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Annals of Surgical Oncology 9:789-798 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Recurrent Differentiated Thyroid Carcinoma: Biological Implications of Age, Method of Detection, and Site and Extent of Recurrence

Alexander Stojadinovic, MD, Margo Shoup, MD, Aviram Nissan, MD, Ronald A. Ghossein, MD, Jatin P. Shah, MD, Murray F. Brennan, MD and Ashok R. Shaha, MD

From the Departments of Surgery (AS, MS, AN, JPS, MFB, ARS) and Pathology (RAG), Memorial Sloan-Kettering Cancer Center, New York, New York.

Correspondence: Address correspondence and reprint requests to: Alexander Stojadinovic, MD, Walter Reed Army Medical Center, General Surgery Service, 6900 Georgia Avenue, N.W., Washington, DC 20307; Fax: 202-782-1234; E-mail: ta.stojadinovic{at}verizon.net


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: We identified factors predictive of outcome for recurrent differentiated thyroid carcinoma (DTC).

Methods: Fifty-seven patients with local (LR), regional (RRec), and/or distant recurrence (DR) of 431 recurrent DTCs were studied. Disease-specific survival (DSS) rate was estimated with the Kaplan-Meier method. Univariate and multivariate comparisons were conducted by log-rank and Cox regression analysis.

Results: The median follow-up was 13 years. Distribution of the first relapse was LR only (35%), LR and RRec (23%), LR and DR (30%), and LR, RRec, and DR (12%). Factors predictive of resectability were a long (>=5-year) disease-free interval (DFI) and subclinical and thyroid remnant recurrence. Only 26% of symptomatic and 45% of thyroid bed LR, and 43% with DFI <5 years, could be resected completely. No isolated thyroid remnant and 75% of thyroid bed LR resulted in tumor-related mortality. Age <45 years, subclinical recurrence, isolated LR, and the ability to render the patient disease free independently predicted DSS. Fifteen-year DSS for LR only; LR and RRec; LR and DR; and LR, RRec, and DR were 49%, 28%, 15%, and 0%, respectively.

Conclusions: Isolated thyroid remnant recurrence defines a benign phenotype. Age, method of detection, site and extent of recurrence, and the ability to render the patient disease free predict outcome for recurrent DTC. Multimodality long-term follow-up is warranted to detect recurrence at a subclinical potentially curative stage.

Key Words: Thyroid • Carcinoma • Recurrence • Outcome


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Well-differentiated thyroid cancers are composed of papillary, follicular, and Hürthle cell carcinomas. Overall survival is excellent for most patients with differentiated thyroid carcinoma (DTC) and is dependent on histology and well-defined prognostic factors. Ten-year survival rates for patients with papillary, follicular, and Hürthle cell carcinoma are 93%, 85%, and 76%, respectively.1 Local (LR) and regional nodal recurrences (RRec) develop in 5% to 20% of patients with papillary carcinoma and in 25% to 73% of patients with widely invasive follicular and Hürthle cell carcinoma.2–5 Although RRec of papillary carcinoma is not considered to adversely affect survival, the development of LR carries a considerable risk of tumor-related death, ranging from 17% to 64% (~50%) in large reported series.2,6–9 The site of LR relative to the thyroid remnant has been shown to correlate strongly with disease-specific survival (DSS), as the 10-year cumulative risk of dying was 0% for recurrence limited to the thyroid remnant and 50% for thyroid bed or adjacent soft tissue recurrence.9

Recurrence among patients with follicular and Hürthle cell carcinoma correlates with the degree of invasion. No patients with minimally invasive follicular and Hürthle cell carcinoma had recurrence or died of disease in two recently reported studies with a median follow-up of 8 to 14 years.3,5 Recurrent disease among patients with widely invasive follicular carcinoma poses a threat to life, because only a third can be rendered disease free and more than half of patients die of disease.3 Recurrence of Hürthle cell carcinoma is associated with poor outcome. Sanders and Silverman3 reported a recurrence rate of 31% among patients with widely invasive Hürthle cell carcinoma, of whom none could be rendered free of disease and 70% experienced tumor-related mortality. In a recent study, no patient with RRec or distant Hürthle cell cancer recurrence could be cured with further treatment.5 Among 24 patients with disease recurrence, 2 (8.3%) were rendered disease free and 75% died of disease. Two of four patients had isolated LR that was curable by reoperation.

