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10.1245/ASO.2006.03.089
Annals of Surgical Oncology 13:425-432 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Hemithyroidectomy: The Optimal Initial Surgical Approach for Individuals Undergoing Surgery for a Cytological Diagnosis of Follicular Neoplasm

Sam M. Wiseman, MD, FRCSC1, Christopher Baliski, MD, FRCSC1, Robert Irvine, MD, FRCSC1, Donald Anderson, MD, FRCSC1, Graeme Wilkins, MD, FRCPC2, Douglas Filipenko, MD, FRCPC3, Hongbin Zhang, MSc, MEng4 and Sam Bugis, MD, FRCSC1

1 Department of Surgery, St. Paul’s Hospital, University of British Columbia, C303-1081 Burrard Street, Vancouver, British Columbia, Canada, V6Z 1Y6
2 Department of Medicine, St. Paul’s Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, British Columbia, Canada, V6Z 1Y6
3 Department of Pathology, St. Paul’s Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, British Columbia, Canada, V6Z 1Y6
4 Knowledge Cycle Office, St. Paul’s Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, British Columbia, Canada, V6Z 1Y6

Correspondence: Address correspondence and reprint requests to: Sam M. Wiseman, MD, FRCSC; E-mail: smwiseman{at}providencehealth.bc.ca.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background: The primary objective of this study was to determine the true proportion and optimal surgical approach for individuals undergoing thyroid operation for a suspicion of cancer based on a fine-needle aspiration biopsy diagnosis of a follicular neoplasm (FN). A secondary objective of this study was to determine whether patient characteristics could assist the clinician in predicting malignancy in this FN patient cohort.

Methods: A retrospective chart, pathology, and cytology review of 370 consecutive primary thyroid operations was performed over a 4-year period at a tertiary care referral center. Clinical patient data were evaluated as an adjunct for predicting malignancy in the FN patient cohort. Univariate and multivariate analyses were used to investigate the association and the predictability.

Results: A total of 80 (22%) of the 370 patients underwent hemithyroidectomy to rule out cancer based on clinical presentation with a fine-needle aspiration biopsy diagnosis of FN. Fifteen (19%) of the FN cases were diagnosed as cancer by histological analysis (4 follicular carcinomas and 11 papillary carcinomas). Hemithyroidectomy was considered adequate treatment for 77 patients (96%). No patient characteristic significantly predicted the presence of cancer by either univariate or multivariate analysis.

Conclusions: Overall, in the FN patient population, five hemithyroidectomies were performed to identify each cancer, and no further operation was required in 96% of patients. New diagnostic tools are needed to reduce the number of operations performed for benign pathology in patients with nodular thyroid disease and a needle biopsy diagnosis of FN.

Key Words: Follicular neoplasm • Thyroid cancer • Needle biopsy • Hemithyroidectomy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Thyroid nodules are extremely common and are palpable in 4% to 7% of adults in North America: new nodules are detected at a yearly rate of .1%, and approximately 5% of nodules harbor malignancy.1,2 Currently, fine-needle aspiration biopsy (FNAB) is the most important initial test for diagnosing malignancy in individuals who present with nodular thyroid disease. Most individuals (80%) who harbor thyroid cancer will have disease diagnosed as papillary carcinoma (PTC), whereas the remainder of thyroid malignancies are follicular (FTC), medullary (MTC), or anaplastic thyroid carcinomas.3–6 Unfortunately, on the basis of cytological characteristics alone, the pathologist cannot reliably distinguish benign from malignant follicular thyroid lesions, and approximately 20% of FNABs will be given a final diagnosis of follicular neoplasm (FN).7–16 The term FN has been used to describe the cytological presence of abundant follicular epithelial cells in sheets, in microfollicles, or in a trabecular pattern with scanty colloid.17 FTC can be distinguished from benign FNs only on the basis of pathologic evidence of vascular invasion, extrathyroidal tumor extension, or nodal and/or distant metastasis.17 The follicular variant of PTC, a follicular adenoma, and other benign thyroid lesions may also be diagnosed as FN by FNAB.18 Overall, approximately 20% to 30% of thyroid tumors diagnosed by FNAB as an FN will be found to harbor malignancy by pathologic assessment.7–18

