JOURNAL
OF SURGICAL
RESEARCH
52,113-117
Management
(19%)
of Local Recurrence in Well-Differentiated Thyroid Carcinoma
LEIGH S. HAMBY, M.D., PATRICK C. MCGRATH, M.D.,’ RICHARD W. SCHWARTZ, M.D., DAVID A. SLOAN, M.D., WILLIAM G. SIMPSON, M.D., AND DANIEL E. KENADY, M.D. Lexington Veterans Administration Medical Center and the Department of Surgery, University of Kentucky Chandler Medical Center, Lexington, Kentucky 40536 Presented
at the Annual
Symposium
of the Association
of Veterans
Administration
Surgeons, Milwaukee,
Wisconsin,
May 9-11, 1991
mortality rate [l-3]. Thus, many surgeons advocate total thyroidectomy as the initial surgical treatment to facilitate the use of I-131 scanning in the early detection and treatment of postoperative recurrence. However, this aggressive approach has not been clearly shown to decrease the recurrence rate or impact on overall survival. The University of Kentucky experience with welldifferentiated thyroid carcinoma was reviewed to determine factors influencing the development of local recurrence and to identify successful management strategies.
Local recurrence of well-differentiated thyroid carcinoma has a reported mortality approaching 50%. The University of Kentucky experience was reviewed to determine whether aggressive surveillance and treatment with reoperation and/or I- 13 1 ablation increased survival following recurrence. Records of 66 consecutive patients with well-differentiated thyroid carcinoma treated at the University of Kentucky Medical Center (1980-1989) were reviewed. Forty-nine cases of papillary carcinoma and 17 cases of follicular carcinoma were studied; median follow-up was 68 months. At ‘presentation, patients with follicular carcinoma were older (48 versus 35 years; P < 0.05) and more frequently had metastatic disease (17% versus 2%, P < 0.05). Fifty-eight (88%) patients were alive and diseasefree at last follow-up. Fifteen patients (24%) had developed recurrent disease; median time to recurrence was 24 months. Multivariate regression examined the variables of age, sex, histology, tumor size, cervical adenopathy, capsular and vascular invasion, multicentricity, and surgical procedure. While distant metastases affected actuarial survival, no factor independently predicted local recurrence. In six patients with local recurrence, nonpalpable disease was detected by I-131 scan. All were treated with ablation and remain disease-free (mean follow-up 42 months). Eight patients with local recurrence presented with palpable lesions; seven underwent surgery. While two patients developed repeated local recurrences, the other five remain diseasefree (mean follow-up 52 months). Early detection and aggressive treatment of local recurrence improve survival in patients with well-differentiated thyroid carcinoma. To facilitate use of I-131, we advise total thyroidectomy for patients with welldifferentiated thyroid carcinoma. o 1992 Academic PEST, I~C.
MATERIALS
AND
METHODS
A retrospective review of patients treated at the University of Kentucky Medical Center from 1980-1989 for thyroid malignancy identified 66 patients with well-differentiated tumors (papillary or follicular carcinoma). Tumors which were clinically occult or detected at autopsy were excluded. Charts and histopathologic slides were reviewed to determine clinical presentation, histologic type and pathologic features of the tumor, extent of the surgical resection, use of I-131 ablation in addition to surgery, development of recurrence, and survival. Patients undergoing total thyroidectomy had a postoperative I-131 uptake scan and received I-131 ablation for any thyroid remnant. Patients routinely had repeat I-131 scans at 6 months and then annually. For the purpose of this review, a subtotal thyroidectomy was defined as any procedure leaving visible thyroid gland in place. A local recurrence was determined by biopsy, when possible, or by the appearance of I-131 tracer uptake in the neck on surveillance scanning more than 6 months after initial treatment in patients with previously negative I-131 scans. Distant metastasis was documented by tissue diagnosis or I-131 uptake other than in the neck. The variables of age, sex, histology, nodal involvement, microscopic capsular invasion, vascular invasion, multicentricity, tumor size, surgical procedure, local recurrence, and distant metastasis were examined using stepwise multivariate regression by the Kaplan-Meier method [4]. Comparison of means was performed using x2 or Fisher’s exact test where appropriate with the level
INTRODUCTION
The development of local recurrence of well-differentiated thyroid carcinoma reportedly carries a 30-50% ’ To whom reprint requests should be addressed at Department of Surgery, University of Kentucky Chandler Medical Center, 800 Rose Street, Lexington, KY 40536. 113
All
0022-4804/92 $1.50 Copyright 0 1992 by Academic Press, Inc. rights of reproduction in any form reserved.
