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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 41-47

BRAF status in the variants of papillary thyroid carcinoma


1 Department of Laboratory Medicine, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad, Telangana, India
2 Department of Surgical Oncology, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad, Telangana, India

Date of Web Publication24-Apr-2019

Correspondence Address:
Daphne Fonseca
Department of Laboratory Medicine, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JHNP.JHNP_1_19

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  Abstract 


Aim: The aim was to study the BRAF status by immunohistochemistry (IHC) in the variants of papillary carcinoma thyroid and compare it with the clinicopathological parameters.
Materials and Methods: All the thyroid carcinomas diagnosed during the period of January 2015–June 2018 were reviewed and classified according to the WHO 2017 criteria. The demographic and clinicopathological features were noted. Microarrays were prepared on 27 cases, including classic and variants of papillary thyroid carcinoma (PTC), poorly differentiated thyroid carcinoma (PDTC), and medullary thyroid carcinoma (MTC). IHC was performed with BRAF V600E by automated staining. The BRAF status was correlated with known prognostic markers.
Results: There were 23 PTC, 3 PDTC, and one MTC. The PTC included seven classic, three solid, two each of microcarcinoma, infiltrative and encapsulated follicular variant, tall-cell variant (TCV), oncocytic and one each of diffuse sclerosing, nodular fasciitis-like stroma, and Warthin-like variants. BRAF positivity was seen in 44.44%, including 11 PTC and one PDTC. The positivity was 85.71% in classic and 31.25% in variants. The age (>45 vs. <45 years), gender (male vs. female), number of lesions (unifocal vs. multifocal), type of tumor (PTC vs. other tumors), subtype of PTC (classic PTC vs. variants), invasion (capsular vs. lymphovascular), and aggressive features (extrathyroidal extension vs. lymph nodal involvement) between BRAF positive and negative tumors were not statistically significant (Fisher's exact test at P < 0.05).
Conclusion: BRAF status did not show correlation with known prognostic variables in classic as well as variants of PTC.

Keywords: BRAF immunohistochemistry, papillary thyroid carcinoma, prognostic markers, variants


How to cite this article:
Fonseca D, Murthy SS, Tagore R, Rao V, Rao CS, N. Raju K V, Nemade HK, Challa S. BRAF status in the variants of papillary thyroid carcinoma. Int J Head Neck Pathol 2018;1:41-7

How to cite this URL:
Fonseca D, Murthy SS, Tagore R, Rao V, Rao CS, N. Raju K V, Nemade HK, Challa S. BRAF status in the variants of papillary thyroid carcinoma. Int J Head Neck Pathol [serial online] 2018 [cited 2019 May 22];1:41-7. Available from: http://www.ijhnp.org/text.asp?2018/1/2/41/257041




  Introduction Top


Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma, accounting for nearly 85% of all cases.[1] PTC is characterized histologically by nuclear features (clearing, grooves, and inclusions). However, PTC is a heterogeneous entity with many histological variants, but few are clinically significant because of prognostic implications. Some of the variants such as tall cell, columnar, hobnail, and diffuse sclerosing are associated with aggressive behavior.[2] The clinicopathological features associated with aggressive behavior include male gender, older age, extrathyroidal extension, recurrence, lymph nodal involvement, and distant metastases.[3],[4]

With significant advances in the understanding of the molecular basis of PTC, mutually exclusive mutations of genes encoding for effector signals through the mitogen-activated protein kinase (MAPK) pathway were identified.[5],[6] The different histologic subtypes are associated with different mutations.[6] BRAF V600E mutations account for 60% and tumors with these mutations are associated with more frequency of lymph node metastases, recurrence, and poor response to radioiodine therapy.[6]

We aimed to study the clinicopathologic features of PTC variants and correlate the histologic type with BRAF mutation status by immunohistochemistry (IHC).


  Materials and Methods Top


All thyroid tumors diagnosed between January 2015 and July 2018 were reviewed and classified according to the WHO 2017 criteria.[7] Demographic and clinical data were obtained from the records. Type of surgery, lymph nodal dissection (if performed), and presence of any distant metastases were noted. Number, size, color, and presence of calcification and capsular thickness and/or invasion were noted on gross examination. On microscopic examination, PTC was classified as classical or variants on morphology.[2],[7] Encapsulated follicular variant was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) according to the criteria proposed by The Endocrine Pathology Society working group in 2015.[8] Microarrays were prepared from the morphologically representative areas from selected variants along with a few classical PTC and other thyroid carcinomas. One core, measuring 4 mm from each case was included. IHC was performed with BRAF V 600E (VE1) mouse monoclonal antibody (ready to use) on Ventana Medical Systems XT platform. Molecularly confirmed case of BRAF-positive PTC was included as positive control.

