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Differentiated thyroid cancer in the elderly: Our experience
International Journal of Surgery xxx (2014) 1e4
Contents lists available at ScienceDirect
International Journal of Surgery journal homepage: www.journal-surgery.net
Original research
Differentiated thyroid cancer in the elderly: Our experience *, Fabio Medas, Giulia Loi, Enrico Erdas, Giuseppe Pisano, Pietro Giorgio Calo Angelo Nicolosi Department of Surgical Sciences, University of Cagliari, Cagliari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 July 2014 Received in revised form 23 August 2014 Accepted 23 August 2014 Available online xxx
Introduction: The objective of this retrospective study was to investigate clinical and pathologic characteristics of differentiated thyroid cancer in elderly patients and to evaluate the results of surgical treatment in this age group. Methods: The clinical records of patients who underwent total thyroidectomy between 2002 and 2012 with histopathological diagnosis of differentiated thyroid cancer were analyzed. Patients were divided into two groups: those 65 years old or older were included in group A (101), those younger in group B (354). Results: The mean surgical time was 100.9 ± 30.5 min in group A and 100.7 ± 27.6 in B. Postoperative stay was significantly longer in group A (2.8 ± 1.5 days vs 2.4 ± 0.7; p < 0.01). Classic papillary carcinoma was more frequent in group B, whereas follicular variant of papillary carcinoma and tall cell carcinoma in A. In group B node metastases were nearly twice. In Group A transient hypoparathyroidism occurred in 25 patients (24.8%), permanent hypoparathyroidism in 4 (4%), hematoma in 6 (5.9%), recurrent nerve palsy in 2 (2%), and wound infection in 2 (2%). In group B transient and permanent hypoparathyroidism occurred in 48 and 7 patients respectively (13.6% and 2%), hematoma in 4 (1.1%), recurrent nerve palsy in 5 (1.4%), and wound infection in 1 (0.3%). Conclusions: Differentiated thyroid carcinoma is more aggressive in elderly patients for biological causes connected to age and to histotype but also for the diagnostic delay. Thyroid surgery in elderly patients is safe when the procedure is carried out by experienced staff. Total thyroidectomy is the surgical operation of choice. © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Thyroid cancer Thyroidectomy Elderly
1. Introduction The incidence of differentiated thyroid cancer (DTC) increases with age [1e6]; between 2.5% and 12% of DTC occur in individuals older than 65 years [7]. Thyroid cancer is the only malignancy with age as a prognostic indicator in the majority of staging systems [4,6,8]; the mortality climbs gradually starting at age 40e45 [4,8]. Elderly patients often present with more aggressive forms of DTC, larger tumors, more extensive local growth, or distant metastases [1,9,10]. A steady decline in survival rates has been reported with increasing age,
Abbreviations: DTC, differentiated thyroid cancer; FT3, free T3; FT4, free T4; TSH, thyroid stimulating hormone; US, ultrasound; FNAC, fine-needle aspiration cytology; PTH, parathyroid hormone; Tg, thyroglobulin; TgAb, thyroglobulin antibodies; rhTSH, recombinant human thyrotropin. * Corresponding author. Department of Surgical Sciences, University of Cagliari, Policlinico Universitario di Monserrato, S.S. 554, Bivio Sestu, 09042 Monserrato, CA, Italy. ), [email protected] (F. Medas), E-mail addresses: [email protected] (P.G. Calo [email protected] (G. Loi), [email protected] (E. Erdas), gpisano@ unica.it (G. Pisano), [email protected] (A. Nicolosi).
regardless of the degree of differentiation of the thyroid cancer [4]. Different histopathological patterns, a poorer general physical condition, and delayed diagnosis are the major reasons for the poor prognosis of these patients [11]. Thyroid cancer recurrence rates have also been shown to be influenced by age [2,4]. The management of DTC in older patients remains controversial [4]. The literature regarding outcomes in this age group remains scarce and analyses of incidence, characteristics, and prognosis in elderly patients are rarely reported [1,7,12e15]. The objective of this retrospective study was to investigate the clinical and pathologic characteristics of DTC in elderly patients and to evaluate the results of surgical treatment in this age group.