114
JOURNAL
TABLE Cases of Well-Differentiated
OF SURGICAL
RESEARCH:
Thyroid
Carcinoma
46 (70%) 20 (30%)
Female Male at presentation
(%)
Palpable nodule Dysphagia Cervical adenopathy
74% 24% 13% evaluation
Abnormal nuclear scan Abnormal ultrasound Diagnostic FNA
1992
TABLE
Sex
Diagnostic
52, NO. 2, FEBRUARY
1
Total cases: 66 Mean age at time of diagnosis: 38.5 years (range 7-76) Number of cases under 45 years of age: 46 (70%)
Symptoms
VOL.
(%) 62% 64% 34%
of significance assigned at P < 0.05. Patients with histology reports labeled as “mixed papillary and follicular elements” were grouped under “papillary.” The analysis was repeated with “mixed” as a separate variable with no difference in the results. Patients presenting with distant metastases were excluded from the multivariate analysis to determine factors affecting disease-free survival in patients initially cleared of disease. RESULTS
Clinical Presentation The mean age of the patients with well-differentiated thyroid cancer was 38 years (range 7-X); 46 (70%) of the patients were younger than 45 years of age at diagnosis. There was a female predominance with a ratio of 2.3:1. Seventy-four percent of patients presented with a palpable nodule, 24% with symptoms of dysphagia, and 13% with palpable cervical lymph nodes. Diagnostic modalities used to evaluate these patients included thyroid nuclear scan (62% sensitivity rate) and ultrasound (64% sensitivity rate). Fine needle aspiration results were available for 30 patients and were diagnostic for malignancy only 34% of the time (Table 1). This low yield reflects our early experience with fine needle aspiration cytology in the diagnosis of thyroid nodules. The results have improved with our increasing experience. Histopathology The distribution of tumors according to histologic type and extent of spread are shown in Table 2. We identified 49 (74%) cases of papillary carcinoma and 17 cases (26%) of follicular carcinoma. Final pathology re-
2
Histopathology of Well-Differentiated Thyroid Carcinomas Tumor
type
Papillary Follicular
49 (74%) 17 (26%) Extent
of disease at diagnosis
Confined to thyroid Spread to cervical nodes Distant metastasis Microscopic
44 (67%) 18 (27%) 4 (6%) characteristics
Capsular invasion Lymph-vascular invasion Multicentric foci
12 (18%) 12 (18%) 14 (21%) 1.8 cm range (0.8-5 cm)
Average tumor size
vealed that, in 67% of the specimens, the tumor was confined to the thyroid gland. In 27% of the patients tumor was found in cervical lymph nodes. Only 6% presented with evidence of distant metastases at initial diagnosis. On microscopic examination, 18% of the specimens showed capsular invasion, 18% demonstrated vascular invasion, and 21% demonstrated multicentric tumor foci. The average tumor size was 1.8 cm (range 0.85.0 cm); tumors from total thyroidectomies tended to be larger than those from subtotal resections (2.1 vs 1.3 cm; P = 0.1). Treatment Forty-two of the 66 patients (64%) underwent total thyroidectomy; 13 of these 42 patients (30%) also underwent cervical node dissection. Twenty-four patients (36%) underwent a subtotal thyroidectomy; only 3 of these patients also underwent a cervical node dissection (Table 3). There was no operative mortality. The morbidity was 3%, including one wound infection and one recurrent nerve injury which resulted in temporary dys-
TABLE Treatment
3
of Well-Differentiated Operative
Thyroid
Procedures
Total thyroidectomy Total thyroidectomy with node dissection Subtotal thyroidectomy Subtotal with node dissection Operative Operative
morbidity mortality
Post-op I-131
Carcinoma
29 13 21 3
(43%) (20%) (32%) (5%)
3% 0% 35 (53%)
HAMBY
ET AL.: TREATMENT
TABLE Outcome of Patients
OF LOCAL
4
with Local Recurrence
Treatment
Outcome
Type of recurrence
N
Nonpalpable
6
I-131
6 alive with no evidence of disease (mean F/U 42 months)
Palpable
8
1 no treatment 2 completion thyroidectomy 5 neck dissection
1 died of disease 2 alive with disease 5 alive with no evidence of disease (mean F/U 52 months)
79% disease free at last follow-up (average 47 months) 7% mortality rate
function. There were no cases of permanent hypoparathyroidism. Thirty-five (53%) patients received I-131 ablation after surgery for residual I-131 tracer uptake on the first thyroid scan postoperatively. Survival
and Recurrence
