Papillary microcarcinoma of the thyroid: a review

Papillary cancers of the thyroid less than 1cm in diameter are defined as microcarcinomas. Although considered as a disease with an indolent course with excellent long term prognosis a significant proportion with this condition will have lymph node metastasis at diagnosis. Clinicians need to be aware of the pathological characteristics, natural history and the internationally accepted treatment strategies when managing patients with micropapillary cancers as increasing numbers of patients are expected to be diagnosed with this condition due to widespread use of imaging modalities for numerous other indications. This brief review aims to summarize these aspects with emphasis on management.


Introduction
Microcarcinoma of the thyroid is defined as a tumor less than 1cm in its maximum diameter [1]. Mostly they are of the papillary variety although rarely they can be of follicular or medullary in type [2]. Although epidemiological data regarding the prevalence of thyroid cancer in Sri Lanka is not readily available, international studies report a rising incidence of thyroid cancers over the past few decades. Increased diagnosis of small papillary cancers accounts for the overwhelming majority of this rise [3]. Despite this increase in the disease burden, management of this entity is controversial [3] with some advocating aggressive treatment and others a more conservative approach.

Clinical presentation
The mean age of diagnosis of thyroid microcarcinoma ranges from 41.9-55 years and there is a female preponderance. Clustering of papillary microcarcinomas (microPTCs) among family members have also been reported [4].
Most of the papillary microPTCs are usually not palpable and they are detected incidentally on thyroidectomy specimens performed for other indications [5]. The detection rate of such 'incidental' microPTC ranges from 2.2 -49.9% in thyroid glands removed for benign causes and depends on the thoroughness of histopathological examination [2].
Asymptomatic, unsuspected thyroid lesions found on imaging studies or surgeries unrelated to the thyroid are defined as 'thyroid incidentalomas' [6]. Increased detection of such lesions mainly due to liberal use of ultra sound scanning has contributed to the rising incidence of thyroid cancer [3]. Nodules are detected on 13-67% of thyroid glands on ultrasound [4]. As they are common findings, to guide clinicians as to when to perform guided fine needle aspiration cytology (FNAC), ultrasonically suspicious features for malignancy have been described such as microcalcifications, increased vascularity in the centre of the tumor compared to surrounding normal thyroid tissue, hypoechogenicity, irregular borders and taller than wider dimensions of the nodule [5,7]. Some thyroid incidentalomas may prove to be malignant upon FNAC.
The entity of 'occult' microPTC includes lesions detected upon search for the origin of lymph node or visceral metastasis [10].

Pathologic characteristics
Pathologically, microPTCs do not exhibit different morphological characteristics compared to classical papillary carcinomas [11]. They are likely to be located near the capsule of the thyroid gland and are non-encapsulated. Histologically, characteristic orphan Annie eyed nuclei are seen. Variants of classical papillary carcinoma such as follicular, tall cell and oncocytic types may also be seen in the microcarcinoma counterpart [4].
Characteristically, microPTCs are slow growing [10]. A Japanese study reported that only 6.4% and 15.9% of followed up microPTCs showed an increase in the size > 3mms at 5 years and 10 years, respectively [12]. However, in contrast a significant proportion of these tumors may be multifocal or bilateral. In surgical specimens, multifocality ranged from 15% -43.8% [9]. So  They identified that nodular hyperplasia of the gland was a risk factor for both multifocal and bilateral tumors. The same authors reported that the presence of multifocal lesions in a single lobe was associated with a higher chance of bilateral tumours [13].
Lymph node metastasis are present in up to 64% of the patients at the time of diagnosis of microPTC [4]. Wada et al who did prophylactic central compartment lymphadenectomy in clinically node negative patients with microPTC who underwent thyroidectomy, reported that up to 60.9% had involved nodes [14]. Larger primary lesions, follicular variant of microPTC and the extension of the lesion beyond the thyroid capsule are identified as risk factors for lymph node metastasis [4].
Although it is a rare possibility, metastatic deposits in organs other than lymph nodes can be present at the diagnosis of microPTC. In the meta analysis published by Roti et al, they noted that out of 9313 patients with microPTC only 35 (0.37%) had such a presentation. The authors noted that larger primary tumors, presence of lymph node metastasis, follicular variant and increasing age as risk factors for distant metastasis at diagnosis [4].
Comparison of clinically overt microPTC versus incidentally detected microPTC have shown that, adverse features such as the presence of multifocality/bilaterality, extension beyond the thyroid capsule, presence of lymph node or extra lymph node metastasis were higher in the former group [4].

Genetics-BRAF mutation
Mutations in the BRAF proto oncogene is considered the most common genetic alteration in papillary thyroid cancers [25]. It is detected in up to 83% of all papillary thyroid cancers and 30% of microPTCs [25,26]. Detection of this mutation may have a role in diagnosis, prognosis and development of management strategies for papillary cancers of the thyroid. Studies have reported a higher incidence of adverse features such as involvement of perithyroidal tissues and nodal metastasis in BRAF mutation associated microPTCs [26]. As there is a lack of specific clinicopathologic indicators to determine which microPTCs need aggressive treatment, detection of BRAF mutation may play a role in solving this dilemma [25].

