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Medullary thyroid cancer presenting with airway obstruction
International Journal of Pediatric Otorhinolaryngology Extra 14 (2016) 1e3
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology Extra journal homepage: http://www.ijporlextra.com/
Case Report
Medullary thyroid cancer presenting with airway obstruction P. Shah a, *, C. Reddy b, R. Lawrence a, P. Sudarshan b, S. Wilne c, M. Daniel a a
Department of Otorhinolaryngology, Nottinghamshire University Hospitals NHS Trust, UK Department of Anaesthetics, Nottinghamshire University Hospitals NHS Trust, UK c Department of Paediatric Oncology, Nottinghamshire University Hospitals NHS Trust, UK b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 July 2016 Received in revised form 11 September 2016 Accepted 13 September 2016 Available online 16 September 2016
A 13-year-old boy with skeletal dysplasia was found to have a subglottic cyst on oesophagogastroduodenoscopy for chronic diarrhoea. He underwent a Laryngotracheobronchoscopy, which showed a narrow subglottis. Tracheal biopsies raised the possibility of a neuroendocrine disease. CT scan showed multiple lung nodules and a thyroid mass. A diagnosis of medullary thyroid carcinoma (MTC) was made based on these findings. He underwent a tracheostomy to relieve airway obstruction and open biopsies of the thyroid were taken, all suggestive of MTC. Genetic testing showed Multiple Endocrine Neoplasia Type 2A and 2B. We discuss the unusual presentation of Medullary Thyroid Carcinoma. Crown Copyright © 2016 Published by Elsevier Ltd. All rights reserved.
Keywords: Airway obstruction Medullary thyroid cancer Multiple endocrine neoplasia Cabozantinib
1. Case report A 13-year-old boy with acromelic skeletal dysplasia presented with chronic diarrhoea for several years, and underwent upper and lower gastrointestinal endoscopy. At Oesophagogastroduodenoscopy, a subglottic lesion with an appearance of a cyst was noticed and he was therefore subsequently listed for laryngotracheobronchoscopy (LTB). At LTB, however, the patient was found to have a very narrow subglottis and upper trachea, which only just managed to accept a 2.9 mm Hopkins rod lens telescope (Fig. 1). The subglottic lesion had an appearance suggestive of Mucopolysaccharoidosis. Tracheal biopsies were taken. Post-operatively, he required nebulised adrenaline and observation on paediatric high dependency unit due to stridor and airway obstruction, but was discharged the day after surgery having returned to his usual state. On review of symptoms, it became apparent that he had been having breathing difficulties, which were diagnosed as asthma, although bronchodilators failed to improve in his symptoms. Initially the patient's symptoms were considered to be related to skeletal dysplasia, as both tracheal stenosis and skeletal dysplasia arise from an underlying storage disorder e an error of metabolism associated with abnormal deposition of incompletely or aberrantly metabolized molecules in the tissues. However, the tracheal
* Corresponding author. E-mail addresses: [email protected], [email protected] (P. Shah). http://dx.doi.org/10.1016/j.pedex.2016.09.003 1871-4048/Crown Copyright © 2016 Published by Elsevier Ltd. All rights reserved.
biopsies raised the possibility of a neuroendocrine tumour. A CT scan of the neck and thorax showed narrowing of the trachea, a mass in the thyroid area and multiple lung nodules in keeping with metastatic disease (Fig. 2). With this additional information, histology was reviewed, and a diagnosis of medullary thyroid cancer made. Subsequently, he underwent a tracheostomy to relieve airway obstruction, and open biopsies of the thyroid undertaken at the same time were positive for synaptophysin, calcitonin, cytokeratin AE1/AE3 and focally positive for TTF1, all suggestive of medullary thyroid carcinoma. Genetic testing showed the patient's DNA contained the RET mutation, which is known to be involved in Multiple Endocrine Neoplasia Type 2A and 2B [3,7]. The patient was discussed at the regional Multidisciplinary team meetings (MDTs) for thyroid cancers and for Head & Neck cancers, and also with national paediatric thyroid cancer experts. It was agreed that, due to its extensive local invasion in particular in the upper mediastinum, it would not be possible to resect the primary tumour. The patient was commenced on oral chemotherapy with Cabozantinib, a non-specific tyrosine kinase inhibitor. He responded well to treatment, with a noticeable reduction in calcitonin levels from 37034ng/L to 10446ng/L and CT scan showing a reduction in tumour size. However, weeks into treatment he developed a tracheooesophageal fistula. Oral intake was therefore prohibited, and a PEG inserted. Six week later a repeat contrast swallow showed that the leak had stopped, and Cabozantinib was restarted.