2. Methods The clinical records of patients who underwent total thyroidectomy between 2002 and 2012 in our Department of Surgical Sciences at the University of Cagliari with histopathological diagnosis of DTC were analyzed. Patients with incomplete data and those lost at follow up were excluded. 455 patients were included in this retrospective study. For each patient preoperative work-up
http://dx.doi.org/10.1016/j.ijsu.2014.08.362 1743-9191/© 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
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et al. / International Journal of Surgery xxx (2014) 1e4 P.G. Calo
2
consisted of free thyroid hormone (FT3, FT4) and thyrotropin (TSH) blood measurements, high resolution ultrasound (US) of the neck and fibrolaryngoscopy for evaluation of vocal fold motility. For patients with suspicious nodules, US-guided fine-needle aspiration cytology (FNAC) was performed. All operations were performed by the same three experienced endocrine surgeons. Serum calcium and intact parathyroid hormone (PTH) were assayed on first postoperative day, and then on the basis of clinical evaluation. Patient demographics and postoperative complications were recorded, including postoperative hematoma, recurrent laryngeal nerve injury, hypoparathyroidism and wound infection. Hypoparathyroidism (defined as a PTH level <10 pg/ml) was considered permanent if it lasted more than 6 months. Recurrent laryngeal nerve palsy was defined as vocal fold paralysis assessed by postoperative fibrolaryngoscopy and was considered permanent if persisting for more than 6 months after surgery. Postoperative radioablation iodine therapy was administered according to guidelines (gross extrathyroidal extension, primary tumor size greater than 4 cm, distant metastases, and selected patients with significant risk of recurrence with primary tumors ranging from 1 to 4 cm confined to the thyroid). Follow-up consisted of neck US examination and monitoring of Tg and TgAb levels every six months during suppressive L-thyroxine treatment; a serum Tg level of 0.2 ng/ml was taken as undetectable. In those with suspicious recurrence a whole-body 131I scanning after recombinant human thyrotropin (rhTSH) stimulation was performed. Diagnosis of disease recurrence in the cervical lymph nodes was based on US-guided FNAC, Tg washing of FNAC aspirates, and serum Tg level monitoring. Patients were divided into two groups: those 65 years old or older were included in group A, those younger in group B. Data were analyzed with descriptive statistics. For categorical variables, the Pearson's chi-squared (exact) test was used; for qualitative variables Student's t-test was used. Differences between the two groups were considered statistically significant for P value <0.05. The study was approved by the Institutional Ethical committee of the University of Cagliari. 3. Results A total of 455 patients were included in the study; 101 were 65 years old or older and were included in group A, whereas the other 354 were younger and were included in group B. Preoperative diagnosis with fine-needle aspiration biopsy was available from 189 patients: an indeterminate or suspicious nodule was found in 145 patients and a carcinoma in 44 patients. In 144 patients a thyroid malignancy was suspected on physical examination and ultrasound features of the nodule. In 102 patients indication to surgery was for benign disease and DTC was an occasional finding after thyroidectomy. Demographic data and indications to thyroidectomy are reported in Table 1. All the patients underwent total thyroidectomy, in 89 cases (13 cases in group A and 76 in group B) associated with central neck compartment lymphadenectomy; concomitant modified lateral neck dissection was performed in 15 cases (5 in group A and 10 in group B). The mean surgical time was 100.9 ± 30.5 min in group A and 100.7 ± 27.6 min in group B (see Table 2). Postoperative stay was significantly longer in group A (2.8 ± 1.5 days vs 2.4 ± 0.7; p < 0.01). Histopathological data are reported in Table 3. Classic papillary carcinoma was more frequent in group B, whereas follicular variant of papillary carcinoma and tall cell carcinoma in group A (p < 0.01). In group B node metastases were nearly twice as many as in the other group (7 patients, 6.93% in group A; 43 patients, 12.15%, in group B). We had no mortality in both groups. In Group A transient hypoparathyroidism occurred in
Table 1 Demographic data and indications to surgery. p value Group B Group A (65 y.o. and older) (younger than 65 y.o.) (n ¼ 354) (n ¼ 101) Sex Male Female Age (years) Indications to surgery Indeterminate or suspicious nodule on cytology Diagnosis of carcinoma on cytology Suspicious nodule on US Benign disease (multinodular goitre and hyperthyroidism)
21 (20.8%) 80 (79.2%) 71.3 ± 5.3
76 (21.5%) 278 (78.5%) 45.6 ± 11.6
0.9929
33 (32.7%)
112 (31.6%)
0.5128
6 (5.9%)
38 (10.7%)
32 (31.7%)
112 (31.6%)
30 (29.7%)
92 (26%)
ns
0.000001 P < 0.01 ns
US: Ultrasound.
Table 2 Surgical procedure and postoperative stay. Group A (65 y.o. Group B (younger p value than 65 y.o.) and older) (n ¼ 354) (n ¼ 101) Surgical procedure Total thyroidectomy Total thyroidectomy and central compartment dissection Total thyroidectomy and modified lateral neck dissection Surgical time (min) Postoperative stay (days)
83 (82.2%) 13 (12.9%)
268 (75.7%) 76 (21.5%)
5 (5%)
10 (2.8%)
100.9 ± 30.5 2.8 ± 1.5
100.7 ± 27.6 2.4 ± 0.7
0.1068 ns
0.4956 ns 0.0009 P < 0.01
Table 3 Histopathological diagnosis. Group A (65 y.o. and older) (n ¼ 101) Histopathological diagnosis Papillary 37 (36.6%) carcinoma Follicular variant 37 (36.6%) of papillary carcinoma Tall cell carcinoma 9 (8.9%) Follicular 10 (9.9%) carcinoma Hurtle cell 7 (6.9%) carcinoma Poorly differenti- 1 (1%) ated papillary carcinoma Multicentric 36 (35.6%) carcinoma Locally invasive 36 (35.6%) carcinoma Node metastases 7 (6.9%)
Group B (younger than 65 y.o.) (n ¼ 354)
p value
196 (55.4%)
0.0061 P < 0.01
86 (24.3%)
26 (7.3%) 35 (9.9%) 9 (2.5%) 2 (0.6%)
109 (30.8%)
0.422
ns
110 (31.1%)
0.455
ns
43 (12.1%)
0.1942 ns
25 patients (24.8%), permanent hypoparathyroidism in 4 (4%), postoperative hematoma in 6 (5.9%), recurrent laryngeal nerve palsy in 2 (2%), and wound infection in 2 (2%). In group B transient and permanent hypoparathyroidism occurred in 48 and 7 patients respectively (13.6% and 2%), postoperative hematoma in 4 (1.1%),
, et al., Differentiated thyroid cancer in the elderly: Our experience, International Journal of Surgery Please cite this article in press as: P.G. Calo (2014), http://dx.doi.org/10.1016/j.ijsu.2014.08.362
et al. / International Journal of Surgery xxx (2014) 1e4 P.G. Calo
