630 Letters to the Editor an underlying ACC was considered because of the imaging characteristics of this gentleman’s adrenal lesion (size >3 cm and attenuation >20 HU)2,3 and because there was evidence of hypersecretion of hormones from two zones of the adrenal cortex. In a recent series of 45 carcinomas compared with 102 adenomas, 12 ACC patients had combined hypersecretion of glucocorticoids and androgens; no patient with benign disease had dual secretion with this combination.1 After spironolactone was withheld, androstenedione levels were normal, which reduced the pre-operative likelihood that the lesion was malignant. It was concluded that spironolactone had interfered with the measurement of androstenedione using the Direct Androstenedione Coat-A-Count (CAC) radioimmunoassay (Siemens Healthcare). There has been one previous report of spironolactone interference with androstenedione measurement by the CAC assay, in a polycystic ovary syndrome (PCOS) patient group treated with 100–200 mg/day spironolactone4, but such interference has never been reported in a patient with hypercortisolaemia or an adrenal lesion, in which diagnosis, prognostication and management would be affected by the result, as we have discussed. In the PCOS group previously reported, three patients had CAC-measured serum androstenedione concentrations on spironolactone therapy that were fourfold higher than the levels measured by the Immulite assay (Siemens). The authors speculated that the androstenedione antibodies in the assay could be reacting with the C/D ring or 7-modified thiol residue of spironolactone or its metabolites.4 The patient was receiving a low dose of spironolactone, but it is apparent that the dose was sufficient to cause interference because serum androstenedione normalized after withdrawal. The manufacturer suggests that the cross-reaction of spironolactone with androstenedione in this assay is 0109%; this implies that our patient’s blood spironolactone concentration would have to have been greater than 4000 ng/ml to give this androstenedione result through interference. The manufacturer of spironolactone quotes a peak plasma concentration of spironolactone of 80 ng/ml, its 7-alpha-(thiomethyl) spironolactone metabolite of 391 ng/ml and its canrenone metabolite of 181 ng/ml, and even levels of this magnitude are unlikely to have been achieved on a dose of 25 mg spironolactone. Clearly, the cross-reactivity of spironolactone with the androstenedione assay in this patient was higher than that quoted by the manufacturer. Liquid chromatography–mass spectrometry is the preferred method for measurement of steroids because it offers improved specificity over immunoassay. Spironolactone does not interfere in a tandem MS assay for androstenedione because of their different molecular weights (416 compared to 286). It is important that endocrinologists are aware of the limitations of their local assay; use LCMS for androstenedione measurement if available; and if LCMS is not locally available, it would be preferable to send samples for androstenedione analysis to a laboratory with this technology. Where cross-reaction of medications with immunoassays is not recognized there is potential for impact upon patient management.
Conflict of interest The authors have no conflict of interest or financial disclosure to declare. Rachel K. Crowley*, Deirdre Broderick*, Triona O’Shea*, Gerard Boran†, Vincent Maher‡, Stephen Crowther§, James Gibney*, Kevin C. Conlon¶ and Mark Sherlock* *Departments of Endocrinology, †Chemical Pathology, ‡Cardiology, §Cellular Pathology, and ¶Professorial Surgical Unit, Tallaght Hospital, Dublin, Ireland E-mail: [email protected] The patient reviewed the manuscript and gave permission for publication.
doi: 10.1111/cen.12372
References 1 Arlt, W., Biehl, M., Taylor, A.E. et al. (2011) Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors. Journal of Clinical Endocrinology and Metabolism, 96, 3775–3784. 2 Zeiger, M.A., Siegelman, S.S. & Hamrahian, A.H. (2011) Medical and surgical evaluation and treatment of adrenal incidentalomas. Journal of Clinical Endocrinology and Metabolism, 96, 2004–2015. 3 Hamrahian, A.H., Ioachimescu, A.G., Remer, E.M. et al. (2005) Clinical utility of noncontrast computed tomography attenuation value (hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience. Journal of Clinical Endocrinology and Metabolism, 90, 871–877. 4 Honour, J.W., Tsilchorozidou, T., Conway, G.S. et al. (2010) Spironolactone interference in the immunoassay of androstenedione. Annals of Clinical Biochemistry, 47, 564–566.
