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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Differentiated thyroid carcinoma

and .

Department of Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany

According to the classification of the WHO, differentiated thyroid carcinoma can be subdivided into papillary and follicular thyroid carcinoma. The histological differentiation seems to be useful since papillary and follicular thyroid carcinoma differ in their biological behavior which may be reflected in a somewhat distinct therapeutic approach. Even though surgery is accepted as the treatment of choice in differentiated thyroid carcinoma no consensus exists neither regarding the extent of thyroidectomy nor regarding the extent of lymph node dissection.

Definition, epidemiology and pathogenesis

Both papillary (PTC) and follicular thyroid carcinoma (FTC) derive from the thyroid follicular epithelial cells. The diagnosis papillary thyroid carcinoma is based on a constellation of features such as papillary architecture, the presence of psammoma bodies, and characteristic nuclear features (e.g. nuclear chromatin, nuclear orientation, nuclear grooving), not all of which may be present in a single tumor. Follicular thyroid carcinoma is defined as a thyroid follicular epithelial cell neoplasm, not belonging to papillary thyroid carcinoma, with evidence of capsular and/or vascular invasion. A variety of subtypes exist in both PTC and FTC.

It is generally estimated that thyroid carcinoma comprises approximately 1% of all malignancies. In Europe and the US, about 3 out of 100,000 people develop a thyroid malignancy, however, considerable regional differences exist. Papillary thyroid carcinoma is the most common malignant thyroid neoplasm in countries with sufficient iodine diets and comprises up to 80% of all thyroid malignancies. It occurs in all age groups but is most common in the 3rd to 5th decades. While lymph node metastases are often present at diagnosis (average about 50%, can be as high as 85–90% in some series), haematogenous spread is rather a rare and late event. In contrast, distant metastases are very frequently found in children and adolescents. Follicular thyroid carcinoma is more common in regions with insufficient iodine diets and represents approximately 10–20% of all thyroid malignancies. It occurs over a wide age range but is most common in the 5th and 6th decades. Distant metastases are more common than lymph node metastases and may be the initial symptom.

Differentiated thyroid carcinoma is generally sporadic but in some studies accumulated familial occurrence has been described. Familial differentiated thyroid carcinoma probably constitutes less than 5% of all thyroid cancer cases.

An association between papillary thyroid carcinoma and colorectal disease (familial adenomatous polyposis (FAP) including its subtype Gardner's syndrome) and breast disease (Cowden disease – multiple hamartoma syndrome) has been described in at least two hereditary cancer syndromes. The genes for both syndromes have been identified: APC (5q21) and PTEN (10q23). Familial forms of differentiated thyroid carcinoma have also been reported without the association of either FAP or Cowden disease. While a gene for familial non-toxic multinodular goiter has been localized to a region of 14q linkage studies suggest that no etiologic gene of familial differentiated thyroid carcinoma is present in this region.

The etiology of sporadic forms of differentiated thyroid carcinoma remains speculative. External radiation is the only exogenous factor which has been clearly identified to be able to cause thyroid carcinoma (almost exclusively the papillary form). Iodine excess and iodine deficiency are also discussed. Genetically, a variety of cytogenetic alterations have been described. Somatic rearrangements of the proto-oncogenes RET and NTRKI are found in up to 50% of papillary thyroid carcinoma.

Interestingly, somatic mutations of APC or PTEN have almost never been reported in sporadic differentiated thyroid carcinomas. Rearrangements involving the proto-oncogene RET (10q11) are the most common somatic genetic changes found in papillary thyroid carcinoma. Irradiation has been shown to be capable to induce these rearrangements. At least five types of RET rearrangements have been described yet. Of note, RET rearrangements have never been reported in undifferentiated thyroid carcinomas. NTRKI (also known as TrkA;1q22) is another gene often activated in papillary thyroid carcinomas. Like RET, the activation of NTRKI is caused by rearrangements, at least three genes are involved.

