Incidental versus clinically evident thyroid cancer: A 5-year follow-up study

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1 ORIGINAL ARTICLE Incidental versus clinically evident : A 5-year follow-up study Michele N. Minuto, MD, PhD, 1 * Mario Miccoli, DStat, 2 David Viola, MD, 3 Clara Ugolini, MD, PhD, 1 Riccardo Giannini, PhD, 1 Liborio Torregrossa, MD, 1 Lucia Antonangeli, MD, 3 Fabrizio Aghini-Lombardi, MD, 3 Rossella Elisei, MD, 3 Fulvio Basolo, MD, 1 Paolo Miccoli, MD 1 1 Department of Surgery, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy, 2 Department of Experimental Pathology (MBIE), University of Pisa, Via Paradisa 2, 56124, Pisa, Italy, 3 Department of Endocrinology, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy. Accepted 20 December 2011 Published online 24 February 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The incidence of differentiated in patients undergoing surgery for presumed benign thyroid disease (incidental ) is not negligible. The purpose of this study was to verify if incidental s have a different clinical course than the clinically evident. Methods. A group of patients with incidental (n ¼ 95) has been compared to a control group with clinically evident thyroid cancer (n ¼ 93). Both the histology and the outcome after a 5-year follow-up have been compared. Results. At the univariate analysis, the groups demonstrated significant differences in many pathologic features, remnant ablation (p <.001), and persistent disease (p ¼.006). Nevertheless, the multivariate analysis revealed that the outcome was not influenced by the preoperative or the incidental diagnosis. Conclusion. Incidental s show a different pathological pattern when compared to clinically evident s. Nonetheless, the final outcome is not influenced by preoperative or postoperative diagnosis. Hence, patients with incidental should follow the same postoperative protocols of patients with clinically evident. VC 2012 Wiley Periodicals, Inc. Head Neck 35: , 2013 KEY WORDS: incidental, differentiated thyroid cancer, preoperative diagnosis, thyroidectomy, follow-up *Corresponding author: M. N. Minuto, Department of Surgery, University of Pisa, Via Paradisa 2, Pisa, Italy. micheleminuto@hotmail.com INTRODUCTION Differentiated papillary and follicular s generally have a nonaggressive behavior and are associated with a low mortality rate. However, the incidence of this diagnosis in patients undergoing surgery for presumed benign thyroid disease is not negligible (ranging from 7% to 12%) and leads to a dramatic change in the postoperative follow-up. 1 6 Apart from the psychological impact of the unexpected diagnosis of cancer on these patients, there is the clinical need to schedule a closer and more expensive follow-up than that necessary for patients who underwent thyroidectomy for benign disease. The need for I 131 treatment in patients must also be determined and is based on the final pathology and stage of the tumor. In 2006, our group published a study on the epidemiology of incidental in patients undergoing thyroidectomy for presumed benign thyroid disease. 7 In that article, the discussion focused on the clinical and prognostic impact of incidental. We also analyzed long-term follow-up in these patients. The purpose of this paper was to analyze a less aggressive follow-up in patients with a postoperative diagnosis of incidental by comparing them with a control group of patients undergoing surgery for clinically evident nonmedullary differentiated. We sought to determine whether the 2 groups demonstrate any significant difference in terms of demographic, clinical, molecular, and/or prognostic features. We also sought to determine if they show any significant difference in these features after a 5-year follow-up period. MATERIALS AND METHODS From February 2002 to November 2003, 1535 consecutive patients followed by the Day-Hospital Unit of the Endocrinology Department underwent surgery in the Department of Surgery of Pisa University, a tertiary care referral center for thyroid and parathyroid diseases. Indications for surgery consisted of benign goiter (both hypo and hyperfunctioning) in 998 cases, differentiated nonmedullary without any preoperative evidence of node metastases in 93 patients (this population is the one defined as "clinically evident ''), suspicious or indeterminate nodules, and other s in the remaining cases. All patients with: (1) a cytology that was either inconclusive or revealed follicular/indeterminate nodules, (2) a history of irradiation on the neck area, and (3) a preoperative elevation in serum calcitonin, were excluded from this study. Among the 998 patients who underwent surgery for presumed benign disease, 104 cases (10.4%) demonstrated at least 1 focus of on final histology (referred to as the incidental group). Ninety-five of 408 HEAD & NECK DOI /HED MARCH 2013