The management of primary DTC has been the subject of continued debate and has received considerable attention in the literature. However, investigators have been reluctant to address the often-challenging treatment of recurrent thyroid carcinoma. Patients with recurrent DTC have a less favorable prognosis than those with primary disease, as more than 50% of patients with recurrence experience tumor-related mortality. Factors predicting subsequent relapse of disease after complete resection of primary DTC with curative intent have been studied extensively and well defined. However, data identifying prognostic variables for survival after treatment of LR and RRec remain limited, as this has been reported infrequently in large retrospective series of papillary thyroid carcinoma and even less frequently in studies of follicular and Hürthle cell carcinoma.

As the biologic implications of LR and RRec after complete resection of DTC remain incompletely defined, factors predictive of resectability and DSS after treatment of recurrence were the subjects of this study. The disease-free interval after primary resection, method of detection, and site and extent of LR, with particular emphasis on thyroid remnant versus thyroid bed recurrence, tumor avidity for radioiodine, and the ability to render the patient free of disease were analyzed and correlated with outcome.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
This was a retrospective, single-institution, longitudinal study over nearly five decades. A search of the Memorial Sloan-Kettering Cancer Center (MSKCC) tumor registry was conducted to identify patients treated for LR well-differentiated thyroid carcinoma during the time period 1948 to 1997. The terms used to perform the search were "thyroid," "recurrence," "metastasis," "papillary," "follicular," and "Hürthle." Four hundred thirty-one patients were identified. A secondary search focusing on "local recurrence" identified 57 of the 431 patients with well-differentiated thyroid carcinoma who developed LR as the site of first disease relapse. These 57 patients form the basis of this analysis.

All study patients underwent thyroidectomy with curative intent .5 to 30 years before the first disease relapse. Distribution of primary treatment according to time period was 1940s, 3.5%; 1950s, 8.8%; 1960s, 17.5%; 1970s, 24.6%; 1980s, 26.3%; and 1990s, 19.3%. Thirty (52.6%) patients underwent primary resection at outside institutions and presented to our institution for treatment of recurrent thyroid cancer. All available operative and pathology reports were reviewed to confirm the completeness of the primary resection. The distribution of primary stage according to the 1997 American Joint Committee on Cancer cancer staging manual included 30% (n = 17) stage I, 9% (n = 5) stage II, and 58% (n = 33) stage III. Detailed staging information was not available for two patients undergoing their primary operation at outside institutions, although it was clear from review of the records that no distant metastatic disease was evident at time of initial diagnosis.

All available clinical, pathologic, treatment, and follow-up data were reviewed and entered into a computerized database. Information in the institutional pathology database and pathology reports of the primary and recurrent tumors were reviewed. Primary histological categories included papillary (as well as mixed papillary/follicular), follicular, and Hürthle cell carcinoma. All recurrent follicular and Hürthle cell carcinomas in this study were the widely invasive type. Widely invasive Hürthle cell carcinomas were defined as lesions demonstrating >75% follicular cells with oncocytic characteristics and more than one focus of intra- or extracapsular vascular invasion, and/or more than one focus of complete capsular invasion.5 Patients with medullary, anaplastic thyroid carcinoma, as well as thyroid lymphoma and sarcoma, were excluded. All available autopsy reports and death certificates were reviewed.

Follow-up was updated by clinical follow-up visits, telephone interviews, or correspondence with physicians or patient family members. The median follow-up of patients that were alive at the last follow-up was 13 years (range, 3–33 years). Four (7%) patients were lost to follow-up 4 to 23 years after treatment of the first recurrence.

Thirty-two (56.1%) study patients were female. The median patient age at the time of first recurrence was 58 years (range, 15–83 years). Detection of recurrent disease was based on history and clinical examination, ultrasonography, plain radiography, computed tomography, whole-body radioactive iodine scanning (iodine-131; 131I), or serum thyroglobulin (Tg) measurement.

