Follicular Variant of Papillary Thyroid Cancer Encapsulated, Nonencapsulated, and Diffuse: Distinct Biologic and Clinical Entities

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 encapsulation 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 cer–relatedC 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.

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©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 described 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 extracted 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 described previously.16,17 The RT-PCR conditions consisted of ini- CLINICAL AND PATHOLOGIC ANALYSIS tial denaturation at 95°C followed by 35 cycles of denaturation 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. reviewed. Indications for surgery included cytologic findings on fine-needle aspiration biopsy, symptomatic or enlarging multinodular goiter, and Graves disease. The extent of thy- STATISTICAL roidectomy (lobectomy vs total thyroidectomy) was deter- ANALYSIS mined by the operating surgeon based on preoperative evaluation, patient preference, and intraoperative findings. A 2-tailed Fisher exact test was used to assess the relationship Central compartment lymph node sampling or central com- between categorical variables. PϽ.05 was considered signifi- partment dissection was performed if suspicious nodes were cant. This study was approved by the NYU Cancer Institute pro- identified at the time of surgery, or electively at the discre- tocol review and monitoring committee and by the NYU insti- tion of the surgeon. tutional review board.

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 1. Clinical, Pathologic, and Molecular Characteristics Table 2. Clinical, Pathologic, and Molecular Characteristics of EFPVTC and NFVPTC of EFPVTC؉NFVPTC and Diffuse FVPTC

Patients, No. (%) Patients, No. (%)

EFPVTC NFVPTC P EFPVTC؉ Diffuse Characteristic (n=22) (n=19) Valuea NFVPTC FVPTC P Characteristic (n=41) (n=4) Valuea Age Median, y 47 52 Age Յ45 9 (41) 5 (26) .51 Median, y 50 32 Ͼ45 13 (59) 14 (74) Յ45 14 (34) 3 (75) .14 Sex Ͼ45 27 (66) 1 (25) Female 16 (73) 16 (84) Sex .47 Male 6 (27) 3 (16) Female 32 (78) 3 (75) Ͼ.99 Tumor size, cm Male 9 (22) 1 (25) Median 1.7 0.9 Tumor size, cm Յ4 20 (91) 19 (100) .49 Median 1.2 2.4 Ͼ4 2 (9) 0 Յ4 39 (95) 4 (100) .50 Vascular invasion Ͼ4 2 (5) 0 Absent 21 (95) 18 (95) Vascular invasion Ͼ.99 Present 1 (5) 1 (5) Absent 39 (95) 1 (25) .003 Extrathyroid extension Present 2 (5) 3 (75) Absent 22 (100) 19 (100) Extrathyroid extension Ͼ.99 Present 0 0 Absent 41 (100) 2 (50) .006 Central nodal metastases Present 0 2 (50) Absent 22 (100) 19 (100) Central nodal metastases Ͼ.99 Present 0 0 Absent 41 (100) 0 Ͻ.001 Thyroid surgery Present 0 4 (100) Lobectomy 5 (23) 2 (11) Thyroid surgery .42 Total thyroidectomy±CLND 17 (77) 17 (89) Lobectomy 7 (17) 0 Ͼ.99 BRAF V600E mutation Total thyroidectomy±CLND 34 (83) 4 (100) Absent 21 (95) 17 (89) BRAF V600E mutation .59 Present 1 (5) 2 (11) Absent 38 (93) 2 (50) .06 RAS mutationsb Present 3 (7) 2 (50) Absent 20 (90) 19 (100) RAS mutationsb .49 Present 2 (10) 0 Absent 39 (95) 4 (100) Ͼ.99 Present 2 (5) 0 Abbreviations: CLND, central lymph node dissection; EFVPTC, encapsulated follicular variant of papillary thyroid carcinoma; NFVPTC, Abbreviations: CLND, central lymph node dissection; EFVPTC, encapsulated nonencapsulated follicular variant of papillary thyroid carcinoma. follicular variant of papillary thyroid carcinoma; NFVPTC, nonencapsulated a Fisher exact test, 2-tailed values. follicular variant of papillary thyroid carcinoma. b RAS mutations assessed include H-RAS, K-RAS, and N-RAS at codons aFisher exact test, 2-tailed values. 12, 13, and 61. bRAS mutations assessed include H-RAS, K-RAS, and N-RAS at codons 12, 13, and 61.

