L E T T E R T O T H E E D I T O R

Papillary thyroid microcarcinoma: a painstakingcategory to manage

We read with interest the article by Dr Walczyk et al.1 concern-

ing the role of BRAFV600E mutation in the management of papil-

lary thyroid microcarcinoma (PTMC), finding some sharing

dismays as well as highlighting our standpoints on this debatable

topic.

Based on literature, the clinical management of patients with

PTMC remains nonstandardized because these tumours generally

are considered clinically indolent and innocuous, although some

of them may pursue an aggressive clinical behaviour.2,3

Refuting this ‘benign’ outcome, a meta-analysis encompassing

more than 4000 papillary microcarcinomas has shown that 28%

of PTMC had lymph node metastases, 0�6% distant metastases

and 3�3% presented disease recurrence.4 These data and several

other studies support the idea that PTMC may include at least

two biologically distinct subpopulations: one indolent tumour

with minimal or no potential of progression and a second one

with more aggressive behaviour.

Many studies, including a review by Mazzaferri and an article

by Basolo, have demonstrated that BRAF expression is signifi-

cantly associated with papillary carcinoma and correlated with

aggressive histopathological features such as extra-thyroid exten-

sion, advanced stage at presentation, nodal metastases, younger

age, tumour size larger than 5 mms and multifocality.5 They

concluded that BRAF evaluation is helpful even in microcarcino-

mas to improve risk stratification and patient management.5

We agree that size should not become a crucial feature, but

the increased use of ultrasound examination in routinely thyroid

investigation allows the easier and more frequent identification

and the cytological aspiration of very small nodules (up to

1 cm), leading to an overall pre-operative reduced risk of malig-

nancy in the general population. The additional BRAF mutation

analysis performed on cytological material from small papillary

cancers could help for a prognostic identification of patients

with higher risk of bilateral spread and nodal involvement that

should be treated with surgery and prophylactic central neck dis-

section. Whereas Walczyk et al. used a selected bias in including

only tumours <1 cm in diameter with no lymph node or distant

metastases, in our paper we overcame the bias with comparative

retrospective data between cytological BRAF analysis and histo-

logical diagnoses. Our recent cytological results clearly support

that the activating mutation of BRAF was particularly frequent

in papillary carcinoma and in its more aggressive variant, such

as tall cell variant (TCV), and less frequent in the follicular vari-

ant of PTC (FVPTC). We stated that in a period of 1-year eval-

uation, 73 cytological microcarcinomas of 230 cancers (32%)

were detected, and all our 11 TCV were up to 1 cm. Further-

more, we demonstrated that the presence of BRAF mutation was

significantly associated with two parameters of aggressiveness in

thyroid tumour, lymph node metastasis and bilateral localization

which should justify a total thyroidectomy and treatment as lar-

ger cancers.3 Hence, our paper highlighted higher correlation

between classical PTC and BRAFV600E (87�5%) than reported in

this paper (72�5%).

From our point of view, and considering our results, the

BRAF mutation analysis performed on cytological material from

FNAC of small papillary cancers could help to identify a group

of patients with higher risk of bilateral spread and nodal

involvement who should be treated with a more extensive

surgery and prophylactic central neck dissection.

We acknowledge that apart from its prognostic role, this

molecular application on pre-operative fine needle aspiration

assumes also a critical significance for the application of specific

targeted therapies against mutated BRAF, which would be

recommended in patients with advanced disease.

We agree with the authors that the clinical management of

patients with microcarcinoma remains nonstandardized, and

although the presence of BRAF mutation in any tumour is not

an absolute predictor of tumour aggressiveness, we encourage

the role of cytology and application of genetic markers to

explore the tumour behaviour even of microcarcinoma.

In conclusion, it is true that cancer-related deaths in the pap-

illary thyroid microcarcinomas are unusual, but to avoid recur-

rences, additional morbidity and higher healthcare costs, BRAF

evaluation plays a useful role in predicting pre-operatively the

behaviour of cytological thyroid microcarcinomas, and it may be

used as an additional tool for planning adequate treatment.

Disclosure statement

None of the authors listed above has a potential conflict of

interest. None of the authors received any funding sources for

the manuscript.

Esther D. Rossi, Maurizio Martini, Guido Fadda and

Luigi M. Larocca

Division of Anatomic Pathology and Histology, Universit�a

Cattolica del Sacro Cuore, “Agostino Gemelli” School of Medicine,

Rome, Italy

E-mail: esther.rossi@rm.unicatt.it

doi: 10.1111/cen.12413

References

1 Walczyk, A., Kowalska, A., Kowalik, A. et al. (2013) The

BRAFV600E mutation in papillary thyroid microcarcinoma: does

the mutation have an impact on clinical outcome. Clinical Endo-

crinology, doi: 10.1111/cen.12386. [Epub ahead of print].

© 2014 John Wiley & Sons Ltd 1

Clinical Endocrinology (2014)

2 Malandrino, P., Pellegriti, G., Attard, M. et al. (2013) Papillary

thyroid microcarcinomas: a comparative study of the charac-

teristics and risk factors at presentation in two cancer registries.

Journal of Clinical Endocrinology & Metabolism, 98, 1427–1434.

3 Rossi, E.D., Martini, M., Capodimonti, S. et al. (2013) BRAF

(V600E) mutation analysis on LBC-processed aspiration biopsies

predicts bilaterality and nodal involvement in papillary thyroid

microcarcinoma. Cancer Cytopathology, 121, 291–297.4 Niemeier, L.A., Kuffner Akatsu, H., Song, C. et al. (2012) A com-

bined molecular-pathologic score improve risk stratification of

papillary micro carcinoma. Cancer, 118, 2069–2077.5 Mazzaferri, E. (2012) Managing thyroid microcarcinoma. Yonsei

Medical Journal, 53, 1–14.

© 2014 John Wiley & Sons Ltd

Clinical Endocrinology (2014), 0, 1–2

2 Letter to the Editor