recurrent laryngeal nerve palsy in 5 (1.4%), and wound infection in 1 (0.3%). Postoperative complications are summarized in Table 4. There were no statistically significant differences in local recurrences (7 cases, 6.9%, in group A and 19 patients, 5.4%, in group B). 4. Discussion An exact definition of the geriatric patient is not available in the medical literature. Various publications use different age definitions, eg. 60, 65, 70, 75, and 80 years [16,17]. As other authors [1,2,15], we have chosen to use as a limit the age of 65 years with the aim of obtaining a larger series. The prevalence of DTC increases significantly with age [13,16,17] and age at diagnosis was identified as a major independent prognostic factor in several large retrospective series [2,6,7,11,13,16]. In the report of Vini [7], for any 10-year difference in age, there was a near doubling of risk. The risk of recurrence and death increased linearly with age [7]. DTC in the elderly can have a more aggressive biologic behavior and a worse prognosis [5e7,12e14,16e19]. This might be due to the higher prevalence of pathologic risk factors like vascular invasion, extracapsular extension, and follicular type in older patients [5,9,13,16e19]. Park et al. [5] showed that patients 65 years demonstrated more aggressive disease with multiple, larger tumors and more advanced-stage disease, non papillary histology, and extra-thyroidal extension. Biliotti et al. [18] report a higher rate of larger tumors, a more elevated incidence of extraglandular spread and a higher rate of distant metastases at the time of surgery. In addition, the effectiveness of radioiodine therapy decreases in the elderly due to the fact that the uptake of 131I is agedependent [7,9,18]. The reduced response is probably to be attributed to the diminished differentiation of follicular and papillary carcinoma in geriatric patients [18]. Well-differentiated carcinomas that display a more aggressive histotype, such as sclerosing and tall-cell papillary variants, have a higher incidence and an unfavorable evolution in patients aged over 50 years of age [13,20]. In the experience of Vini [7], at presentation 70% of patients had locally advanced disease, 44% of patients had associated lymph node disease, and 23% of patients had an evidence of distant metastases; 21% developed locoregional recurrent disease, and 15% of patients developed distant metastases. In our experience there was a higher incidence of follicular (36.6% vs 24.3%) and particularly tall cell papillary variants (8.9% vs 7.3%) and a lower incidence of typical papillary carcinoma, confirming the data reported in the literature. We also observed larger tumors in the elderly patients (20.8 ± 15.9 vs 16.3 ± 10.6) while thyroid weight was 37.4 ± 34.3 vs 28.1 ± 22.6. These data can be attributed to the frequent association of large untreated goiters and to a delayed diagnosis of DTC in the elderly as reported by other
Table 4 Postoperative complications and local recurrence. Group A (65 y.o. and Group B (younger p older) (n ¼ 101) than 65 y.o.) (n ¼ 354) value Hypoparathyroidism Transient 25 Permanent 4 2 Recurrent laryngeal nerve palsy Postoperative 6 haemorrhage Wound infection 2 Local recurrence 7
(24.8%) (4%) (2%)
48 (13.6%) 7 (2%) 5 (1.4%)
(5.9%)
4 (1.1%)
(2%) (6.9%)
1 (0.3%) 19 (5.4%)
0.0107 p < 0.01 0.437 ns 0.9603 ns
0.011
p < 0.01
0.9603 ns 0.7232 ns
3
authors [11,18]. The incidence of lymph node metastasis was lower (6.93% vs 12.15%) as reported by others [10]. The recurrence rate, like the rate of mortality, for DTC is highest among elderly patients [2,8,18]. Lymph node relapses increase in the elderly patients group [13,21]. In the report of Vini [7], the median time from the end of therapy to clinical recurrence was only 9 months, compared with 34 months in the whole series of 1390 adults with DTC. Age influences the probability of developing recurrent disease, the interval from initial treatment to recurrence, and the duration of survival after recurrence [7]. In the report of Toniato [10], the incidence of recurrence was earlier and more frequent in elderly patients, and the outcome of papillary cancer was significantly worse in older than in younger patients. The worse prognosis can have two reasons: the first could be a more advanced stage, particularly IV stage; the second, could be a reduced radioiodine uptake [10]. We found no statistically significant difference in the incidence of recurrence. This is probably related to the fact that the surgical treatment was not different in the different age groups in our experience: we performed in all patients a total thyroidectomy associated to a central neck dissection in high risk patients and in presence of suspicious nodes as previously reported [21e23]. Few reports exist concerning thyroid surgery and survival of thyroid cancer in the elderly patient [10,17]. Surgery in elderly patients has been considered to be more hazardous than in a youthful population; this increased risk appears to be related to the presence of comorbidities rather than to age alone [15]. In the experience of Passler [17] the most common comorbidity was hypertension followed by cardiac disease and arrhythmia, with most patients having one or two comorbidities; eighteen percent of their elderly patients had 3 or more comorbidities [14]. For these reasons, patients 80 years of age can undergo thyroid surgery with significantly higher morbidity [14]; efforts should be made to identify surgical patients earlier than the 8th decade of life and surgery should not be delayed, since delay may lead to the risk of added comorbidities at a more advanced age [14]. Elderly Americans aged 65 years with DTC 1 cm receive less aggressive treatment with near-total or total thyroidectomy and radioactive iodine therapy than their younger counterparts [5]; no surgery and no radioactive iodine therapy were predictors of worse survival in the report of Park [5]. In the report of Vini [7], only 41% of patients underwent total thyroidectomy due mainly to the poor condition of the patient or to the advanced tumor stage, precluding definitive surgery. We always performed total thyroidectomy and we found no statistically significant difference in central or lateral neck dissection, having always treated the elderly patients in the same way as younger patients. Morbidity associated with thyroidectomy in elderly patients may be higher than in youthful patients [15]. Some studies reported a higher incidence of postoperative hematoma in their elderly population [15,17]. Seybt [15] reported that older patients were more likely to be readmitted than their younger counterparts and readmission was usually related to transient hypocalcemia. In our experience the post-operative hospital stay was 2.8 ± 1.5 days vs 2.4 ± 0.7 and we had no mortality. The longest hospital stay was related both to comorbidities and postoperative complications. Incidence of transient hypoparathyroidism was 24.75% vs 13.56% and of postoperative hematoma 5.94% vs 1.13%. The incidence of postoperative bleeding may be related to a higher frequency of use of anticoagulants or antiplatelet drugs in the elderly population [24,25], while the higher incidence of transient hypoparathyroidism may be attributed to the presence of larger tumors and advanced cancer in this age group [26,27].
