Journal of Surgical Oncology 49:140-146 (1992)

Papillary Thyroid Cancer and Its Surgical Management MASAKUNI NOGUCHI, MD, MITSUHARU EARASHI, MU, HlROHlSA KITAGAWA, MU, NAGAYOSHI OHTA, MD, MICHAEL THOMAS, PHD, ITSUO MIYAZAKI, MD, YUJl MIZUKAMI, MD, AND TAKATOSHI MICHIGISHI, MD From The Operation Center (M.N.), the Department of Surgery (I/) (M.N., M.E., H.K., N.O., M.T., I.M.), the Pathology Section (Y.M.), and the Department of Nuclear Medicine (T.M.), Kanazawa University Hospital, School of Medicine, Kanazawa University, Kanazawa, japan

The surgical management in papillary thyroid cancer has been highly controversial. In the Department of Surgery (II), Kanazawa University Hospital, the surgical management especially for cervical lymph node metastases has changed since 1973 from a conservative approach to an aggressive one. In order to determine whether an aggressive approach is warranted, a retrospective multivariate analysis was carried out on 106 cases of papillary thyroid cancer. The patients have been followed for 10-28 years. Multivariate analysis was conducted following Cox’s model. By this analysis, aggressive management appeared to have no impact on survival or relapse-free survival. However, age, sex, tumor size, and cervical lymphadenopathy were confirmed to be important prognostic factors in survival and/or relapse-free survival. 0 1992 WiIey-Liss, Inc. KEYWORDS: neck dissection, prognostic factors, aggressive approach

INTRODUCTION Surgical resection is the most effective treatment for papillary thyroid cancer. However, the extent of surgical resection necessary to control the disease has been controversial over the years. Particularly with regard to the management of cervical lymph node metastases, the controversy exists not only concerning the indication for, but also concerning the extent of cervical lymph node dissection [ 1 9 1 . Since papillary thyroid cancer has a relatively indolent biological behavior, no prospective studies have yet been performed for evaluating the efficacy of cervical lymph node dissection. In the Department of Surgery (11), Kanazawa University Hospital, the surgical strategy for papillary thyroid cancer was changed in 1973 from a conservative approach to an aggressive one. When retrospective analysis was performed in order to determine whether the aggressive approach would be warranted, multivariate analysis was more appropriate because a number of prognostic factors such as age, sex, histological subtypes, tumor size, tumor extension in the thyroid, cervical lymphadenopathy, and lymph node metastases were different and strongly interrelated between the conservative and ag0 1992 Wiley-Liss, Inc.

gressive groups. We therefore undertook multivariate analysis in this study, using 106 patients who were treated by these two different surgical approaches.

PATIENTS AND METHODS Selection of Patients From 1959-1990, 510 patients with malignant tumor of the thyroid were treated in the Department of Surgery (11), Kanazawa University Hospital. Patients with follicular, medullary, and anaplastic cancer and also patients with thyroid lymphomas were deliberately excluded because of the different nature of these malignancies. Furthermore, we excluded patients with incurable papillary thyroid cancer presenting with distant metastases or grossly malignant residues in the neck after the operation since they are unsuitable for evaluation of the efficacy of cervical lymph node dissection. Additionally, patients with less than 10 years of follow-up study were omitted since this is the minimum required for meaningful evaluAccepted for publication December 3, 1991 Address reprint requests to Masakuni Noguchi, MD, The Operation Center, Kanazawa University Hospital, School of Medicine, Kanazawa University, Takara-machi, 13-1, Kanazawa, 920, Japan.

Papillary Thyroid Cancer TABLE I. The Strategy of Cervical Lymph Node Management* Grow A ~

Benign (or minimal cancer) NO(N-) NO(N+) >N 1

N o removal of node N o removal of node NP NP

Grow B ~~

MRND MRND MRND

* NO

= No lymphadenopathy preoperatively; >N 1 = lymphadenopathy preoperatively; N- = no lymphadenopathy at operation; N+ = lymphadenopathy at operation; N P = node plucking; MRND = modified radical neck dissection.

ation of a response to treatment. Finally, 106 patients with potentially curable papillary thyroid cancer, without known distant metastases at the time of initial treatment, and whose follow-up ranged from 10-29 years, were studied.

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35 of the patients. MRND was performed in 51 of the patients in Group B, whereas cervical lymph nodes were not removed in only 3. These 3 patients were included in Group B, since 4 were similarly misdiagnosed as benign at the time of operation in Group A. The surgical management of Group A was designated as Type A, and that of Group B as Type B. Initially, no patient in either group received thyroid ablation with radioactive iodine but all of these patients have been advised to use suppressive doses of thyroid extract after their initial operation.

Histology For histological examination, surgically removed thyroids and lymph nodes were cut sagittally and sectioned into 5 mm thick slices. The slices were then fixed in 10% formalin and stained with hematoxylin-eosin (H&E). All of the thyroid lesions were diagnosed as papillary thyroid cancer by routine histological examination. In this study, moreover, the histological slides of the whole series were reviewed without information on clinical outcome, and reclassified into well differentiated type, follicular variant types, and trabecular type of papillary carcinoma according to the World Health Organization classification [5] and currently available pathological observation of thyroid tumors [6,7]. The well differentiated and follicular variant types of papillary carcinoma were designated as well differentiated carcinoma while the trabecular type of papillary carcinoma was classified as poorly differentiated carcinoma.

