Abstract
Objective
To examine genotypic and clinical differences between encapsulated, non-encapsulated and diffuse follicular variant of papillary thyroid carcinoma (EFVPTC, NFVPTC, diffuse FVPTC), in order to characterize the entities and identify predictors of their behavior.
Design
Retrospective chart review and molecular analysis.
Setting
Referral center of a university hospital.
Patients
The pathology of 484 consecutive patients with differentiated thyroid cancer who underwent surgery by the 3 members of the NYU Endocrine Surgery Associates from January 1, 2007 to August 1, 2010 was reviewed. Forty-five patients with FVPTC and in whom at least 1 central compartment lymph node was removed were included.
Main Outcome Measures
Patients with FVPTC were compared in terms of age, gender, tumor size, encapsulation, extrathyroid extension, vascular invasion, central nodal metastases, and the presence or absence of mutations in BRAF, H-RAS 12/13, K-RAS 12/13, N-RAS 12/13, H-RAS 61, K-RAS 61, N-RAS 61 and RET/PTC1.
Results
No patient with EFVPTC had central lymph node metastasis and in this group, 1 patient (4.5%) had a BRAFV600E mutation and 2 patients (9%) had RAS mutations. Of the patients with NFVPTC, 0 had central lymph node metastasis (p=1) and 2 (11%) had a BRAFV600E mutation (p=0.59). Of the patients with diffuse FVPTC, all had central lymph node metastasis (p=0.0001) and 2 (50%) had a BRAFV600E mutation (p=0.12).
Conclusions
FVPTC consists of several distinct subtypes. Diffuse FVPTC seems to present and behave in a more aggressive fashion. It has a higher rate of central nodal metastasis and BRAFV600E mutation in comparison to EFVPTC and NFVPTC. Both EFVPTC and NFVPTC behave in a similar fashion. The diffuse infiltrative pattern and not just presence/absence of encapsulation seems to determine the tumor phenotype. Understanding the different subtypes of FVPTC will help guide appropriate treatment strategies.
Introduction
Cancer of the thyroid gland is the most common endocrine malignancy and accounts for the majority of endocrine cancer-related deaths each year1. Well-differentiated thyroid cancer is usually associated with a good prognosis. The most common histologic type is papillary thyroid carcinoma (PTC)1. Many subtypes of PTC have been described, of which classical PTC (cPTC) is the most common (80%). The follicular variant of PTC (FVPTC) is the second most common subtype, being found in 9–22.5% of patients with PTC2–5. The first histologic description of FVPTC was by Lindsay in 1960, followed by Chen in 1977 and Rosai in 19836–8. It is characterized as a tumor possessing both nuclear features typical of PTC (e.g. nuclear clearing, grooves, and pseudoinclusions) and a follicular growth pattern.
FVPTC presents several diagnostic and management challenges. Most FVPTC are encapsulated tumors, which are cytologically difficult to distinguish from benign follicular lesions such as follicular adenoma (FTA). Several studies highlight this by demonstrating the considerable interobserver variability involved with the diagnosis of FVPTC 9–10. In addition to the encapsulated subtype (EFVPTC), there is also a non-encapsulated subtype of FVPTC (NFVPTC). These subtypes appear to be distinct both clinically and genetically. A study by Liu et al. showed that while EFVPTC rarely exhibited lymph node metastases (5% of cases), NFVPTC was associated with lymph node metastases in 65%11. They concluded that most EFVPTC behave like a FTA or follicular thyroid carcinoma (FTC), while NFVPTC behaves like cPTC.
On a molecular level, Rivera et al. examined the oncogenic mutations present in EFPVTC and NFVPTC12. They found that EFVPTC was similar to FTA and FTC, with a high rate of RAS mutations (36%), and no BRAF mutations (0%). In contrast, they found NFVPTC to be more similar to cPTC, with a significantly higher rate of BRAF mutations (26%) and a lower rate of RAS mutations (10%).
In addition to the encapsulated and non-encapsulated subtypes of FVPTC, Sobrinho-Simões et al.13 described the diffuse follicular variant of PTC (diffuse FVPTC). This variant occurred primarily in young females, and was characterized on a histological level by extensive, multinodular involvement of one or both lobes of the thyroid gland. The 8 patients in their series with diffuse FVPTC developed distant metastases in the lungs and/or bones with or without concurrent regional lymph node metastases. Diffuse FVPTC was further studied by Ivanova et al.14, who found that patients with diffuse FVPTC had notably increased local, nodal, and vascular invasiveness as compared to other cases of FVPTC. They concluded that diffuse FVPTC is a distinct tumor carrying a guarded prognosis that has to be appropriately diagnosed and treated.