The current approach at our center is to offer a thyroid lobectomy and isthmusectomy as the primary operation for individuals with a diagnosis of FN by FNAB. Only if at the time of operation in the FN patient there is evidence of gross extrathyroidal tumor extension or nodal metastases would total thyroidectomy and lymph node dissection be performed. This was not the case for any of the FN patients in the study cohort. We do not use intraoperative frozen-section examination, which has been demonstrated to be unhelpful and even misleading in directing therapy for the FN patient population.19,20 If a cancer is diagnosed by pathologic review of the surgical specimen, both tumor pathology and patient characteristics determine whether we recommend removal of the remaining thyroid lobe. The primary objective of this study was to determine the optimal surgical approach for individuals undergoing thyroidectomy for a suspicion of cancer based on a preoperative FNAB diagnosis of FN. A secondary objective of this study was to determine whether patient characteristics could assist the clinician in predicting malignancy in the FN patient cohort.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
A retrospective chart, pathology, and cytology review was performed for 370 consecutive primary thyroid operations performed at a tertiary care referral endocrine surgical center over a 4-year period (January 1, 2000, to December 31, 2004). All cases were identified from a prospective thyroid surgery patient database maintained by one of the authors (S.M.W.). All patients included in this study had their final cytological diagnosis reported as FN and underwent thyroid lobectomy and isthmusectomy at a single center (St. Paul’s Hospital, Vancouver, BC, Canada) to establish a histological tissue diagnosis. Patients with an FNAB diagnosis of Hürthle cell neoplasm, which has its own unique clinical and cytopathologic characteristics, were not included in the study cohort.17 The FNABs and the final pathologic diagnoses were reported by a group of experienced endocrine pathologists at our center. Clinicopathologic data that were evaluated as an adjunct for predicting malignancy in the FN patient cohort included patient age, patient sex, tumor size, tumor location within the thyroid lobe (superior, middle, inferior, or diffuse replacement), side of thyroid gland involved (left or right), and ipsilateral thyroid lobe nodularity (single nodule or multinodular). None of the patients in this study had a history of head and neck irradiation or clinical evidence of either neck lymph node or distant metastatic disease at presentation.

FN patient preoperative characteristics were compared between patients with benign and malignant thyroid histological characteristics. Fischer’s exact test was used to evaluate nominal variables, and an unpaired t-test was used for continuous variables. A P value of <.05 was considered significant. Multivariate analysis of the data was performed by using stepwise logistic regression. This study was performed with the approval of the Providence Health Care/University of British Columbia Research Ethics Board.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Over the 4-year study period, 370 consecutive patients with no history of thyroid surgery who presented with either a solitary thyroid nodule or a dominant nodule within a multinodular goiter underwent a thyroid operation at our center. Eighty (21.6%) of the 370 thyroid operations were performed in individuals with a preoperative FNAB diagnosis of FN. Overall, after histological evaluation, 15 (19%) of these 80 cases were diagnosed as cancer, whereas 65 (81%) were diagnosed as benign thyroid lesions. The 65 cases diagnosed as benign thyroid pathology included 32 follicular adenomas, 5 cases of nodular hyperplasia, and 28 other nonneoplastic benign thyroid nodules. Of the 15 FN cancer cases, there were 4 cases (27%) diagnosed as minimally invasive FTC (mean tumor size, 3.5 cm) and 11 (73%) diagnosed as PTC. Eight of the PTCs were incidentally diagnosed papillary microcarcinomas (mean tumor size, .5 cm), and three other cases were diagnosed as papillary tumors>1 cm in diameter (mean tumor size, 2.5 cm). All of the larger papillary cancers were diagnosed as the follicular variant of PTC. All the FTCs and the PTCs >1 cm in diameter were located within the lesions that underwent FNAB. Only one of the papillary microcarcinomas was associated with the dominant thyroid lesion that underwent FNAB.