2
P. Shah et al. / International Journal of Pediatric Otorhinolaryngology Extra 14 (2016) 1e3 Table 1 Classification of MEN 2A and 2B syndromes (adapted from Wells et al., 2015 [2]). Type 2A MEN2A classical (medullary thyroid cancer, phaeochromocytoma, primary hyperparathyroidism MEN2A with cutaneous lichen amyloidosis MEN2A with Hirschsprung disease Familial Medullary cancer without phaeochromocytoma or parathyroid hyperplasia Type 2B Medullary Thyroid Cancer, Phaeochromocytoma ± Mucosal Neuromas, Intestinal ganglioneuromas, Marfanoid Habitus
Fig. 1. The very narrow airway found at LTB.
Fig. 2. CT demonstrating narrowed trachea and the thyroid mass.
He continues on Cabozantinib and to date has shown a good tumour response. 2. Discussion Medullary Thyroid Carcinoma (MTC) is a neuroendocrine tumour of the parafollicular C-cells of the thyroid gland [1]. MTCs generally present as a solitary thyroid nodule, usually first noticed as a neck lump [2]. The unusual presentation in our case was with airway obstruction, although on history review the patient had actually had another feature of MTC, diarrhoea, for several years. MTCs typically secrete calcitonin [4], which is known to cause diarrhoea. Both diarrhoea and airway obstruction are also seen in skeletal dysplasia, and certainly in the case of airway difficulties, our initial diagnosis was thought to be related to the underlying skeletal dysplasia. Small airway biopsies were also initially difficult to interpret, and it was not until the CT scan detected presence of multiple lung metastases that the diagnosis became clear; subsequent open, larger biopsies were of course easier to interpret. Most MTCs are sporadic but approximately 25% are a result of Multiple Endocrine Neoplasia (MEN) syndrome [2]. There are two types of MEN, MEN 1 and MEN 2, the latter further divided into MEN 2A and MEN 2B. Familial MTC alone (Table 1) is now considered a part of MEN 2A syndrome, which mainly manifests in the upper 1/3 of the thyroid gland [4]. MEN 2B has similar characteristics as MEN 2A but tend to present earlier [5]. MEN 2B patients
also display marfanoid habitus, although they do not have Marfan's syndrome; they have mucosal neuromas and also have internal ganglion neuromatosis, along with Medullary Thyroid Carcinoma and Phaeochromocytoma [6]. Our patient had a shorter habitus due to his skeletal dysplasia. Treatment of MTC with curative intent is surgical. In our patient, surgery was considered despite the presence of lung metastases, but due to extensive local invasion particularly in the mediastinum it was not deemed possible to resect the primary tumour. This decision was taken in conjuncture with the American Thyroid Association Guidelines, where the patient was felt not to be suitable to surgical treatment, rather more suitable for a tyrosine kinase inhibitor (Fig. 3) [2]. Unresectable medullary thyroid carcinoma is incurable. Recently, two tyrosine kinase inhibitors, cabozantinib and vandetanib, have been licensed for the treatment of progressive and symptomatic unresectable, locally advanced or metastatic medullary thyroid carcinoma [8,9]. A randomised controlled trial looking at the use of Cabozantinib showed a response rate of 60%, with patients experiencing an improvement in quality of life and symptom-free time from 4 months in the placebo arm to 11 months in the Cabozantinib arm [10]. The rationale for starting Cabozantinib in this patient was that he had an advanced, symptomatic and metastatic disease, which was likely to be slow growing. The evidence for the slow growing nature of the tumour was the diarrhoea the patient had had for several years. Diarrhoea only occurs in large