kristen J. Otto, MD, 1 Jacqueline S. C. Lam, MBBS, 2 Christina MacMillan, MD, 3 Jeremy L. Freeman, MD, FRCSC 2 1 Department of Otolaryngology and Communicative Sciences, University of Mississippi Medical Center, Jackson, MS. kotto@ent.umsmed.edu 2 Department of Otolaryngology Head and Neck Surgery, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada 3 Department of Laboratory Medicine and Pathobiology, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada Accepted 18 December 2009 Published online 25 May 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: /hed Correspondence to: K. J. Otto VC 2010 Wiley Periodicals, Inc. Abstract: Background. Follicular carcinomas have been reported as 10% to 15% of thyroid malignancies. Refinements in the histologic criteria applied in the classification of follicular lesions have occurred. We aim to document the true incidence of follicular cancers in a cohort from a high-volume endocrine practice. Methods. Patient charts were reviewed and cancers were classified into major subtypes; papillary cancers were further classified by common variants. Proportions were compared to historic Surveillance, Epidemiology, and End Results (SEER) database proportions. Results. Only 2.7% of patients had follicular carcinoma. The proportion of patients with follicular cancer was less than the reported rates of 10% to 15%, and less than the 6.7% extrapolated from SEER. Conclusion. The proportion of follicular cancers is less than traditionally reported. This change is due to an increased incidence of papillary cancers, and modifications of the histologic criteria used for classification of encapsulated follicular lesions. There are potential prognostic consequences, as follicular cancers have been perceived as more aggressive. VC 2010 Wiley Periodicals, Inc. Head Neck 32: , 2010 Although accounting for only 1% of all reportable malignancies, the number of internationally documented well-differentiated thyroid carcinomas (WDTC) has shown a sustainable rise over the past 30 years. Thyroid cancer has become the seventh leading cause of cancer among white women in the United States. 1 5 There has been considerable debate about the true cause of this apparent rise; whether there is an actual increase in the number of thyroid malignancies developing versus whether more early thyroid cancers are being detected with improved sensitivity in our diagnostic imaging and evolving histopathologic criteria remains to be determined. Either way, few will argue that the number of patients presenting for treatment with WDTC is increasing. It has also long been recognized that in contrast to many malignancies, the treatment for WDTC is remarkably successful, with 5-year survival rates reaching close to 97%. 6 Diminishing Diagnosis of Follicular Thyroid Carcinoma HEAD & NECK DOI /hed December

2 Thyroid cancers comprise a heterogeneous group of malignancies with the most common categories including papillary, follicular, medullary, and poorly differentiated and undifferentiated/anaplastic carcinomas. WDTC typically refers to those tumors of follicular cell origins that are largely indolent in nature, and include papillary and follicular carcinomas. Hürthle cell carcinomas are currently categorized as papillary carcinoma, oncocytic variant; follicular carcinoma, oncocytic variant; or medullary carcinoma, oncocytic variant. This classification schema recognizes that the Hürthle cell change is a metaplastic change in the cell and that the underlying biologic behavior of the tumor depends on whether it is a papillary, follicular, or medullary carcinoma. Making the distinction between the various subtypes of WDTC is important as variations do exist in the recommendations for treatment and the overall prognosis. Classically, papillary carcinomas have been reported to represent approximately 80% of all thyroid malignancies, whereas follicular cancers are reported as 10% to 15%. 1 The problem with these figures is that they fail to account for changing diagnostic criteria and incidence patterns among papillary cancers. A review of the epidemiologic data reveals a 2.4-fold increase in incidence of thyroid cancer over the past 30 years. This increase in incidence is attributable solely to papillary thyroid carcinoma. Further scrutiny of the evidence supporting such a drastic increase in incidence reveals an emerging belief that papillary thyroid carcinoma is currently over-diagnosed and that the current diagnostic criteria are probably inconsistently implemented. This is best exemplified by the fact that papillary thyroid carcinoma lacks a single diagnostic cytologic feature, and even among experienced pathologists, there remains poor diagnostic concordance. 