The 2009 American Thyroid Association (ATA) Guidelines provide little direction for the surgical management of FVPTC. Recommendation 26 states that for patients with thyroid cancer >1 cm, the initial surgical procedure should be a near-total or total thyroidectomy. Recommendation 27b states that elective (prophylactic) central-compartment neck dissection may be considered in patients with PTC and clinically uninvolved central neck lymph nodes, especially in patients with advanced primary tumors (T3 or T4)15. Importantly, these recommendations do not distinguish between cPTC and FVPTC and they may not necessarily apply to all variants of PTC. The aim of this study was to examine clinical and genotypic differences between the encapsulated, non-encapsulated, and diffuse subtypes of FVPTC, in order to characterize the entities and identify predictors of their behavior, which may help guide their management.
Methods
Clinical and Pathologic Analysis
The medical records of all 484 patients who underwent thyroid operations with a postoperative diagnosis of thyroid cancer at NYU Langone Medical Center by the 3 members of NYU Endocrine Surgery Associates from January 1, 2007 through August 1, 2010 were reviewed. Indications for surgery included cytologic findings on fine-needle aspiration biopsy (FNAB), symptomatic or enlarging multinodular goiter, and Graves’ disease. The extent of thyroidectomy (lobectomy versus total thyroidectomy) was determined by the operating surgeon based on preoperative evaluation, patient preference, and intraoperative findings. Central compartment lymph node sampling or central compartment dissection was performed if suspicious nodes were identified at the time of surgery, or electively at the discretion of the surgeon.
Of these patients, 103 with FVPTC were identified by 2 experienced thyroid pathologists (DN, BW). The diagnosis of FVPTC was made when nuclear characteristics of cPTC were present with a follicular growth pattern. From this group of 103 patients with FVPTC, 45 patients in whom at least one central compartment lymph node was removed were included in the study. Pathology was reviewed for tumor size, the presence of encapsulation, extrathyroidal extension, vascular invasion, and central nodal metastases. These 45 patients were divided into our three study groups (EFVPTC, NFVPTC and diffuse FVPTC).
Molecular Analysis
The presence of the BRAFV600E mutation, RAS (H-RAS, K-RAS, N-RAS) point mutations (codons 12, 13, and 61), and the RET-PTC1 rearrangement was identified in excised surgical specimens by direct sequencing. For analysis of BRAF and RAS genes, DNA was extracted from 10 μm sections of paraffin-embedded tumor blocks using a commercial kit (Qiagen, Germantown, MD). The extracted DNA was quantified using a NanoDrop 2000c spectrophotometer (Thermo Fisher Scientific Inc.). The BRAF gene was amplified with primers as previously described16–18. Codons 12/13 and 61 of H-RAS, K-RAS, and N-RAS genes were amplified using primers as previously described 16–18. Polymerase chain reaction (PCR) was then performed in a 20-μL mixture containing primer, dNTP, DNA polymerase, and genomic DNA. PCR conditions consisted of initial denaturation at 95°C followed by 35 cycles of denaturation at 95°C for 30 seconds, annealing at 58°C for 40 seconds, and extension at 72°C for 40 seconds. The final extension step was performed at 72°C for 1 minute. The DNA PCR products’ integrity was then evaluated using 2% agarose gel electrophoresis. The products were purified using a commercial PCR purification kit (Qiagen, Germantown, MD) according to the manufacturer’s instructions. The purified PCR products were sequenced commercially (Genewiz, South Plainfield, NJ).
For analysis of the RET-PTC1 rearrangement, RNA was extracted from 10 μm sections of each tumor’s paraffin-embedded block using a commercial kit (Qiagen, Germantown, MD). The extracted RNA was quantified using a NanoDrop 2000c spectrophotometer (Thermo Fisher Scientific Inc.). Complementary DNA (cDNA) was synthesized using 0.5 μg of extracted RNA and a commercial kit (Qiagen, Germantown, MD). Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed in a 20-μL mixture containing primer, dNTP, DNA polymerase, and 500 ng of cDNA. Primers used for RET-PTC1 have been described previously16–17. The RT-PCR conditions consisted of initial denaturation at 95°C followed by 35 cycles of denaturation at 95°C for 30 seconds, annealing at 58°C for 40 seconds, and extension at 72°C for 40 seconds. The RT-PCR products were then visualized using 2% agarose gel electrophoresis. Complementary DNA from the TPC-1 cell line served as a positive control for the RET-PTC1 rearrangement. RP1 was used in all reactions as a housekeeping gene.