Noninvasive encapsulated follicular variant of papillary thyroid carcinoma: is lobectomy sufficient for tumours ≥1 cm? Dear Editor, Some authors have shown that the encapsulated follicular variant of papillary thyroid carcinoma (E-FVPTC) has a better prognosis than encapsulated classic PTC1,2 and nonencapsulated FVPTC.3,4 In patients with PTC restricted to the gland (i.e. without extrathyroid invasion or apparent metastases), lobectomy is considered sufficient for unifocal tumours ≤1 cm, whereas total thyroidectomy followed by 131I ablation is recommended for tumours >4 cm.5 In the case of tumours >1 cm and ≤4 cm, more aggressive initial therapy should be considered in the presence of vascular invasion.5 Therefore, doubts remain regarding the treatment of intrathyroid PTC when the tumour measures 1–4 cm and does not exhibit vascular invasion. As the hypothesis is that E-FVPTC is more indolent, it is important to know
© 2013 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 629–632
Letters to the Editor 631 the evolution of patients with this histological subtype when treated less aggressively. To our knowledge, only two studies reported the long-term results of patients with E-FVPTC ≥1 cm and without vascular invasion who were treated only by lobectomy.1,3 The objective of the present study was to report the long-term evolution of patients with noninvasive E-FVPTC >1 cm when treated only by lobectomy. At our institution, well-differentiated thyroid carcinomas that exhibit the following histological criteria have been classified as noninvasive E-FVPTC1,3: (i) tumour totally surrounded by a fibrous capsule; (ii) follicular architecture; (iii) unequivocal nuclear changes of PTC (multifocal or diffuse); (iv) absence of capsular or vascular invasion. Capsular invasion is defined as complete penetration of the entire thickness of the tumour capsule. Vascular invasion is defined as invasion of a vessel located in or outside the tumour capsule. All patients with this diagnosis (noninvasive E-FVPTC) and followed up for a minimum period of 1 year after surgery were initially selected (n = 112). As consensus exists regarding the conservative management of microcarcinomas,5 these cases were excluded (n = 4). Patients submitted to total thyroidectomy (n = 51) were also excluded. The sample of interest for this study consisted of patients treated by lobectomy (n = 57), including 47 women and 10 men ranging in age from 11 to 72 years (mean 45 years). Tumour size ranged from 11 to 4 cm (mean 29 cm). Three patients had papillary microcarcinoma associated with the main tumour. The following protocol was used for the follow-up of all patients. After surgery, levothyroxine therapy was initiated to maintain TSH between 05 and 2 mIU/l. Approximately 6 months later, the patients were evaluated by clinical examination, chest X-ray, neck ultrasonography (US), and measurement of thyroglobulin (Tg) and anti-Tg antibodies (TgAb). Patients with clinically or radiologically apparent metastases or with Tg > 10 ng/ml were submitted to complementary surgery. Subsequently, clinical examination, unstimulated Tg, TgAb, US and chest X-ray were obtained annually. Six of the 57 patients studied had a pre- or perioperative suspicion of lymph node involvement and were submitted to cervical lymph node dissection, but metastases were not confirmed in any of these patients. Fifty-five patients had no apparent disease and presented Tg 10 ng/ml persisted in two patients who were submitted to complementary thyroidectomy, but no additional focus of the tumour or metastases were detected. None of the patients received 131I. The patients were followed up for 12–122 months (median 72 months), and no recurrence or elevation of Tg or TgAb was observed. In the last assessment, a reduction in Tg was seen in 41 of 50 patients without TgAb compared with the results of the first assessment after surgery. Among the seven patients with TgAb, these antibodies disappeared in three, decreased in two, and titres remained stable (slightly above the reference values) in two. © 2013 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 629–632