For the entire FN cohort, the mean patient age was 44 years (range, 15–72 years; SD, 11.38 years), and there were 66 women (83%) and 14 men (17%). The mean nodule size was 3.38 cm (range, .5–9.3 cm; SD, 1.63 cm). The lesion was most commonly located within the right hemithyroid (51% of cases), the nodule mostly originated from the inferior aspect of the gland (43% of cases), and 58 patients (73% of cases) had a multinodular ipsilateral thyroid lobe.

The results of univariate analysis evaluating the ability of FN patient characteristics to predict a cancer diagnosis, a nonoccult thyroid cancer diagnosis (PTC >1 cm in diameter and FTC), or a diagnosis of FTC are summarized in Tables 1Go, 2Go, and 3Go, respectively. Patient age, sex, nodule size, gland nodularity, the side of the gland involved, and the location of the lesion within the thyroid lobe did not differ significantly between FN patients with malignant histological results and FN patients with benign histological results. Each of the patient and tumor characteristics evaluated by univariate analysis was entered into a standard stepwise logistic regression analysis to test for independence among the patient and tumor preoperative clinical variables for the prediction of malignancy. All variables analyzed failed to achieve statistical significance.


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  		TABLE 1. Results of a univariate analysis presenting the likelihood of malignancy as a percentage within a specific group for each variable examined for all follicular neoplasm patients diagnosed with cancer
 

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  		TABLE 2. Results of a univariate analysis presenting the likelihood of malignancy as a percentage within a specific group for each variable examined for all follicular neoplasm patients diagnosed with follicular carcinoma or papillary carcinoma >1 cm in diameter
 

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  		TABLE 3. Results of a univariate analysis presenting the likelihood of malignancy as a percentage within a specific group for each variable examined for all follicular neoplasm patients diagnosed with follicular carcinoma
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
FNAB is a rapid, safe, sensitive, and specific diagnostic test that has become the gold standard for the initial evaluation of individuals who present with nodular thyroid disease. In a retrospective review of >18,000 thyroid FNABs performed by the Mayo Clinic, Gharib6 reported an average sensitivity of 83%, a specificity of 92%, and an overall accuracy of 95%. In a separate study from the Mayo Clinic, Hamberger et al.21 compared patients managed before and after the adoption of FNAB into the management of nodular thyroid disease. They reported a decrease in the number of patients undergoing thyroid surgery (67% to 43%) and an increase in the proportion of cancers resected (14% to 29%). They also found that FNAB reduced the cost of medical care per patient by 25%. FNAB has been used with great success for the preoperative diagnosis of PTC, anaplastic thyroid carcinoma, and MTC.4–6 However, the role of FNAB in evaluating follicular thyroid lesions, which include benign multinodular goiters, follicular adenomas, and FTC, is currently limited. 7–16 This limitation arises because the diagnosis of FTC is contingent on pathologic evidence of vascular or capsular invasion, which cannot be determined by cytological analysis alone.17 This led Swedish authors to propose the cytological term follicular neoplasia based on the presence of a high number of follicular cells, a microfollicular arrangement, and absent or scanty colloid.22 Treatment recommendations for FN have included surgery, further investigation, and close follow-up.23–25 Identification of cancer in 19% of our FN cohort is consistent with most other recent surgical series, which report these lesions to have a cancer rate that ranges from 16% to 47% (Table 4Go).7–16


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  		TABLE 4. Summary of current literature cohorts evaluating clinical data in predicting malignancy in the FN patient population
 