Statistical Analysis
Two-tailed Fisher’s exact test was used to assess the relationship between categorical variables. The P-value of <0.05 was considered significant. This study was approved by the NYU Cancer Institute Protocol Review and Monitoring Committee and by the NYU Institutional Review Board.
Results
Clinical and Pathologic Analysis
A total of 45 cases were included in the study (22 EFVPTC, 19 NFVPTC, and 4 diffuse FVPTC). Table 1 compares the clinical and pathologic features of EFVPTC and NFVPTC. The two histologic subtypes appear identical. There was no significant difference in terms of age, gender, tumor size, vascular invasion, extrathyroid extension, central nodal metastasis, or extent of initial thyroid surgery between the two groups. Vascular invasion was present in only 1 patient in each group and no patient in either group had extrathyroid tumor invasion or central lymph node metastases.
Table 1.
Clinical, pathologic, and molecular characteristics of EFPVTC and NFVPTC
| No. of patients (%) | |||
|---|---|---|---|
| Characteristic | EFPVTC (n=22) | NFVPTC (n=19) | P-valuea |
| Age | |||
| Median (years) | 47 | 52 | 0.51 |
| ≤ 45 | 9 (41) | 5 (26) | |
| > 45 | 13 (59) | 14 (74) | |
| Gender | 0.47 | ||
| Female | 16 (73) | 16 (84) | |
| Male | 6 (27) | 3 (16) | |
| Tumor size (cm) | |||
| Median | 1.7 | 0.9 | 0.49 |
| ≤ 4 | 20 (91) | 19 (100) | |
| > 4 | 2 (9) | 0 (0) | |
| Vascular invasion | 1 | ||
| Absent | 21 (95) | 18 (95) | |
| Present | 1 (5) | 1 (5) | |
| Extrathyroid extension | 1 | ||
| Absent | 22 (100) | 19 (100) | |
| Present | 0 (0) | 0 (0) | |
| Central nodal metastases | 1 | ||
| Absent | 22 (100) | 19 (100) | |
| Present | 0 (0) | 0 (0) | |
| Thyroid surgery | 0.42 | ||
| Lobectomy | 5 (23) | 2 (11) | |
| Total thyroidectomy +/− CLNDb | 17 (77) | 17 (89) | |
| BRAF V600E mutation | 0.59 | ||
| Absent | 21 (95) | 17 (89) | |
| Present | 1 (5) | 2 (11) | |
| RAS mutations c | 0.49 | ||
| Absent | 20 (90) | 19 (100) | |
| Present | 2 (10) | 0 (0) | |
Fisher’s exact test, two-tailed values
Central lymph node dissection
RAS mutations assessed include H-RAS, K-RAS, and N-RAS at codons 12, 13, and 61
Table 2 compares the combined clinical and pathologic characteristics of EFVPTC and NFVPTC with diffuse FVPTC. Again, there was no significant difference in terms of age, gender, or tumor size. There were significant differences in vascular invasion (p=0.003), extrathyroid extension (p=0.006), and central lymph nodal metastases (p<0.001). Importantly, whereas none of the patients with EFVPTC or NFVPTC had clinically palpable or radiograph evidence of lymph node metastasis in the central or lateral compartment, all four of the patients with diffuse FVPTC had clinically palpable and/or radiographic evidence of lymph node metastasis (31/50 central lymph nodes positive). All 4 patients (100%) with diffuse FVPTC had total thyroidectomy with central lymph node dissection.
Table 2.