Management
MicroPTC is considered as a disease with a good prognosis and the mortality is considered to be less than 1% [2]. In their meta-analysis, Roti et al. reported a disease specific death rate of 0.34% (32/9379) [4]. However, some authors describe two biologically distinct subtypes of microPTC, one type with an indolent behavior with minimal or no disease progression, the other type being more aggressive with potential for dissemination [15]. However the authors agree that clearly defined criteria to determine which type is which are still lacking.
The local recurrence rates after resection of primary microPTCs ranges from 3.8-20%, and cervical lymph nodes are the preferred site of recurrence [2]. Patient age (<45 years), clinically overt disease, lymph node metastasis at diagnosis, cancer multifocality [4], poorly differentiated cancers, presence of a desmoplastic reaction and/or invasion of perithyroidal tissue [2] have been identified as risk factors for recurrent disease. Male gender, primary tumour size and presence of tumor extension beyond the thyroid capsule have been recognized by some as predictors of local recurrence but not by others [2,4,16].
The long term survival is virtually 100% in microPTC without clinical evidence of nodal or distal metastasis at diagnosis, hence the aim of treatment should be to achieve disease control without undue treatment associated morbidity [2].
For unifocal microPTC with no extension beyond the thyroid capsule, lymph node or distant metastasis resection of the affected lobe is the recommended treatment [2]. National Comprehensive Cancer Network (NCCN) guidelines recommends consideration of total thyroidectomy if there are additional risk factors such as a history of irradiation of the neck, poorly differentiated tumors, or bilateral nodularity of the gland [17].
If a microPTC is detected in a lobectomy specimen performed for another indication, staging of the neck by ultrasound should be considered. Completion thyroidectomy is indicated for FNAC proven contralateral lesions or lymph node metastasis [17].
Follow up of patients who have undergone lobectomy is by physical examination, serum TSH, thyroglobulin and antithyroid antibodies at 6 and 12 months after surgery and annually thereafter if there is no evidence of recurrent or residual disease as recommended by NCCN guidelines [17]. However, it has been argued that patients with microPTC without risk factors on whom lobectomy has been performed have no additional risk of dying from thyroid cancer compared to the general population. Hence British guidelines for the management of thyroid cancer advocates no further follow-up regarding cancer care in such patients [2].
Total thyroidectomy is the standard treatment for microPTC with lymph node metastasis, distant metastasis, or local invasion [17]. According to British guidelines for the management of thyroid cancer, total thyroidectomy is also indicated for patients with microPTC and familial non medullary thyroid cancer [4].
For patients with multifocal microPTC total thyroidectomy should be offered [2]. According to literature lobectomy/and or isthmathectomy for multifocal disease leads to higher recurrence rates (8.2-25%) compared to total thyroidectomy done for the same indication (2.3-5%) [17].
Therapeutic neck dissection combined with total thyroidectomy should be performed for microPTC presenting with lymph node metastasis [2]. Lymph node involvement at diagnosis has a 11-22% risk of future recurrence in lymph nodes [18]. It is also associated with higher risk of distant metastasis [4,19].
According to British guidelines prophylactic central compartment neck dissection(PCCND) in microPTC can be considered for multi focal disease, presence of perithyroidal tissue invasion and extra thyroidal disease [2]. However, PCCND in node negative papillary thyroid carcinoma does not offer a survival benefit nor does it significantly reduce local recurrence rates [20]. Regarding the morbidity of prophylactic neck dissection Caliskan et al. reported permanent hypoparathyroidism and recurrent laryngeal nerve palsy at a rate of 2.6%. And 0.5% after performing the procedure on 842 patients with micoPTC [21].
MicoPTC presenting with extra nodal metastasis is extremely rare, and it should be managed with multimodality treatment including surgery and radioactive iodine (RAI) [18].
Routine RAI treatment for uncomplicated microPTC is not recommended [18]. According to the European consensus on management of differentiated thyroid cancer there is no benefit in RAI for unifocal microcancers without extension beyond the thyroid capsule or lymph node involvement [22]. There is place for RAI in patients with lymph node or distant metastasis, local invasion, and multifocal disease. However RAI has no proven benefit in reducing the higher recurrence rates associated with multifocal or lymph node positive disease [18].
TSH suppression for patients with micro PTC should be based on the stage of disease and risk of recurrence. For low risk patients a TSH target of 0.1-0.5 mU/L is suggested and for those with stage III or IV disease TSH should be suppressed below 0.1mU/L [18]. Although there is evidence for benefit of TSH suppression on differentiated thyroid cancer, Noguchi et al. who studied 2070 patients with microPTC found out no increase in recurrent disease in those who discontinued suppressive treatment [23]. The risks of TSH suppression such as osteoporosis in postmenopausal women and cardiovascular complications in the elderly warrants consideration risks and benefits of treatment rather than routine TSH suppression as advocated by some [24].
There is no role for adjuvant systemic therapy other than RAI and TSH suppression for microPTC as it is a type of different-iated thyroid cancer [5].
Observation without therapeutic intervention has been studied as a management option for microPTC. Ito et al. followed up 340 patients diagnosed with microPTC without adverse features such as unfavorable tumour location, clinically node positive disease and high grade on FNAC. At the end of 10 years 15.9 % had tumour size enlargement of >3mm and 3.4% had new nodal metastasis. Out of 340, 109 (32%) patients underwent thyroidectomy for various reasons during this period and none developed recurrent disease. Patient and clinical characteristics such as gender, age, tumour size at diagnosis, multcentricity or TSH suppression were not associated with enlargement of the lesions [12].

Conclusions
In summary, microPTC of the thyroid is a disease with an excellent prognosis. It is being more commonly diagnosed as a result of liberal use of imaging modalities. Clinicians need to be aware of the natural history and treatment options available including surgery, RAI, TSH suppression and active observation in order to avoid over/under treatment. Association of BRAF proto oncogene mutation with microPTC and its role on determining prognosis and treatment of this disease entity is an ongoing area of research with exciting prospects.