Definitions
A primary tumor was defined as a localized, previously untreated or biopsied thyroid mass. LR was detected by signs, symptoms, radiography (x-ray or computed tomography), radioiodine scintigraphy, or serum Tg. The few (5.3%) recurrences detected by serum Tg reflect the fact that this mode of surveillance was not practiced at our institution until the late 1980s. Locoregional recurrence causing symptoms (dysphagia, dyspnea, hoarseness, pain, and so on) was categorized as a "symptomatic" recurrence, whereas recurrence identified on clinical examination was designated as one identified by "signs." Tumor recurrence diagnosed by x-ray, ultrasound (US), computed tomography, or magnetic resonance imaging was categorized as a radiological recurrence. Recurrent disease in the setting of normal clinical and radiological examination, but a new focus or area of increased 131I uptake on whole-body radioiodine scan, was regarded as a recurrence detected by radioiodine scan. A recurrence that was identified after initial recognition of abnormally increased serum Tg concentration was designated as a recurrence detected by Tg. LR was defined as a tumor of the same histological type within the remnant thyroid gland, resected thyroid bed, or nonnodal surrounding soft tissues in the neck. Nodal recurrence was defined by pathologically confirmed metastases to draining regional cervical lymph nodes. Distant recurrence (DR) was defined by clinical, radiological, or scintigraphic evidence of systemic disease spread outside the primary tumor and regional nodal basins. Macroscopic margins were assessed at the time of surgery, and microscopic margins were defined histopathologically. Complete surgical resection was defined as the absence of gross residual disease after surgical excision of the recurrence. Microscopic margin was defined as positive if the tumor was present at the inked margin and negative if the inked margin was tumor free. Disease-free interval was calculated from the time of primary resection to first recurrence. Follow-up was calculated from the time of the primary operation to the date of last follow-up.

Data
Clinical, pathological, and treatment-related variables were correlated with the primary study end point, postrecurrence DSS. The clinical variables analyzed included sex, age at the time of recurrence (<45 or >=45 years), method of detection of LR (symptoms, signs, radiology, radioiodine scan, or serum Tg), type of first recurrence (LR only; LR and RRec; LR and DR; LR, RRec, and DR; and LR or LR and other), and disease-free interval (<2 or >=2 years; <5 or >=5 years). Pathological variables included the location of LR (thyroid bed or thyroid remnant) and tumor histology (papillary, follicular, or Hürthle cell carcinoma). Treatment-related variables included resection (surgery or no surgery), type of initial procedure (total or subtotal thyroidectomy or lobectomy/isthmusectomy), completeness of resection (complete resection or not), type of treatment (surgery or 131I ablation), and radioiodine tumor avidity (positive or negative 131I uptake).

Treatment
Patients were treated according to the standard of care at MSKCC. In light of the long study period, the patients included in this article were treated by various physicians with differing treatment philosophies. All patients underwent primary treatment with thyroid resection, including lobectomy and isthmusectomy, subtotal thyroidectomy, or total thyroidectomy. Patients with grossly abnormal cervical lymph nodes also underwent regional lymphadenectomy. Clinical surveillance after thyroidectomy included one or more of the following: history and physical examination, diagnostic whole-body 131I (radioiodine) scanning in the presence of high serum thyroid-stimulating hormone (TSH) levels, serum Tg, chest radiography (x-ray with or without computed tomography), and cervical US, with US-guided fine-needle aspiration (US-FNA) as appropriate. Most (88%) patients in this study had locally recurrent DTC detected by clinical signs or symptoms.