7,8 Furthermore, the histologic classification specific to papillary thyroid carcinomas has undergone drastic revisions over the past 40 years. In 1969, the Armed Forces Institute of Pathology (AFIP) fascicle on thyroid tumors described only 1 histologic variant of papillary carcinoma, whereas by 2004, the World Health Organization (WHO) monograph on tumors of endocrine origin agreed on 15 separate variants. In fact, applying the WHO subtyping schema, many thyroid tumors considered to be follicular thyroid carcinomas in the past, would actually currently be classified as papillary carcinomas of the follicular variant. 9 While many large epidemiologic studies have attempted to redefine the true incidence rates of thyroid cancer subtypes seen currently, the shortcomings of such multi-institutional series are apparent in the lack of diagnostic consensus. Moreover, currently reported incidence rates determined from long-term single-institution studies can be confusing and perhaps misleading to the daily practices of thyroid surgeons and endocrinologists as long-term studies are not reflective of current trends. We attempt to define the true incidence of thyroid cancer subtypes, using a retrospective single-institution model from a busy head and neck endocrine surgery practice. PATIENTS AND METHODS Record Review. With the approval of the Mount Sinai Hospital Research Ethics Board, a retrospective review was undertaken of all patients presenting for thyroidectomy in the 2- year period from January 2006 through December All patients were treated by 1 of 3 head and neck surgeons at Mount Sinai Hospital. Patient charts were reviewed for demographic information, and details regarding the extent of surgery performed, the histologic description of the tumor, and final diagnosis. The primary goal was to pinpoint all patients with a diagnosis of primary thyroid malignancy and create a database from which the incidence of the various subtypes of thyroid cancer could be determined. Cancers were classified into major subtypes: papillary, follicular, Hürthle cell not otherwise specified (NOS), medullary, and undifferentiated/anaplastic. Papillary carcinomas were further classified into 7 common variants: classic, follicular, tall cell, insular, oncocytic, microcarcinomas, and cystic. Patients with benign pathology or cumulative disease foci less than 1 cm were excluded from review. Totals and percentages of major subtypes and minor variants were calculated and compared to previously published historic control proportions. In all, 740 thyroid operations were performed at Mount Sinai Hospital during the study period. Of these, 258 patients (34.9%) met inclusion criteria having a diagnosis of primary thyroid cancer and were able to be entered into the database for incidence comparison Diminishing Diagnosis of Follicular Thyroid Carcinoma HEAD & NECK DOI /hed December 2010

3 Histopathologic Diagnostic Criteria. During this time period, the surgical specimens consisting of hemi-thyroidectomy, subtotal thyroidectomy, or total thyroidectomy, were reviewed and diagnosed by pathologists in our institution who also had experience in fine-needle aspiration (FNA) thyroid cytology. There were 8 pathologists, including 1 with specialty training in head and neck/thyroid pathology. The standard criteria for follicular carcinoma and papillary carcinomas were applied, including the presence of lesional capsular invasion and/or angioinvasion within or outside the capsule for encapsulated neoplasms. In the situation of an encapsulated follicular neoplasm with or without evidence of capsular and/or vascular invasion and with papillary carcinoma nuclei recognized cytologically, a diagnosis of follicular variant of papillary carcinoma was made. The features of papillary carcinoma nuclei were defined as nuclear clearing (optically clear nuclei or Orphan Annie nuclei), numerous nuclear grooves, overlapping, enlargement, nuclear membrane irregularity, and intranuclear pseudoinclusions. Other softer features were micronucleoli, hypereosinophilic ( hard ) colloid, irregularly shaped or elongated follicles, psammoma bodies, and small abortive papillae. The papillary carcinoma nuclei