Sixty-six patients with well-differentiated thyroid carcinoma were treated at our institution with a mean follow-up of 84.5 months. No patient was lost to follow-up. Four of these patients exhibited evidence of distant metastasis at the time of initial presentation, and all four died of their disease a mean of 20 months after diagnosis. Of the 62 remaining patients, 15 (24%) developed recurrent disease with a median time to recurrence of 24 months. All recurrences were within the neck except for one patient with follicular carcinoma who developed distant metastases 12 months after a total thyroidectomy and died of disease 5 months later. A total of 14 patients developed local recurrence. The average age, extent of disease, histologic characteristics, and surgical procedures of patients developing local recurrence were not significantly different from those of the remaining patients. Of the patients with local recurrence, six had nonpalpable disease which was detected by I-131 scan; these patients received additional I-131 ablation and remained free of disease an average of 42 months after treatment of recurrence (Table 4). The other eight patients with local recurrence had palpable tumors. One patient refused treatment and remains alive with disease. The other seven patients underwent surgical resection; two completion thyroidectomies and five modified radical neck dissections were performed. Two of these patients received I-131 following surgical excision of the recurrence. One patient deveioped multiple recurrences refractory to both surgery and I-131 and died of disease 10 years after initial diagnosis. Another patient developed two additional recurrences which were treated with surgical excision. This patient
RECURRENCE
IN THYROID
115
CARCINOMA
remains alive with disease. The remaining five patients treated with surgery are alive and disease-free an average of 52 months after treatment of the recurrence. While the local recurrence has been successfully managed in 79% of the patients, 7% have died of recurrent disease. Overall, 58 of the 66 patients (88%) remain alive and disease-free at last follow-up. Five patients (8%) died of thyroid cancer during follow-up, with a median survival of 30 months. Three patients (4%) remain alive with active disease, two with local recurrence, and one with distant metastases. Analysis
of Prognostic Factors
Various prognostic factors were analyzed to determine their effect on survival. Table 5 shows a comparison of age, sex, tumor characteristics, and operative procedure stratified by tumor histology. Patients with follicular carcinoma were older, had more tumors with vascular invasion, and exhibited a higher incidence of distant metastasis as compared to those patients with papillary carcinoma. No significant differences were revealed by the other comparisons. Follicular tumors tended to be larger, although the difference was not statistically significant. The mean times to recurrence in patients with follicular and papillary carcinoma were not significantly different. Initial multivariate analysis found that the only factor which influenced actuarial survival was the presence of distant metastases (P < 0.006). However, since only 8% of the population died during the follow-up period, this
TABLE Comparison
5
of Prognostic Factors Stratified Histology
by P
Total cases Average age (years) Sex (%) Male Female Extent of disease at diagnosis (%) Confined to thyroid Spread to cervical nodes Distant metastasis Histologic characteristics (a) Capsular invasion Vascular invasion Multicentric foci Average tumor size (cm) Operative procedures ( % ) Total thyroidectomy Subtotal thyroidectomy
Papillary
Follicular
value
49 35
17 48
OF SURGICAL
RESEARCH
52,113-117
Management
(19%)
of Local Recurrence in Well-Differentiated Thyroid Carcinoma
LEIGH S. HAMBY, M.D., PATRICK C. MCGRATH, M.D.,’ RICHARD W. SCHWARTZ, M.D., DAVID A. SLOAN, M.D., WILLIAM G. SIMPSON, M.D., AND DANIEL E. KENADY, M.D. Lexington Veterans Administration Medical Center and the Department of Surgery, University of Kentucky Chandler Medical Center, Lexington, Kentucky 40536 Presented
at the Annual
Symposium
of the Association
of Veterans
Administration
Surgeons, Milwaukee,
Wisconsin,
May 9-11, 1991
mortality rate [l-3]. Thus, many surgeons advocate total thyroidectomy as the initial surgical treatment to facilitate the use of I-131 scanning in the early detection and treatment of postoperative recurrence. However, this aggressive approach has not been clearly shown to decrease the recurrence rate or impact on overall survival. The University of Kentucky experience with welldifferentiated thyroid carcinoma was reviewed to determine factors influencing the development of local recurrence and to identify successful management strategies.