The results of IHC were correlated with morphological variant, number of lesions (unifocal/multifocal), angiolymphatic/capsular invasion (CI), lymph node involvement, and extrathyroidal extension (ETE).

Fisher's exact test was used for statistical analysis.


  Results Top


There were 629 thyroid carcinomas in the study period. Twenty-seven cases were included for microarray preparation. There were 10 males and 17 females with age ranging from 17 to 85 (median 45) years. These included 7 classic PTC, 16 PTC variants (three solid; two each of tall cell, microcarcinoma, follicular variant of PTC [FVPTC], NIFTP, oncocytic variant; and one each of nodular fasciitis-like [NF like], Warthin-like, and diffuse sclerosing), 3 poorly differentiated thyroid carcinoma (PDTC), and 1 medullary thyroid carcinoma (MTC). NIFTP was included as a variant of PTC in the present study. The demographic, clinicopathological features and BRAF status are given in [Table 1].
Table 1: The demographic, clinicopathological features and BRAF V600 E status in papillary thyroid carcinoma variants and other thyroid neoplasms (n = 27)

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Classic papillary thyroid carcinoma (n = 7)

There were four males and three females with age ranging from 20 to 70 (median 52) years. Total thyroidectomy (TT) was done in 4 and hemithyroidectomy (HT) in 3. The lesions were multifocal in 4, unifocal in 2, and diffuse in 1. The cells were in papillae lined by columnar to cuboidal cells with PTC-like nuclear features. Capsular and lymphovascular invasions (LVI) were seen in 6 (85.71%) and ETE was seen in 2 (28.57%). Six cases (85.71%) were positive for BRAF V 600 E by IHC.

Follicular variant of papillary thyroid carcinoma (n = 2)

There were two females aged 30 and 29 years. TT and HT were done in one each. The lesions were unifocal in both. The cells were in macro and microfollicles with PTC-like nuclear features. Capsular and LVI were seen in both whereas ETE was not seen in both. One was positive for BRAF V 600 E by IHC.

Microcarcinoma (n = 2)

There were one male and one female, aged 48 and 24 years. HT was done in both. The lesions were solitary, <1 cm, and subcapsular in both. The lesion was encapsulated, and the cells were in microfollicles with PTC-like nuclear features. Capsular, LVI, and ETE were not seen. There was no lymph nodal involvement. One was positive for BRAF V 600 E by IHC.

Solid papillary thyroid carcinoma (n = 3)

There were two females and one male aged 30, 66, and 72 years. TT and HT were done in one each. One was a recurrent lesion following hemithyroidectomy with tumor in the thyroid bed with lymph nodal disease. The lesion was unifocal in two and multifocal and bilateral in one. The lesion showed cells in solid nests, lobules, and trabeculae with PTC-like nuclear features. Microfollicles with scant colloid were seen. There were mitoses and thick fibrous septae in one case. There was capsular and LVI in all three and ETE in two. Lymph nodes were involved in two cases with perinodal spread. All three were negative for BRAF V 600 E by IHC.

Tall-cell variant papillary thyroid carcinoma (n = 2)

There were two females aged 50 and 60 years. TT and HT were done in one each. The lesions were unifocal in one and diffuse in one. The cells were in papillae and trabeculae lined by tall cells with acidophilic cytoplasm with elongated nuclei showing PTC-like nuclear features. Capsular and LVI were seen in one whereas ETE was not seen in both. Both were negative for BRAF V 600 E by IHC.

Diffuse sclerosing variant papillary thyroid carcinoma (n = 1)

This was a female aged 38 years, who underwent hemithyroidectomy. There was single lesion with dense sclerosis and lymphocytic infiltrate. The cells were in small sheets and trabeculae with PTC-like nuclear features. There was no capsular or LVI or ETE. It was negative for BRAF V 600 E by IHC.