Clinical, pathologic, and molecular characteristics of EFPVTC+NFVPTC and Diffuse FVPTC
| No. of patients (%) | |||
|---|---|---|---|
| Characteristic | EFPVTC+NFVPTC (n=41) | Diffuse FVPTC (n=4) | P-valuea |
| Age | |||
| Median (years) | 50 | 32 | 0.14 |
| ≤ 45 | 14 (34) | 3 (75) | |
| > 45 | 27 (66) | 1 (25) | |
| Gender | 1 | ||
| Female | 32 (78) | 3 (75) | |
| Male | 9 (22) | 1 (25) | |
| Tumor size (cm) | |||
| Median | 1.2 | 2.4 | 0.5 |
| ≤ 4 | 39 (95) | 4 (100) | |
| > 4 | 2 (5) | 0 (0) | |
| Vascular invasion | 0.003 | ||
| Absent | 39 (95) | 1 (25) | |
| Present | 2 (5) | 3 (75) | |
| Extrathyroid extension | 0.006 | ||
| Absent | 41 (100) | 2 (50) | |
| Present | 0 (0) | 2 (50) | |
| Central nodal metastases | <0.001 | ||
| Absent | 41 (100) | 0 (0) | |
| Present | 0 (0) | 4 (100) | |
| Thyroid surgery | 1 | ||
| Lobectomy | 7 (17) | 0 (0) | |
| Total thyroidectomy +/− CLNDb | 34 (83) | 4 (100) | |
| BRAF V600E mutation | 0.06 | ||
| Absent | 38 (93) | 2 (50) | |
| Present | 3 (7) | 2 (50) | |
| RAS mutations c | 1 | ||
| Absent | 39 (95) | 4 (100) | |
| Present | 2 (5) | 0 (0) | |
Fisher’s exact test, two-tailed values
Central lymph node dissection
RAS mutations assessed include H-RAS, K-RAS, and N-RAS at codons 12, 13, and 61
Table 3 details the distribution of central lymph nodes from patients with EFVPTC and NFVPTC. Patients with diffuse FVPTC were excluded from this analysis, as they uniformly underwent total thyroidectomy with central lymph node dissection, resulting in 50 central lymph nodes evenly distributed among the 4 patients.
Table 3.
Central lymph nodes sampled in EFVPTC and NFVPTC
| No. of patients (%) | ||
|---|---|---|
| Number of central lymph nodes | EFVPTC (n=22) | NFVPTC (n=19) |
| 1 | 11 (50) | 10 (53) |
| 2–3 | 7 (32) | 5 (26) |
| >3 | 4 (18) | 4 (21) |
Molecular Analysis
Table 1 compares the molecular features of EFPVTC and NFVPTC. In the EFVPTC group of 22 patients, 1 patient (5%) had a BRAFV600E mutation (Figure 1), 1 patient (5%) had a N-RAS 61 mutation (Figure 2), and 1 patient (5%) had a K-RAS 61 mutation (Figure 3). In the NFVPTC group of 19 patients, 2 patients (11%) had a BRAFV600E mutation (Figure 4), while no patients had RAS mutations. The rates of RAS and BRAFV600E mutations between EFPVTC and NFVPTC were not statistically significant (p=0.49 and p=0.59 respectively).
Figure 1.
Gene sequencing tracing showing BRAFV600E mutation in a patient with nonencapsulated follicular variant of papillary thyroid carcinoma.
Figure 2.
Gene sequencing tracing showing N-RAS 61 mutation in a patient with nonencapsulated follicular variant of papillary thyroid carcinoma.
Figure 3.
Gene sequencing tracing showing K-RAS 61 mutation in a patient with nonencapsulated follicular variant of papillary thyroid carcinoma.
Figure 4.
Gene sequencing tracings showing BRAFV600E mutations in patients with nonencapsulated follicular variant of papillary thyroid carcinoma and diffuse follicular variant of papillary thyroid carcinoma.
Table 2 compares the combined molecular features of EFVPTC and NFVPTC with diffuse FVPTC. In the 4 patients with diffuse FVPTC, 2 patients (50%) had a BRAFV600E mutation (Figure 4), while no patients had RAS mutations. The difference between the rates of BRAFV600E mutation in the two groups approached statistical significance (p=0.06). No RET/PTC1 mutations were seen in any of the patients in the study.
Comment
The management of papillary thyroid cancer is dependent on the biologic behavior of the tumor. The role of completion thyroidectomy, central neck dissection, and post-operative radioiodine (RAI) to help prevent recurrent disease is all dependent on the malignant potential of the primary tumor. Previous studies have shown that EFVPTC behaves less like cPTC and more like FTA/FTC, with a lower rate of BRAFV600E mutations and nodal metastases11,12. NFVPTC, on the other hand, has been shown to behave more like cPTC, with a significantly higher rate of BRAFV600E mutations and nodal metastases12.
These previous studies, however, did not specifically separate patients with diffuse FVPTC from NFVPTC. This study shows that diffuse FVPTC is a distinct subtype of FVPTC with aggressive clinical and genotypic characteristics that are important to recognize for appropriate management. When diffuse FVPTC is specifically separated from NFVPTC, it appears that NFVPTC and EFVPTC have similar molecular profiles and clinical behavior with low rates of nodal metastases and BRAFV600E mutations. Previous studies may have overestimated differences between EFVPTC and NFVPTC by failing to recognize diffuse FVPTC as a distinct clinical entity.