were present either diffusely or in a multifocal pattern throughout the tumor. The Hürthle cell (oncocytic) variant of follicular carcinoma was diagnosed when the criteria for follicular carcinoma were identified, and the follicular cells showed extensive Hürthle cell metaplasia. The Hürthle cell (oncocytic) variant of papillary carcinoma was likewise diagnosed when the findings of either a conventional or follicular variant of papillary carcinoma were present and there was extensive Hürthle cell metaplasia. Two of our cases were diagnosed solely as Hürthle cell carcinomas and were not further categorized as either papillary or follicular carcinomas. FIGURE 1. Breakdown of thyroid cancers diagnosed at Mount Sinai Hospital during [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Of the 258 patients studied, 205 (79.5%) were women, and 53 (20.5%) were men. The age range of patients included was 16 to 86 years (mean 48, median 48). Of the 258 patients, 218 (84.5%) underwent total thyroidectomy, whereas 40 patients (15.5%) had subtotal or partial thyroidectomy operations. Papillary carcinoma was by far the most common thyroid cancer diagnosis in the study group. Papillary carcinoma was the dominant diagnosis in 243 (94.2%) of 258 cases. An additional 9 cases showed multifocal papillary microcarcinomas but had other concurrent dominant diagnoses, making the total number of cases in which papillary cancer was diagnosed 252. The other diagnoses were as follows: 5 cases (1.9%) of medullary carcinoma, 7 cases (2.7%) of follicular carcinoma, 2 cases (0.8%) of Hürthle cell carcinoma NOS, and 1 case (0.3%) of anaplastic carcinoma (Figure 1). In 60% 9 of these nonpapillary cases, papillary carcinoma foci were identified. There were 7 variants of papillary cancer identified in the study group. The dominant variant was RESULTS FIGURE 2. Breakdown of papillary carcinoma variants diagnosed at Mount Sinai Hospital during [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Diminishing Diagnosis of Follicular Thyroid Carcinoma HEAD & NECK DOI /hed December

4 follicular variant, identified in 125 of 252 cases (49.6%). Other less commonly identified variants included: 98 cases (38.9%) of classical variant, 4 cases (1.6%) of tall cell variant, 2 cases (0.8%) of insular variant, 9 cases (3.6%) of oncocytic variant, 12 cases (4.8%) of papillary microcarcinoma (cumulative foci were greater than 1 cm in all cases), and 2 cases (0.8%) of cystic variant of papillary carcinoma (Figure 2). DISCUSSION We identified only 7 cases of true follicular thyroid cancer in 258 total thyroid cancers diagnosed over a 2-year period in our institution. This number corresponds to 2.7% of thyroid cancer diagnoses. This number is not only drastically lower than many previously published historic references which typically indicate a 10% to 15% rate of follicular cancers, but also much lower than recently collected data from multi-institutional, large, prospective series. Hundahl et al 1 reported on the National Cancer Database (NCD) registry for thyroid cancers, a cohort consisting of more than 53,000 cases of thyroid cancer diagnosed in the United States between 1985 and In the NCD report, the proportion of papillary cancers was 79% of the total, whereas follicular cancers made up 13%. For a more recent perspective, the National Cancer Institute s Surveillance Epidemiology and End Results (SEER) database, a comprehensive cancer database that captures a crosssection of approximately 26% of the United States population, can be evaluated. From the 2005 SEER report (capturing cases diagnosed between 2001 and 2005), papillary cancers comprised 85% of thyroid cancer diagnoses, whereas follicular carcinomas made up 6.7% 6 (Figure 3 and Figure 4). Because the NCD and SEER make no attempt to collect specific histologic description of tumors entered into the registries, it is obvious that the diagnoses reported in these databases are made by many pathologists from many different regions of the country and likely represent many nuances in diagnostic inquiry. There are several contributing factors that underlie the change in thyroid cancer demographics over the last 30 years. First, analysis of SEER reveals that although the overall incidence of thyroid cancer has significantly increased in 30 years, the increase is nearly all attributable to cancer of the papillary subtype. FIGURE 3. Comparison of thyroid cancer cases from Mount Sinai, SEER, and NCD by percentage of cases diagnosed. