AACE/ACE Disease State Commentary AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE COMMENTARY: MANAGING THYROID TUMORS DIAGNOSED AS NONINVASIVE FOLLICULAR THYROID NEOPLASM WITH PAPILLARY-LIKE NUCLEAR FEATURES Zubair W. Baloch, MD, PhD1; R. Mack Harrell, MD, FACP, FACE, ECNU2; Elise M. Brett, MD, FACE, CNSC, ECNU3; Gregory Randolph, MD, FACS, FACE4; Jeffrey R. Garber, MD, FACP, FACE5; On behalf of AACE Endocrine Surgery Scientific Committee and Thyroid Scientific Committee ABSTRACT EXECUTIVE SUMMARY This commentary summarizes the history and reclassification of noninvasive follicular thyroid neoplasm with papillary-like nuclei (NIFTP). It reviews the salient histopathologic features that are based on immunohistochemical and molecular profiles and serve as inclusion and exclusion criteria. The authors also provide their own point of view regarding the practical issues and possible concerns that may be raised by both clinicians and patients based on the diagnosis of NIFTP. (Endocr Pract. 2017;23:1153-1158) Historically, the definition of papillary thyroid carcinoma (PTC) versus follicular thyroid carcinoma was predicated on the predominant tumor growth pattern. Thus if the tumor was mostly follicular in pattern on low-power microscopic examination, it was classified as “follicular carcinoma” (1,2). Once the importance of nuclear morphology was appreciated in the diagnosis of PTC (3), experts agreed that thyroid epithelial cell tumors should be identified as papillary by nuclear features, whether or not papillary or follicular architecture was present (4). The “follicular variant of papillary thyroid carcinoma” (FVPTC) was described in the mid-1970s as a tumor with a predominantly follicular growth pattern and the nuclear cytomorphology of PTC (4). Following this, 2 major subtypes of FVPTC were described: infiltrative and encapsulated (5,6). Accumulated data suggest that infiltrative FVPTC, which grows in the manner of follicular carcinoma with invasion into either its thick capsule or vessels within the capsule, is more likely to behave aggressively. In contrast, noninvasive encapsulated FVPTC (EFVPTC) has been observed to behave in a benign fashion like follicular adenoma (7-10). This variable morphologic and clinical course has led to much controversy in the diagnosis and management of noninvasive EFVPTC. Confusion has been amplified by the lack of interobserver agreement on the minimal diagnostic criteria for EFVPTC among endocrine pathology experts, causing angst among pathologists and clinicians alike (11,12). Recent clinical follow-up and case-control studies have confirmed that noninvasive EFVPTC behaves in a benign fashion and may be overtreated (10,13). Moreover, recent molecular analyses of EFVPTC tumors have suggested that these tumors may have a unique set of genetic mutations and fusions (14-17). Abbreviations: AACE = American Association of Clinical Endocrinologists; EFVPTC = encapsulated FVPTC; FNA = fine-needle aspiration; FVPTC = follicular variant of papillary thyroid carcinoma; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; PTC = papillary thyroid carcinoma Submitted for publication April 27, 2017 Accepted for publication June 8, 2017 From the 1Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania; 2Memorial Health Systems, Inc, Memorial Center for Integrative Endocrine Surgery, Hollywood, Florida; 3Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York; 4Mass Eye and Ear Infirmary/Mass General Hospital, Harvard Medical School, Boston, Massachusetts; 5Endocrine Division, Harvard Vanguard Medical Associates, Boston, Massachusetts, Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. Address correspondence to Dr. Zubair W. Baloch; Hospital of the University of Pennsylvania, Perelman School of Medicine; 6 Founders, Rm 6.043, 3400 Spruce Street, Philadelphia, PA 19104. E-mail: email@example.com Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org. DOI:10.4158/EP171940.DSCR To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2017 AACE. Copyright © 2017 AACE ENDOCRINE PRACTICE Vol 23 No. 9 September 2017 1153 1154 Managing Thyroid Tumors Diagnosed as NIFTP, Endocr Pract. 2017;23(No. 9) In response to the confusion, a multidisciplinary panel, the Endocrine Pathology Society (EPS) Working Group including thyroid pathologists, endocrinologists, and an endocrine surgeon, was established to address the important controversies surrounding the diagnosis of encapsulated and noninvasive FVPTC. The panel deliberations were based on the clinical outcomes and tumor molecular analyses of a case cohort of noninvasive EFVPTC patients for whom there was diagnostic consensus among the pathology experts in the group. All noninvasive EFVPTC patients, followed for 10 to 26 years after diagnosis, were alive without evidence of disease. Importantly, none of these patients received radioiodine ablation, and >50% were treated by lobectomy only. In addition, molecular alterations typically seen in classic PTC (BRAF V600E mutations or RET gene