volume or metastatic disease. Hence, achieving a degree of tumour control or shrinkage was likely to be associated with a significant improvement in quality of life and prolongation of life. Fistula development secondary to Cabozantinib is a rare but recognised complication of the treatment. The risk factors for this are previous radiotherapy or invasion of trachea and oesophagus with the tumour (as was the case in this patient). The patient was restarted on Cabozantinib after the fistula was managed. Although restarting Cabozantinib can be associated with recurrent fistulae, in the absence of any other treatment, the patient and his family were willing to continue with Cabozantinib and this was supported by the paediatric oncology MDT. Our patient's presentation was unusual, in that the diagnosis was made on the basis of ENT referral following discovery of a lump at OGD. In retrospect, diarrhoea was likely linked, and symptoms of airway obstruction existed also. The challenge of making a cancer diagnosis in a young patient with atypical symptoms and related pathology that could explain presenting symptoms is clearly great. Airway obstruction as the presenting symptom of MTC is rare [11]. This is a rare case, with unusual presentation. Airway problems were not the presenting issue, and initial thoughts that skeletal dysplasia related-airway abnormality was responsible proved wrong. Instead, a second, rare pathology was discovered. The case illustrates how presentation is not always obvious, and the need to
P. Shah et al. / International Journal of Pediatric Otorhinolaryngology Extra 14 (2016) 1e3
3
Fig. 3. Revised ATA guidelines outlining the management of suspected MTC. Our patient fit into the metastatic MTC arm and therefore was started on tyrosine kinase inhibitor. Image taken from Wells SA Jr, Asa SL, Dralle H et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25:567.
consider a wide differential diagnosis to ensure that rare cases of cancer in childhood are identified. References [1] E. Kebebew, P.H. Ituarte, A.E. Siperstein, et al., Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems, Cancer 88 (2000) 1139. [2] S.A. Wells Jr., S.L. Asa, H. Dralle, et al., Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma, Thyroid 25 (2015) 567. [3] F. Pacini, M.G. Castagna, C. Cipri, M. Schlumberger, Medullary thyroid carcinoma, Clin. Oncol. R. Coll. Radiol. 22 (2010) 475. [4] M.J. Bugalho, J.R. Santos, L. Sobrinho, Preoperative diagnosis of medullary thyroid carcinoma: fine needle aspiration cytology as compared with serum calcitonin measurement, J. Surg. Oncol. 91 (2005) 56. [5] F. Raue, K. Frank-Raue, A. Grauer, Multiple endocrine neoplasia type 2. Clinical
features and screening, Endocrinol. Metab. Clin. North Am. 23 (1994) 137. [6] Brandi, et al., Guidelines for diagnosis and therapy of MEN type 1 and type 2, J. Clin. Endocrinol. Metab. 86 (12) (2001) 5658. [7] R.M. Hofstra, R.M. Landsvater, I. Ceccherini, et al., A mutation in the RET protooncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma, Nature 367 (1994) 375. [8] J. Smit, Treatment of advanced medullary thyroid cancer, Thyroid Res. 6 (Suppl 1) (2013) S7. [9] R. Elisei, et al., Cabozantinib in progressive medullary thyroid Cancer, J. Clin. Oncol. 31 (2013) 3639e3646. [10] P. Schoffski, et al., An international, double blind, randomized, placebocontrolled phase III trial (EXAM) of cabozantinib (XL-184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline, J. Clin. Oncol. 30 (15-Suppl5508) (2012). [11] P. Dharmshaktu, et al., MEN2B syndrome presenting as an acute respiratory emergency, BMJ Case Rep. (2013), http://dx.doi.org/10.1136/bcr-2013-201080 [Published Online].