, et al., Differentiated thyroid cancer in the elderly: Our experience, International Journal of Surgery Please cite this article in press as: P.G. Calo (2014), http://dx.doi.org/10.1016/j.ijsu.2014.08.362
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In conclusion, DTC generally is more aggressive in elderly patients for biological causes connected to the age and to the histotype but also for the considerable diagnostic delay. Thyroid surgery in elderly patients is safe and no more dangerous than surgery in younger patients when the procedure is carried out by experienced staff. Age alone should not be a consideration when deciding whether or not to operate. Total thyroidectomy is the surgical operation of choice, because age alone does not represent an important factor of perioperative mortality and morbidity. Ethical approval Ethical approval was requested and obtained from the “University of Cagliari” ethical committee. Funding All Authors have no source of funding. Author contribution : Participated substantially in conception, Pietro Giorgio Calo design, and execution of the study and in the analysis and interpretation of data; also partecipated substantially in the drafting and editing of the manuscript. Fabio Medas: Participated substantially in conception, design, and execution of the study and in the analysis and interpretation of data. Giulia Loi: Participated substantially in conception, design, and execution of the study and in the analysis and interpretation of data. Enrico Erdas: Participated substantially in conception, design, and execution of the study and in the analysis and interpretation of data. Giuseppe Pisano: Participated substantially in conception, design, and execution of the study and in the analysis and interpretation of data. Angelo Nicolosi: Participated substantially in conception, design, and execution of the study and in the analysis and interpretation of data; also partecipated substantially in the drafting and editing of the manuscript. Conflict of interest statement The authors declare that they have no competing interests or any financial support. References [1] M.M. Boltz, C.S. Hollenbeak, E. Schaefer, D. Goldenberg, B.D. Saunders, Attributable costs of differentiated thyroid cancer in the elderly medicare population, Surgery 154 (2013) 1363e1369.
[2] C.S. Hollenbeak, M.M. Boltz, E.W. Schaefer, B.D. Saunders, D. Goldenberg, Recurrence of differentiated thyroid cancer in the elderly, Eur. J. Endocrinol. 168 (2013) 549e556. [3] A. Marrazzo, P. Taormina, M. David, et al., Il carcinoma della tiroide: dalla diagnosi alla terapia, Chir. Ital. 60 (2008) 685e695. [4] M. Papaleontiu, M.R. Haymart, Approach to and treatment of thyroid disorders in the elderly, Med. Clin. North Am. 96 (2012) 297e310. [5] H.S. Park, S.A. Roman, J.A. Sosa, Treatment patterns of aging Americans with differentiated thyroid cancer, Cancer 116 (2010) 20e30. [6] M. Raffaelli, R. Bellantone, P. Princi, et al., Surgical treatment of thyroid diseases in elderly patients, Am. J. Surg. 200 (2010) 467e472. [7] B. Amato, R. Compagna, L. Sivero, A. Rocca, M. Donisi, Lymphectomy for elderly in thyroid surgery, Chir. (Turin) 26 (4) (2013) 303e306. [8] M.R. Haymart, Understanding the relationship between age and thyroid cancer, Oncologist 14 (2009) 216e221. , A. Nicolosi, B. Massidda, A. Tarquini, Il carcinoma della [9] A. Malloci, P.G. Calo geriatrica, Chirurgia 11 (1998) 361e364. tiroide in eta [10] A. Toniato, C. Bernardi, A. Piotto, D. Rubello, M.R. Pelizzo, Features of papillary carcinoma in patients older than 75 years, Updat. Surg. 63 (2011) 115e118. [11] C. Rispoli, N. Rocco, L. Iannone, B. Amato, Developing guidelines in geriatric surgery: role of the grade system, BMC Geriatr. 9 (Suppl. 1) (2009) A99. [12] R. Bliss, N. Patel, A. Guinea, T.S. Reeve, L. Delbridge, Age is no contraindication to thyroid surgery, Age Ageing 28 (1999) 363e366. [13] L. Falvo, A. Catania, S. Sorrenti, et al., Prognostic significance of the age factor in the thyroid cancer: statistical analysis, J. Surg. Oncol. 88 (2004) 217e222. [14] M. Mekel, A.E. Stephen, R.D. Gaz, A. Muzikansky, R.A. Hodin, S. Parangi, Thyroid surgery in octogenarians with higher complication rates, Surgery 146 (2009) 913e921. [15] M.W. Seybt, S. Khichi, D.J. Terris, Geriatric thyroidectomy: safety of thyroid surgery in an aging population, Arch. Otolaryngol. Head. Neck Surg. 135 (2009) 1041e1044. [16] R. Gervasi, G. Orlando, M.A. Lerose, et al., Thyroid surgery in geriatric patients: a literature review, BMC Surg. 12 (Suppl. 1) (2012) S16. [17] C. Passler, R. Avanessian, K. Kaczirek, G. Prager, C. Scheuba, B. Niederle, Thyroid surgery in the geriatric patient, Arch. Surg. 137 (2002) 1243e1248. [18] G.C. Biliotti, F. Martini, V. Vezzosi, et al., Specific features of differentiated thyroid carcinoma in patients over 70 years of age, J. Surg. Oncol. 