Surgical Treatment for Papillary Thyroid Carcinoma in Japan: Differences from Other Countries

REVIEW ARTICLE J Korean Thyroid Assoc Vol. 4, No. 2, November 2011 Surgical Treatment for Papillary Thyroid Carcinoma in Japan: Differences from Other Countries Yasuhiro Ito, MD and Akira Miyauchi, MD Department of Surgery, Kuma Hospital, Kobe, Japan Papillary thyroid carcinoma (PTC) is the most representative carcinoma among thyroid malignancies. The treatment strategy, especially surgery, in Japan traditionally differs from that in other countries, including Korea. Total thyroidectomy has been less frequently adopted, but lymph node dissection has been more actively performed in Japan than in other countries. Based on our data, total thyroidectomy is not necessary for low-risk patients, while it is, of course, mandatory for patients with high-risk features. Prophylactic central node dissection may not prolong patients survival, but we routinely perform it because reoperation for recurrence to this compartment is troublesome. In the past, Japanese endocrine surgeons actively performed prophylactic lateral node dissection, but indications are narrowing. However, it may be better to perform prophylactic modified radical neck dissection for patients exhibiting certain characteristics to reduce the rate of lymph node recurrence. I hope that surgical strategies in Japan and other countries will fuse with each other in order to identify the best treatments for PTC patients throughout the world. Key Words: Papillary thyroid carcinoma, Surgery, Prognosis Introduction Papillary thyroid carcinoma (PTC) is the most common malignancy arising from thyroid follicular cells. Although PTC generally has an indolent character, the presence of certain clinicopathological features indicates a dire prognosis. Therapeutic, especially surgical, strategies for PTC in Japan differ from those of other countries, including Korea. In 2011, The Japanese Society of Endocrine Surgeons and the Japanese Society of Thyroid Surgeons published guidelines for the management of thyroid tumors. An extract of the guidelines was published in English at approximately the same time, 1) and a full English version of the guidelines will be published at the beginning of 2012. These will contribute greatly to understanding of the current condition of therapy for thyroid carcinoma in Japan. In this short editorial, differences in therapies for PTC between Japan and other countries, including Korea, are described, along with guidelines and supporting data in our department. Observation for papillary microcarcinoma (PMC) Observation for PMC (PTC 1 cm) has been actively performed by some departments in Japan, and it was adopted in the Japanese guidelines. It is well-known that PTC measuring 0.3 1.0 cm can be detected in autopsy specimens at very high rates, up to 5%. 2-4) Clinically, Takebe et al., 5) reported the detection of papillary carcinoma in 3.5% of otherwise healthy women aged 30 years or older by ultrasonography and ultrasonography-guided fine needle aspiration biopsy (FNAB). They also showed that 75% of these lesions measured 1.5 cm or smaller. Furthermore, the prevalence of clinical thyroid papillary Received September 28, 2011 / Accepted October 14, 2011 Correspondence: Yasuhiro Ito, Department of Surgery, Kuma Hospital, 8-2-35, Shimoyamate-dori, Chuo-ku, Kobe 650-0011, Japan Tel: 81-78-371-3721, Fax: 81-78-371-3645, E-mail: ito01@kuma-h.or.jp 75

Yasuhiro Ito and Akira Miyauchi carcinoma was 1.9 11.7 per 100,000 females of all ages, 6) which is about 1,000 times lower than that of PMC detected on ultrasonography. These findings strongly suggest that most PMC do not or very slowly grow and become clinical only occasionally, although PMC shows latent multiplicity and lymph node metastasis at high rates. 7-9) Our department actively performs PMC observation. 7-10) Table 1 summarizes our criteria of highrisk features for observation. Patients with at least one of these features are considered unsuitable for observation and immediate surgery is recommended. Cases with clinical node metastasis and/or distant metastasis should be considered to be biologically at high-risk, and careful therapies must be performed, even though the primary lesions are small. It is not clear whether PMC located adjacent to the trachea or on the dorsal surface of the thyroid lobe is biologically high-risk, but when it grows, it may invade the trachea, recurrent laryngeal nerve, or esophagus. Then, these patients are considered high-risk for observation, and immediate surgery is recommended for them. Patients without any high-risk features are candidates for observation. Tumor multiplicity and a family history are not adopted as high- risk features for observation in our department. 10) How to observe PMC is simple, as summarized in Fig. 1. At first, we perform ultrasonography to examine the size and location of primary lesions and whether clinical node metastases are present. Chest CT scan is also performed at the first stage. Then, we present two therapy options, observation and immediate surgery, to patients without any high-risk features. For patients who chose observation, we follow them by ultrasonography once or twice per year to assess whether their tumors show any progressive signs such as size enlargement and the novel appearance of node metastasis. We judge PMC as showing size enlargement when the size is 3 mm larger compared to that at the initiation of observation (NOT the size at the last examination). For such cases, we usually repeat ultrasonography 3 6 months later, because there are observable variations in size on ultrasonography. If the size at the next examination does not differ from or even enlarges compared to that at the last, we recommend surgery. Patients showing the novel appearance of node metastasis are also strong candidates for immediate surgery. The appearance of multiplicity is not regarded as a progression sign in our department. To date, in our department, about 400 patients with low-risk PMC have been observed without immediate surgery. The incidence of size enlargement was around 6%, and that of the novel appearance of lymph node metastasis was about 1% after 5-year follow-up. 8,10) Importantly, none of the patients, who underwent surgery after observation because of the appearance of progression signs, have shown any postoperative recurrence or died of carcinoma to date. Therefore, we can conclude that observation without Table 1. High-risk features for observation of papillary microcarcinoma 1. Tumors located adjacent to the trachea 2. Tumors located on the dorsal surface of the thyroid lobe with the possibility of invading the recurrent laryngeal nerve 3. Fine-needle aspiration biopsy findings suggesting highgrade malignancy 4. Presence of regional node metastasis or distant metastasis at diagnosis 5. Appearance of progression signs (size enlargement and/ or lymph node metastasis) Fig. 1. Flow chart of treatment for papillary microcarcinoma. PMC: papillary microcarcinoma, FNAB: fine needle aspiration biopsy. Vol. 4, No. 2, 2011 76

