Therapeutic Strategy of Papillary Microcarcinoma of the Thyroid Gland: A Nuclear Medicine Perspective
Patients with papillary thyroid microcarcinoma (PTMC) have an excellent prognosis with a normal life expectancy. According to the literature, the incidence of PTMC is increasing. To date, PMTCs account for up to 30 % of all differentiated thyroid cancers. Because of the differential definitions of the PTMC, the therapeutic approaches of the national Scientific Societies have not been standardised. The therapeutic algorithms have to be adjusted with regard to current thyroid surgery, radioiodine ablation and thyrotropin-suppressive therapy as well as follow-up. Recently, the Therapy Committee of the European Association of Nuclear Medicine (EANM) has recommended a risk-adapted therapy and follow-up. Risk factors which require a more aggressive therapeutic approach are multifocality, thyroid capsule infiltration, evidence of locoregional or distant metastasis and unfavourable histology. It was the aim to review the current therapeutic concepts in patients with PTMC from a nuclear medicine perspective.
KeywordsThyroid Carcinoma Papillary Thyroid Carcinoma Papillary Carcinoma Differentiate Thyroid Cancer Follicular Thyroid Carcinoma
Differentiated thyroid carcinomas constitute about 90 % of all thyroid carcinoma (Sherman 2003). They can be further classified according to their papillary or follicular growth. Papillary thyroid carcinomas amount to about 80–90 % of thyroid cancers and follicular thyroid carcinoma to 10–15 % (Rahbar et al. 2008). In general, both papillary and follicular thyroid carcinoma have an excellent prognosis with five-year survival rates exceeding 90 %, following the hitherto therapy and follow-up (Lerch et al. 1997). In recent years, the use of ultrasound and fine-needle aspiration biopsies in the examination of the thyroid is steadily increasing, thereby allowing the detection and diagnosis of thyroid cancer much earlier than it can be clinically diagnosed. This may explain a considerable increase in the incidence of PTMC in recent years (Pelizzo et al. 2006). According to the literature, PMTCs account for up to 30–40 % of all differentiated thyroid cancers (Roti et al. 2006; Cheema et al. 2006). PTMC have been demonstrated in up to 36 % of autopsy studies depending on the intensity of the histopathological workup (Reiners et al. 2005). They occur with the same rate in each decade in adults and have an excellent prognosis (Pazaitou-Panayiotou et al. 2007). Patients with PTMC have survival rates indistinguishable from those of the normal population (Rosai et al. 2003; Hay et al. 2009; Ross et al. 2009). However, a subgroup of PTMC with a more virulent biological behaviour has to be considered if the therapeutic strategy of PTMC has to be defined (Roti et al. 2008).
2 Definition of PTCM
The conception of the “papillary thyroid microcarcinoma”
latent papillary carcinoma
minimal papillary carcinoma
minute/tiny papillary carcinoma
occult papillary carcinoma
small papillary carcinoma
non-encapsulated thyroid tumour
occult sclerosing carcinoma
papillary microtumour, excluding patients <19 years and metastasized tumours
Although PTMCs are frequently found at autopsy they are often not detectable in clinical examination but found incidentally during ultrasound and fine-needle aspiration and thyroidectomy for benign disease. Therefore, the new WHO classification (2004) has proposed the following characterisation of PTMC: “The term microcarcinoma should be used for a papillary carcinoma, which is found incidentally, and which measures 1 cm or less in diameter” (DeLellis et al. 2004). In individual cases, this definition may encompass tumours with multifocality, extrathyroidal extension, lymph node and distant metastasis (Roti et al. 2008).
Until 2002, the large majority of PTMC agreed with the T1-category of the TNM-classification of the International Union Against Cancer (UICC) and the American Joint Commission on Cancer (AJCC) (5th edition, 1997). In 2002, the consistency between PMTC and the T1-category was renounced (6th edition) (Sobin and Wittekind 2002; Greene et al. 2002; Gospodarowicz et al. 2004). Therefore, the tumour size had to be documented in addition to the primary tumour stage. With respect to this difficulty, a supplement was published shortly after the introduction of the 6th edition of the TNM classification in order to divide T1-tumours into T1a for all tumours ≤1 cm and T1b for all tumours >1 cm but ≤2 cm (Wittekind et al. 2003). The proposal to classify T1-tumours into T1a and T1b was adopted in the current 7th edition of the TNM-system (Sobin et al. 2009).