Radioiodine scintigraphy has been in use at MSKCC since the 1950s, and routine monitoring with serum Tg was implemented in our institution in the late 1980s. Computed tomography has been in use since the mid-1980s, and cervical US, over the past decade. In recent years, patients with increased serum Tg concentrations after withdrawal of thyroid-suppressive therapy or exogenous administration of recombinant TSH, but with tumors that fail to concentrate 131I, have been evaluated further with flourine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scanning in an effort to distinguish between benign tissue and thyroid carcinoma recurrence. FDG-PET has been in use for the past 4 years. The timing of follow-up and the studies used for surveillance varied with time and developing technology and were at the discretion of the treating physician. Surgical management of recurrent disease was based on review of clinical, radiological, and pathological data and the size, anatomical location, and extent of the recurrent tumor. Review of prior treatment included the extent of thyroidectomy and lymphadenectomy; resection margins; tumor radioiodine uptake; results of whole-body radioiodine scan; 131I dose; type, dose, and technique of external beam radiotherapy and thyroid-suppressive therapy; and the nature of treatment-related morbidity. Locally recurrent disease was confirmed by needle biopsy. Clinical, radiological, and nuclear imaging examinations facilitated determination of the nature and extent of recurrent disease and proximity to vital neurovascular anatomy.

The goal of surgical treatment of locoregional recurrence of well-differentiated thyroid carcinoma is complete resection of all grossly evident disease, with functional preservation of speech, swallowing, and protective airway mechanisms. Surgery is the preferred treatment modality for resectable locoregional recurrence, followed by 131I treatment for iodide-concentrating thyroid carcinoma or external beam radiation for tumors that are not radioiodine avid. Patients with increased serum Tg concentrations (>10 ng/mL) but negative radiological and scintigraphic studies received 100 to 150 mCi of 131I therapy. Further radioiodine therapy is guided by posttreatment whole-body 131I scans.

Statistics
Associations between categorical variables were evaluated by using Fisher’s exact test or the {chi}2 test, as appropriate. The clinical outcome studied was postrecurrence DSS. Locoregional recurrence-free survival was defined as the time to locoregional recurrence of thyroid carcinoma from the time of primary thyroidectomy. For LR, only the first LR that was not preceded by any other recurrences was considered; all other LRs were excluded.

The median time to recurrence or tumor-related death is the time when 50% of patients have had recurring disease or have died of disease. Deaths that were confirmed to be due to thyroid carcinoma were treated as end points for DSS; all other deaths were censored at the time of demise. DSS was calculated from the time of treatment of the first LR to the time of tumor-related death. The rate of recurrence or death was estimated with the Kaplan-Meier product-limit method.

The univariate influence of prognostic factors on DSS was analyzed with the log-rank test. Multivariate analysis based on Cox’s proportional hazards regression model was used to associate covariates to time-dependent end points. Only those factors identified to be potentially significant in the univariate analysis were evaluated in the multivariate analysis to assess the independent prognostic effect of these variables. Statistical analysis was performed with the JMP® statistical package (SAS Institute, Cary, NC). A P value <.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient, Tumor, and Treatment Characteristics
Clinical, pathological, and treatment characteristics for patients with locally recurrent well-differentiated thyroid carcinoma are shown in Table 1. Thirty-three (57.9%) patients had stage III disease at the time of treatment of the primary thyroid carcinoma. The type of first disease relapse was local or locoregional in 20 (35.1%) and 13 (22.8%) patients, respectively. Twenty-four (42.1%) patients had synchronous distant metastasis at the time of LR or locoregional recurrence. The distribution of DR by site among the 24 patients was lung only (n = 15), bone only (n = 6), lung and bone (n = 1), and mediastinum (n = 2). Recurrent thyroid cancer was separated into two categories: LR (n = 20) and LR and other (RRec and/or DR, n = 37).


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  		TABLE 1. Clinical, pathological, and treatment characteristics for patients with locally recurrent thyroid carcinoma (n = 57)
 
The median age at time of recurrence was 58 years (range, 15 to 83 years). Forty-two percent of patients developed recurrent disease within 2 years, and 35% had disease recurrence >=5 years after resection of the primary tumor. The median time to recurrence after treatment of the primary tumor was 2.6 years (range, .5–30 years). Most LRs were detected clinically (signs or symptoms, 84.1%) and located in the prior thyroid tumor resection bed (73.7%).