The commonly used thyroid cancer patient risk assessment systems include AMES (Lahey Clinic), AGES/MACIS (Mayo Clinic), and GAMES (Memorial Sloan-Kettering).26–30 These risk stratification systems assign patients with a preoperative diagnosis of thyroid cancer to outcome risk groups according to a combination of established risk factors. The extent of surgery and the use of adjuvant therapy for individuals with a diagnosis of cancer by FNAB are influenced by patient risk grouping. In a similar manner, but with the goal of predicting patient diagnosis rather than prognosis, multiple investigators have also attempted to use clinical and tumor characteristics in individuals with a diagnosis of FN by FNAB (Tables 4Go and 5Go).7–16 Tyler at al.8 prospectively evaluated a cohort of 571 patients who underwent FNAB, of whom 81 (14%) had results interpreted as indeterminate and underwent thyroidectomy. This indeterminate group included 43 FNs (53%), and pathologic examination of these tumors identified 8 thyroid cancers (19%). They found that FN patients <50 years had a significantly lower (10%) rate of malignancy than older patients (39%; P = .01; Fisher’s exact test). This group recommended a total thyroidectomy in patients >50 years after a diagnosis of FN was confirmed by intraoperative frozen section. Schlinkert et al.9 reported the opposite prognostic significance of patient age in a cohort of 219 FN patients who underwent operation at the Mayo Clinic between 1992 and 1994. By histological assessment, 35 thyroid tumors (16%) harbored malignancy (including 9 occult papillary cancers). Of the remaining 26 cancers, there were 19 FTCs (9%) and 7 PTCs (including 4 cases [3%] of the follicular variant of PTC). They found that large thyroid lesion size (>4 cm), tumor "fixation" on examination, and young patient age were each associated with an increased cancer risk. A Korean group recently reported that extremes of patient age were predictive of cancer in a cohort of 215 individuals with FN. In this retrospectively evaluated cohort, there were 102 patients (47%) with a pathologic diagnosis of malignancy, and the cancers identified in this cohort included 29 (13.5%) PTCs, 57 (26.5%) FTCs, 15 (7%) Hürthle cell carcinomas, and 1 (.5%) MTC. Patient age <20 years (relative risk [RR], 3.98; 95% confidence interval [CI], 1.07–14.9) or >60 years (RR, 3.98; 95% CI, 1.25–12.6) was associated with an increased cancer risk.16 In this study, the large number of FNs that were diagnosed as cancer (47%) and the large proportion of FTC (27%) differ significantly from both our experience and the current literature (Table 4Go). An Israeli study that evaluated 58 FN patients who underwent thyroidectomy also found large nodule diameter to be an independent predictor (P < .0001) of malignancy.15


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  		TABLE 5. Summary of current literature evaluating clinical characteristics useful for prediction of malignancy in the FN patient population
 
Although similar to prior studies, the results reported from Chicago by Zdon et al.13 are difficult to interpret because their evaluation of 36 FNs, which included 6 patients with a preoperative diagnosis of "Hürthle cell histology" and 2 survivors of the Chernobyl nuclear accident, also identified large tumor size and older patient age to be predictors of thyroid cancer. They also found that FN patients from a hospital serving a primarily socioeconomically disadvantaged population (n = 12) had a significantly higher malignancy rate (50%) when compared with the cancer rate (3%) observed in FN patients from a hospital serving a socioeconomically affluent (n = 24) population. A possible explanation for this observation, not suggested by the authors, is that it was due to a lack of standardization of the pathologic evaluation performed at the two different hospital study centers.

In a cohort of 122 FN patients who underwent thyroidectomy, Baloch et al.14 also found large lesion size to predict a cancer diagnosis. They reported a tumor size >3 cm (55% vs. 23%; P < .0001), patient age >40 years (20% vs. 10%; P = .0001), and male sex (47% vs. 29%; P < .0004) to predict malignant histological results. Similarly, Tuttle et al.10 also reported large tumor size and male sex to predict an increased FN patient cancer risk. Of 1121 patients who underwent FNAB at their study centers between 1990 and 1995, 149 (13%) received a diagnosis of FN, and 103 of these patients eventually underwent thyroid operation. Twenty-two (21%) of these 103 patients had a diagnosis of a thyroid malignancy (15 patients with PTC and 7 with FTC). Multiple patient characteristics (sex, race, and a personal and family history of thyroid disease), multiple tumor characteristics (tumor size; change in size; worrisome clinical features, including dysphagia, pain, or hoarseness; gland nodularity; and palpable nodal disease), and whether the tumor was detected by the clinician or patient were evaluated for their ability to predict cancer in this FN patient population. The investigators found that the risk of malignancy was significantly higher when a FN was diagnosed in a man (43% vs. 16% for women; P = .007), when the nodule was >4 cm by palpation (40% vs. 13% for nodules <4 cm; P = .03), or when the nodule was solitary on palpation (25% vs. 6% for a dominant nodule in a multinodular goiter; P = .02). A bayesian analysis of their data revealed that after an FN was diagnosed by FNAB, the risk of malignancy in men with large nodules was nearly 80%, compared with a cancer rate of only 3% in women with small nodules.10