fusions) were not seen in noninvasive EFVPTC cases. The molecular profiles of these cases included RAS gene mutations (30% cases) and PPARG or THADA gene fusions (44% cases). Based on the benign clinical outcomes and characteristic molecular analysis data in these patients, the Copyright © 2017 AACE EPS Working Group recommended that truly noninvasive EFVPTC tumors be redesignated as nonmalignant entity termed “noninvasive follicular thyroid neoplasms with papillary-like nuclear features” (NIFTP). This reclassification will have a significant effect on a large population of patients worldwide, hopefully resulting in a diminution of overaggressive treatment with a concomitant reduction in clinical consequences and psychologic sequelae related to the diagnosis of “cancer” (18). Although the case cohort long-term outcome data supporting the nomenclature change is strong, in the absence of prospective study confirmation, it is essential that endocrine physicians prospectively follow patients with NIFTP pathology to verify that these patients’ postoperative courses are truly indolent. NIFTP – DIAGNOSTIC CRITERIA For optimal clinical management, it is important that NIFTP is a surgical disease and this diagnosis cannot be rendered on pre-operative fine-needle aspiration (FNA). Table 1 Diagnostic Histopathologic Criteria for NIFTP Diagnostic criteria Comments Inclusion criteria (Fig. 2 A-C) 1. Well demarcated/encapsulated follicular patterned tumor 2. Nuclear cytology of PTC 3. Noninvasive characteristics a. No tumor capsule invasion or invasion into the surrounding thyroid parenchyma b. No lymphovascular invasion It is of utmost importance that a thorough sampling of tumor and its interface with either tumor capsule or surrounding uninvolved thyroid parenchyma is carried out to exclude invasive characteristics Exclusion criteria Invasion • Invasion beyond the periphery of tumor excludes the diagnosis of NIFTP • This includes invasion by the tumor cells into the tumor capsule, extension into the surrounding thyroid parenchyma, and/or vascular invasion into vessels within the tumor capsule or beyond • NIFTP predominantly shows a follicular growth pattern. However, the presence of <1% papillary structuresa and ≤30% of solid growth pattern (by area) is allowed (papillary structures are hallmark features of conventional carcinoma) • Presence of any other growth patterns indicative of aggressive variants of PTC such as tall cell, columnar cell, and hobnail variant exclude the diagnosis of NIFT • Psammoma bodies represent “dead” papillary structures and can be seen in tumor as well as within the lymphatics away from tumor • Any form of “true” tumor necrosis (excludes necrosis associated with preoperative fine-needle aspiration) and or mitoses can be associated with high-grade transformation and/or aggressive clinical behavior • Three or more mitotic figures in 10 consecutive high-power fields exclude the diagnosis of NIFTP (this criterion requires future clinicopathologic validation) Tumor growth pattern Lymphovascular invasion and/or lymph node metastases Psammoma bodies Tumor necrosis and or mitoses Abbreviation: NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclei. aBased on a study by Cho et al (19), 3% lymph node metastases were noted in cases with a 1% cutoff value for papillary structures. These authors have suggested not to render a diagnosis of NIFTP even in the presence of a single papillary structure. Copyright © 2017 AACE A Managing Thyroid Tumors Diagnosed as NIFTP, Endocr Pract. 2017;23(No. 9) 1155 B C Fig. 1. NIFTP: Low-power view showing a thinly encapsulated noninvasive follicular patterned nodule (A-B) comprised of macro- and microfollicles lined by cells showing papillary-like nuclei (C). NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclei. A B C D Fig. 2. A cartoon depiction of diagnostic criteria for encapsulated follicular lesions of the thyroid gland: follicular adenoma, follicular carcinoma, NIFTP, and the follicular variant of papillary thyroid carcinoma (lightest blue, black asterisk = tumor capsule, medium blue = tumor, red asterisk = tumor cells without nuclear features of PTC, darkest blue = invasive tumor). The follicular adenoma is encapsulated and shows no invasion (A), whereas the follicular carcinoma shows tumor cells invading into or beyond the tumor capsule (red arrows) and/or showing vascular invasion into the capsular vessels (black arrow, B). The NIFTP is an encapsulated tumor that shows PTC-like nuclei without invasive characteristics (C). The encapsulated follicular variant of PTC shows nuclear features of PTC and invasion into or beyond the tumor capsule (red arrows) and/or vascular invasion (black arrows, D). NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclei; PTC = papillary thyroid carcinoma. The diagnosis of NIFTP be made with strict adherence to the following inclusion and especially to, exclusion histomorphologic criteria (18) (Table 1, Fig. 1 and 2). As mentioned above, the renaming of noninvasive