Ten (17.5%) patients developed LR in the thyroid remnant, five each in the contralateral lobe after thyroid lobectomy/isthmusectomy and subtotal thyroidectomy. Seven of the 10 remnant recurrences were identified as a palpable mass, 6 by the patient and 1 by the physician; radiological tests (computed tomography scan [n = 2] or US [n = 1]) identified the remaining 3. The median tumor size of the remnant recurrence was 2.0 cm (range, 1.0–6.0 cm). The median time to relapse in the patients with remnant recurrence was 6.8 years. Sixteen (28.1%) recurrent tumors failed to concentrate radioiodide.

Factors Associated With Complete Resection of LR
Seventy-five percent (15 of 20) of isolated LRs could be completely resected, as compared with 43% (16 of 37) in patients with LR and synchronous RRec and/or DR (69% LR and RRec; 41% LR and DR; 0% LR, RRec, and DR). Rates of complete resection of LR did not differ according to sex (P = .07), age category (P = .76), tumor histology (P = .27), or tumor avidity for radioiodide (P = .83). Factors that were significantly associated with resectability included disease-free interval, method of detection, and site of LR. A disease-free interval of >=5 years (75% vs. 43%, P = .02), thyroid remnant recurrence (90% vs. 45%, P = .02), and asymptomatic recurrence (80% vs. 26%, P = .001) were associated with significantly increased rates of complete resection of recurrent disease in the neck (Table 2). Only 26% of symptomatic LRs, 43% of LRs diagnosed within 5 years of the primary operation, and 45% of thyroid bed recurrences could be resected completely.


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  		TABLE 2. Factors associated with complete resection of local recurrence
 
Effect of Thyroid Remnant Versus Thyroid Bed Recurrence on Tumor-Related Mortality
Patient clinical, radiological, operative, and pathological reports contained sufficient and accurate information regarding the local extent of recurrent disease in the neck for 52 patients. Ten patients had LR limited to the contralateral thyroid remnant, and in 42 patients, treatment failed in the region of the previously resected thyroid bed or adjacent soft tissues in the neck. The risk of tumor-related mortality was significantly greater in patients with thyroid bed than with thyroid remnant recurrence (74% vs. 10%, P = .001). When one considers patients with isolated LR, no patient with thyroid remnant–only recurrence (n = 6) died of disease, whereas 75% of those with recurrence outside the remnant (9 of 12) experienced tumor-related mortality (Table 3, P = .007).


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  		TABLE 3. Tumor-related mortality according to the extent of thyroid carcinoma recurrence
 
There was no significant difference in distribution of extent of recurrence (LR vs. LR and RRec vs. LR and DR vs. LR, RRec, and DR) between patients with thyroid bed and remnant recurrence (P = .15). Nine (90.0%) of 10 patients with thyroid remnant and 19 (45.2%) of 42 with thyroid bed recurrence underwent complete resection of locally recurrent disease (P = .006). Patients who underwent complete resection of locoregional recurrence had a significantly improved DSS (median, 11.5 vs. 3 years; P < .001; Fig. 1). When patients with distant metastatic disease were excluded from the analysis, similar survival improvement was associated with resection of locoregional disease with negative gross surgical margins (median, 14.6 vs. 5.5 years). Analysis of only those patients who underwent complete surgical clearance of locoregional recurrence identified a significant survival benefit among patients with relapse of disease in the thyroid remnant as opposed to the thyroid bed or adjacent soft tissues in the neck (P = .02, Fig. 2). The distribution of the extent of recurrence was similar between the two comparison groups (Table 4).



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  		FIG. 1. Disease-specific survival for patients undergoing complete and incomplete resection of locoregional recurrence of differentiated thyroid carcinoma.

 


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  		FIG. 2. Disease-specific survival for patients who underwent complete resection of locoregional recurrence according to the site of local recurrence (thyroid remnant vs. thyroid bed).