RESULTS Table 3. Central Lymph Nodes Sampled in EFVPTC and NFVPTC CLINICAL AND PATHOLOGIC ANALYSIS Patients, No. (%) A total of 45 cases were included in the study (22 cases of EFVPTC; 19, NFVPTC; and 4, diffuse FVPTC). Central Lymph Nodes, EFVPTC NFVPTC Table 1 compares the clinical and pathologic features No. (n=22) (n=19) of EFVPTC and NFVPTC. The 2 histologic subtypes seem 1 11 (50) 10 (53) 2-3 7 (32) 5 (26) to be identical. There were no significant differences in Ͼ terms of age, sex, tumor size, vascular invasion, extra- 3 4 (18) 4 (21) thyroid extension, central nodal metastasis, or extent of Abbreviations: EFVPTC, encapsulated follicular variant of papillary thyroid initial thyroid surgery between the 2 groups. Vascular in- carcinoma; NFVPTC, nonencapsulated follicular variant of papillary thyroid vasion was present in only 1 patient in each group, and carcinoma. no patient in either group had extrathyroid tumor invasion or central lymph node metastases. tients with EFVPTC or NFVPTC had clinically palpable Table 2 compares the combined clinical and patho- or radiograph evidence of lymph node metastasis in the logic characteristics of EFVPTC and NFVPTC with those central or lateral compartment, all 4 of the patients with of diffuse FVPTC. Again, there were no significant dif- diffuse FVPTC had clinically palpable and/or radio- ferences in terms of age, sex, or tumor size. There were graphic evidence of lymph node metastasis (31 of 50 cen- significant differences in vascular invasion (P=.003), ex- tral lymph nodes were positive for metastasis). All 4 pa- trathyroid extension (P=.006), and central lymph nodal tients with diffuse FVPTC (100%) had total thyroidectomy metastases (PϽ.001). Note that whereas none of the pa- with central lymph node dissection.

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> 1661-braf-f_C10.ab1 NNNNNNNNNNNNNNNNNNNNNT NNN TACCCC T AGGGGGGGGGA T AA T TTT C TT C AT AAA CCCC T AA T AAAAAA T T A TTTT T C T A G C T AAC GGT A AAT C T C G A T G GGA GGGT TTC C C A T C A G TT G A A C A GGTT TC T G G A T C C A TTTTGGTTTG A G GAAG AA TTG A G G C TTTTA TTCCA C T G A T T A A A TTTT T GNG C C C A N C A N A T G A T G GGAA G CCT G T T G CCG C TTGNA G A C T C TTCCA N G A GGGGG AAC C TTG C GNGNT N CCT G T T A CCGNA A A C N C C A C GGC C GGN G C A NGA C G G T T

Figure 1. Gene sequencing tracing showing BRAF V600E mutation in a patient with nonencapsulated follicular variant of papillary thyroid carcinoma.

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> 1884-n61-f_B11.ab1 NNNNN A C T GNNNGTTTGNAAT A C TTG G AAC A G C T G G AAC A G A A G AAG T A C A GGT CC T GGA A G A CCAATT AC A G AGGA C A G G C G A A G G C T T C CCTTG T G T A TTT G C C A T C A AAT A A T G C A A G T C A TTT T G C GGA T A T A A C C TTC T A C AAN NGG C TTTTTTT TTA T AAG CCG T G G C T A C T A T GGN A A G A G T G G AAA A A T TTC T CC CCT CCCCN T G CC CN CC T C CCCT C A A N AAN N

Figure 2. Gene sequencing tracing showing N-RAS 61 mutation in a patient with nonencapsulated follicular variant of papillary thyroid carcinoma.