Warthin-like variant papillary thyroid carcinoma (n = 1)

This was a female aged 28 years who underwent TT and lymph node dissection (LND). The lesion was diffuse involving both lobes and isthmus. There were papillary processes with the fibrovascular cores containing dense lymphocytic infiltrate forming follicles. The cells had oncocytic cytoplasm and PTC-like nuclear features. There was capsular and LVI but no ETE. There was lymph nodal involvement. It was positive for BRAF V 600 E by IHC.

Nodular fasciitis-like papillary thyroid carcinoma (n = 1)

This was a male aged 54 years who underwent TT and LND. The lesion was multifocal involving both lobes. There was spindle cell stroma with sparse lymphocytic infiltrate. The cells were in papillae, tubules, and solid sheets and had PTC-like nuclear features. There was capsular and LVI with ETE. There was lymph nodal involvement. It was positive for BRAF V 600 E by IHC.

Oncocytic variant papillary thyroid carcinoma (n = 2)

There were two females aged 66 and 42 years. TT and HT were done in one each. The lesion was unifocal in both. The cells were in lobules and trabeculae, having abundant oncocytic cytoplasm, prominent nucleoli with PTC-like nuclear features. There was capsular and LVI in one with no ETE. One was positive for BRAF V 600 E by IHC.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (n = 2)

There were two males aged 48 and 51 years. Hemithyroidectomy was done in both. The lesions were unifocal in both. The cells were in macro and micro follicles with PTC like nuclear features. There was no capsular and LVI or ETE. Both were negative for BRAF V 600 E by IHC.

Poorly differentiated thyroid carcinoma (n = 3)

There were two females and one male aged 37, 43, and 45 years. TT was seen in all. All were multifocal lesions. All the cases showed solid, trabecular, and insular patterns with mitoses and focal necrosis. Transition from PTC was seen in two cases (by nuclear features). CI was seen in 2, LVI in all, and ETE in one. Lymph nodal involvement was seen in two cases. One case was positive for BRAF V 600 E by IHC.

Medullary thyroid carcinoma (n = 1)

This was a female aged 43 years who underwent TT. The lesion was unifocal. Capsular, LVI, and ETE were seen. The case was negative for BRAF V 600 E by IHC.

BRAF V 600 E status [Figure 1]

BRAF V 600 E positivity was seen in 12 (44.44%) cases which included 6 classical (6/7), one each in Warthin-like PTC (1/1), NF-like PTC (1/1), oncocytic variant (1/2), microcarcinoma (1/2), FVPTC (1/2), and PDTC (1/3). The positivity was 85.71% in classic and 31.25% in variants. BRAF was negative in the variants with known aggressive behavior such as solid variant, TCV, and diffuse sclerosing variant (DSV). BRAF was also negative in NIFTP and MTC.
Figure 1: (a) Classic papillary thyroid carcinoma (H and E × 100): inset showing psammoma body; (b) papillary thyroid carcinoma with nuclear clearing, grooving, and overlapping; (c) BRAFV600E positivity by immunohistochemistry; (d) microcarcinoma (H and E × 100); (e) Warthin-like variant (H and E × 40): inset shows BRAF-positive staining; (f) nodular fasciitis-like variant (H and E × 100); (g) solid variant (H and E × 40); (h) Tall-cell variant (H and E × 100); (i) Infiltrative follicular variant of papillary thyroid carcinoma with capsular and vascular invasion (H and E × 100): inset showing papillary thyroid carcinoma-like nuclear features

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Statistical analysis

The age (>45 vs. <45 years), gender (male vs. female), number of lesions (unifocal vs. multifocal), type of tumor (PTC vs. other tumors), subtype of PTC (classic PTC vs. variants), invasion (capsular vs. lymphovascular), and aggressive features (extra-thyroidal extension vs. lymph nodal involvement) between BRAF positive and negative tumors were not statistically significant (Fisher's exact test at P < 0.05).

Follow-up

There was no evidence of recurrence or metastases seen on follow-up of these 27 patients for a period ranging from 6 to 36 months irrespective of their BRAF status.