 

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  		TABLE 4. Extent of first recurrence and disease-specific survival among patients with thyroid remnant and thyroid bed recurrence undergoing complete resection of locoregional disease
 
Analysis of Prognostic Factors for DSS
Univariate comparisons were made among clinical, histopathological, and treatment-related categorical variables for the study end point—DSS—for the entire study cohort. In the univariate analysis, male sex (P = .001), age >=45 years (P = .003), follicular cell carcinoma (P = .03), disease-free interval <5 years (P = .02), thyroid bed recurrence (P = .001), symptomatic recurrence (P = .06), multisite recurrence (P = .001), and the inability to render the patient disease free (P < .001) were associated with reduced DSS (Table 5). Age <45 years at time of recurrence, subclinical recurrence, isolated LR, and the ability to render the patient free of disease emerged as independent predictors of DSS by multivariate analysis (Fig. 3). When the multivariate analysis was conducted for patients with locoregional recurrence in the absence of distant metastasis, age (<45 years: relative risk [RR], .30; 95% CI, .10–.73; P = .005), extent of recurrence (LR only: RR, .40; 95% CI, .20–.80; P = .009), and the ability to render the patient disease free (RR, .42; 95% CI, .23–.76) were found to independently predict survival.


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  		TABLE 5. Analysis of disease-specific survival in (DSS) locally recurrent thyroid carcinoma (n = 57)
 


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  		FIG. 3. Disease-specific survival according to age at the time of first recurrence, method of detection of recurrence, type of first recurrence, and ability to render the patient free of disease after relapse of differentiated thyroid carcinoma. RAI, radioiodine; Tg, thyroglobulin; LR, local recurrence; RRec, regional recurrence; DR, distant recurrence; RAD, radiological.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
LR of thyroid cancer is a difficult surgical problem, and its potential lethality contrasts with the excellent prognosis for the vast majority of patients with completely resected primary DTC. Data defining clinicopathological and treatment-related variables predictive of survival among patients with locally and regionally recurrent DTC is limited by the infrequent occurrence of disease relapse after potentially curative resection of the primary tumor. This analysis suggests that survival is improved significantly for patients rendered disease free after LR of DTC.

This study further underscores the dichotomy in biology between thyroid remnant and thyroid bed recurrence. Site of disease significantly correlated with resectability, as 90% of thyroid remnant and 45% of thyroid bed recurrences were completely resectable. Complete resection of LR was associated with a significantly improved DSS. Among patients with completely resected recurrence confined to the neck, DSS was significantly greater among patients with thyroid remnant than thyroid bed relapse (15-year survival, 88% vs. 17%). No patient in this study with LR limited to the thyroid remnant died of disease, whereas 75% with recurrence localized to the thyroid bed or adjacent cervical soft tissues experienced tumor-related mortality. These data, although limited by a small sample size, suggest that completely resected recurrence limited to the remnant thyroid demonstrates a benign clinical course. LR in the thyroid bed represents an aggressive phenotype that is potentially lethal even after complete eradication of disease (Table 6).


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  		TABLE 6. Recurrent well-differentiated thyroid carcinoma: recurrence, follow-up, and survival (n = 57)
 
Disease-free interval and method of detection of recurrence also correlated significantly with resectability of LR in this study. A disease-free interval of >=5 years after treatment of the primary DTC was associated with a significantly increased rate of complete resection of recurrent disease. The contrasting findings of Coburn et al.,10 which demonstrate favorable postrecurrence overall survival despite short disease-free intervals, can be explained by the mode of detection and recurrent tumor burden, because all patients in that study had subclinical scintigraphically detected recurrences, unlike those in our study, in which most recurrences were diagnosed clinically. The long study period and limited diagnostic modalities available for surveillance during the early study period may explain the disproportionately greater number of clinically apparent recurrences in this patient cohort.9,11–14

The clinical significance and management of recurrent DTC in regional cervical lymph nodes remain controversial.9,13,14 Coburn et al.10 reported cumulative tumor-related mortality rates of 10%, 36%, 50%, and 100% among patients with LR, RRec, LR and RRec, and DR, respectively. Our results are consistent with these data, as the extent of disease recurrence was an independent predictor of outcome (Table 6). Isolated LR was associated with significantly increased DSS on multivariate analysis (RR, .52; 95% CI, .31–.85). This likely represents the extent of tumor burden, as reflected by the independent favorable prognostic effect of subclinical detection of recurrence (RR, .37; 95% CI, .11–.87). Two other variables—young age (<45 years) at the time of recurrence and the ability to render the patient free of disease—also emerged as independent predictors of DSS.