93 (2006) 194e198. [19] P. Miccoli, M.N. Minuto, C. Ugolini, et al., Papillary thyroid cancer: pathological parameters as prognostic factors in different classes of age, Otolaryngol. Head. Neck Surg. 138 (2008) 200e203. [20] M.L. Carcangiu, G. Zampi, A. Pupi, A. Castagnoli, J. Rosai, Papillary carcinoma of the thyroid. A clinicopathologic study of 241 cases treated at the University of Florence, Italy, Cancer 55 (1985) 805e828. , A.A. Sinisi, et al., Impact of prophylactic central [21] G. Conzo, P.G. Calo compartment neck dissection on locoregional recurrence of differentiated thyroid cancer in clinically node-negative patients: a retrospective study of large clinical series, Surgery 155 (2014) 998e1005. , F. Medas, G. Pisano, et al., Differentiated thyroid cancer: indications [22] P.G. Calo and extent of central neck dissection e our experience, Int. J. Surg. Oncol. 2013 (2013) 625193. , G. Pisano, F. Medas, et al., Total thyroidectomy without prophylactic [23] P.G. Calo central neck dissection in clinically node-negative papillary thyroid cancer: is it an adequate treatment? World J. Surg. Oncol. 12 (2014) 152. , E. Erdas, F. Medas, et al., Late bleeding after total thyroidectomy: [24] P.G. Calo report of two cases occurring 13 days after operation, Clin. Med. Insights Case Rep. 6 (2013) 165e170. , G. Pisano, G. Piga, et al., Postoperative hematoma after thyroid [25] P.G. Calo surgery. Incidence and risk factors in our experience, Ann. Ital. Chir. 81 (2010) 343e347. [26] G. Guerra, M. Cinelli, M. Mesolella, D. Tafuri, et al., Morphological, diagnostic and surgical features of ectopic thyroid gland: a review of literature, Int. J. Surg. 12S1 (2014) S3eS11, http://dx.doi.org/10.1016/j.ijsu.2014.05.076 [Epub 2014 Jun 2]. [27] A. Puzziello, L. Rosato, N. Innaro, et al., Hypocalcemia following thyroid surgery: incidence and risk factors. A longitudinal multicenter study comprising 2631 patients, Endocrine (2014 Feb 22), http://dx.doi.org/10.1007/s12020014-0209-y [Epub ahead of print].
, et al., Differentiated thyroid cancer in the elderly: Our experience, International Journal of Surgery Please cite this article in press as: P.G. Calo (2014), http://dx.doi.org/10.1016/j.ijsu.2014.08.362
Contents lists available at ScienceDirect
International Journal of Surgery journal homepage: www.journal-surgery.net
Original research
Differentiated thyroid cancer in the elderly: Our experience *, Fabio Medas, Giulia Loi, Enrico Erdas, Giuseppe Pisano, Pietro Giorgio Calo Angelo Nicolosi Department of Surgical Sciences, University of Cagliari, Cagliari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 July 2014 Received in revised form 23 August 2014 Accepted 23 August 2014 Available online xxx
Introduction: The objective of this retrospective study was to investigate clinical and pathologic characteristics of differentiated thyroid cancer in elderly patients and to evaluate the results of surgical treatment in this age group. Methods: The clinical records of patients who underwent total thyroidectomy between 2002 and 2012 with histopathological diagnosis of differentiated thyroid cancer were analyzed. Patients were divided into two groups: those 65 years old or older were included in group A (101), those younger in group B (354). Results: The mean surgical time was 100.9 ± 30.5 min in group A and 100.7 ± 27.6 in B. Postoperative stay was significantly longer in group A (2.8 ± 1.5 days vs 2.4 ± 0.7; p < 0.01). Classic papillary carcinoma was more frequent in group B, whereas follicular variant of papillary carcinoma and tall cell carcinoma in A. In group B node metastases were nearly twice. In Group A transient hypoparathyroidism occurred in 25 patients (24.8%), permanent hypoparathyroidism in 4 (4%), hematoma in 6 (5.9%), recurrent nerve palsy in 2 (2%), and wound infection in 2 (2%). In group B transient and permanent hypoparathyroidism occurred in 48 and 7 patients respectively (13.6% and 2%), hematoma in 4 (1.1%), recurrent nerve palsy in 5 (1.4%), and wound infection in 1 (0.3%). Conclusions: Differentiated thyroid carcinoma is more aggressive in elderly patients for biological causes connected to age and to histotype but also for the diagnostic delay. Thyroid surgery in elderly patients is safe when the procedure is carried out by experienced staff. Total thyroidectomy is the surgical operation of choice. © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Thyroid cancer Thyroidectomy Elderly
1. Introduction The incidence of differentiated thyroid cancer (DTC) increases with age [1e6]; between 2.5% and 12% of DTC occur in individuals older than 65 years [7]. Thyroid cancer is the only malignancy with age as a prognostic indicator in the majority of staging systems [4,6,8]; the mortality climbs gradually starting at age 40e45 [4,8]. Elderly patients often present with more aggressive forms of DTC, larger tumors, more extensive local growth, or distant metastases [1,9,10]. A steady decline in survival rates has been reported with increasing age,
Abbreviations: DTC, differentiated thyroid cancer; FT3, free T3; FT4, free T4; TSH, thyroid stimulating hormone; US, ultrasound; FNAC, fine-needle aspiration cytology; PTH, parathyroid hormone; Tg, thyroglobulin; TgAb, thyroglobulin antibodies; rhTSH, recombinant human thyrotropin. * Corresponding author. Department of Surgical Sciences, University of Cagliari, Policlinico Universitario di Monserrato, S.S. 554, Bivio Sestu, 09042 Monserrato, CA, Italy. ), [email protected] (F. Medas), E-mail addresses: [email protected] (P.G. Calo [email protected] (G. Loi), [email protected] (E. Erdas), gpisano@ unica.it (G. Pisano), [email protected] (A. Nicolosi).