2 INCIDENTAL VERSUS PREOPERATIVELY DIAGNOSED THYROID CANCER TABLE 1. Histologic variants of the incidental and clinically evident groups. Variant Incidental Papillary Classic Follicular Tall cells 4 15 Solid 1 5 Diffuse sclerosing 0 1 Follicular Minimally invasive 3 2 Poorly differentiated 1 1 Total Clinically evident 104 patients who were diagnosed with incidental thyroid cancer were followed for 5-years; the 9 patients who were excluded lacked significant clinical information. The incidental group was compared to the group of 93 consecutive patients with clinically evident, without evidence of node or distant metastases, who were followed during the same time period. Incidental group The incidental cohort consisted of 67 women and 28 men. The mean age was 48.2 years (range, years; SD 13.9). The indication for thyroidectomy included nonfunctioning multinodular goiter (n ¼ 57), hyperfunctioning multinodular goiter, 8 Graves' disease, 9 and unilateral nodular goiter. 2 Clinically evident group The clinically evident cohort consisted of 72 women and 21 men. The mean age was 41.3 years (range, years; SD 13.6). The 2 groups were compared with regard to patient demographics (sex and age); clinical, pathologic, and molecular features of the primary tumors (size, histologic variant, number of foci, presence of a tumor capsule, extrathyroidal extension, concomitant thyroiditis, Braf mutation, nodal metastases, and tumor stage); and 5-year follow-up data in terms of cure, remission, or persistence of the disease. Follow-up After the operation, the follow-up examination included a serum thyroglobulin, whole-body 131-I scintiscan, and ultrasonography followed by fine-needle aspiration on suspicious findings, performed at least 6 months after surgery and then annually, according to the most recent guidelines for differentiated A thyroid remnant ablation with I 131 was indicated when the tumor size exceeded 1 cm, in the presence of several tumor foci (multifocality), when a tumor infiltrated beyond the thyroid capsule, or in the presence of node or distant metastases. Disease cure was defined when serum thyroglobulin was undetectable, in the absence of thyroglobulin autoantibodies, and/or in the absence of any residual/persistent disease on ultrasonography, and/or 131-I scintiscan after surgery and 131-I ablation. Persistent disease was defined as the presence of residual tumor after surgery and 131-I ablation. Statistical analysis was conducted using the following tests: Mann Whitney, f test, t test, chi-square test, and the multivariate analysis performed through a logistic regression. The analyses have been performed with the SPSS and the R (version 2.11) software. With regard to the clinical outcome, the statistical analysis was conducted only on patients who completed the 5-year follow-up. All patients gave their written informed consent before each surgical procedure and about using their clinical TABLE 2. Demographic, clinical features, and outcome of the incidental and clinically evident groups. Incidental thyroid cancer (n ¼ 95) Clinically evident thyroid cancer (n ¼ 93) p value Age 6 SD Sex, F:M 67:28 72:21.36 Mean size 6 SD, cm (range) ( ) (0.3--5).0001* Median size, cm and mode 0.7 and and 1.2 Multiple foci (in the same lobe) 21 (21.6%) 41 (45.1%).001 Bilateral 14 (14.4%) 29 (37.2%) <.05 Associated thyroiditis 6 28 <.0001 Tumor capsule infiltration 35 (37%) 75 (82%) <.0001 Infiltration beyond the thyroid capsule 3 (3%) 28 (30%) <.0001 Presence of Braf mutation 13 (17%) 36 (39%).002 Lymph node metastases 2 25 <.0001 Distant metastases 1 3 (5.3%).2 I 131 remnant ablation 58/94 (61.7%) 80/83 (96.4%) <.0001 Persistent disease at 5 y 8/69 (11.6%) 24/75 (32%).006 Note: Statistically significant results are shown in boldface. * Significance reached through the Fisher--Snedecor distribution, referring to data variance. Of 78 cancers (incidental group) and of 93 cancers (clinically evident group) analyzed for the presence of Braf mutation. Of 5 patients (incidental group) and 36 patients (clinically evident group) who underwent central neck node dissection for the intraoperative presence of suspicious nodes. HEAD & NECK DOI /HED MARCH