Table 3 details the distribution of central lymph nodes (5%) had a BRAF V600E mutation (Figure 1), 1 patient from patients with EFVPTC and NFVPTC. Patients with (5%) had an N-RAS 61 mutation (Figure 2), and 1 pa- diffuse FVPTC were excluded from this analysis be- tient (5%) had a K-RAS 61 mutation (Figure 3). In the cause they uniformly underwent total thyroidectomy with NFVPTC group of 19 patients, 2 patients (11%) had a BRAF central lymph node dissection, resulting in 50 central V600E mutation (Figure 4), whereas no patients had RAS lymph nodes evenly distributed among the 4 patients. mutations. The rates of RAS and BRAF V600E mutations between EFPVTC and NFVPTC were not statistically sig- MOLECULAR ANALYSIS nificant (P=.49 and P=.59, respectively). Table 2 compares the combined molecular features of Table 1 compares the molecular features of EFPVTC and EFVPTC and NFVPTC with diffuse FVPTC. In the 4 pa- NFVPTC. In the EFVPTC group of 22 patients, 1 patient tients with diffuse FVPTC, 2 patients (50%) had a BRAF

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T C G A C A C A G C A G G T C A A G A G G A G T A C A 30 35 40 45 50 55 15979-k61-f 1979-k61-f_G02.ab1 908

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Sequence File: 15979-k61-f.seq

> 15979-k61-f_G02.ab1 NNNNNNNNNNNNNGT T C T C TTGNG A AAAT T C T CCG C A G C A GGT C AAAAAGGA GGA TTC GGC A T G A GGG A CCAAGGT C A T A GGA C A GGGGGGA G C TTTC TTTG TGGAAA A GG A GGG A G C A G CCC GGGGGG T C TTGGGG A A TTG GGGG A G T GGA G GC TTTC T TTG T GGA GGG A G G G C TTTC TTT G T G A A A N T C CCC N A C G G A C NN C T T N T N TTC C N A G T A T C AAA TTG G T T C T A N G N C A N T N C T C G T AAA NNNNA T G AATTA N N C G AAT CCCT A N A T N C C N A C A NGGG CCT GGG C T C C A T T C T G G C T A T T G AAN C GNGA TTG N AAN G C T TTN C N T T GGA N T G C C T G GGGNC N C C T G G AAT C TTC TTC TNAAG C NNC NG GGG GA A T NNAAT G C A C T T G T N T NN C T C T G CCT CCA C G A T GNA C TTG G C AAT C G GG GC G C TTG C G A NNG G NN T C TTT G T GNA

Figure 3. Gene sequencing tracing showing K-RAS 61 mutation in a patient with nonencapsulated follicular variant of papillary thyroid carcinoma.

V600E mutation (Figure 4), whereas no patients had RAS FVPTC, all of whom had clinically palpable and/or radio- mutations. The difference between the rates of BRAF graphic evidence of lateral and/or central nodal metastases, V600E mutation in the 2 groups was not statistically sig- had pathologically positive central nodal metastases. When nificant (P=.06). No RET/PTC1 mutations were seen in compared with patients with EFVPTC and NFVPTC, this any of the patients in the study. was statistically significant (PϽ.001). The observed rate of nodal metastasis in diffuse FVPTC was higher than that COMMENT reported in FTC (5%-10%), and similar to that reported for cPTC(45%-65%).18 Inaddition,patientswithdiffuseFVPTC The treatment of papillary thyroid cancer is dependent had a statistically significant increase in vascular invasion on the biologic behavior of the tumor. The role of comple- (P=.003)andextrathyroidalextension(P=.006)whencom- tion thyroidectomy, central neck dissection, and post- pared with those with EFVPTC and NFVPTC. Although operative radioiodine (RAI) ablation to help prevent re- the comparisons were not statistically significant, they did current disease is all dependent on the malignant potential not differ in terms of BRAF V600E mutation (P=.06). This of the primary tumor. Previous studies11,12 have shown is most likely due to the small cohort of patients with dif- that EFVPTC behaves less like cPTC and more like FTA/ fuse FVPTC. Further studies, with a larger number of pa- FTC, with a lower rate of BRAF V600E mutations and tients with diffuse FVPTC, are necessary to better under- nodal metastases. NFVPTC, however, has been shown stand this entity at the molecular level. to behave more like cPTC, with a significantly higher rate The follicular variant of PTC is a unique tumor with of BRAF V600E mutations and nodal metastases.12 distinct subtypes. These subtypes need to be considered These previous studies, however, did not specifically in the treatment of patients with this tumor. Because of separate patients with diffuse FVPTC from those with the absence of lymph node metastases in patients with NFVPTC. This study shows that diffuse FVPTC is a dis- EFVPTC and NFVPTC, more limited surgery may be pos- tinct subtype of FVPTC with aggressive clinical and ge- sible in individuals with these entities. The need for RAI notypic characteristics that are important to recognize for ablation in these patients should also be reconsidered. appropriate treatment. When diffuse FVPTC is specifi- The risks of completion thyroidectomy (hypoparathy- cally separated from NFVPTC, it seems that NFVPTC and roidism, recurrent laryngeal nerve injury) and RAI ab- EFVPTC have similar molecular profiles and clinical be- lation (salivary dysfunction, second primary) may out- havior with low rates of nodal metastases and BRAF V600E weigh the benefits in these patients. Patients with diffuse mutations. Previous studies may have overestimated dif- FVPTC, however, probably should be treated aggres- ferences between EFVPTC and NFVPTC by failing to rec- sively with total thyroidectomy, central-compartment neck ognize diffuse FVPTC as a distinct clinical entity. dissection, and RAI ablation. In this study, no patients with EFVPTC or NFVPTC had There are a few limitations to this study. First, this central nodal metastases. Only the 4 patients with diffuse study includes patients who had various degrees of ini-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 A Trace File: 12479-braf-f.ab1 Utilities Next N Find.... Data Screen H 2 V 2 T T G G T C T A G C T A C A G T G A A A T C T C G A T G 75 80 85 90 95 100 12479-braf-f 1816 12479-braf-f_809.ab1 1362