3 Ultrasound and Fine-Needle Biopsy
The increased sensitivity of imaging modalities such as ultrasound, computed tomography and magnetic resonance imaging has resulted in the identification of thyroid lesions, measuring 10 mm or less. To date, ultrasound-guided fine-needle aspiration cytology is sufficiently accurate to evaluate thyroid nodules as small as 2 mm (Yang et al. 2002). However, prospective studies on the diagnostic accuracy of small lesion biopsy are still lacking. The major reason for a missed tumour diagnosis on fine-needle aspiration may be inadequate tumour sampling due to the heterogeneity of the nodule (Siddiqui et al. 2008). Interestingly, Papini et al. have found that the cancer prevalence is not significantly different in nodules between 8 and 10 mm and nodules between 11 and 15 mm (Papini et al. 2002).
Certain morphological and functional parameters are significant predictors of malignancy. Already Schober and Schwarzrock 1986 discussed the relative probabilities for malignancy in low-uptake lesions of the thyroid using sonographic criteria. In particular, irregular margins, intranodular vascular spots and microcalcifications are independent risk factors in patients with small hypoechogenic lesions (Yamamoto et al. 1990; Papini et al. 2002). Furthermore, some authors have found that an anteroposterior and transverse diameter ratio of non-palpable thyroid nodules ≥1 was associated with malignancy (Yamamoto et al. 1990; Cappelli et al. 2005). Accordingly, the American (ATA) and European Thyroid Associations (ETA) recommend that nodules up to 1 cm should be submitted to fine-needle aspiration in the event of suspicious findings at ultrasound or a history of radiation to the head and neck region (Pacini et al. 2006; Cooper et al. 2009).
Summary of the international guidelines on the indication of radioiodine ablation in patients with papillary thyroid microcarcinoma
No patients with T1 N0 M0
Selected patients with T1 N0 M0
Selected patients with T1 N0 M0
history of radiation
Patients with T3 or N1/M1-categories
Patients with T3, R1 or N1/M1-categories; relative indication for <18 years
Patients with T3 or N1/M1-categories
5 Molecular Characteristics of PTMC
From a nuclear medicine perspective, the deeper insights into the molecular characteristics of PTMC will have a growing impact on the therapeutic management of these patients. Several genetic alterations have been described in PTMC which are associated with distinct biological features. Most common mutations in papillary carcinoma are point mutations of the BRAF and RAS genes and receptor tyrosine kinase (RET) rearrangements, all of which encode proteins that act along the same intracellular signalling pathway leading to the activation of the mitogen-activated protein kinase (MAPK) cascade (Nikiforov 2008). Chromosomal rearrangements of the RET gene represent the most common structural genetic alterations in papillary carcinoma. These rearrangements have been found in up to 52 % of PTMC and represent an early event in the process of thyroid cell transformation (Adeniran et al. 2006; Viglietto et al. 1995). More aggressive PTMCs which present with cervical lymph node metastases often show loss of the p27 gene (Khoo et al. 2002). In addition, cyclin D1 showed significantly higher median expression in PTMC with metastases compared to those without, indicating a correlation to tumour aggressiveness (Londero et al. 2008). Lim et al. (2007) have shown that the absence of epidermal growth factor receptor expression is closely correlated with lymph node metastasis and extrathyroidal growth. Furthermore, they have demonstrated that the absence of cyclooxygenase-2 expression is associated with multiplicity and bilaterality.
The guidelines of the ATA, ETA and the Therapy Committee of the EANM agree on a risk-adapted therapeutic management of patients with PTMC as outlined below (Pacini et al. 2006; Cooper et al. 2006a, b; Luster et al. 2008).
The optimal surgical treatment of PTMC is still debatable (Roti et al. 2006; Besic et al. 2008). In a meta-analysis, Roti et al. have found that total/near-total thyroidectomy is performed in 72 %, subtotal thyroidectomy in 11 % and lobectomy in 17 % of cases (Roti et al. 2008). According to Ito et al. therapeutic lymph node dissection is carried out in about 10 %, whereas prophylactic lymph node excision is performed in about 56 % (Ito et al. 2004).
- (a)When PTMC is diagnosed after lobectomy for benign thyroid disease completion thyroidectomy should be performed in case of the following risk factors:
columnar cell variant
tall cell variant
diffuse sclerosing variant
In case of a preoperative diagnosis of the PTMC by fine-needle aspiration cytology standard (near-)total thyroidectomy should be performed. This procedure allows the elimination of multifocal disease and decreases recurrence rates.