Experimental Design and Treatment Since the surgical strategy for papillary thyroid cancer changed in 1973 from a conservative approach to an aggressive one, the management of cervical lymph nodes and the extent of thyroidectomy were very different in the patients treated from 1962-1972 (Group A) from those treated from 1973-1980 (Group B). The surgical procedures are summarized as follows: the whole thyroid gland was thoroughly inspected and palpated before performing the thyroidectomy in both groups. The extent of thyroidectomy largely depended on the extent of cancer invasion or benign lesions in the thyroid tissue. The thyroidStatistical Methods ectomy, along with lymph node dissection of the central Group comparisons were performed for qualitative pacervical compartment, was performed en bloc. In the patients in Group A, however, total lobectomy was the rameters, using the chi-square test. The length of survival preferred operation, whereas subtotal thyroidectomy was or disease-free survival was calculated as the interval preferred for those in Group B . Consequently, the thyroid- from the operation to death from thyroid cancer-related ectomies included total thyroidectomy in 6, subtotal thy- causes or to recurrence, respectively. Patients who had roidectomy in 13, total lobectomy in 32, and isthmus- died without recurrence were censored at death. Curves ectomy in one of the patients in Group A. In Group B, of survival were constructed using the Kaplan-Meier they included total thyroidectomy in 4, subtotal thyroid- method and analyzed using the log-rank test. A multivariate analysis was performed to examine several parameectomy in 37, and total lobectomy in 13. For the Group A patients, only enlarged ipsilateral or ters simultaneously according to Cox’s proportional hazbilateral jugular lymph nodes were excised by a method ard model [8]. Sex, age, histological subtype, tumor size, of node plucking (NP) in most patients in whom cervical tumor extension in the thyroid, clinical lymphadenopalymphadenopathy was found preoperatively or at the time thy, histologically confirmed lymph node metastases, of their operation. In Group B patients, however, modi- and types of surgical management were tested as the fied radical neck dissection (MRND) was therapeutically prognostic factors. or electively performed, excluding a few patients in RESULTS whom the lesion was minimal or misdiagnosed as benign Characteristics of Patients at the time of operation. Ipsilateral or bilateral jugular There were 52 patients in Group A treated from 1962lymph nodes were resected by a method of MRND which preserves the sternocleidomastoid muscle, internal jugu- 1972, and 54 patients in Group B treated from 1973lar vein, transverse cervical artery, accessory nerve, bra- 1981. Table I1 gives the distribution of patients’ characchial plexus, sympathetic trunk, and phrenic nerve (Table teristics possibly related to prognosis in both groups. Ten I). In Group A patients, consequently, cervical lymph of the patients were male, and 96 were female. Patients nodes were not removed in 17 and NP was performed in fell into the following three age ranges: I_ 35 years, 39;

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Noguchi et al. TABLE 11. Characteristicsof the Patients in Groups A and B Group A (n = 52) Male/female Age 5 3 5 years 36-50 years 1 5 1 years Histological subtypes Well differentiated Poorly differentiated Tumor size 52.0 cm 2.1-5.0 crn 25.1 cm Tumor extension in thyroid Confined to one lobe and/or isthmus Extended to both lobes Cervical lymphadenopathy NO >N I Homolateral/bilaterala Regional lymph node metastases Positive Negative Unknown

Group B (n = 54)

2/50

8/46

23 14 15

16 18 20

41 11

46 8

10 37 5

ill

P value NSb NS

NS

5.0 cm), 9 patients. Tumor extension in the thyroid was judged at the time of operation: single or multiple cancer nodules were confined to one lobe and/or isthmus in 105 patients and multiple cancer nodules extended to both lobes only in two. Clinical lymphadenopathy was judged at the time of first clinical examination: there were 28 with cervical lymphadenopathy preoperatively, and 78 without. Histologically there were positive regional lymph nodes in 70 patients and negative lymph nodes in 16. The regional lymph node status was unknown in the other 20 patients. The tumor size was significantly different between the two groups but there was no significant difference between the two groups in the other prognostic variables (Table 11).

Outcome of Patients The clinical outcome (until March 1991) of the patients in these two groups were as follows. For the patients in Group A, two (4%) died of disease recurrence (one died of respiratory obstruction and the other died of distant metastases), 8 (15%) were alive after reoperation for locoregional recurrence, 6 (12%) died of unrelated or

TABLE 111. TvDes of Recurrence in GrouDs A and B Types of recurrence Thyroid Lymph node Trachea Esophagus Distant

Group A (n = 52)

Group B (n = 54)

4(8%) 6( 12%) 1(2%) O(O%)

O(O%) 7(13%)a 1(2%) 2(4%)

aOne case developed mediastinal lymph node recurrence and was included in the study.

unknown diseases, and one (2%) was lost to follow-up in Group A. In Group B, 3 (6%) patients died of disease recurrence (all of them died of distant metastases), 3 (6%) were alive after reoperation for locoregional recurrence, and 6 ( I 1%) died of unrelated or unknown diseases.