A variety of factors have been shown to affect the prognosis of differentiated thyroid carcinoma. These factors include histological type and subtype, tumor stage, age, gender, histology type and differentiation, DNA euploidy, microvessel count, CD97, E-cadherin, telomerase activity, capsular and vascular invasion.

However, the value of most of these prognosis factors is not uniform in all studies. Primary tumor size, extrathyroidal extension and distant metastases, however, are among those factors generally correlated with outcome. In contrast, the prognostic significance of lymph nodes remains controversial. While it has been repeatedly shown that their initial presence is correlated with tumor recurrence, most studies could not prove a significant influence on survival.

A variety of prognostic scoring systems have been published, e.g. AGES, AMES, DAMES, MACIS, age-related pTNM, EORTC prognostic index. Unfortunately, none of them is widely used, thus making comparison of studies extremely difficult if not impossible.

The subtype Hürthle cell carcinoma (also known as oxyphilic or oncocytic thyroid carcinoma) is believed to be associated with a poorer prognosis. One explanation might be that these tumors are less likely to uptake radioiodine.

Of special note is the insular type. It belongs to the low-differentiated thyroid carcinomas. The overall survival rate is lower in comparison to well-differentiated thyroid carcinoma, In some studies, insular thyroid carcinoma was more often associated with extrathyroidal tumor extension, lymphogenous and haematogenous spread as opposed to classical differentiated thyroid carcinoma. Despite the lower degree of differentiation, insular thyroid carcinoma is often still susceptible to radioiodine treatment which may be used as a therapeutic option if surgery is not feasible.

The overall 5-year-survival-rate of patients with papillary thyroid carcinoma is about 90–95%, the 10-year survival rate is about 80–95%. The survival rate of patients with follicular thyroid carcinoma is slightly lower compared to papillary thyroid carcinoma with 10-year survival rates between 70–95%. In some subtypes, e.g. widely invasive follicular carcinoma, survival statistics rival those of poorly differentiated thyroid carcinomas, with 25–45% 10-year survival rates. Of note, differentiated thyroid carcinoma may become less differentiated and even undifferentiated in time.

Diagnosis

In order to plan the adequate therapeutic strategy, the diagnosis of differentiated thyroid carcinoma should be made preoperatively. In quite a few patients, however, the diagnosis will be made postoperatively. In these cases, the carcinoma is often still limited to the thyroid gland and the necessity to perform reoperation (completion thyroidectomy and/or lymph node dissection) needs to be carefully assessed according to the definite pathohistological evaluation of the surgical specimen.

A thyroid nodule is the most common symptom of patients with differentiated thyroid carcinoma. Most of these nodules are scintigraphically cold. Anyhow, most cold thyroid nodules are benign and a scintigraphically normal or hot nodule does not exclude the presence of a differentiated thyroid carcinoma. In papillary thyroid, the initial symptom may be enlarged cervical lymph nodes as a sign of metastatic involvement.

A fine-needle aspiration cytology (FNAC) should be performed if thyroid nodules are clinically suspicious to be malignant (e.g. solid, rapidly growing). FNAC might also be helpful in the evaluation of suspicious lymph nodes. Recently, a PCR-based method analyzing thyroid specific transcripts of the TSH-receptor and thyroglobulin has been shown to facilitate preoperative diagnosis of differentiated thyroid carcinoma in small lymph nodes. Cytologic features of papillary thyroid carcinoma are diagnostic by FNAC. In follicular thyroid carcinoma, however, the contribution of FNAC in making the diagnosis is limited. The preoperative value of thyroglobulin measurements is not known.

At primary operation, extensive imaging techniques are often not required unless invasion of the trachea or oesophagus or distant metastases are suspected. Ultrasound, however, should be performed to identify the extent and localization of the primary and coexisting thyroid nodules and to diagnose enlarged cervical lymph nodes. Radioiodine can not be used as a diagnostic tool unless the thyroid gland has been removed. Prior to extensive operation, distant macrometastases (most often found in lung and bones) should be ruled out. Their presence can often already be shown on a plain chest x-ray.