  Discussion Top


BRAF V600E mutation is restricted to PTC and PDTC and ATC arising from PTC.[9] In the present study, BRAF V600E mutation was found in 11/23 PTC (47.83%) and one PDTC (33.33%). The case of PDTC showed PTC-like nuclear features focally on morphology, suggesting that it progressed from PTC. BRAF was negative in MTC. The BRAF positivity was comparable to other studies.[10],[11],[12] BRAF V600E mutation can be detected by various molecular techniques using DNA isolated from fresh or fixed samples with high sensitivity.[13],[14] Sun et al. in a study of 556 cases of PTC by real-time polymerase chain reaction (RT-PCR) and IHC with mouse monoclonal antibody by automated staining, found IHC with 98.8% sensitivity and 100% specificity.[15] In the present study, IHC was performed by automated staining with RT-PCR confirmed case as positive control in the microarray.

In the present study, there was 85.71% positivity for BRAF in classic PTC compared to 31.25% in the variants; however, it had no statistically significant difference. The prevalence of BRAF mutation was reported to be more frequent in tall cell and classic PTC and less in PTC variants including the aggressive variants.[16],[17],[18],[19],[20]

The presence of BRAF mutation was shown to correlate with aggressive tumor characteristics such as ETE, advanced tumor stage at presentation, tumor recurrence, and lymph node or distant metastases.[9],[21],[22] BRAF mutate tall cell and classic PTC were shown to have lymph nodal metastases and ETE.[21] However, this association was variably reported in many studies, and the mutational status was reported to be not significantly associated with aggressive features and poor outcome.[11],[12],[23],[24],[25],[26],[27],[28],[29] BRAF positivity did not correlate with known prognostic variables such as age, gender, number of lesions, histologic subtype, invasion, lymph nodal, and ETE in the present study.

Microcarcinomas generally have excellent prognosis; however, a few microcarcinomas can exhibit malignant behavior, particularly if the tumors carry the BRAF V600E mutation.[30] One of the two cases in the present study was positive for BRAF, though both cases did not show other features of aggressiveness.

FVPTC with capsular and/or vascular invasion and PTC-like nuclei were defined as infiltrative FVPTC, and the encapsulated, noninvasive tumors were reclassified as NIFTP.[8] FVPTC and NIFTP are characterized by RAS mutations. BRAF mutations were reported in 0%–26% of FVPTC.[3],[13],[31] One of the two cases of infiltrative FVPTC and both the cases of NIFTP in the present study were negative for BRAF. These results were similar to other studies.[10],[19],[31]

Solid variant was reported to constitute 3% of PTC with frequent distant metastases. This variant is more common in children, and after radiation exposure, it is usually associated with RET (Receptor tyrosine kinase)/PTC rearrangements but not BRAF mutations.[32] All the three cases of this variant in the present study were adults (one male, two more than 40 years), with capsular and vascular invasion in 3 and extrathyroidal extension in 2. One was recurrent and two had lymph node metastases. All were negative for BRAF by IHC. These results were in agreement with other studies.[33]

TCV was reported in 3%–19% of PTC and associated with more aggressive behavior than classic PTC.[34] Both the cases in the present study were adult females with diffuse involvement and capsular and LVI in one each. There was no ETE and both cases were negative for BRAF. BRAF mutations were reported in 79%–100% of this variant.[3],[19]

DSV occurs in younger patients with strong female preponderance. It is an aggressive variant associated with distant metastases.[35] The patient in the present study was a 38-year-old female with no extrathyroidal extension or evidence of metastases and also negative for BRAF. The reported frequency of BRAF mutations is 0%–66%.[3],[19]

The prognosis of Warthin-like variant was reported to be good, and BRAF mutations were reported in 75% of tumors.[4],[36],[37] However, lymph node involvement along with capsular and LVI was seen, and it was positive for BRAF.

The prognosis of PTC with NF-like stroma and oncocytic variant of PTC was uncertain, and BRAF was positive in one each case in the present study. BRAF mutations were reported in both these variants.[3],[19],[38],[39]

BRAF mutations in PTC have gained importance because BRAF mutated tumors have poor response to radioiodine therapy due to high MAPK output which inhibits the expression of genes required for iodide uptake and metabolism.[10],[21] As BRAF is downstream of RET and RAS, inhibitors to BRAF can be effective therapeutic targets in tumors having not only BRAF mutated tumors but also in tumors with RET- or RAS-mutated tumors.[14],[40]

BRAF status per se was not considered to be an independent prognostic factor for PTC variants.[10] The present study showed no statistically significant differences between BRAF status and clinicopathological parameters, but the study is limited by numbers.


  Conclusion Top


Morphologic parameters in PTC variants remain important prognostic factors and BRAF status does not correlate with known prognostic factors.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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