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Sequence File: 12479-braf-f.seq > 12479-braf-f_B09.ab1 NNNNN N N N N N N N N N NNNNNTANTACNCCTCAGAATATTTT CTTTCAAAGGAA ACC TCCAGTA AAATAGGTGATTTTTGG C TAGCTAAC GGT AAATCTCGATGGAGTGGGTCCCATCAGTTTGAACAGTTGTCTGGATCCATTTTTGTGGGAAG T AGAATT GAGGCTGTTT TTCCACTGATTAAATTTTTGNCCNANNNCNCTAATANGNTT NAAGCCGCNNA NGCCCGCTTNCCAGCNNG GAAGGTTG CGGT CCAACGCATTAATGAAA CGGCCANN

B Trace File: 12649-braf-f.ab1 Utilities Next N Find.... Data Screen H 2 V 2 T G G T C T A G C T A C A G T G A A A T C T C G A T 85 90 95 100 105 12649-braf-f 1816 12649-braf-f_E11.ab1 1362

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Sequence File: 12649-braf-f.seq > 12649-braf-f_E11.ab1 NNNNN N NT NN NT NN NNNNNNNN NATNNGNNNNN N TCAAATTTATTTC TCATGAAGACCCT AACAGTAAAA A T GGTGATTT TGGTCTAGCTAAC GTGAAATCCT GGATG AGTGGGTCCCATCACTTTTGAACAGT GTCTGGATTCCATTTGTGGATGGTAA GAATTGAGGCTATTTTTCCACTGATTAAATTTTTGCCCNCTNACTCACATTAATTGCGTTGGCCGCTCA T CCCGCTTTCC

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Sequence File: 534b-braf-f.seq > 534b-braf-f_E11.ab1 NNNNNNN N N NT NN NCNNNNNTTTAC ACCCCA T AGGGGGGGGGA TTTTTTT AA C C AT AAA CCCC T AA T AAAAAA T TTTTT A TCTAGCTACAGGT AAATCTCGATGGGAGTGG TTCCCATCAGTT GAACAGTTGTCTGGATCCATTTTGGTTGA G GTAAGAA TTGAGGCTTA TTTTCCACTGATTAAATTTTTGGGCCNNNN CAG TNTGGGGT CAGNTTGTCGG TGATTCAATTNTTTTNNN NCGANGGACANCNCCGNCACCTTTATTAACTNGACTANN