Although not included in the present study, there was no case of recurrence among the 51 patients with noninvasive E-FVPTC >1 cm submitted to total thyroidectomy without 131 I ablation. First, in the present series, none of the cases exhibited extrathyroid invasion or apparent lymph node metastases. This observation confirms the results of previous studies (for a total of 90 cases), which also showed that all noninvasive FVPTCs ≥1 cm were restricted to the thyroid on presentation.1,3,4 Some studies have shown that recurrences are exceptional in patients with noninvasive E-FVPTC,2,4 but almost all patients were submitted to total thyroidectomy with or without 131I ablation. The present results suggest that in patients with noninvasive E-FVPTC lobectomy is sufficient, even in cases of tumours ≥1 cm. Although further recurrences are possible, we do not believe that they will occur in a sufficient number to significantly alter the conclusion. It is known that approximately 80% of tumour recurrences are diagnosed in the first 5 years of follow-up. Moreover, a reduction in Tg and TgAb concentrations, a known predictor of disease-free survival, was reported in 46 of 57 patients; and no elevation of Tg or TgAb was observed. In agreement with this proposal, Liu et al.3 observed no recurrence in 31 patients with tumours of this subtype ≥1 cm treated only by lobectomy and followed up for 11 years. The same was reported by Rivera et al.1 for 30 patients followed up for 9 years. In the study of Baloch et al.,2 one patient with noninvasive E-FVPTC developed bone metastases 7 years after initial surgery. Elevation of serum Tg is useful for the detection of these exceptional cases of recurrence. The demonstration that lobectomy is sufficient for noninvasive FVPTC >1 cm may spare some patients with thyroid cancer from the costs and risks of complementary surgery, 131I ablation, and TSH suppression.5 Obviously, this conclusion applies even more to tumours presenting equivocal nuclear changes of PTC (indeterminate for malignancy).
Conflict of interest The author(s) declared no potential conflicts of interest. Pedro Weslley Rosario, Gustavo Cancela Penna and Maria Regina Calsolari Santa Casa de Belo Horizonte, Minas Gerais, Brasil E-mail: [email protected] doi: 10.1111/cen.12387
References 1 Rivera, M., Tuttle, R.M., Patel, S. et al. (2009) Encapsulated papillary thyroid carcinoma: a clinico-pathologic study of 106 cases with emphasis on its morphologic subtypes (histologic growth pattern). Thyroid, 19, 119–127. 2 Baloch, Z.W., Shafique, K., Flannagan, M. et al. (2010) Encapsulated classic and follicular variants of papillary thyroid carcinoma:
632 Letters to the Editor comparative clinicopathologic study. Endocrine Practice, 16, 952– 959. 3 Liu, J., Singh, B., Tallini, G. et al. (2006) Follicular variant of papillary thyroid carcinoma: a clinicopathologic study of a problematic entity. Cancer, 107, 1255–1264. 4 Vivero, M., Kraft, S. & Barletta, J.A. (2013) Risk stratification of follicular variant of papillary thyroid carcinoma. Thyroid, 23, 273– 279.
5 Cooper, D.S., Doherty, G.M., Haugen, B.R. et al. (2009) Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 19, 1167–1214.
© 2013 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 629–632
Conflict of interest The authors have no conflict of interest or financial disclosure to declare. Rachel K. Crowley*, Deirdre Broderick*, Triona O’Shea*, Gerard Boran†, Vincent Maher‡, Stephen Crowther§, James Gibney*, Kevin C. Conlon¶ and Mark Sherlock* *Departments of Endocrinology, †Chemical Pathology, ‡Cardiology, §Cellular Pathology, and ¶Professorial Surgical Unit, Tallaght Hospital, Dublin, Ireland E-mail: [email protected] The patient reviewed the manuscript and gave permission for publication.