regardless of the degree of differentiation of the thyroid cancer [4]. Different histopathological patterns, a poorer general physical condition, and delayed diagnosis are the major reasons for the poor prognosis of these patients [11]. Thyroid cancer recurrence rates have also been shown to be influenced by age [2,4]. The management of DTC in older patients remains controversial [4]. The literature regarding outcomes in this age group remains scarce and analyses of incidence, characteristics, and prognosis in elderly patients are rarely reported [1,7,12e15]. The objective of this retrospective study was to investigate the clinical and pathologic characteristics of DTC in elderly patients and to evaluate the results of surgical treatment in this age group.
2. Methods The clinical records of patients who underwent total thyroidectomy between 2002 and 2012 in our Department of Surgical Sciences at the University of Cagliari with histopathological diagnosis of DTC were analyzed. Patients with incomplete data and those lost at follow up were excluded. 455 patients were included in this retrospective study. For each patient preoperative work-up
http://dx.doi.org/10.1016/j.ijsu.2014.08.362 1743-9191/© 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
, et al., Differentiated thyroid cancer in the elderly: Our experience, International Journal of Surgery Please cite this article in press as: P.G. Calo (2014), http://dx.doi.org/10.1016/j.ijsu.2014.08.362
et al. / International Journal of Surgery xxx (2014) 1e4 P.G. Calo
2
consisted of free thyroid hormone (FT3, FT4) and thyrotropin (TSH) blood measurements, high resolution ultrasound (US) of the neck and fibrolaryngoscopy for evaluation of vocal fold motility. For patients with suspicious nodules, US-guided fine-needle aspiration cytology (FNAC) was performed. All operations were performed by the same three experienced endocrine surgeons. Serum calcium and intact parathyroid hormone (PTH) were assayed on first postoperative day, and then on the basis of clinical evaluation. Patient demographics and postoperative complications were recorded, including postoperative hematoma, recurrent laryngeal nerve injury, hypoparathyroidism and wound infection. Hypoparathyroidism (defined as a PTH level <10 pg/ml) was considered permanent if it lasted more than 6 months. Recurrent laryngeal nerve palsy was defined as vocal fold paralysis assessed by postoperative fibrolaryngoscopy and was considered permanent if persisting for more than 6 months after surgery. Postoperative radioablation iodine therapy was administered according to guidelines (gross extrathyroidal extension, primary tumor size greater than 4 cm, distant metastases, and selected patients with significant risk of recurrence with primary tumors ranging from 1 to 4 cm confined to the thyroid). Follow-up consisted of neck US examination and monitoring of Tg and TgAb levels every six months during suppressive L-thyroxine treatment; a serum Tg level of 0.2 ng/ml was taken as undetectable. In those with suspicious recurrence a whole-body 131I scanning after recombinant human thyrotropin (rhTSH) stimulation was performed. Diagnosis of disease recurrence in the cervical lymph nodes was based on US-guided FNAC, Tg washing of FNAC aspirates, and serum Tg level monitoring. Patients were divided into two groups: those 65 years old or older were included in group A, those younger in group B. Data were analyzed with descriptive statistics. For categorical variables, the Pearson's chi-squared (exact) test was used; for qualitative variables Student's t-test was used. Differences between the two groups were considered statistically significant for P value <0.05. The study was approved by the Institutional Ethical committee of the University of Cagliari. 3. Results A total of 455 patients were included in the study; 101 were 65 years old or older and were included in group A, whereas the other 354 were younger and were included in group B. Preoperative diagnosis with fine-needle aspiration biopsy was available from 189 patients: an indeterminate or suspicious nodule was found in 145 patients and a carcinoma in 44 patients. In 144 patients a thyroid malignancy was suspected on physical examination and ultrasound features of the nodule. In 102 patients indication to surgery was for benign disease and DTC was an occasional finding after thyroidectomy. Demographic data and indications to thyroidectomy are reported in Table 1. All the patients underwent total thyroidectomy, in 89 cases (13 cases in group A and 76 in group B) associated with central neck compartment lymphadenectomy; concomitant modified lateral neck dissection was performed in 15 cases (5 in group A and 10 in group B). The mean surgical time was 100.9 ± 30.5 min in group A and 100.7 ± 27.6 min in group B (see Table 2). Postoperative stay was significantly longer in group A (2.8 ± 1.5 days vs 2.4 ± 0.7; p < 0.01). Histopathological data are reported in Table 3. Classic papillary carcinoma was more frequent in group B, whereas follicular variant of papillary carcinoma and tall cell carcinoma in group A (p < 0.01). In group B node metastases were nearly twice as many as in the other group (7 patients, 6.93% in group A; 43 patients, 12.15%, in group B). We had no mortality in both groups. In Group A transient hypoparathyroidism occurred in
Table 1 Demographic data and indications to surgery. p value Group B Group A (65 y.o. and older) (younger than 65 y.o.) (n ¼ 354) (n ¼ 101) Sex Male Female Age (years) Indications to surgery Indeterminate or suspicious nodule on cytology Diagnosis of carcinoma on cytology Suspicious nodule on US Benign disease (multinodular goitre and hyperthyroidism)
21 (20.8%) 80 (79.2%) 71.3 ± 5.3
76 (21.5%) 278 (78.5%) 45.6 ± 11.6
0.9929
33 (32.7%)
112 (31.6%)
0.5128
6 (5.9%)
38 (10.7%)
32 (31.7%)
112 (31.6%)
30 (29.7%)
92 (26%)
ns
0.000001 P < 0.01 ns
US: Ultrasound.