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] The overall incidence of follicular thyroid cancer, however, has remained stable since Because of the relative stability in follicular carcinoma incidence, it can be surmised that the increase in papillary thyroid cancer is real and cannot solely be accounted for by redistribution in the histopathologic classification of follicular carcinomas to other diagnostic categories such as follicular variant of papillary carcinoma. If this were the case, the incidence of follicular cancers would have been expected to decrease as these diagnoses were replaced by diagnoses of papillary carcinoma variants. As papillary cancers have become significantly more common, the relative proportion of follicular cancer has seemingly gone down. Analysis of SEER has also shown that since tumor size has been reported in the database (1988), the largest group of new papillary cancers diagnosed is the group of tumors 2 cm or less. 6 Although there have been demonstrable FIGURE 4. Comparison of follicular thyroid carcinomas from Mount Sinai, SEER, and NCD by percentage of cases diagnosed. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 1632 Diminishing Diagnosis of Follicular Thyroid Carcinoma HEAD & NECK DOI /hed December 2010

5 increases in the incidence rates for the larger tumors, these rates do not come close to comparing to the rates for the smaller tumors. There is an ever-increasing use of high-resolution neck ultrasound scan and FNA biopsy which has likely contributed to improved detection of early thyroid cancers. Over time, this fact may also explain the steady decrease in the group of undifferentiated and anaplastic thyroid carcinomas as well. The change in papillary cancer incidence rates and relative stability of follicular cancer incidence is not likely enough to explain such a reduction in the proportion of follicular cancers currently diagnosed on its own. Changing diagnostic criteria must be considered important in contributing to the current numbers. The most important has been the increased recognition and refinement of criteria by surgical pathologists of the entity of follicular variant of papillary carcinoma, which is based on well-defined cytologic (nuclear) features of papillary carcinoma in a follicular patterned lesion When these well-differentiated tumors are completely encapsulated and show minimal to no invasion, it may be difficult to distinguish them from adenomatous hyperplastic nodules, follicular adenomas, or minimally invasive follicular carcinomas. 12 Particularly problematic to pathologists is defining and applying the so-called minimal diagnostic criteria of the follicular variant of papillary carcinoma, and interobserver variability among expert consultants in thyroid pathology has been documented. 7,8 It has been recognized that papillary carcinoma nuclei may be present in a multifocal pattern and may merge with otherwise benign appearing nuclei within a single lesion, even in a macrofollicular hyperplastic nodule. 12 In addition to the follicular variant of papillary carcinoma, the oncocytic (Hürthle cell) variant of papillary carcinoma has been defined. Indeed, Hürthle cell carcinomas are now classified as the oncocytic variants of 1 of the following: follicular carcinoma, papillary carcinoma, insular carcinoma, or medullary carcinoma. 11 Lastly, adenomatous hyperplastic nodules and follicular adenomas may be overdiagnosed as encapsulated or minimally invasive follicular carcinomas due to the difficulties in diagnosing true capsular and vascular invasion and due to pseudoinvasion of the capsule caused by a previous FNA biopsy. 12 All of these refinements in diagnostic criteria have led to a decreased incidence in the diagnosis of follicular adenomas, encapsulated follicular carcinomas, and Hürthle cell adenomas/carcinomas, not otherwise specified. Recognizing that there exists a group of well-differentiated follicular neoplasms that are difficult to classify histologically as either benign or malignant, the Chernobyl group of pathologists has recently proposed a new term for labeling lesions with either incomplete features of papillary cancer or equivocal invasion. The encapsulated, well-differentiated, follicular neoplasm of undetermined malignant potential has been proposed as a bridging term between lesions that are clearly benign, and those that are clearly malignant. 