If infiltration of the oesophagus or trachea is suspected computed tomography or, preferably, nuclear resonance imaging and endoscopy (tracheoscopy, oesophagoscopy) should be performed. In recurrent disease, other imaging techniques have been shown to be helpful (e.g. Technetium-99m, Thallium-201, FDG-PET).

Surgical treatment

Surgery is the treatment of choice in both papillary and follicular thyroid carcinoma. The extent of surgery in regard to thyroid gland and lymph nodes, however, varies from conservative treatment to radical approaches.

In papillary thyroid carcinoma, total thyroidectomy is advocated by some surgeons as the treatment of choice regarding the thyroid gland for the following reasons:

1.

Papillary thyroid carcinoma is often multifocal (> 25%).

2.

Small lesions may grow aggressively with the potential of dedifferentiation.

3.

Rate of local recurrences is increased after less than total thyroidectomy.

4.

An experienced surgeon can perform a total thyroidectomy with minimal or no long-term complications.

5.

Completion thyroidectomy of thyroid remnants may be associated with a higher morbidity.

6.

Measurement of thyroglobulin can be used during follow-up.

7.

Radioiodine can be used for diagnostic and therapeutic purposes of metastatic disease.

8.

Ablation of gross thyroid thyroid remnants with radioiodine can be associated with pain.

Less than total thyroidectomy has been recommended for the following reasons:

1.

Scoring systems enable to identify lowrisk patients who have a 20-year survival rate of 99% and a 20-year disease-free survival of > 90%.

2.

Low risk (< 1%) of conversion of differentiated thyroid carcinoma to undifferentiated (anaplastic) thyroid carcinoma.

3.

No difference in survival as compared to total thyroidectomy.

4.

Local recurrences can be managed by reoperation.

5.

Development of a recurrent thyroid cancer in the remnant thyroid lobe is considerably less common then the reported incidence of microscopic disease.

6.

Decreased morbidity after lobar or subtotal thyroidectomy as compared to total thyroidectomy.

7.

If necessary, ablation of the thyroid remnant with radioiodine can be accomplished with no morbidity.

The prognostic significance of lymph node metastases is also controversial. While it is generally accepted that lymph node metastases are associated with an increased rate of tumor recurrence only a few studies could show a significant influence on survival. However, the mean follow-up time in those studies showing a prognostic significance was usually longer than 10–15 years. The average follow-up time in those studies not showing an influence was often shorter than 10 years. Thus, the clinical significance of lymph node metastases in papillary thyroid carcinoma might not be obvious after short-term follow-up. In this regard, it is of note that papillary thyroid carcinoma as recurrent disease in regional lymph nodes may undergo anaplastic transformation. However, the prognostic significance of lymph node metastases differs considerably in some studies. The reason is not known.

Surgery is the treatment of choice if lymph node metastases are present. Lymph node metastases of papillary thyroid carcinoma are often macrometastases, however, they can be very small in size. Diagnosis might be only possible histologically. Lymph node dissection should therefore not only include obviously enlarged lymph nodes but also the whole adipose and connective tissue in order to dissect also the very small, possibly metastatic lymph nodes within this compartment. The prognostic significance of these micro metastases, however, is unknown. And despite high frequencies of microscopic lymph node metastases (60–90%) only 5–15% of patients with papillary thyroid carcinoma in whom no prophylactic dissection was performed develop nodes at a later time. Of note, radioiodine might fail to ablate especially these micrometastases. In regard to lymph nodes, several classifications have been proposed (table I).

Table 1. Classification systems of the cervicomediastinal lymph nodes.

Table 1

Classification systems of the cervicomediastinal lymph nodes.

In follicular thyroid carcinoma total thyroidectomy is widely accepted as the treatment of choice. Haematogenous metastases are more common and can not be treated adequately with radioiodine if a thyroid remnant exists. Lymph node metastases seem to be less common in comparison to papillary thyroid carcinoma.

