Follicular Variant of Papillary Thyroid Cancer Encapsulated, Nonencapsulated, and Diffuse: Distinct Biologic and Clinical Entities
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ORIGINAL ARTICLE Follicular Variant of Papillary Thyroid Cancer Encapsulated, Nonencapsulated, and Diffuse: Distinct Biologic and Clinical Entities Sachin Gupta, MD; Oluyomi Ajise, MD; Linda Dultz, MD; Beverly Wang, MD; Daisuke Nonaka, MD; Jennifer Ogilvie, MD; Keith S. Heller, MD; Kepal N. Patel, MD Objective: To examine genotypic and clinical differ- tions in BRAF, H-RAS 12/13, K-RAS 12/13, N-RAS 12/13, ences between encapsulated, nonencapsulated, and dif- H-RAS 61, K-RAS 61, N-RAS 61, and RET/PTC1. fuse follicular variant of papillary thyroid carcinoma (EFVPTC, NFVPTC, and diffuse FVPTC, respectively), Results: No patient with EFVPTC had central lymph node to characterize the entities and identify predictors of their metastasis, and in this group, 1 patient (4.5%) had a BRAF behavior. V600E mutation and 2 patients (9%) had RAS mutations. Of the patients with NFVPTC, none had central lymph Design: Retrospective medical chart review and mo- node metastasis (PϾ.99) and 2 (11%) had a BRAF V600E lecular analysis. mutation (P=.59). Of the patients with diffuse FVPTC, all had central lymph node metastasis (PϽ.001), and 2 (50%) Setting: Referral center of a university hospital. had a BRAF V600E mutation (P=.06). Patients: The pathologic characteristics of 484 con- Conclusions: FVPTC consists of several distinct sub- secutive patients with differentiated thyroid cancer who types. Diffuse FVPTC seems to present and behave in a underwent surgery by the 3 members of the New York more aggressive fashion. It has a higher rate of central University Endocrine Surgery Associates from January nodal metastasis and BRAF V600E mutation in compari- 1, 2007, to August 1, 2010, were reviewed. Forty-five pa- son with EFVPTC and NFVPTC. Both EFVPTC and tients with FVPTC and in whom at least 1 central com- NFVPTC behave in a similar fashion. The diffuse infil- partment lymph node was removed were included. trative pattern and not just presence or absence of en- capsulation seems to determine the tumor phenotype. Un- Main Outcome Measures: Patients with FVPTC were derstanding the different subtypes of FVPTC will help compared in terms of age, sex, tumor size, encapsula- guide appropriate treatment strategies. tion, extrathyroid extension, vascular invasion, central nodal metastases, and the presence or absence of muta- Arch Otolaryngol Head Neck Surg. 2012;138(3):227-233 ANCER OF THE THYROID nuclear features typical of PTC (eg, nuclear gland is the most com- clearing, grooves, and pseudoinclusions) mon endocrine malig- and a follicular growth pattern. nant tumor and accounts FVPTC presents several diagnostic and for most endocrine can- management challenges. Most FVPTCs are Ccer–related deaths each year.1 Well- encapsulated tumors, which are cytologi- differentiated thyroid cancer is usually as- cally difficult to distinguish from benign sociated with a good prognosis. The most follicular lesions such as follicular ad- common histologic type is papillary thy- enoma (FTA). Several studies highlight this roid carcinoma (PTC).1 Many subtypes of by demonstrating the considerable in- PTC have been described, of which clas- terobserver variability involved with the sical PTC (cPTC) is the most common diagnosis of FVPTC.9,10 In addition to the Author Affiliations: (80%). The follicular variant of PTC encapsulated subtype (EFVPTC), there is Departments of (FVPTC) is the second most common sub- also a nonencapsulated subtype of FVPTC Otolaryngology–Head and Neck type, being found in 9% to 22.5% of pa- (NFVPTC). These subtypes seem to be dis- Surgery (Dr Gupta), Pathology tients with PTC.2-5 The first histologic de- tinct both clinically and genetically. A study (Drs Ajise, Wang, and Nonaka), 6 11 and Surgery (Drs Dultz, Ogilvie, scription of FVPTC was by Lindsay in by Liu et al showed that while EFVPTC 7 Heller, and Patel), New York 1960, followed by Chen and Rosai in rarely exhibited lymph node metastases (in University Langone Medical 1977, and Rosai et al8 in 1983. It is char- 5% of cases), NFVPTC was associated with Center, New York, New York. acterized as a tumor possessing both lymph node metastases in 65% of cases. ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 138 (NO. 3), MAR 2012 WWW.ARCHOTO.COM 227 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 They concluded that most EFVPTCs behave like an FTA Of these patients, 103 with FVPTC were identified by 2 or follicular thyroid carcinoma (FTC), whereas NFVPTCs experienced thyroid pathologists (B.W. and D.N.). The diag- behave like cPTC. nosis of FVPTC was made when nuclear characteristics of On a molecular level, Rivera et al12 examined the on- cPTC were present with a follicular growth pattern. From cogenic mutations present in EFPVTC and NFVPTC. They this group of 103 patients with FVPTC, 45 patients in whom at least 1 central compartment lymph node was removed found that EFVPTC was similar to FTA and FTC, with a were included in the study. Pathologic findings were high rate of RAS mutations (36%), and no BRAF muta- reviewed for tumor size, the presence of encapsulation, tions (0%). In contrast, they found NFVPTC to be more extrathyroidal extension, vascular invasion, and central similar to cPTC, with a significantly higher rate of BRAF nodal metastases. These 45 patients were divided into our 3 mutations (26%) and a lower rate of RAS mutations (10%). study groups (those with EFVPTC, NFVPTC, and diffuse In addition to the encapsulated and nonencapsu- FVPTC). lated subtypes of FVPTC, Sobrinho-Simo˜esetal13 de- scribed the diffuse follicular variant of PTC (diffuse MOLECULAR ANALYSIS FVPTC). This variant occurred primarily in young fe- males and was characterized on a histologic level by ex- The presence of the BRAF V600E mutation, RAS (H-RAS, tensive, multinodular involvement of 1 or both lobes of K-RAS, N-RAS) point mutations (codons 12, 13, and 61), the thyroid gland. The 8 patients in their series with dif- and the RET-PTC1 rearrangement were identified in excised fuse FVPTC developed distant metastases in the lungs surgical specimens by direct sequencing. For analysis of and/or bones with or without concurrent regional lymph BRAF and RAS genes, DNA was extracted from 10-µm sec- node metastases. Diffuse FVPTC was further studied by tions of paraffin-embedded tumor blocks using a commercial 14 kit (Qiagen, Germantown, Maryland). The extracted DNA Ivanova et al, who found that patients with diffuse was quantified using a NanoDrop 2000c spectrophotometer FVPTC had notably increased local, nodal, and vascular (Thermo Fisher Scientific Inc). The BRAF gene was ampli- invasiveness compared with other patients with FVPTC. fied with primers as previously described.16-18 Codons 12/13 They concluded that diffuse FVPTC is a distinct tumor and 61 of H-RAS, K-RAS, and N-RAS genes were amplified carrying a guarded prognosis that has to be appropri- using primers as previously described.16-18 Polymerase chain ately diagnosed and treated. reaction (PCR) was then performed in a 20-µL mixture con- The 2009 American Thyroid Association Guide- taining primer, deoxyribonucleotide triphosphated (NTP), lines15 provide little direction for the surgical treatment DNA polymerase, and genomic DNA. The PCR conditions of FVPTC. Recommendation 26 states that for patients consisted of initial denaturation at 95°C followed by 35 with thyroid cancer larger than 1 cm, the initial surgical cycles of denaturation at 95°C for 30 seconds, annealing at 58°C for 40 seconds, and extension at 72°C for 40 seconds. procedure should be a near-total or total thyroidec- The final extension step was performed at 72°C for 1 min- tomy. Recommendation 27b states that elective (prophy- ute. The DNA PCR products’ integrity was then evaluated lactic) central-compartment neck dissection may be con- using 2% agarose gel electrophoresis. The products were sidered in patients with PTC and clinically uninvolved purified using a commercial PCR purification kit (Qiagen) central neck lymph nodes, especially in patients with ad- according to the manufacturer’s instructions. The purified vanced primary tumors (T3 or T4).15 It is important to PCR products were sequenced commercially (Genewiz, note that these recommendations do not distinguish be- South Plainfield, New Jersey). tween cPTC and FVPTC, and they may not necessarily For analysis of the RET-PTC1 rearrangement, RNA was ex- apply to all variants of PTC. We examined clinical and tracted from 10-µm sections of each tumor’s paraffin- genotypic differences between the encapsulated, nonen- embedded block using a commercial kit (Qiagen). The ex- tracted RNA was quantified using a NanoDrop 2000c capsulated, and diffuse subtypes of FVPTC to character- spectrophotometer (Thermo Fisher Scientific Inc). Comple- ize the entities and identify predictors of their behavior, mentary DNA (cDNA) was synthesized using 0.5 µg of ex- which may help guide their management. tracted RNA and a commercial kit (Qiagen). Reverse transcrip- tase-polymerase chain reaction (RT-PCR) was performed in a METHODS 20-µL mixture containing primer, dNTP, DNA polymerase, and 500 ng of cDNA. Primers used for RET-PTC1 have been de- scribed previously.16,17 The RT-PCR conditions consisted of ini- CLINICAL AND PATHOLOGIC ANALYSIS tial denaturation at 95°C followed by 35 cycles of denatur- ation at 95°C for 30 seconds, annealing at 58°C for 40 seconds, The medical records of all 484 patients who underwent thy- and extension at 72°C for 40 seconds. The RT-PCR products roid operations with a postoperative diagnosis of thyroid were then visualized using 2% agarose gel electrophoresis. The cancer at New York University (NYU) Langone Medical cDNA from the TPC-1 cell line served as a positive control for Center by the 3 members of NYU Endocrine Surgery Associ- the RET-PTC1 rearrangement. RP1 was used in all reactions as ates from January 1, 2007, through August 1, 2010, were a housekeeping gene.