doi: 10.1111/cen.12372
References 1 Arlt, W., Biehl, M., Taylor, A.E. et al. (2011) Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors. Journal of Clinical Endocrinology and Metabolism, 96, 3775–3784. 2 Zeiger, M.A., Siegelman, S.S. & Hamrahian, A.H. (2011) Medical and surgical evaluation and treatment of adrenal incidentalomas. Journal of Clinical Endocrinology and Metabolism, 96, 2004–2015. 3 Hamrahian, A.H., Ioachimescu, A.G., Remer, E.M. et al. (2005) Clinical utility of noncontrast computed tomography attenuation value (hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience. Journal of Clinical Endocrinology and Metabolism, 90, 871–877. 4 Honour, J.W., Tsilchorozidou, T., Conway, G.S. et al. (2010) Spironolactone interference in the immunoassay of androstenedione. Annals of Clinical Biochemistry, 47, 564–566.
Noninvasive encapsulated follicular variant of papillary thyroid carcinoma: is lobectomy sufficient for tumours ≥1 cm? Dear Editor, Some authors have shown that the encapsulated follicular variant of papillary thyroid carcinoma (E-FVPTC) has a better prognosis than encapsulated classic PTC1,2 and nonencapsulated FVPTC.3,4 In patients with PTC restricted to the gland (i.e. without extrathyroid invasion or apparent metastases), lobectomy is considered sufficient for unifocal tumours ≤1 cm, whereas total thyroidectomy followed by 131I ablation is recommended for tumours >4 cm.5 In the case of tumours >1 cm and ≤4 cm, more aggressive initial therapy should be considered in the presence of vascular invasion.5 Therefore, doubts remain regarding the treatment of intrathyroid PTC when the tumour measures 1–4 cm and does not exhibit vascular invasion. As the hypothesis is that E-FVPTC is more indolent, it is important to know
© 2013 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 629–632
Letters to the Editor 631 the evolution of patients with this histological subtype when treated less aggressively. To our knowledge, only two studies reported the long-term results of patients with E-FVPTC ≥1 cm and without vascular invasion who were treated only by lobectomy.1,3 The objective of the present study was to report the long-term evolution of patients with noninvasive E-FVPTC >1 cm when treated only by lobectomy. At our institution, well-differentiated thyroid carcinomas that exhibit the following histological criteria have been classified as noninvasive E-FVPTC1,3: (i) tumour totally surrounded by a fibrous capsule; (ii) follicular architecture; (iii) unequivocal nuclear changes of PTC (multifocal or diffuse); (iv) absence of capsular or vascular invasion. Capsular invasion is defined as complete penetration of the entire thickness of the tumour capsule. Vascular invasion is defined as invasion of a vessel located in or outside the tumour capsule. All patients with this diagnosis (noninvasive E-FVPTC) and followed up for a minimum period of 1 year after surgery were initially selected (n = 112). As consensus exists regarding the conservative management of microcarcinomas,5 these cases were excluded (n = 4). Patients submitted to total thyroidectomy (n = 51) were also excluded. The sample of interest for this study consisted of patients treated by lobectomy (n = 57), including 47 women and 10 men ranging in age from 11 to 72 years (mean 45 years). Tumour size ranged from 11 to 4 cm (mean 29 cm). Three patients had papillary microcarcinoma associated with the main tumour. The following protocol was used for the follow-up of all patients. After surgery, levothyroxine therapy was initiated to maintain TSH between 05 and 2 mIU/l. Approximately 6 months later, the patients were evaluated by clinical examination, chest X-ray, neck ultrasonography (US), and measurement of thyroglobulin (Tg) and anti-Tg antibodies (TgAb). Patients with clinically or radiologically apparent metastases or with Tg > 10 ng/ml were submitted to complementary surgery. Subsequently, clinical examination, unstimulated Tg, TgAb, US and chest X-ray were obtained annually. Six of the 57 patients studied had a pre- or perioperative suspicion of lymph node involvement and were submitted to