Technique

Technically helpful are the use of magnifying glasses, bipolar coagulation forceps and neuromonitoring of the recurrent laryngeal nerve. These tools facilitate the identification and preparation of important structures (e.g. recurrent laryngeal nerve, parathyroid glands) and enable complete dissection of each compartment while preserving these structures.

It has been an unresolved issue whether the parathyroid glands should routinely be autotransplanted or remain in situ, The incidence of hypoparathyroidism seems to be similar in either case (grade C). The preservation of the upper glands is almost always feasible. In contrast, as a consequence of the cervicocentral lymph node dissection preservation of the lower glands is rarely manageable. Any clearly tumor-free parathyroid gland with insufficient vascularization should be cut into many little pieces and autotransplanted either into the sternocleidoid muscle or the forearm. The location of the autotransplant should be marked with a non-resorbable suture in case reoperation is required.

Primary therapy

Survival data's, locoregional control and the morbidity of the treatment are equally important considerations in determining the optimal treatment of differentiated thyroid carcinoma.

Therefore, we advocate total thyroidectomy and lymph node dissection of the cervicocentral compartment as the minimal treatment in differentiated thyroid carcinoma (grade C).

The reasons that speak in favor of total thyroidectomy in differentiated thyroid carcinoma are outlined above. In addition, we consider routine dissection of the cervicocentral compartment to be adequate since at least the rate of locoregional recurrences will be decreased. Pre- and intraoperative distinction between follicular and papillary thyroid carcinoma might be impossible. Therefore, we favor the general dissection of the cervicocentral compartment to prevent reoperation in those cases when follicular carcinoma is suspected but postoperative histology reveals papillary carcinoma. It is further generally accepted to dissect compartments obviously involved with lymph node metastases. Lymph node metastases of papillary thyroid carcinoma are almost as often found in the ipsilateral cervicolateral compartment as in the cervicocentral compartment. However, there is neither a general recommendation to include this compartment nor has it been shown that general inclusion decreases the rate of recurrence.

Technique

After exposure of the thyroid gland both lobes should be mobilized to enable identification of the recurrent laryngeal nerve. Thereafter follows the preparation of the cervicocentral compartment anterior and posterior of the recurrent laryngeal nerve. This lymph node compartment is removed en bloc with the thyroid gland. If indicated, lymphadenectomy of the cervicolateral compartments should be performed in a centripetal manner. Important is the dissection of inter- and retrofascicular lymph nodes. Lymph node dissection of the mediastinal compartment is rarely indicated in differentiated thyroid carcinoma. It is performed by a transsternal approach and should extent caudally to the azygous vein and laterally to the pleura.

Locally advanced thyroid cancer

Oesophageal and laryngotracheal invasion by differentiated thyroid carcinoma is a rare but surgically challenging situation. Even though controversies continue to exist regarding the optimal surgical treatment, most experts recommend the removal of all gross tumor while function should be preserved whenever possible. The surgical treatment may consist of a shave procedure to resect tumor that adheres to tracheal and/or laryngeal cartilage. When parts of the upper aerodigestive tract structures are transmurally invaded, radical excisions such as total laryngectomy, circumferential tracheal resection, or oesophagectomy may be required. In patients with distant metastases, tracheal or oesophageal stent implantation are alternative therapeutic options to prevent airway obstruction and hemorrhage. In these cases, radioactive iodine and external radiation should be used only as additional therapies.

In addition, it needs to be considered that the laryngeal nerve, if infiltrated by differentiated thyroid carcinoma, might be worsewhile to be preserved for maintenance of postoperative vocal cord function without affecting the incidence of local recurrences or progression.

Completion surgery and reoperation

Completion surgery might be indicated if a resected thyroid nodule turns out to be malignant. Generally, the same considerations as in primary therapy apply. Therefore in our opinion, the indication for completion thyroidectomy is given if:

1.

Tumor remnant is proven.

2.

Histology shows multifocality of the tumor in the resected lobe.

3.

Size of primary tumor > 1 cm (> pT1).

4.