This increased cancer risk associated with solitary thyroid nodules in FN patients was also reported by an Austrian group that evaluated 120 FN patients from a series of 1100 individuals who underwent FNAB as part of an investigation of nodular thyroid disease. Malignancy was identified in 21 (18%) of these FN patients, and 12 of these cancers were PTCs (all >1 cm in diameter) and 9 were FTCs. Clinical, imaging, and cytological (cellular atypia) characteristics were evaluated for their ability to predict malignant pathology. This group found "hard" lesions by palpation (RR, 2.6; 95% CI, 1.2–5.6), solitary nodules (RR, 2.6; 95% CI, 1.7–4.0), and hypoechoic FNABs by ultrasonography (RR, 3.4; 95% CI, 2.0–5.7) to have an increased risk of malignancy.12

Similar to our experience, other investigators have also not found any FN patient or tumor characteristics to predict thyroid malignancy. McHenry et al.11 evaluated a cohort of 66 patients with a cytological diagnosis of FN who underwent a thyroid operation. From this cohort, 14 FN patients (21%) harbored malignancy, which included 6 FTCs and 8 PTCs (including 5 occult PTCs). This FN cohort was evaluated as to whether patient characteristics could predict malignancy, and the patient data evaluated included age, sex, history of head and neck irradiation, nodule size, and the presence of cytological atypia within the FNAB. None of these clinical or cytological characteristics was helpful in predicting a diagnosis of thyroid cancer. Layfield et al.7 found the same result when they evaluated 35 individuals with an FNAB diagnosis of FN for clinical (age, sex, thyroid disease history in the patient or family, radiation exposure, and symptoms), pathologic (nodule size, extent of disease, multiplicity, location, fixation, and nodal disease), radiographical (evidence of metastatic disease, ultrasonography, and radioiodine scan), and laboratory (thyroid function, calcium level, antithyroid antibody level) characteristics. Thus, the current literature evaluating the utility of FN patient clinical characteristics in predicting the presence of thyroid malignancy consists of multiple small conflicting studies (Table 5Go). Potential explanations for these conflicting findings include variation in cytological and pathologic assessment performed by different centers and true epidemiological differences in disease presentation at these diverse study locations. However, it is interesting that many of the patient characteristics that have been reported to predict malignancy in FN patients (i.e., old age, male sex, and large tumor size) are also predictors of a worse disease prognosis in individuals who were diagnosed with thyroid malignancy.26–30

When the data from this study and the nine studies listed in Table 3Go are evaluated, the overall proportion of individuals with a cytological diagnosis of FN who will eventually be given a tissue diagnosis of cancer ranges from 13% to 47%.7–16 However, many of these reports include patients with a diagnosis of papillary microcarcinoma. Papillary microcarcinoma represents an incidental pathologic finding that has an autopsy prevalence ranging from 3% to 36%.31 In a recent study from Japan, 162 papillary microcarcinoma cases diagnosed by ultrasound-guided FNAB of thyroid nodules were followed up clinically. More than 70% of nodules either did not enlarge or decreased in size when followed up by ultrasound examination for 18 to 113 months. Nodules enlarged by >10 mm developed in 10.2% of cases, and lateral compartment lymph node metastases developed in only 1.2% of cases.32 This study and others support the view that occult PTC is an innocuous lesion, and unless the affected individual presents with lymph node or distant metastatic disease, completion thyroidectomy is generally not warranted.31–33 When the rate of nonoccult thyroid cancer is evaluated by eliminating the papillary microcarcinomas from the cancer rate calculations, in this study and the three other studies in which these data are available (Table 3Go), the proportion of thyroid malignancies observed in the FN population decreases from 18% (range, 16%–19%) to 13% (range, 9%–18%). Also important is the observation in this study and in the literature that PTC, most commonly the follicular variant of PTC, accounts for a large proportion of the cancers identified by histological analysis in the FN patient population.18