3 MINUTO ET AL. TABLE 3. edition. T Classification Stage calculated (when possible) according to the last TNM Incidental T T2 6 6 T3 5 6 T4 2 5 Total Clinically evident data for scientific purposes, according to the guidelines of our institution. RESULTS All patients from both groups underwent a total thyroidectomy. A therapeutic central lymph node compartment dissection (level VI) was performed in 5 patients in the incidental group and in 36 patients with clinically evident due to the presence of suspicious lymph nodes found at the time of surgery. Final histology demonstrated the presence of papillary in 92 patients from the incidental thyroid cancer group and in 91 patients from the clinically evident group; a follicular was demonstrated in 3 patients from the incidental thyroid cancer group and in 2 patients from the clinically evident group. The histologic variants of both groups are summarized in Table 1. Additional features of the tumors from both groups are summarized in Table 2. Among the patients who underwent central compartment lymph node dissection, the presence of at least 1 metastatic lymph node was demonstrated in 25 cases from the clinically evident group and in 2 cases from the incidental group. The classification of the primary tumors from both groups, following the 6th edition of Union Internationale Contre le Cancer/ American Joint Committee on Cancer (TNM), 11 is reported in Table 3. Follow-up Five years after surgery, 67 patients (incidental thyroid cancer group) and 77 patients (clinically evident thyroid cancer group) completed follow-up. No patient died in either group. Among patients who completed the 5-year follow-up and were affected with incidental, 56 of 67 patients (84%) were selected for thyroid remnant ablation, whereas 74 patients (96%) with clinically evident received the same treatment. At the end of follow-up, the presence of persistent disease was recorded in 8 patients from the incidental thyroid cancer group (12%), and 24 patients (31%) in the clinically evident group, whereas 59 and 53 patients, respectively, were free of disease. The incidental population had a statistically significant (p ¼.006) better outcome. Table 4 summarizes the most relevant features and prognostic factors of the incidental and clinically evident groups, in patients who, after surgery, have been treated with I 131 remnant ablation. Finally, the final outcome at the 5-year follow-up was used to divide the 144 patients into 2 groups: the diseasefree group (112 patients) and the persistent-disease group (32 patients). The analysis was performed through 2 statistical analyses: univariate and multivariate (logistic regression). The differences in terms of clinical and pathological features and preoperative or postoperative diagnosis of the tumor (incidental or clinically evident) are summarized in Tables 5 and 6. DISCUSSION The 2 populations studied are significantly different in terms of age, but this finding is biased based on the nature of the incidental population. All patients in the incidental group had wellknown thyroid disease that led to elective thyroidectomy, generally after long-term treatment and follow-up. The different behavior of the 2 types of tumors was evident on the intraoperative findings: enlarged lymph nodes were noted in 5 patients with incidental thyroid cancer (in which 2 metastases were revealed) and in 36 patients with clinically evident (in which 25 metastases were revealed). It is worth noting that preoperative ultrasound did not reveal the presence of suspicious lymph node metastases in the central neck compartment in any case, and, therefore, the finding was based only upon a careful neck exploration that can nevertheless be misleading (the incidental group revealed node metastases in only 2 of 5 cases and the TABLE 4. Different clinical, pathologic, and therapeutic features in patients who completed the 5-year follow-up, and who were treated with I 131 remnant ablation. Clinical features Incidental (n ¼ 52) Clinically evident (n ¼ 74) p value Age, mean 6 SD Tumor size, mean 6 SD, cm Presence of Braf mutation Lymph node metastases 1 24 <.0001 Distant metastases 0 4/72.2 Stage III þ IV 7 10/72.4 Activity administered, mean 6 SD, mci Outcome, persistent disease 8 (15.4%) 24 (32.4%).05 Statistically significant results are shown in boldface. 410 HEAD & NECK DOI /HED MARCH 2013