In this study, no patients with EFVPTC or NFVPTC had central nodal metastases. Only the 4 patients with diffuse FVPTC, all of whom had clinically palpable and/or radiographic evidence of lateral and/or central nodal metastases, had pathologically positive central nodal metastases. When compared to EFVPTC and NFVPTC, this was statistically significant (p=0.0001). The observed rate of nodal metastasis in diffuse FVPTC was higher than that reported in FTC (5–10%), and similar to that reported for cPTC (45–65%)18. In addition, patients with diffuse FVPTC had a statistically significant increase in vascular invasion (p=0.003) and extrathyroidal extension (p=0.006) when compared to EFVPTC and NFVPTC. Although there was a trend towards significance, they did not differ in terms of BRAFV600E mutation (p=0.06). This is most likely due to the small cohort of patients with diffuse FVPTC. Further studies, with a larger number of diffuse FVPTC patients, are necessary to better understand this entity at the molecular level.
The follicular variant of PTC is a unique tumor with distinct subtypes. These subtypes need to be considered in the management of patients with this tumor. Because of the absence of lymph node metastases in patients with EFVPTC and NFVPTC, more limited surgery may be possible in patients with these entities. The need for RAI ablation in these patients should also be reconsidered. The risks of completion thyroidectomy (hypoparathyroidism, recurrent laryngeal nerve injury) and RAI ablation (salivary dysfunction, second primary) may outweigh the benefits in these patients. Patients with diffuse FVPTC on the other hand, probably should be managed aggressively with total thyroidectomy, central-compartment neck dissection, and RAI ablation.
There are a few limitations to this study. First, this study includes patients who had various degrees of initial thyroid surgery, ranging from lobectomy to total thyroidectomy with central-compartment neck dissection. Only patients with at least one central lymph node in the pathological specimen were included. A total number of 145 central lymph nodes were evaluated. We feel that this number is likely representative of central nodal status in FVPTC, but since only a minority underwent formal central-compartment neck dissection, it’s possible that this study underestimates the incidence of central nodal metastasis in FVPTC. This may help account for the observed lower rates of central nodal metastasis in this study as compared to other studies of FVPTC.
In conclusion, this study supports the argument that FVPTC can be separated into distinct entities: EFVPTC, NFVPTC, and diffuse FVPTC. EFVPTC and NFVPTC appear to have a clinical and genetic profile more like FTA/FTC, while diffuse FVPTC has a clinical and genetic profile more like cPTC with increased rates of BRAFV600E mutation and central nodal metastases. This study suggests that patients who undergo thyroid surgery for indeterminate lesions where the final pathology reveals an EFVPTC or NFVPTC, with no evidence of diffuse infiltrative disease, are at low risk of harboring metastatic disease and may benefit from close observation instead of completion thyroid surgery and RAI. Understanding the biology of the disease may help guide the management for these distinct entities.
Acknowledgments
We would like to acknowledge the Tissue Acquisition and Biorepository Core at the NYU Langone Medical Center which is supported by the NYUCI Center Support Grant NIH/NCI 5 P30CA16087-31.
Footnotes
Drs. Gupta and Patel had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Gupta, Ogilvie, Heller, Patel. Acquisition of data: Gupta, Ajise, Dultz, Wang, Nonaka, Ogilvie, Heller, Patel. Analysis and interpretation of data: Gupta, Ajise, Ogilvie, Heller, Patel. Drafting of the manuscript: Gupta. Critical revision of the manuscript for important intellectual content: Gupta, Ogilvie, Heller, Patel. Statistical analysis: Gupta, Dultz. Administrative, technical, and material support: Ajise, Wang, Nonaka, Ogilvie, Heller, Patel. Study supervision: Gupta, Ajise, Ogilvie, Heller, Patel.