The reason for the recently observed worldwide decrease in the incidence of FTC of the thyroid has not been well explained, although it has been suggested that increased dietary iodide supplementation and improved histological diagnostic accuracy may be responsible.34–36 Recent reports have found FTC to account for only 1% to 2% of newly diagnosed thyroid malignancies.34,35 Thus, it is not surprising that FTC is also rarely diagnosed in the FN population, as seen in both this study (5%) and in the recent literature (Table 4Go).7–16 FTC can be classified as either a minimally invasive type or, less commonly, as the widely invasive type, according to the degree of capsular invasion by tumor and the presence of angioinvasion. 17,36 All of the four FTCs in this study were the minimally invasive type with no evidence of angioinvasion. In a retrospectively reviewed cohort of 132 FTC patients, D’Avanzo et al.36 reported that patients with minimally invasive FTC with evidence of capsular invasion had a better 5-year survival (98%) than patients with evidence of angioinvasion with or without capsular invasion (80%) and those with widely invasive FTC (38%). Given the excellent long-term prognosis, our center and others currently do not recommend completion thyroidectomy for patients with minimally invasive FTC and no evidence of angioinvasion.36–38


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Overall, of the 80 patients in this study who underwent hemithyroidectomy with a preoperative FNAB diagnosis of FN, 15 cancers were diagnosed: these included 4 minimally invasive FTCs and 8 papillary microcarcinomas, which have an excellent prognosis and do not require subsequent removal of the remaining thyroid lobe. Therefore, hemithyroidectomy was considered adequate treatment for 77 (96%) of the 80 FN patients in our study population. Even if all our FN patients with FTC who received a diagnosis by histological analysis underwent a completion thyroidectomy, most individuals (73 of 80 patients; 91%) would still not require any further surgery. However, our data also suggest that the surgeon must perform five thyroid lobectomies to diagnose a single cancer in the FN patient population and that preoperative patient characteristics are of no value in assisting the surgical selection process.

In the recent literature, multiple investigators have used molecular biology techniques to improve the diagnostic yield of FNAB. Segev et al.39 have reviewed 12 promising molecular markers that have been studied as adjuncts to FNAB for diagnosis of thyroid cancer. The markers evaluated were galectin 3, thyroid peroxidase, p27 (KIP1), telomerase, ceruloplasmin and lactoferrin, dipeptidyl aminopeptidase (DAP4), CD44, cytokeratin 19, HBME-1, high-mobility group I protein, thyroid-specific transcription factor (PAX-8), and RET/PTC. The potential for clinical adoption of immunodiagnostic methods for preoperative FNAB diagnosis can be appreciated in the multicenter prospective study reported by Bartolazzi et al.,40 in which galectin 3 and CD44v6 were evaluated as adjuncts to FNAB cytological results. They reported a sensitivity, specificity, positive predictive value, and diagnostic accuracy of coexpression of the 2 markers for making a cancer diagnosis of 88%, 98%, 91%, and 97%, respectively. Molecular profiling of thyroid tumors with DNA microarray methods has also shown promising results. In small thyroid tumor patient cohorts, Mazzanti et al.41 and Finley et al.42 have demonstrated that DNA microarrays can be used to accurately differentiate benign and malignant thyroid tumors. Thus, our present study suggests that the development of these and other improved diagnostic tools would be an important advance in the management of individuals with nodular thyroid disease and FNAB results suggestive of a FN.

Received for publication March 22, 2005. Accepted for publication August 29, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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