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology Extra journal homepage: http://www.ijporlextra.com/
Case Report
Medullary thyroid cancer presenting with airway obstruction P. Shah a, *, C. Reddy b, R. Lawrence a, P. Sudarshan b, S. Wilne c, M. Daniel a a
Department of Otorhinolaryngology, Nottinghamshire University Hospitals NHS Trust, UK Department of Anaesthetics, Nottinghamshire University Hospitals NHS Trust, UK c Department of Paediatric Oncology, Nottinghamshire University Hospitals NHS Trust, UK b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 July 2016 Received in revised form 11 September 2016 Accepted 13 September 2016 Available online 16 September 2016
A 13-year-old boy with skeletal dysplasia was found to have a subglottic cyst on oesophagogastroduodenoscopy for chronic diarrhoea. He underwent a Laryngotracheobronchoscopy, which showed a narrow subglottis. Tracheal biopsies raised the possibility of a neuroendocrine disease. CT scan showed multiple lung nodules and a thyroid mass. A diagnosis of medullary thyroid carcinoma (MTC) was made based on these findings. He underwent a tracheostomy to relieve airway obstruction and open biopsies of the thyroid were taken, all suggestive of MTC. Genetic testing showed Multiple Endocrine Neoplasia Type 2A and 2B. We discuss the unusual presentation of Medullary Thyroid Carcinoma. Crown Copyright © 2016 Published by Elsevier Ltd. All rights reserved.
Keywords: Airway obstruction Medullary thyroid cancer Multiple endocrine neoplasia Cabozantinib
1. Case report A 13-year-old boy with acromelic skeletal dysplasia presented with chronic diarrhoea for several years, and underwent upper and lower gastrointestinal endoscopy. At Oesophagogastroduodenoscopy, a subglottic lesion with an appearance of a cyst was noticed and he was therefore subsequently listed for laryngotracheobronchoscopy (LTB). At LTB, however, the patient was found to have a very narrow subglottis and upper trachea, which only just managed to accept a 2.9 mm Hopkins rod lens telescope (Fig. 1). The subglottic lesion had an appearance suggestive of Mucopolysaccharoidosis. Tracheal biopsies were taken. Post-operatively, he required nebulised adrenaline and observation on paediatric high dependency unit due to stridor and airway obstruction, but was discharged the day after surgery having returned to his usual state. On review of symptoms, it became apparent that he had been having breathing difficulties, which were diagnosed as asthma, although bronchodilators failed to improve in his symptoms. Initially the patient's symptoms were considered to be related to skeletal dysplasia, as both tracheal stenosis and skeletal dysplasia arise from an underlying storage disorder e an error of metabolism associated with abnormal deposition of incompletely or aberrantly metabolized molecules in the tissues. However, the tracheal
* Corresponding author. E-mail addresses: [email protected], [email protected] (P. Shah). http://dx.doi.org/10.1016/j.pedex.2016.09.003 1871-4048/Crown Copyright © 2016 Published by Elsevier Ltd. All rights reserved.
biopsies raised the possibility of a neuroendocrine tumour. A CT scan of the neck and thorax showed narrowing of the trachea, a mass in the thyroid area and multiple lung nodules in keeping with metastatic disease (Fig. 2). With this additional information, histology was reviewed, and a diagnosis of medullary thyroid cancer made. Subsequently, he underwent a tracheostomy to relieve airway obstruction, and open biopsies of the thyroid undertaken at the same time were positive for synaptophysin, calcitonin, cytokeratin AE1/AE3 and focally positive for TTF1, all suggestive of medullary thyroid carcinoma. Genetic testing showed the patient's DNA contained the RET mutation, which is known to be involved in Multiple Endocrine Neoplasia Type 2A and 2B [3,7]. The patient was discussed at the regional Multidisciplinary team meetings (MDTs) for thyroid cancers and for Head & Neck cancers, and also with national paediatric thyroid cancer experts. It was agreed that, due to its extensive local invasion in particular in the upper mediastinum, it would not be possible to resect the primary tumour. The patient was commenced on oral chemotherapy with Cabozantinib, a non-specific tyrosine kinase inhibitor. He responded well to treatment, with a noticeable reduction in calcitonin levels from 37034ng/L to 10446ng/L and CT scan showing a reduction in tumour size. However, weeks into treatment he developed a tracheooesophageal fistula. Oral intake was therefore prohibited, and a PEG inserted. Six week later a repeat contrast swallow showed that the leak had stopped, and Cabozantinib was restarted.