Table 2 Surgical procedure and postoperative stay. Group A (65 y.o. Group B (younger p value than 65 y.o.) and older) (n ¼ 354) (n ¼ 101) Surgical procedure Total thyroidectomy Total thyroidectomy and central compartment dissection Total thyroidectomy and modified lateral neck dissection Surgical time (min) Postoperative stay (days)
83 (82.2%) 13 (12.9%)
268 (75.7%) 76 (21.5%)
5 (5%)
10 (2.8%)
100.9 ± 30.5 2.8 ± 1.5
100.7 ± 27.6 2.4 ± 0.7
0.1068 ns
0.4956 ns 0.0009 P < 0.01
Table 3 Histopathological diagnosis. Group A (65 y.o. and older) (n ¼ 101) Histopathological diagnosis Papillary 37 (36.6%) carcinoma Follicular variant 37 (36.6%) of papillary carcinoma Tall cell carcinoma 9 (8.9%) Follicular 10 (9.9%) carcinoma Hurtle cell 7 (6.9%) carcinoma Poorly differenti- 1 (1%) ated papillary carcinoma Multicentric 36 (35.6%) carcinoma Locally invasive 36 (35.6%) carcinoma Node metastases 7 (6.9%)
Group B (younger than 65 y.o.) (n ¼ 354)
p value
196 (55.4%)
0.0061 P < 0.01
86 (24.3%)
26 (7.3%) 35 (9.9%) 9 (2.5%) 2 (0.6%)
109 (30.8%)
0.422
ns
110 (31.1%)
0.455
ns
43 (12.1%)
0.1942 ns
25 patients (24.8%), permanent hypoparathyroidism in 4 (4%), postoperative hematoma in 6 (5.9%), recurrent laryngeal nerve palsy in 2 (2%), and wound infection in 2 (2%). In group B transient and permanent hypoparathyroidism occurred in 48 and 7 patients respectively (13.6% and 2%), postoperative hematoma in 4 (1.1%),
, et al., Differentiated thyroid cancer in the elderly: Our experience, International Journal of Surgery Please cite this article in press as: P.G. Calo (2014), http://dx.doi.org/10.1016/j.ijsu.2014.08.362
et al. / International Journal of Surgery xxx (2014) 1e4 P.G. Calo
recurrent laryngeal nerve palsy in 5 (1.4%), and wound infection in 1 (0.3%). Postoperative complications are summarized in Table 4. There were no statistically significant differences in local recurrences (7 cases, 6.9%, in group A and 19 patients, 5.4%, in group B). 4. Discussion An exact definition of the geriatric patient is not available in the medical literature. Various publications use different age definitions, eg. 60, 65, 70, 75, and 80 years [16,17]. As other authors [1,2,15], we have chosen to use as a limit the age of 65 years with the aim of obtaining a larger series. The prevalence of DTC increases significantly with age [13,16,17] and age at diagnosis was identified as a major independent prognostic factor in several large retrospective series [2,6,7,11,13,16]. In the report of Vini [7], for any 10-year difference in age, there was a near doubling of risk. The risk of recurrence and death increased linearly with age [7]. DTC in the elderly can have a more aggressive biologic behavior and a worse prognosis [5e7,12e14,16e19]. This might be due to the higher prevalence of pathologic risk factors like vascular invasion, extracapsular extension, and follicular type in older patients [5,9,13,16e19]. Park et al. [5] showed that patients 65 years demonstrated more aggressive disease with multiple, larger tumors and more advanced-stage disease, non papillary histology, and extra-thyroidal extension. Biliotti et al. [18] report a higher rate of larger tumors, a more elevated incidence of extraglandular spread and a higher rate of distant metastases at the time of surgery. In addition, the effectiveness of radioiodine therapy decreases in the elderly due to the fact that the uptake of 131I is agedependent [7,9,18]. The reduced response is probably to be attributed to the diminished differentiation of follicular and papillary carcinoma in geriatric patients [18]. Well-differentiated carcinomas that display a more aggressive histotype, such as sclerosing and tall-cell papillary variants, have a higher incidence and an unfavorable evolution in patients aged over 50 years of age [13,20]. In the experience of Vini [7], at presentation 70% of patients had locally advanced disease, 44% of patients had associated lymph node disease, and 23% of patients had an evidence of distant metastases; 21% developed locoregional recurrent disease, and 15% of patients developed distant metastases. In our experience there was a higher incidence of follicular (36.6% vs 24.3%) and particularly tall cell papillary variants (8.9% vs 7.3%) and a lower incidence of typical papillary carcinoma, confirming the data reported in the literature. We also observed larger tumors in the elderly patients (20.8 ± 15.9 vs 16.3 ± 10.6) while thyroid weight was 37.4 ± 34.3 vs 28.1 ± 22.6. These data can be attributed to the frequent association of large untreated goiters and to a delayed diagnosis of DTC in the elderly as reported by other
Table 4 Postoperative complications and local recurrence. Group A (65 y.o. and Group B (younger p older) (n ¼ 101) than 65 y.o.) (n ¼ 354) value Hypoparathyroidism Transient 25 Permanent 4 2 Recurrent laryngeal nerve palsy Postoperative 6 haemorrhage Wound infection 2 Local recurrence 7
(24.8%) (4%) (2%)
48 (13.6%) 7 (2%) 5 (1.4%)
(5.9%)
4 (1.1%)
(2%) (6.9%)
1 (0.3%) 19 (5.4%)
0.0107 p < 0.01 0.437 ns 0.9603 ns
0.011
p < 0.01
0.9603 ns 0.7232 ns
3