4 INCIDENTAL VERSUS PREOPERATIVELY DIAGNOSED THYROID CANCER TABLE 5. Results according to the final outcome of all patients who completed the 5-year follow-up. Clinical features Disease free (n ¼ 112) Persistent disease (n ¼ 32) p value Age, mean 6 SD Male sex 28 (25%) 10 (32.3%).63 Tumor size, mean 6 SD, cm Presence of Braf mutation 28 of of Extrathyroidal extension 17/99 (17.2%)* 11/30* (36.7%).04 Tumor capsule infiltration 62 (55.4%) 28 (87.5%).002 Lymph node metastases 10 (8.9%) 15 (46.9%) <.0001 Stage III þ IV 9/94* (9.6%) 8/30* (26.7%).04 Activity administered, mean 6 SD, mci Preoperative diagnosis, incidental thyroid cancer or clinically evident 61 (54.5%) 8 (25%).006 Note: The 2 groups have been divided on the basis of the final outcome at the 5-year follow-up. The clinical and pathological features and the timing of the diagnosis (incidental or clinically evident cancer) have been analyzed and compared. * Some parameters were unknown.statistically significant results are shown in boldface. clinically evident in 25 of 36 cases), thus confirming data from other studies. 14,15 If we then examine the data from a strictly pathological point of view, incidental s seem to have a different and less aggressive pattern of growth when compared to the clinically evident in terms of local extension of the primary tumor and its related and most commonly used prognostic factors In particular, the size of the tumors belonging to the 2 groups looks apparently similar, leading to the impression that the incidental group might be a population that received a diagnostic error. This finding was already reported in our previous study 7 in which we discussed on how to carefully select the nodules that should undergo fine-needle aspiration on the basis of their pattern at ultrasound, and not only their "dominant'' size. Nevertheless, to avoid this delicate issue, many authors limit their definition of incidental to those tumors measuring less than 1 cm 3 : we strongly disagree with this definition because an incidentally discovered tumor cannot have a dimensional threshold. When analyzing data at follow-up, we know that mortality is strictly related to tumor recurrence, particularly in regional lymph nodes that are revealed shortly after the first surgery (certainly not much later than 2 3 years). 9 This follow-up period may therefore be, in our opinion, long enough to draw some conclusions about the outcome, although certainly not about mortality. After examining all of the tumor features, I 131 ablation was recommended in a significantly higher proportion of patients from the clinically evident group TABLE 6. The multivariate analysis was performed using the final outcome (cured vs persistent disease). Clinical and pathological features p value Pre/postoperative diagnosis.73 (incidental vs clinically evident ) Presence of Braf mutation.27 Tumor capsule infiltration.34 Extrathyroidal extension.41 Lymph node metastasis <.0016 Advanced stage (I þ II vs III þ IV).18 who, after the 5-year follow-up, had a higher prevalence of persistent disease. When we decided to compare patients from both groups who needed an I 131 ablation, we wanted to verify which prognostic factor could have an influence on the outcome of the disease. The results confirmed, once again, the prognostic value of the commonly known prognostic factors (age and local extension), also adding a prognostic value to the presence of lymph node metastases (arguably an important feature in determining the prognosis of these tumors), 8,19 and the positive impact on prognosis of a complete tumor capsule. 18 Furthermore, the activity administered in terms of mci of I 131 was found to be significantly different in the 2 populations. This difference might suggest that some patients from the incidental group were overly treated, a conclusion that may be reinforced by the different outcome of these 2 populations in terms of persistent disease. It is not negligible, although large goiters in endemic areas tend to have higher I 131 uptake after surgery. We also decided to split the study population into 2 additional groups (following the results obtained from the 5-year follow-up): those patients who were free of the disease and those demonstrating persistent disease. The univariate