Lymph node or distant metastases are proven.

In addition, we recommend dissection of the cervicocentral compartment. The search for additional metastatic spread is mandatory and extension of the lymph node dissection to the cervicolateral or even mediastinal compartment may be required.

Reoperation in differentiation thyroid carcinoma is indicated if locoregional tumor recurrence is proved. Thyroid remnants which due to size are inaccessible to radioiodine ablation should be resected too.

Technique

Generally, the surgical approach during reoperation does not differ from the primary operation. Scar tissue and previous external radiation, however, can make a meticulous preparation more difficult.

Non-surgical treatment modalities

In Europe it is common to treat patients with differentiated thyroid carcinoma postoperatively with radioiodine. This approach is less common in the US. The different frequency regarding the use of postoperative radioiodine is mainly because total thyroidectomy, which is a prerequisite for successful radioiodine ablation, is rarely performed routinely in the US. Radioiodine has been shown to be effective in ablation of small thyroid remnants and pulmonal metastases. Bone metastases are less likely to respond to radioiodine. Recently, it has been shown that Lithium may be a useful adjuvant for radioiodine therapy of thyroid cancer, augmenting both the accumulation and retention of radioiodine in lesions.

Another therapeutic option might be retinoids which are capable to induce redifferentiation of less-differentiated thyroid carcinoma.

Routine use of external radiation must be avoided. However, external radiation can very well be indicated in the treatment of in the presence of non-resectable tumor and bone metastases.

The use of chemotherapy is limited, remission could only be achieved in single patients.

Conclusion

Surgery is the treatment of choice for primary and recurrent differentiated thyroid carcinoma. The surgical extent of intrathyroidal tumors and the extent of lymph node dissection, however, remain controversial. In Europe, total thyroidectomy and routine cervicocentral lymphadenectomy is widely recommended. A less extended approach is only recommended in the following situation:

1.

Primary tumor is unifocal and less than 1 cm in diameter (pT1a).

2.

Absence of lymph node and distant metastases (N0, M0).

3.

Patient's compliance in regard to follow-up is ensured.

4.

Absence of individual risk factors (e.g. familiar differentiated thyroid carcinoma, history of external radiation).

However, less extensive surgical strategies have been recommended. Especially surgeons in the US advocate a less aggressive approach in intrathyroidal differentiated thyroid carcinomas. Other risk factors (e.g. age) are used to determine the extent of surgery. As long as no prospective randomized longterm follow-up studies exist, no consensus will be achieved. Different genetic and epigenetic factors may exist that contribute to a different biological behavior of differentiated thyroid carcinoma in Europe and the US.

According to the German Cancer Society and the Guidelines of the German Society of Surgery total thyroidectomy and lymphadenectomy of the cervicocentral compartment are considered to be the standard therapy of differentiated thyroid carcinoma. Total thyroidectomy is advocated because it enables the diagnostic and therapeutic use of radioiodine. Furthermore, thyroglobulin measurements can be done during follow-up. The recommendation to perform routine cervicocentral lymph node dissection is given due to the high incidence of lymph node metastases in this compartment. Reoperation due to persistent cervicocentral lymph node metastases is associated with an increased morbidity and can be avoided.

The prognostic significance of metastases in cervicolateral lymph nodes has not been proven yet. Their dissection is indicated if metastases are proven. The dissection of the cervicolateral compartments should be performed systematically (i.e. compartment-oriented microdissection), not selectively. The rate of reoperation which harbors an increased risk of morbidity can be decreased if the dissection is performed in this manner. The routine use of postoperative radioiodine is more and more accepted. In recent studies, an improved outcome of patients has been repeatedly shown if radioiodine was given postoperatively. External radiation may be considered if tumors are non-resectable. Whether any patient with extrathyroidal tumor extension or lymph node metastases should undergo postoperative external radiation is controversial, we do not recommend this approach.

Chemotherapy should currently only be used as a therapeutic option if all of the above described therapeutic modalities prove ineffective.

References

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Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6979

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