Local recurrence of well-differentiated thyroid carcinoma has a reported mortality approaching 50%. The University of Kentucky experience was reviewed to determine whether aggressive surveillance and treatment with reoperation and/or I- 13 1 ablation increased survival following recurrence. Records of 66 consecutive patients with well-differentiated thyroid carcinoma treated at the University of Kentucky Medical Center (1980-1989) were reviewed. Forty-nine cases of papillary carcinoma and 17 cases of follicular carcinoma were studied; median follow-up was 68 months. At ‘presentation, patients with follicular carcinoma were older (48 versus 35 years; P < 0.05) and more frequently had metastatic disease (17% versus 2%, P < 0.05). Fifty-eight (88%) patients were alive and diseasefree at last follow-up. Fifteen patients (24%) had developed recurrent disease; median time to recurrence was 24 months. Multivariate regression examined the variables of age, sex, histology, tumor size, cervical adenopathy, capsular and vascular invasion, multicentricity, and surgical procedure. While distant metastases affected actuarial survival, no factor independently predicted local recurrence. In six patients with local recurrence, nonpalpable disease was detected by I-131 scan. All were treated with ablation and remain disease-free (mean follow-up 42 months). Eight patients with local recurrence presented with palpable lesions; seven underwent surgery. While two patients developed repeated local recurrences, the other five remain diseasefree (mean follow-up 52 months). Early detection and aggressive treatment of local recurrence improve survival in patients with well-differentiated thyroid carcinoma. To facilitate use of I-131, we advise total thyroidectomy for patients with welldifferentiated thyroid carcinoma. o 1992 Academic PEST, I~C.
MATERIALS
AND
METHODS
A retrospective review of patients treated at the University of Kentucky Medical Center from 1980-1989 for thyroid malignancy identified 66 patients with well-differentiated tumors (papillary or follicular carcinoma). Tumors which were clinically occult or detected at autopsy were excluded. Charts and histopathologic slides were reviewed to determine clinical presentation, histologic type and pathologic features of the tumor, extent of the surgical resection, use of I-131 ablation in addition to surgery, development of recurrence, and survival. Patients undergoing total thyroidectomy had a postoperative I-131 uptake scan and received I-131 ablation for any thyroid remnant. Patients routinely had repeat I-131 scans at 6 months and then annually. For the purpose of this review, a subtotal thyroidectomy was defined as any procedure leaving visible thyroid gland in place. A local recurrence was determined by biopsy, when possible, or by the appearance of I-131 tracer uptake in the neck on surveillance scanning more than 6 months after initial treatment in patients with previously negative I-131 scans. Distant metastasis was documented by tissue diagnosis or I-131 uptake other than in the neck. The variables of age, sex, histology, nodal involvement, microscopic capsular invasion, vascular invasion, multicentricity, tumor size, surgical procedure, local recurrence, and distant metastasis were examined using stepwise multivariate regression by the Kaplan-Meier method [4]. Comparison of means was performed using x2 or Fisher’s exact test where appropriate with the level
INTRODUCTION
The development of local recurrence of well-differentiated thyroid carcinoma reportedly carries a 30-50% ’ To whom reprint requests should be addressed at Department of Surgery, University of Kentucky Chandler Medical Center, 800 Rose Street, Lexington, KY 40536. 113
All
0022-4804/92 $1.50 Copyright 0 1992 by Academic Press, Inc. rights of reproduction in any form reserved.