These findings support our current long-term surveillance of patients with DTC aimed at identifying recurrence early in its natural history, when tumor burden is low and more amenable to treatment. The importance of multimodality surveillance is underscored by data demonstrating a significant survival benefit among patients with subclinical recurrence of DTC detected by radioiodine scan compared with those with clinically apparent disease relapse and relatively greater tumor burden.10,14,15 The follow-up algorithm includes history and physical examination; diagnostic whole-body 131I (radioiodine) scanning in the presence of high serum TSH levels, serum-free thyroxine, TSH, and Tg; chest imaging; and cervical US with US-FNA, as appropriate (Fig. 4). 16–18



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  		FIG. 4. Surveillance and treatment algorithm for primary differentiated thyroid carcinoma (DTC). H&P, history and physical examination; RAI, radioiodine; Tg, thyroglobulin; CXR, chest x-ray; CT, computed tomography; US, ultrasound; FNA, fine-needle aspiration; EBRT, external beam radiation; Sx, symptoms; Chemo, chemotherapy; FDG-PET, flourine-18 fluorodeoxyglucose positron emission tomography.

 
Cervical US is not recommended for routine surveillance; it is obtained in the presence of increased serum Tg but a normal radioiodine scan. US-FNA is obtained when recurrent neck disease is suspected clinically, but cross-sectional imaging is unrevealing. Cervical US and US-FNA are the most sensitive modalities in detecting locoregional neck recurrence, with true-positive rates exceeding 95%.19,20 Grigsby et al.21 found that negative radioiodine uptake on two annual whole-body 131I scans after complete ablative therapy had a 97% predictive value for relapse-free survival at 10 years of follow-up; thus, radioiodine scanning is performed yearly until two consecutive negative studies are obtained. Radioiodine scintigraphy is then obtained in the setting of increasing serum Tg or clinically or radiographically evident disease recurrence. Patients with increased serum Tg concentrations after exogenous administration of recombinant TSH but with tumors that fail to concentrate 131I are evaluated further with FDG-PET scanning in an effort to distinguish between benign tissue and thyroid cancer recurrence.

An aggressive surgical approach is warranted for resectable neck recurrence, because complete resection of disease correlates with improved survival. The goal of surgical treatment is complete extirpation of all grossly evident disease, with functional preservation of speech, swallowing, and protective airway mechanisms whenever possible. Our current postoperative treatment approach for resectable locoregional recurrence includes 131I treatment for iodide-concentrating DTC or external beam radiation for tumors that are not radioiodine avid. Patients with increased serum Tg concentrations (>10 ng/mL) but negative radiological and scintigraphic studies receive 100 to 150 mCi of 131I therapy. Further radioiodine therapy is guided by posttreatment whole-body 131I scans (Fig. 4).

For locoregional recurrence of DTC, resectability is determined by tumor biology and tumor volume in the form of disease-free interval, method of detection, and site of recurrence. Resectable thyroid remnant recurrence, although uncommon, defines a benign phenotype, unlike recurrence in the thyroid bed or adjacent soft tissues, which is potentially lethal despite aggressive surgical resection. Independent predictors of DSS are young age, subclinical recurrence, isolated LR, and the ability to render the patient free of disease. This study supports multimodality life-long follow-up in an effort to detect recurrence at a subclinical potentially curative stage.


   Footnotes
 
Isolated thyroid remnant recurrence of differentiated thyroid carcinoma (DTC) defines a benign phenotype. Age, method of detection, site and extent of recurrence, and the ability to render the patient free of disease predict outcome for recurrent DTC. Multimodality long-term follow-up is warranted to detect recurrence at a subclinical potentially curative stage.

Received for publication February 4, 2002. Accepted for publication June 4, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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