authors [11,18]. The incidence of lymph node metastasis was lower (6.93% vs 12.15%) as reported by others [10]. The recurrence rate, like the rate of mortality, for DTC is highest among elderly patients [2,8,18]. Lymph node relapses increase in the elderly patients group [13,21]. In the report of Vini [7], the median time from the end of therapy to clinical recurrence was only 9 months, compared with 34 months in the whole series of 1390 adults with DTC. Age influences the probability of developing recurrent disease, the interval from initial treatment to recurrence, and the duration of survival after recurrence [7]. In the report of Toniato [10], the incidence of recurrence was earlier and more frequent in elderly patients, and the outcome of papillary cancer was significantly worse in older than in younger patients. The worse prognosis can have two reasons: the first could be a more advanced stage, particularly IV stage; the second, could be a reduced radioiodine uptake [10]. We found no statistically significant difference in the incidence of recurrence. This is probably related to the fact that the surgical treatment was not different in the different age groups in our experience: we performed in all patients a total thyroidectomy associated to a central neck dissection in high risk patients and in presence of suspicious nodes as previously reported [21e23]. Few reports exist concerning thyroid surgery and survival of thyroid cancer in the elderly patient [10,17]. Surgery in elderly patients has been considered to be more hazardous than in a youthful population; this increased risk appears to be related to the presence of comorbidities rather than to age alone [15]. In the experience of Passler [17] the most common comorbidity was hypertension followed by cardiac disease and arrhythmia, with most patients having one or two comorbidities; eighteen percent of their elderly patients had 3 or more comorbidities [14]. For these reasons, patients 80 years of age can undergo thyroid surgery with significantly higher morbidity [14]; efforts should be made to identify surgical patients earlier than the 8th decade of life and surgery should not be delayed, since delay may lead to the risk of added comorbidities at a more advanced age [14]. Elderly Americans aged 65 years with DTC 1 cm receive less aggressive treatment with near-total or total thyroidectomy and radioactive iodine therapy than their younger counterparts [5]; no surgery and no radioactive iodine therapy were predictors of worse survival in the report of Park [5]. In the report of Vini [7], only 41% of patients underwent total thyroidectomy due mainly to the poor condition of the patient or to the advanced tumor stage, precluding definitive surgery. We always performed total thyroidectomy and we found no statistically significant difference in central or lateral neck dissection, having always treated the elderly patients in the same way as younger patients. Morbidity associated with thyroidectomy in elderly patients may be higher than in youthful patients [15]. Some studies reported a higher incidence of postoperative hematoma in their elderly population [15,17]. Seybt [15] reported that older patients were more likely to be readmitted than their younger counterparts and readmission was usually related to transient hypocalcemia. In our experience the post-operative hospital stay was 2.8 ± 1.5 days vs 2.4 ± 0.7 and we had no mortality. The longest hospital stay was related both to comorbidities and postoperative complications. Incidence of transient hypoparathyroidism was 24.75% vs 13.56% and of postoperative hematoma 5.94% vs 1.13%. The incidence of postoperative bleeding may be related to a higher frequency of use of anticoagulants or antiplatelet drugs in the elderly population [24,25], while the higher incidence of transient hypoparathyroidism may be attributed to the presence of larger tumors and advanced cancer in this age group [26,27].
, et al., Differentiated thyroid cancer in the elderly: Our experience, International Journal of Surgery Please cite this article in press as: P.G. Calo (2014), http://dx.doi.org/10.1016/j.ijsu.2014.08.362
et al. / International Journal of Surgery xxx (2014) 1e4 P.G. Calo
4
In conclusion, DTC generally is more aggressive in elderly patients for biological causes connected to the age and to the histotype but also for the considerable diagnostic delay. Thyroid surgery in elderly patients is safe and no more dangerous than surgery in younger patients when the procedure is carried out by experienced staff. Age alone should not be a consideration when deciding whether or not to operate. Total thyroidectomy is the surgical operation of choice, because age alone does not represent an important factor of perioperative mortality and morbidity. Ethical approval Ethical approval was requested and obtained from the “University of Cagliari” ethical committee. Funding All Authors have no source of funding. Author contribution : Participated substantially in conception, Pietro Giorgio Calo design, and execution of the study and in the analysis and interpretation of data; also partecipated substantially in the drafting and editing of the manuscript. Fabio Medas: Participated substantially in conception, design, and execution of the study and in the analysis and interpretation of data. Giulia Loi: Participated substantially in conception, design, and execution of the study and in the analysis and interpretation of data. Enrico Erdas: Participated substantially in conception, design, and execution of the study and in the analysis and interpretation of data. Giuseppe Pisano: Participated substantially in conception, design, and execution of the study and in the analysis and interpretation of data. Angelo Nicolosi: Participated substantially in conception, design, and execution of the study and in the analysis and interpretation of data; also partecipated substantially in the drafting and editing of the manuscript. Conflict of interest statement The authors declare that they have no competing interests or any financial support. References [1] M.M. Boltz, C.S. Hollenbeak, E. Schaefer, D. Goldenberg, B.D. Saunders, Attributable costs of differentiated thyroid cancer in the elderly medicare population, Surgery 154 (2013) 1363e1369.
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, et al., Differentiated thyroid cancer in the elderly: Our experience, International Journal of Surgery Please cite this article in press as: P.G. Calo (2014), http://dx.doi.org/10.1016/j.ijsu.2014.08.362