If the PTMC presents with locoregional or distant metastases routine total or near-total thyroidectomy with lymph node dissection is recommended.
The two major complications of thyroid surgery are permanent post-operative recurrent laryngeal nerve palsy and hypocalcaemia. According to the prospective German Thyroid Multicentre Study performed 1998 through 2001, Dralle et al. have found complication rates of only 1.7 % for permanent recurrent laryngeal nerve palsy per nerves at risk and 6.8 % for permanent hypocalcaemia (Dralle et al. 2004). The complication rates depend on the indication and extent of surgery as well as the specialisation of the surgeons (Dralle and Sekulla 2005). Thus, in centres of endocrine surgery the complication rates of permanent hypocalcaemia and recurrent laryngeal nerve palsy are significantly lower than those in low-volume hospitals. In our tertiary referral centre the rates of transient and/or permanent unilateral recurrent laryngeal nerve palsy vary between 1 and 15 % and are inversely proportional to the experience of the surgeon.
6.2 Radioiodine Ablation
The relatively low prevalence and lengthy overall survival of patients with differentiated thyroid cancer and, particularly, PTMC constrain the execution of large-scale prospective studies. Therefore, the level of evidence with regard to the therapeutic management of these patients is low in many instances. Accordingly, the authors of the EANM guidelines relied significantly on their clinical experience to supplement the observations reported in the literature (Luster et al. 2008). Thereby, the current EANM guidelines provide clear and comprehensive therapeutic algorithms of high relevance to everyday practice. This is of particular importance for the adequate therapeutic management of patients with PTMC and diverse risk-profiles.
According to the results of a meta-analysis only about 17 % of patients with PTMC undergo radioiodine ablation (Roti et al. 2008). Chow et al. have found a lower rate of lymph node recurrence after radioiodine ablation in patients with initially lymph node-negative PTMC (Chow et al. 2003). However, these findings could not be confirmed (Baudin et al. 1998). Most PTMC are diagnosed incidentally after surgery for benign thyroid disease and lack the risk factors mentioned above (Pazaitou-Panayiotou et al. 2007). However, in selected patients with PTMC at higher risk (unfavourable histology, multifocality, extrathyroidal growth or metastasis) post-surgical radioiodine ablation is definitively indicated (Table 1).
positive family history
history of neck radiation exposure
larger tumour size
closeness of the tumour to the thyroid capsule
cancer-related genetic findings (in the future).
In these cases, the decision on the post-operative radioiodine treatment should be made after individual discussions of the pros and cons with each patient. In general, radioiodine ablation has only minor side effects, such as sialadenitis, xerostomia or nausea (Dietlein et al. 2007). In addition, the patient′s needs of security or possible fears of radiation should be addressed.
6.3 Thyrotropin-Suppressive Therapy
The American and European guidelines recommend a differential L-thyroxine therapy according to the risk profile of the patients with PTMC mentioned above (Pacini et al. 2006; Cooper et al. 2009). In low-risk patients, L-thyroxine replacement therapy is adequate. In these cases Schlumberger et al. recommend to aim for a serum TSH level within the lower part of the normal range (0.5–1.0 mU/l) (Schlumberger et al. 2004). In high-risk PTMC patients with apparent remission after treatment TSH-suppressive therapy (serum TSH ≤ 0.1 mU/l) may be persued for 3–5 years in order to inhibit the TSH-dependent growth of residual cancer cells (Cooper et al. 1998; McGriff et al. 2002). In high-risk patients considered in complete remission therapy can be shifted from suppressive to replacement (Pazaitou-Panayiotou et al. 2007).
In summary, the PTMC comprises a spectrum of thyroid carcinomas with different risk stratifications. Therefore, the term PTMC is not suited for planning of the therapeutic management of individual patients. However, the European guidelines have defined distinct risk factors which should be considered in clinical routine. In particular, the Therapy Committee of the EANM has published an excellent guideline for risk-adapted therapy and follow-up of this multi-faceted thyroid cancer from a nuclear medicine perspective. This guideline has successfully integrated all relevant procedures with regard to clinical routine. In general, patients with PTMC have a normal life expectancy. Therefore, it should be the joint aim of the interdisciplinary medical team to guarantee an excellent quality of life. In addition, there is no difference in the clinical outcome of patients with papillary and follicular microcarcinoma (Rahbar et al. 2008; Riemann and Schober 2007). Accordingly, the therapeutic algorithms of patients with PTMC can be transferred to those with follicular microcarcinoma.
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