cervical lymph node dissection, but metastases were not confirmed in any of these patients. Fifty-five patients had no apparent disease and presented Tg 10 ng/ml persisted in two patients who were submitted to complementary thyroidectomy, but no additional focus of the tumour or metastases were detected. None of the patients received 131I. The patients were followed up for 12–122 months (median 72 months), and no recurrence or elevation of Tg or TgAb was observed. In the last assessment, a reduction in Tg was seen in 41 of 50 patients without TgAb compared with the results of the first assessment after surgery. Among the seven patients with TgAb, these antibodies disappeared in three, decreased in two, and titres remained stable (slightly above the reference values) in two. © 2013 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 629–632
Although not included in the present study, there was no case of recurrence among the 51 patients with noninvasive E-FVPTC >1 cm submitted to total thyroidectomy without 131 I ablation. First, in the present series, none of the cases exhibited extrathyroid invasion or apparent lymph node metastases. This observation confirms the results of previous studies (for a total of 90 cases), which also showed that all noninvasive FVPTCs ≥1 cm were restricted to the thyroid on presentation.1,3,4 Some studies have shown that recurrences are exceptional in patients with noninvasive E-FVPTC,2,4 but almost all patients were submitted to total thyroidectomy with or without 131I ablation. The present results suggest that in patients with noninvasive E-FVPTC lobectomy is sufficient, even in cases of tumours ≥1 cm. Although further recurrences are possible, we do not believe that they will occur in a sufficient number to significantly alter the conclusion. It is known that approximately 80% of tumour recurrences are diagnosed in the first 5 years of follow-up. Moreover, a reduction in Tg and TgAb concentrations, a known predictor of disease-free survival, was reported in 46 of 57 patients; and no elevation of Tg or TgAb was observed. In agreement with this proposal, Liu et al.3 observed no recurrence in 31 patients with tumours of this subtype ≥1 cm treated only by lobectomy and followed up for 11 years. The same was reported by Rivera et al.1 for 30 patients followed up for 9 years. In the study of Baloch et al.,2 one patient with noninvasive E-FVPTC developed bone metastases 7 years after initial surgery. Elevation of serum Tg is useful for the detection of these exceptional cases of recurrence. The demonstration that lobectomy is sufficient for noninvasive FVPTC >1 cm may spare some patients with thyroid cancer from the costs and risks of complementary surgery, 131I ablation, and TSH suppression.5 Obviously, this conclusion applies even more to tumours presenting equivocal nuclear changes of PTC (indeterminate for malignancy).
Conflict of interest The author(s) declared no potential conflicts of interest. Pedro Weslley Rosario, Gustavo Cancela Penna and Maria Regina Calsolari Santa Casa de Belo Horizonte, Minas Gerais, Brasil E-mail: [email protected] doi: 10.1111/cen.12387
References 1 Rivera, M., Tuttle, R.M., Patel, S. et al. (2009) Encapsulated papillary thyroid carcinoma: a clinico-pathologic study of 106 cases with emphasis on its morphologic subtypes (histologic growth pattern). Thyroid, 19, 119–127. 2 Baloch, Z.W., Shafique, K., Flannagan, M. et al. (2010) Encapsulated classic and follicular variants of papillary thyroid carcinoma:
632 Letters to the Editor comparative clinicopathologic study. Endocrine Practice, 16, 952– 959. 3 Liu, J., Singh, B., Tallini, G. et al. (2006) Follicular variant of papillary thyroid carcinoma: a clinicopathologic study of a problematic entity. Cancer, 107, 1255–1264. 4 Vivero, M., Kraft, S. & Barletta, J.A. (2013) Risk stratification of follicular variant of papillary thyroid carcinoma. Thyroid, 23, 273– 279.
5 Cooper, D.S., Doherty, G.M., Haugen, B.R. et al. (2009) Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 19, 1167–1214.
© 2013 John Wiley & Sons Ltd Clinical Endocrinology (2014), 81, 629–632