References
- 1.Patel KN, Singh B. Molecular Advances in the Diagnosis and Treatment of Thyroid Cancer. In: Terris David, Gourin Christine., editors. Thyroid and Parathyroid Diseases: Medical and Surgical Management. Thieme; 2008. [Google Scholar]
- 2.Passler C, Prager G, Scheuba C, et al. Follicular variant of papillary thyroid carcinoma: a long-term follow-up. Arch Surg. 2003;138:1362–1366. doi: 10.1001/archsurg.138.12.1362. [DOI] [PubMed] [Google Scholar]
- 3.Carcangiu ML, Zampi G, Pupi A, et al. Papillary carcinoma of the thyroid. A clinicopathologic study of 241 cases treated at the University of Florence, Italy. Cancer. 1985;55:805–828. doi: 10.1002/1097-0142(19850215)55:4<805::aid-cncr2820550419>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
- 4.Tielens ET, Sherman SI, Hruban RH, et al. Follicular variant of papillary thyroid carcinoma. A clinicopathologic study. Cancer. 1994;73:424–431. doi: 10.1002/1097-0142(19940115)73:2<424::aid-cncr2820730230>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
- 5.Sebastian SO, Gonzalez JM, Paricio PP, et al. Papillary thyroid carcinoma: prognostic index for survival including the histological variety. Arch Surg. 2000;135:272–277. doi: 10.1001/archsurg.135.3.272. [DOI] [PubMed] [Google Scholar]
- 6.Lindsay S. Carcinoma of the Thyroid Gland: A Clinical and Pathologic Study of 293 Patients at the University of California Hospital. Springfield, Ill: Charles C Thomas Publisher; 1960. [Google Scholar]
- 7.Chen KTK, Rosai J. Follicular variant of papillary thyroid carcinoma: a clinicpathologic study of six cases. Am J Surg Pathol. 1977;1:123–130. doi: 10.1097/00000478-197706000-00003. [DOI] [PubMed] [Google Scholar]
- 8.Rosai J, Zampi G, Carcangiu ML. Papillary carcinoma of the thyroid: a discussion of its several morphologic expressions, with particular emphasis on the foliicular variant. Am J Surg Pathol. 1983;7:809–817. [PubMed] [Google Scholar]
- 9.Chan JK. Strict criteria should be applied in the diagnosis of encapsulated follicular variant of papillary thyroid carcinoma. Am J Clin Pathol. 2002;117:16–18. doi: 10.1309/P7QL-16KQ-QLF4-XW0M. [DOI] [PubMed] [Google Scholar]
- 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;28:1336–1340. doi: 10.1097/01.pas.0000135519.34847.f6. [DOI] [PubMed] [Google Scholar]
- 11.Liu J, Singh B, Tallini G, et al. Follicular variant of papillary thyroid carcinoma: a clinicopathologic study of a problematic entity. Cancer. 2006;107:1255–1264. doi: 10.1002/cncr.22138. [DOI] [PubMed] [Google Scholar]
- 12.Rivera M, Ricarte-Filho J, Knauf J, et al. Molecular genotyping of papillary thyroid carcinoma follicular variant according to its histological subtypes (encapsulated vs infiltrative) reveals distinct BRAF and RAS mutation patterns. Modern Pathology. 2010;23:1191–1200. doi: 10.1038/modpathol.2010.112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Sobrinho-Simões M, Soares J, Carneiro F, Limbert E. Diffuse follicular variant of papillary carcinoma of the thyroid: report of eight cases of a distinct aggressive type of hyroid tumor. Surg Pathol. 1990;3:189–203. [Google Scholar]
- 14.Ivanova R, Soares P, Castro P, Sobrinho-Simões M. Diffuse (or multinodular) follicular variant of papillary thyroid carcinoma: a clinicopathologic and immunohistochemical analysis of ten cases of an aggressive form of differentiated thyroid carcinoma. Virchows Arch. 2002;440:418–424. doi: 10.1007/s00428-001-0543-3. [DOI] [PubMed] [Google Scholar]
- 15.Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2009;19:1167–1214. doi: 10.1089/thy.2009.0110. [DOI] [PubMed] [Google Scholar]
- 16.Vasko V, Ferrand M, Di Cristofaro J, Carayon P, Henry JF, de Micco C. Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J Clin Endocrinol Metab. 2003;88:2745–2752. doi: 10.1210/jc.2002-021186. [DOI] [PubMed] [Google Scholar]
- 17.Xu L, Zhou J, Cohen M, Bar-Sagi D, Patel KN. SPRY2 expression correlates with BRAF mutation status in thyroid cancer. Surgery. 2010;148:1282–88. doi: 10.1016/j.surg.2010.09.028. [DOI] [PubMed] [Google Scholar]
- 18.Zhu Z, Gandhi M, Nikiforova MN, et al. Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma: an unusually high prevalence of ras mutations. Am J Clin Pathol. 2003;120:71–77. doi: 10.1309/ND8D-9LAJ-TRCT-G6QD. [DOI] [PubMed] [Google Scholar]