Types and Rates of Recurrence The types and rates of recurrence were analyzed as shown in Table 111. Intrathyroidal recurrence was found in 4 patients who were initially treated by lobectomy from Group A (8%), but was not found in any patient from Group B. Lymph node recurrence was found in 6 patients from Group A ( 12%) and 7 from Group B ( 13%). Mediastinal lymph node recurrence was found only in one patient from Group B, but she remains alive after reoperation. A few recurrences in the trachea or esophagus were found in patients from both groups. Distant recurrences

Papillary Thyroid Cancer

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TABLE IV. Types of Thyroidectomy and Intrathyroidal Recurrence Tumor extension in thyroid lobes Confined to one lobe and/or isthmus

Extended to both lobes

Thyroidectom y

Rate of intrathyroidal recurrence

Partial thyroidectomy Isthmusectom y Total lobectomy Subtotal thyroidectomy Total thyroidectomy Total thyroidectomy

O%(O/ 1) O%(O/ 1) 6.8%(3 /44) 0%(0/50) 0%(0/8) 0%(0/2)

TABLE V. The Rate of Regional Lymph Node Metastases and Recurrences in Groups A and B* Group A (n = 52) Metastases Benign NO(N-)

NO(N+) >N 1(Nf)

?/4 ?/I3 14/20(70%) 14/15(93%)

Group B (n = 54)

Recurrence

-- 0/4(0%) 1/13(8%)

-- 4/15(27%) /20(5%)1 1

Metastases

?/3 2/33(6%)a

Recurrence

- 0/3(0%)

- 2/38(5%) 13/13(100%) - 4/13(31%)b

29/38(76%)

*NO = no lymphadenopathy preoperatively; >N1 = lymphadenopathy preoperatively; N- = no lymphadenopathy at operation; N f = lymphadenopathy at operation. "Regional lymph node recurrence rate in patients with NO(N-) or NO(N+). patient who developed mediastinal lymph node recurrence was excluded from the study.

in the lung, bone, or brain also were found in the patients from both groups. There was essentially no difference between the two groups in the types and rates of recurrence except for the intrathyroidal recurrence (Table 111).

Types of Thyroidectomy and Intrathyroidal Recurrence The types of thyroidectomy and rates of intrathyroidal recurrence were analyzed as shown in Table IV. Of 44 patients with single or multiple nodules confined to one lobe who underwent lobectomy , the intrathyroidal recurrence was found in 3 (6.8%). No intrathyroidal recurrence was found in patients who underwent partial thyroidectomy, isthmusectomy, or subtotal thyroidectomy. The number of patients who underwent partial thyroidectomy or isthmusectomy was too small. Total thyroidectomy was performed in 8 patients with single or multiple nodules in one lobe and benign lesions in another lobe, and 2 patients with multiple nodules in both lobes (Table IV). Lymph Node Metastases and Recurrence Seven patients, 4 from Group A and 3 from Group B did not have any lymph nodes removed because the thyroid lesion was misdiagnosed as benign either preoperatively or perioperatively . However, lymph node recurrence has not yet developed in these patients. All the other patients were accurately diagnosed as thyroid cancer preoperatively or at the time of operation. In the Group A patients, however, no lymph nodes were removed in 13 patients in whom no lymphadenopathy was

found. NP was performed in the other 20 patients because lymphadenopathy was noted at the time of operation. Lymph node metastases were confirmed histologically in 14 of these patients (70%). Lymph node recurrence developed in 2 of these 33 patients without preoperative lymphadenopathy (6%). In 15 patients in whom lymphadenopathy was found preoperatively , NP was performed and lymph node metastases were histologically found in 14 of these patients (93%). In these patients, lymph node recurrence developed in four (27%). In the Group B patients, on the other hand, MRND was performed routinely in 38 patients in whom no lymphadenopathy was found preoperatively, and lymph node metastases were detected histologically in 29 of these patients (76%). Lymph node recurrence developed in 2 of these patients (5%). In 13 patients in whom lymphadenopathy was found preoperatively , the MRND was therapeutically performed and lymph node metastases were histologically found in all of them (100%).Of these patients, cervical lymph node recurrence developed in 4 (31%) (Table V). Consequently, in 20 patients with no lymphadenopathy who underwent neither NP nor MRND, only one (5%) had lymph node recurrence. But lymph node recurrence developed in 5 of 35 patients (14%) who underwent NP, and in 6 of 5 1 patients (1 2%) who underwent MRND.

Prognostic Factors By univariate analysis, age and tumor size were found to be significant factors affecting survival, and sex and

Noguchi et al.

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TABLE VI. Factors Affecting Survival and Disease-Free Survival in Univariate Analysis of Operable Papillary Thyroid Cancer Factors

Survival

Sex Age Histological subtypes Tumor size Tumor extension in thyroid Cervical lymphadenopathy Regional lymph node metastases Surgical management a NS

Disease-free survival