Surgical Treatment for Papillary Thyroid Carcinoma in Japan immediate surgery for low-risk PMC patients is an important therapy option. The ATA guidelines stated that nodules under 5 mm without the suspicion of node metastasis are not candidates for further examination such as FNAB. 11) This indirectly supports observation for low-risk PMC. Surgery for PTC Surgery for PTC consists of two procedures, thyroidectomy and lymph node dissection. Historically, the extent of thyroidectomy and lymph node dissection in Japan has significantly differed from that in other countries, including Korea. Extent of thyroidectomy: In many countries, including Korea, total thyroidectomy is a standard therapy for PTC patients. Most of these patients undergo radioactive iodine (RAI) ablation and then thyroid stimulating hormone suppression. However, limited thyroidectomy such as lobectomy with isthmectomy and subtotal thyroidectomy has been widely adopted by Japanese endocrine surgeons, which is based on two reasons. One is that the capacity of RAI ablation and RAI therapy has been limited in Japan due to legal restrictions. Furthermore, from the standpoint of medical economics, RAI therapy is not profitable for Japanese hospitals, resulting in the number of beds for RAI therapy failing to increase. The second reason, which might be more important, is that most PTC patients are unlikely to die of carcinomas even though they undergo limited thyroidectomy without RAI therapy, which is empirically known by Japanese endocrine surgeons. Total thyroidectomy has benefits such as: 1) postoperative thyroglobulin (Tg) can be used as a tumor marker, 2) RAI ablation and RAI therapy can be immediately performed, and 3) recurrence to the remnant thyroid can be prevented. In contrast, there are some demerits, such as: 1) risks of hypoparathyroidism and recurrent nerve paralysis increase and 2) thyroid hormone administration is absolutely necessary. Hypoparathyroidism and recurrent nerve paralysis (especially bilateral paralysis) are unlikely to occur, and the administration of thyroid hormone might not be necessary for patients who have undergone limited thyroidectomy. The Japanese guidelines state that total thyroidectomy is not needed for patients with T1N0M0 PTC, who are regarded as low-risk. 1) Indeed, in our department, the prognosis of solitary T1N0M0 patients was excellent. The 10-year disease-free survival (DFS) rate was 97%. Four of the 2,638 patients showed distant recurrence and only one died of carcinoma. 12) The DFS rate of patients who underwent limited thyroidectomy did not differ from that of those who underwent total thyroidectomy if recurrence to the remnant thyroid is not included. The rate of recurrence to the remnant thyroid was only 1% in patients who underwent limited thyroidectomy. Based on these findings, it is clear that total thyroidectomy is not mandatory for such low-risk patients. In contrast, total thyroidectomy is mandatory for PTC patients with biological features predicting recurrence and carcinoma death at high incidences. In the Japanese guidelines, total thyroidectomy is strongly or moderately recommended for PTC patients having one or more of the clinicopathological features shown in Table 2. 1) We previously identified six prominent clinicopathological features affecting patients prognosis, which were age at 55 years or older, male gender, lymph node metastasis >3 cm, tumor size >4 cm, significant extrathyroid extension (corresponding to T4 in UICC [Union for International Cancer Control] classification), and extranodal tumor extension requiring at least the partial excision of organs adjacent to metastatic nodes. 13) Of these factors, lymph node >3 cm and extrathyroid extension were regarded as independent prognostic factors for recurrence not only to the regional lymph nodes, but also to the lung and Table 2. Indications of total thyroidectomy in the Japanese guidelines 1. Strongly recommended Tumor size>5 cm Extrathyroid extension to the trachea or esophagus Large number of lymph node metastasis Node metastasis>3 cm Distant metastasis 2. Moderately recommended Tumor size>4 cm Clinical lymph node metastasis 77 J Korean Thyroid Assoc