114
JOURNAL
TABLE Cases of Well-Differentiated
OF SURGICAL
RESEARCH:
Thyroid
Carcinoma
46 (70%) 20 (30%)
Female Male at presentation
(%)
Palpable nodule Dysphagia Cervical adenopathy
74% 24% 13% evaluation
Abnormal nuclear scan Abnormal ultrasound Diagnostic FNA
1992
TABLE
Sex
Diagnostic
52, NO. 2, FEBRUARY
1
Total cases: 66 Mean age at time of diagnosis: 38.5 years (range 7-76) Number of cases under 45 years of age: 46 (70%)
Symptoms
VOL.
(%) 62% 64% 34%
of significance assigned at P < 0.05. Patients with histology reports labeled as “mixed papillary and follicular elements” were grouped under “papillary.” The analysis was repeated with “mixed” as a separate variable with no difference in the results. Patients presenting with distant metastases were excluded from the multivariate analysis to determine factors affecting disease-free survival in patients initially cleared of disease. RESULTS
Clinical Presentation The mean age of the patients with well-differentiated thyroid cancer was 38 years (range 7-X); 46 (70%) of the patients were younger than 45 years of age at diagnosis. There was a female predominance with a ratio of 2.3:1. Seventy-four percent of patients presented with a palpable nodule, 24% with symptoms of dysphagia, and 13% with palpable cervical lymph nodes. Diagnostic modalities used to evaluate these patients included thyroid nuclear scan (62% sensitivity rate) and ultrasound (64% sensitivity rate). Fine needle aspiration results were available for 30 patients and were diagnostic for malignancy only 34% of the time (Table 1). This low yield reflects our early experience with fine needle aspiration cytology in the diagnosis of thyroid nodules. The results have improved with our increasing experience. Histopathology The distribution of tumors according to histologic type and extent of spread are shown in Table 2. We identified 49 (74%) cases of papillary carcinoma and 17 cases (26%) of follicular carcinoma. Final pathology re-
2
Histopathology of Well-Differentiated Thyroid Carcinomas Tumor
type
Papillary Follicular
49 (74%) 17 (26%) Extent
of disease at diagnosis
Confined to thyroid Spread to cervical nodes Distant metastasis Microscopic
44 (67%) 18 (27%) 4 (6%) characteristics
Capsular invasion Lymph-vascular invasion Multicentric foci
12 (18%) 12 (18%) 14 (21%) 1.8 cm range (0.8-5 cm)
Average tumor size
vealed that, in 67% of the specimens, the tumor was confined to the thyroid gland. In 27% of the patients tumor was found in cervical lymph nodes. Only 6% presented with evidence of distant metastases at initial diagnosis. On microscopic examination, 18% of the specimens showed capsular invasion, 18% demonstrated vascular invasion, and 21% demonstrated multicentric tumor foci. The average tumor size was 1.8 cm (range 0.85.0 cm); tumors from total thyroidectomies tended to be larger than those from subtotal resections (2.1 vs 1.3 cm; P = 0.1). Treatment Forty-two of the 66 patients (64%) underwent total thyroidectomy; 13 of these 42 patients (30%) also underwent cervical node dissection. Twenty-four patients (36%) underwent a subtotal thyroidectomy; only 3 of these patients also underwent a cervical node dissection (Table 3). There was no operative mortality. The morbidity was 3%, including one wound infection and one recurrent nerve injury which resulted in temporary dys-
TABLE Treatment
3
of Well-Differentiated Operative
Thyroid
Procedures
Total thyroidectomy Total thyroidectomy with node dissection Subtotal thyroidectomy Subtotal with node dissection Operative Operative
morbidity mortality
Post-op I-131
Carcinoma
29 13 21 3
(43%) (20%) (32%) (5%)
3% 0% 35 (53%)
HAMBY
ET AL.: TREATMENT
TABLE Outcome of Patients
OF LOCAL
4
with Local Recurrence
Treatment
Outcome
Type of recurrence
N
Nonpalpable
6
I-131
6 alive with no evidence of disease (mean F/U 42 months)
Palpable
8
1 no treatment 2 completion thyroidectomy 5 neck dissection
1 died of disease 2 alive with disease 5 alive with no evidence of disease (mean F/U 52 months)