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Sequence File: 1619b-braf-f.seq > 1619b-braf-f_G11.ab1 NNNNNNN N N NT NNC NNNTACTTTAC ACCCCN T AGGGGGGGGGA TTTTTTT AA C C AT AAA CCCC T AA T AAAAAA T TTTTT A TCTAGCTACAGGT AAATCTCGATGGGAGTGG TTCCCATCAGTT GAACAGTTGTCTGGATCCATTTTGGTTGA G GTAAGAA TTGAGGCTTA TTTTCCACTGATTAAATTTTTGCCACANCCCAATTTGGAT CGAGGCATCCAGGTGAGT CNTTTCTGNCCG NAAAACAGNACTGGGTCCGCATTAATCAATCGGCNANCCCCN CGGGAGANGNCGTTT TGCTAATGGNNGCTTC GCCGC

Figure 4. Gene sequencing tracings showing BRAF V600E mutations in patients with nonencapsulated follicular variant of papillary thyroid carcinoma and diffuse follicular variant of papillary thyroid carcinoma.

tial thyroid surgery, ranging from lobectomy to total thy- pathologic specimen were included. A total number of roidectomy with central compartment neck dissection. 145 central lymph nodes were evaluated. We feel that this Only patients with at least 1 central lymph node in the number is likely representative of central nodal status in

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 FVPTC, but since only a minority underwent formal cen- REFERENCES tral compartment neck dissection, it is possible that this study underestimates the incidence of central nodal me- 1. Patel KN, Singh B. Molecular Advances in the Diagnosis and Treatment of Thy- tastasis in FVPTC. This may help account for the ob- roid Cancer. In: Terris D, Gourin C, eds. Thyroid and Parathyroid Diseases: Medi- served lower rates of central nodal metastasis in this study cal and Surgical Management. New York, NY: Thieme; 2008. as compared with other studies of FVPTC. 2. Passler C, Prager G, Scheuba C, et al. Follicular variant of papillary thyroid car- In conclusion, this study supports the argument that cinoma: a long-term follow-up. Arch Surg. 2003;138(12):1362-1366. FVPTC can be separated into distinct entities: EFVPTC, 3. Carcangiu ML, Zampi G, Pupi A, Castagnoli A, Rosai J. 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Strict criteria should be applied in the diagnosis of encapsulated fol- Submitted for Publication: May 26, 2011; final revision licular variant of papillary thyroid carcinoma. Am J Clin Pathol. 2002;117(1): received October 2, 2011; accepted December 5, 2011. 16-18. Correspondence: Kepal N. Patel, MD, Department of Oto- 10. 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 laryngology–Head and Neck Surgery, New York Univer- (10):1336-1340. sity Langone Medical Center, 530 First Ave, Ste 6H, New 11. Liu J, Singh B, Tallini G, et al. Follicular variant of papillary thyroid carcinoma: a York, NY 10016 ([email protected]). clinicopathologic study of a problematic entity. Cancer. 2006;107(6):1255- Author Contributions: Drs Gupta and Patel had full ac- 1264. cess to all the data in the study and take responsibility 12. Rivera M, Ricarte-Filho J, Knauf J, et al. Molecular genotyping of papillary thyroid carcinoma follicular variant according to its histological subtypes (encap- for the integrity of the data and the accuracy of the data sulated vs infiltrative) reveals distinct BRAF and RAS mutation patterns. Mod Pathol. analysis. Study concept and design: Gupta, Ajise, Wang, 2010;23(9):1191-1200. Nonaka, Ogilvie, Heller, and Patel. Acquisition of data: 13. Sobrinho-Simo˜es M, Soares J, Carneiro F, Limbert E. Diffuse follicular variant Gupta, Ajise, Dultz, Wang, Ogilvie, Heller, and Patel. of papillary carcinoma of the thyroid: report of eight cases of a distinct aggres- Analysis and interpretation of data: Gupta, Ajise, Ogilvie, sive type of hyroid tumor. Surg Pathol. 1990;3(theme issue):189-203. Heller, and Patel. Drafting of the manuscript: Gupta, Ajise, 14. Ivanova R, Soares P, Castro P, Sobrinho-Simo˜es M. Diffuse (or multinodular) follicular variant of papillary thyroid carcinoma: a clinicopathologic and immu- and Dultz. 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