Yasuhiro Ito and Akira Miyauchi bone. 14) Therefore, patients having these features are strong candidates for total thyroidectomy regardless of the size of primary lesions, which is consistent with the Japanese guidelines. In the Japanese guidelines, PTC that was not classified as high- or low-risk was regarded as a grey-zone, and there was no recommendation concerning the extent of thyroidectomy. 1) At present, our department performs total thyroidectomy for PTC patients except for solitary T1N0M0, but the extent of thyroidectomy for grey-zone patients varies from department to department in Japan. Importantly, in our department, only 0.82% of patients with PTC without clinical lymph node metastasis or significant extrathyroid extension showed distant recurrence during follow-up, regardless of the tumor size. The mortality of these patients was only 0.13% (our unpublished data). These findings suggest that total thyroidectomy is not mandatory for most grey-zone patients. Extent of lymph node dissection: There are two prominent regional lymph node compartments of PTC, central and lateral compartments, and there are two kinds of lymph node dissection, therapeutic and prophylactic dissection. Therapeutic node dissection is mandatory for patients with clinical lymph node metastases detected on preoperative imaging studies. However, the indication of prophylactic node dissection remains controversial. Ultrasonography is the most useful tool to detect and diagnose regional lymph node metastasis preoperatively. In our study, the positive predictive value (PPV) and specificity of ultrasonography for central node metastasis were 92 and 98%, respectively, while its negative predictive value (NPV) and sensitivity were only 37 and 12%, respectively. PPV and specificity for lateral node metastasis were 95 and 97%, respectively, and its NPV and sensitivity were only 43 and 29%, respectively. 15) These indicate that ultrasonography often overlooks lymph node metastasis in these compartments. a) Prophylactic central node dissection: PTC can metastasize not only to the central compartment but also to the lateral compartment in similar incidences. These metastases are frequently overlooked on preoperative ultrasonography, as indicated above. Therefore, central node dissection does not warrant local cure. Although there are no comparative studies using a large series of patients, prophylactic central node dissection is not likely to significantly improve patients prognosis, especially cause-specific survival. However, it is apparent that reoperation involving the central compartment for recurrence is technically difficult and severe complications such as recurrent laryngeal nerve injury and persistent hypoparathyroidism may possibly occur. Furthermore, it is not evident that all small node metastases can be ablated by RAI. For these reasons, the Japanese guidelines recommend routine central node dissection, even though it is prophylactic. 1) b) Prophylactic lateral node dissection (modified radical neck dissection [MND]): In contrast to central node dissection, MND requires wound extension and is time-consuming. In the past, Japanese endocrine surgeons almost routinely performed prophylactic MND in order to reduce lymph node recurrence. However, the rate of prophylactic MND is decreasing in Japan, because it is considered as oversurgery for low-risk patients. The indication of prophylactic MND varies according to departments in Japan at present, and the Japanese guidelines do not provide any indication for prophylactic MND. There are no prospective comparative studies on whether and how prophylactic MND affects patients prognosis. However, in our series, patients with tumors larger than 3 cm or with significant extrathyroid extension are more likely to show lymph node recurrence than those without these features, even though they undergo prophylactic MND. Ten-year lymph node recurrence rates for patients with tumors larger than 3 cm was 13%, while that for those with tumors measuring 3 cm or less was only 3%. Similarly, 16% of patients having significant extrathyroid extension showed lymph node recurrence after 10-year follow-up, while the incidence was much lower at 5% of patients showing tumors without extension. 16) If prophylactic MND were not performed, the recurrence rates of patients with these features would be even higher. Based on these findings, we actively perform Vol. 4, No. 2, 2011 78

Surgical Treatment for Papillary Thyroid Carcinoma in Japan prophylactic MND for patients with these features. The indication of prophylactic MND, however, varies according to the incidence of lymph node recurrence that patients and physicians accept. Closing Remarks We have to note that the prognosis of PTC patients is excellent unless they have high-risk features such as clinically apparent node metastasis, significant extrathyroid extension, and distant metastasis at diagnosis. As indicated above, only 0.13% of low-risk PTC patients died of carcinoma regardless of the tumor size and extent of surgery in our department (our unpublished data). In Western countries and also Korea, however, total thyroidectomy is almost routinely performed. It may be time to reconsider whether such a procedure is truly mandatory and beneficial for low-risk PTC patients. For high-risk patients, it goes without saying that total thyroidectomy is mandatory. Although the lymph node is the organ in which PTC most frequently recurs, extensive lymph node dissection is mandatory only for high-risk patients. Especially, prophylactic MND is unnecessary for patients without high-risk features. It is debatable whether prophylactic central node dissection should be routinely performed, because it is not likely to contribute to improve patients prognosis, especially cause-specific survival. However, recurrence to this compartment should be a stressor for patients and physicians, because reoperation can lead to severe complications. Therefore, most Japanese endocrine surgeons routinely perform central node dissection as recommended in the Japanese guidelines. In this editorial, the differences in PTC surgery between Japan and other countries, including Korea, were described. I am confident that PTC patients can receive the best treatment anywhere in the world by fusing our treatment strategies with those of other countries. 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