EFVPTC to NIFTP may prove to be beneficial to patients; however, it may also raise the following questions for both clinicians and patients: Invasive Characteristics The diagnosis of tumor capsule invasion can be a difficult task for the surgical pathologist, partly due to lack of consensus among experts in defining the diagnostic criteria (8). Various criteria have been cited in the literature for the diagnosis of invasion into the tumor capsule (8). Some debate the importance of capsular invasion in the absence of vascular invasion (20). Since it has been associated with metastatic disease, any form of invasion by the tumor cells into its capsule (usually traversing the entire thickness of capsule) or into the surrounding normal thyroid parenchyma should exclude the diagnosis of NIFTP. Multifocal Tumors and Staging The diagnosis of NIFTP does not preclude the diagnosis of another distinct tumor(s) in the thyroid gland. Cancer staging in such cases should not include NIFTP lesions. Tumor Size The NIFTP proposal study did not include tumors measuring <1.0 cm; however, a recent study has shown that these tiny tumors can be included in the new category (21). A recent study by Xu et al demonstrated that NIFTP tumors measuring ≥4.0 cm appear to have an extremely low risk of recurrence, even when treated with conservative surgical treatment without radioiodine therapy (22). However, 1156 Managing Thyroid Tumors Diagnosed as NIFTP, Endocr Pract. 2017;23(No. 9) the diagnosis of NIFTP in large-sized tumors should only be entertained, when the entire tumor capsule has been evaluated by histopathologic evaluation to exclude invasive characteristics. Impact of Preoperative FNA Diagnosis The most important issue that has surfaced with the newly created diagnosis of NIFTP is the inevitable increase in the “false-positive” rates for cases diagnosed as suspicious or consistent with PTC by preoperative FNA cytology and molecular assessment (23-25). Recent studies have shown that noninvasive EFVPTC have previously comprised a significant proportion of malignant diagnoses associated with the indeterminate diagnostic categories of The Bethesda System for Reporting Thyroid Cytology (TBSRTC) (26-29): atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), and suspicious for malignancy (14). However, one would predict no appreciable change in the risk of malignancy for FNA cases diagnosed as benign (Bethesda 2) and malignant (Bethesda 6) based on the NIFTP nomenclature change. The initial studies have shown an appreciable decrease in the rate of malignancy for indeterminate categories of TBSRTC. The reported ranges for changes in the rate of malignancy are AUS/ FLUS 19 to 45% to 15-30%, FN/SFN –22 to 45% to 10 to 37%, and SM 72 to 87% to 46 to 68% (24,25,29,30) (Table 2) . Such alterations in the rate of malignancy for the indeterminate diagnostic categories (Bethesda III-V) may lead to changes in the thyroid nodule pre- and postsurgical management paradigms, especially for those classified as SM, as recommended by the American Association of Clinical Endocrinologists (AACE) and American Thyroid Association for low-risk thyroid neoplasms (31-33). It is hoped that with the emergence of this new nonmalignant category, physicians may tend to recommend lobectomy with greater assurance in patients with Bethesda III-IV cytology, especially in those with RAS mutations and PPARG or THADA gene fusions (18). Recent retrospective studies have shown that NIFTP comprises approximately 5% of thyroid FNA speci- Copyright © 2017 AACE mens diagnosed as malignant (25,28,30,36). Though this percentage may not appear significant, even a small decrease in risk of malignancy for the “malignant” FNA category could raise concerns about potential medicolegal implications in the pathology community. As a result, some pathologists have suggested that the diagnosis of PTC in FNA specimens be limited to cases that demonstrate diagnostic features of the classic or tall cell variants of PTC: papillary architecture, psammomatous calcifications, and well-formed pseudo-inclusions. Based on these potential future concerns, some pathologists are now including an explanatory note regarding the possibility that NIFTP tumors are part of the differential diagnosis list for Bethesda III-VI cytology results and that this new noncancerous diagnostic category may change Bethesda III-V categorybased performance characteristics (25). It is also crucial to understand and explain to patients that NIFTP is not a “benign tumor” but a “low-risk neoplasm” that requires surgical excision for diagnosis followed by comprehensive pathologic evaluation of the tumor contents and its capsule. Moreover, it is reasonable to suggest that in thyroid nodules demonstrating indeterminate or low-risk ultrasound features, FNAs in the Bethesda III-V categories and/or with NIFTP-suggestive molecular profiles (only RAS-mutations and/or PPARG and THADA gene fusions, without BRAF or TERT promoter mutations), conservative management with hemithyroidectomy