13 The issue of long-term clinical predictability and utility of this proposed diagnostic category becomes questionable as surgeons would still be forced to make traditional therapeutic decisions (ie, surgery for malignant lesions and observation for benign ones). To date, this diagnosis has not been employed at our institution, but it could be speculated that if it were widely adopted, there would be some decrease in the diagnosis of the follicular variant of papillary carcinoma, and thus, the overall incidence of papillary cancer as a subtype, would be expected to decrease. CONCLUSION In our series of 258 primary thyroid malignancies treated over a 2-year period, we identified only 7 cases (2.7%) of true follicular thyroid carcinoma. When compared to large, cross-sectional and multi-institutional cancer databases such as SEER and NCD, and previously established thyroid cancer proportions, this number is not only drastically lower, but reflects an emerging trend away from the follicular cancer diagnosis; favoring diagnoses such as follicular adenoma and follicular variant of papillary carcinoma. Our proportion of 7 of 258 cases can be favorably compared to series previously reported by LiVolsi and Asa, and DeMay 14,15 in which follicular cancers were identified in just 2% and 1%, respectively. In these reports, similar diagnostic scrutiny was utilized. Lesions with nuclear features suggestive of papillary carcinoma were classified as such, and care was taken to exclude pseudocapsular invasion that may be traumatic in nature. Both improved clinical diagnostics, and evolving diagnostic criteria in thyroid cancer histopathology, has led to a drastic increase in Diminishing Diagnosis of Follicular Thyroid Carcinoma HEAD & NECK DOI /hed December

6 the incidence and proportion of papillary thyroid cancers being diagnosed. This multifactorial change has led to an overall shrinkage in the numbers of true follicular carcinomas seen currently. A change in expected proportions is important for clinicians to take into account when therapeutic options are being considered and when patients are being counseled about their diagnoses. Over time, it seems we are likely to see a continued trend toward decreasing numbers of the nonpapillary subtypes; and, as such, a shift in thyroid cancer management and thyroid cancer outcomes may follow. REFERENCES 1. 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., Cancer 1998;83: Albores-Saavedra J, Henson DE, Glazer E, Schwartz AM. Changing patterns in the incidence and survival of thyroid cancer with follicular phenotype-papillary, follicular, and anaplastic: a morphological and epidemiological study. Endocr Pathol 2007;18: Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, JAMA 2006;295: Hodgson NC, Button J, Solorzano CC. Thyroid cancer: is the incidence still increasing? Ann Surg Oncol 2004;11: Hundahl SA, Cady B, Cunningham MP, et al. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the United States during U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study. Cancer 2000;89: National Cancer Institute. Surveillance, Epidemiology and End Results Program. Available at cancer.gov. 7. Lloyd RV, Erickson LA, Casey MB, et al. Observer variation in the diagnosis of follicular variant of papillary thyroid carcinoma. Am J Surg Pathol 2004;28: Elsheikh TM, Asa SL, Chan JK, et al. Interobserver and intraobserver variation among experts in the diagnosis of thyroid follicular lesions with borderline nuclear features of papillary carcinoma. Am J Clin Pathol 2008;130: Albores-Saavedra J, Wu J. The many faces and mimics of papillary thyroid carcinoma. Endocr Pathol 2006;17: Rosai J, Carcangiu ML, DeLellis RA. Tumors of the Thyroid Gland. Atlas of Tumor Pathology, Third Series, Fascicle 5. Armed Forces Institute of Pathology, Washington, D.C DeLellis RA, Lloyd RV, Heitz PU, Eng C. World Health Organization Classification of Tumours. Tumours of Endocrine Organs. IARC, LiVolsi VA, Baloch ZW. Follicular neoplasms of the thyroid: view, biases, and experiences. Adv Anat Pathol 2004;11: Williams ED. Guest Editorial: Two proposals regarding the terminology of thyroid tumors. Int J Surg Pathol 2000;8: LiVolsi VA, Asa SL. The demise of follicular carcinoma of the thyroid gland. Thyroid 1994;4: DeMay RM. Follicular lesions of the thyroid. W(h)ither folicular carcinoma? Am J Clin Pathol 2000;114: Diminishing Diagnosis of Follicular Thyroid Carcinoma HEAD & NECK DOI /hed December 2010