79% disease free at last follow-up (average 47 months) 7% mortality rate
function. There were no cases of permanent hypoparathyroidism. Thirty-five (53%) patients received I-131 ablation after surgery for residual I-131 tracer uptake on the first thyroid scan postoperatively. Survival
and Recurrence
Sixty-six patients with well-differentiated thyroid carcinoma were treated at our institution with a mean follow-up of 84.5 months. No patient was lost to follow-up. Four of these patients exhibited evidence of distant metastasis at the time of initial presentation, and all four died of their disease a mean of 20 months after diagnosis. Of the 62 remaining patients, 15 (24%) developed recurrent disease with a median time to recurrence of 24 months. All recurrences were within the neck except for one patient with follicular carcinoma who developed distant metastases 12 months after a total thyroidectomy and died of disease 5 months later. A total of 14 patients developed local recurrence. The average age, extent of disease, histologic characteristics, and surgical procedures of patients developing local recurrence were not significantly different from those of the remaining patients. Of the patients with local recurrence, six had nonpalpable disease which was detected by I-131 scan; these patients received additional I-131 ablation and remained free of disease an average of 42 months after treatment of recurrence (Table 4). The other eight patients with local recurrence had palpable tumors. One patient refused treatment and remains alive with disease. The other seven patients underwent surgical resection; two completion thyroidectomies and five modified radical neck dissections were performed. Two of these patients received I-131 following surgical excision of the recurrence. One patient deveioped multiple recurrences refractory to both surgery and I-131 and died of disease 10 years after initial diagnosis. Another patient developed two additional recurrences which were treated with surgical excision. This patient
RECURRENCE
IN THYROID
115
CARCINOMA
remains alive with disease. The remaining five patients treated with surgery are alive and disease-free an average of 52 months after treatment of the recurrence. While the local recurrence has been successfully managed in 79% of the patients, 7% have died of recurrent disease. Overall, 58 of the 66 patients (88%) remain alive and disease-free at last follow-up. Five patients (8%) died of thyroid cancer during follow-up, with a median survival of 30 months. Three patients (4%) remain alive with active disease, two with local recurrence, and one with distant metastases. Analysis
of Prognostic Factors
Various prognostic factors were analyzed to determine their effect on survival. Table 5 shows a comparison of age, sex, tumor characteristics, and operative procedure stratified by tumor histology. Patients with follicular carcinoma were older, had more tumors with vascular invasion, and exhibited a higher incidence of distant metastasis as compared to those patients with papillary carcinoma. No significant differences were revealed by the other comparisons. Follicular tumors tended to be larger, although the difference was not statistically significant. The mean times to recurrence in patients with follicular and papillary carcinoma were not significantly different. Initial multivariate analysis found that the only factor which influenced actuarial survival was the presence of distant metastases (P < 0.006). However, since only 8% of the population died during the follow-up period, this
TABLE Comparison
5
of Prognostic Factors Stratified Histology
by P
Total cases Average age (years) Sex (%) Male Female Extent of disease at diagnosis (%) Confined to thyroid Spread to cervical nodes Distant metastasis Histologic characteristics (a) Capsular invasion Vascular invasion Multicentric foci Average tumor size (cm) Operative procedures ( % ) Total thyroidectomy Subtotal thyroidectomy
Papillary
Follicular
value
49 35
17 48