for diagnosis may be the best surgical approach (18,23,25). What to advise patients whose tumors have been reclassified as NIFTP? (37) (1) “I was told that I had a follicular variant of papillary carcinoma. Did I have cancer?” (a) In order to confirm that a tumor originally classified as a follicular variant of papillary cancer is a NIFTP, it needs to be reread by a pathologist familiar with the new criteria. Some patients will have invasive tumors, some may have classic papillary cancer, and some may be NIFTP. The diagnosis cannot be based on the original pathology report. Within a few years of diagnosis, the original pathology tissue specimen blocks may still be available for resectioning and re-evalua- Table 2 Change in the Risk of Malignancy of TBSRTC Diagnostic Categories due to NIFTP Diagnosis Cancer risk based on TBSRTC 2007 (34) Cancer risk based on post-2007 studies (24,27,28,35) NIFTP effect on lowest to highest cancer risk (24,28,30) AUS/FLUS (TBSRTC Cat-3) 5-15% 19-45% 15-30% FN/SFN (TBSRTC Cat-4) 15-30% 22-45% 10-37% SM (TBSRTC Cat-5) 60-75% 72-87% 46-68% TBSRTC Abbreviations: AUS/FLUS = atypia/follicular lesion of undetermined significance; Cat = category; FN/SFN = follicular neoplasm/suspicious for follicular neoplasm; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclei; SM = suspicious for malignancy; TBSRTC = The Bethesda System for Reporting Thyroid Cytology. Copyright © 2017 AACE Managing Thyroid Tumors Diagnosed as NIFTP, Endocr Pract. 2017;23(No. 9) 1157 tion; however, there is no guarantee that the entire tumor periphery was submitted for histopathologic evaluation to exclude invasion either into the tumor capsule, surrounding thyroid, or vessels. Thus, NIFTP should be viewed as a newly appreciated pathologic diagnosis that should not be applied retrospectively. (b) A benign clinical course after surgery with a low serum thyroglobulin test and a negative neck ultrasound is the most important outcome and ultimately is more important than the pathologic nomenclature. Moving forward, the AACE favors careful education of pathologists and endocrinologists regarding the precise and prospective diagnosis of NIFTP tumors to allow for unbiased clinical and pathological study of the new category and its outcomes. (2) “If my tumor is reclassified as NIFTP, do I still need any long-term follow-up with an endocrinologist? “ (a) Since NIFTP cannot be diagnosed prior to surgery, at a minimum, removal of at least half of the thyroid is still required. Although many patients may have had more aggressive surgery and/or treated with radioiodine, these patients were treated according to the best knowledge available at the time of their diagnosis. (b) Since NIFTP is a new diagnostic entity, at this point what constitutes optimal follow-up is uncertain. In the absence of data, we are unable to provide evidence-based recommendations. Until data are available, each case should be considered individually based on risk factors. (3) “I was told I had cancer and now I am told I do not. Who is responsible for my misdiagnosis?” (a) Things change regularly in medicine as our knowledge advances. At the time of the original treatment, no one (surgeon, endocrinologist, nuclear medicine physician) knew that the follicular variant of PTC diagnosis was in question. You were treated appropriately according to treatment guidelines at the time. In general, the AACE does not advocate for retrospective review of previously adjudicated EFVPTCs because: (i) Proper reclassification demands retrieval of the tumor block with repeat comprehensive sectioning to document the integrity of surrounding tissue and tumor capsule and the absence of papillary structures, lymphovascular invasion, papillary cancer variants, psammoma bodies and tumor necrosis. (ii) In many cases, the tumor block and appropriate slides are no longer available or interpretable. (iii)In most cases, the clinical course over the first 5 to 10 years after primary therapy is as powerful a predictor of future tumor behavior as the pathologist’s impression of the recut tumor block. (iv) Most thyroid cancer experts believe that the new NIFTP criteria should optimally be implemented in prospective rather than retrospective fashion to allow for unbiased clinical and pathological study of the new category and its outcomes. CONCLUSION Based on clinical cohort studies demonstrating favorable long-term outcomes, the Endocrine Pathology Society Working Group has reclassified a noninvasive subset of follicular variant of papillary cancers (noninvasive EFVPTC) as NIFTP, thereby diminishing the psychologic stigma of the word “cancer” for patients worldwide. It is our hope that the new NIFTP classification will eventually diminish clinical confusion among pathologists, endocrinologists, and endocrine surgeons and increase the use of diagnostic (and therapeutic) thyroid lobectomy while diminishing thyroid hormone dependency and radioiodine use in affected patients. 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