analysis shows that patients with incidental seem to have a much better course than the clinically evident ones, thus confirming the possibility of a more limited follow-up for those patients with a thyroid cancer that have never demonstrated any aggressive behavior (like those belonging to the incidental thyroid cancer population). It is necessary to point out that the incidence of on autopsy examination is not negligible, 20 and incidental s could eventually reflect this category of tumors. Nevertheless, when the multivariate analysis is performed, the impact on the prognosis of a correct preoperative diagnosis is not demonstrated, and only the lymph node metastases prove to be significantly associated with a worse prognosis after 5-year follow-up. In conclusion, all of the commonly used parameters for the classification of differentiated s that have been taken into consideration in this study (age, size, histological variant, and local extension of the primary tumor) proved to have a significant impact on the prognosis HEAD & NECK DOI /HED MARCH

5 MINUTO ET AL. of patients. Aside from age, the incidental group had all of the most favorable characteristics, thus indicating that the majority of these tumors were in the low-risk category. Nevertheless, a postoperative diagnosis of differentiated in patients who underwent surgery for a presumed benign disease does not seem to be sufficient enough to change the clinical behavior and follow-up in the postoperative period. Follow-up should thus be tailored in every patient on the basis of standard parameters and the most recent guidelines. REFERENCES 1. Sakorafas GH, Stafyla V, Kolettis T, Tolumis G, Kassaras G, Peros G. Microscopic papillary as an incidental finding in patients treated surgically for presumably benign thyroid disease. J Postgrad Med 2007;53: Koh KB, Chang KW. Carcinoma in multinodular goitre. Br J Surg 1992; 79: Bradly DP, Reddy V, Prinz RA, Gattuso P. Incidental papillary carcinoma in patients treated surgically for benign thyroid diseases. Surgery 2009; 146: Ito Y, Higashiyama T, Takamura Y, et al. Prognosis of patients with benign thyroid diseases accompanied by incidental papillary carcinoma undetectable on preoperative imaging tests. World J Surg 2007;31: Lin JD, Kuo SF, Chao TC, Hsueh C. Incidental and nonincidental papillary thyroid microcarcinoma. Ann Surg Oncol 2008;15: Tezelman S, Borucu I, Senyurek Giles Y, Tunca F, Terzioglu T. The change in surgical practice from subtotal to near-total or total thyroidectomy in the treatment of patients with benign multinodular goiter. World J Surg 2009;33: Miccoli P, Minuto MN, Galleri D, et al. Incidental thyroid carcinoma in a large series of consecutive patients operated on for benign thyroid disease. ANZ J Surg 2006;76: Scheumann GF, Gimm O, Wegener G, Hundeshagen H, Dralle H. Prognostic significance and surgical management of locoregional lymph node metastases in papillary. World J Surg 1994;18: ; discussion Mazzaferri EL, Kloos RT. Clinical review 128: current approaches to primary therapy for papillary and follicular. J Clin Endocrinol Metab 2001;86: Pacini F, Schlumberger M, Dralle H, et al. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 2006;154: Cooper DS, Doherty GM, Haugen BR, et al. Management guidelines for patients with thyroid nodules and differentiated. Thyroid 2006;16: American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated. Thyroid 2009;19: AJCC Cancer Staging Manual, 6th ed., 2002, XIV. 14. Noguchi S, Murakami N. The value of lymph-node dissection in patients with differentiated. Surg Clin North Am 1987;67: Hartl DM, Travagli JP. The updated American Thyroid Association Guidelines for management of thyroid nodules and differentiated thyroid cancer: a surgical perspective. Thyroid 2009;19: Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 1988;104: Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through Surgery 1993;114: ; discussion Miccoli P, Minuto MN, Ugolini C, et al. Intrathyroidal differentiated thyroid carcinoma: tumor size-based surgical concepts. World J Surg 2007; 31: White ML, Gauger PG, Doherty GM. Central lymph node dissection in differentiated. World J Surg 2007;31: Bisi H, Fernandes VS, de Camargo RY, Koch L, Abdo AH, de Brito T. The prevalence of unsuspected thyroid pathology in 300 sequential autopsies, with special reference to the incidental carcinoma. Cancer 1989;64: HEAD & NECK DOI /HED MARCH 2013