2
P. Shah et al. / International Journal of Pediatric Otorhinolaryngology Extra 14 (2016) 1e3 Table 1 Classification of MEN 2A and 2B syndromes (adapted from Wells et al., 2015 [2]). Type 2A MEN2A classical (medullary thyroid cancer, phaeochromocytoma, primary hyperparathyroidism MEN2A with cutaneous lichen amyloidosis MEN2A with Hirschsprung disease Familial Medullary cancer without phaeochromocytoma or parathyroid hyperplasia Type 2B Medullary Thyroid Cancer, Phaeochromocytoma ± Mucosal Neuromas, Intestinal ganglioneuromas, Marfanoid Habitus
Fig. 1. The very narrow airway found at LTB.
Fig. 2. CT demonstrating narrowed trachea and the thyroid mass.
He continues on Cabozantinib and to date has shown a good tumour response. 2. Discussion Medullary Thyroid Carcinoma (MTC) is a neuroendocrine tumour of the parafollicular C-cells of the thyroid gland [1]. MTCs generally present as a solitary thyroid nodule, usually first noticed as a neck lump [2]. The unusual presentation in our case was with airway obstruction, although on history review the patient had actually had another feature of MTC, diarrhoea, for several years. MTCs typically secrete calcitonin [4], which is known to cause diarrhoea. Both diarrhoea and airway obstruction are also seen in skeletal dysplasia, and certainly in the case of airway difficulties, our initial diagnosis was thought to be related to the underlying skeletal dysplasia. Small airway biopsies were also initially difficult to interpret, and it was not until the CT scan detected presence of multiple lung metastases that the diagnosis became clear; subsequent open, larger biopsies were of course easier to interpret. Most MTCs are sporadic but approximately 25% are a result of Multiple Endocrine Neoplasia (MEN) syndrome [2]. There are two types of MEN, MEN 1 and MEN 2, the latter further divided into MEN 2A and MEN 2B. Familial MTC alone (Table 1) is now considered a part of MEN 2A syndrome, which mainly manifests in the upper 1/3 of the thyroid gland [4]. MEN 2B has similar characteristics as MEN 2A but tend to present earlier [5]. MEN 2B patients
also display marfanoid habitus, although they do not have Marfan's syndrome; they have mucosal neuromas and also have internal ganglion neuromatosis, along with Medullary Thyroid Carcinoma and Phaeochromocytoma [6]. Our patient had a shorter habitus due to his skeletal dysplasia. Treatment of MTC with curative intent is surgical. In our patient, surgery was considered despite the presence of lung metastases, but due to extensive local invasion particularly in the mediastinum it was not deemed possible to resect the primary tumour. This decision was taken in conjuncture with the American Thyroid Association Guidelines, where the patient was felt not to be suitable to surgical treatment, rather more suitable for a tyrosine kinase inhibitor (Fig. 3) [2]. Unresectable medullary thyroid carcinoma is incurable. Recently, two tyrosine kinase inhibitors, cabozantinib and vandetanib, have been licensed for the treatment of progressive and symptomatic unresectable, locally advanced or metastatic medullary thyroid carcinoma [8,9]. A randomised controlled trial looking at the use of Cabozantinib showed a response rate of 60%, with patients experiencing an improvement in quality of life and symptom-free time from 4 months in the placebo arm to 11 months in the Cabozantinib arm [10]. The rationale for starting Cabozantinib in this patient was that he had an advanced, symptomatic and metastatic disease, which was likely to be slow growing. The evidence for the slow growing nature of the tumour was the diarrhoea the patient had had for several years. Diarrhoea only occurs in large volume or metastatic disease. Hence, achieving a degree of tumour control or shrinkage was likely to be associated with a significant improvement in quality of life and prolongation of life. Fistula development secondary to Cabozantinib is a rare but recognised complication of the treatment. The risk factors for this are previous radiotherapy or invasion of trachea and oesophagus with the tumour (as was the case in this patient). The patient was restarted on Cabozantinib after the fistula was managed. Although restarting Cabozantinib can be associated with recurrent fistulae, in the absence of any other treatment, the patient and his family were willing to continue with Cabozantinib and this was supported by the paediatric oncology MDT. Our patient's presentation was unusual, in that the diagnosis was made on the basis of ENT referral following discovery of a lump at OGD. In retrospect, diarrhoea was likely linked, and symptoms of airway obstruction existed also. The challenge of making a cancer diagnosis in a young patient with atypical symptoms and related pathology that could explain presenting symptoms is clearly great. Airway obstruction as the presenting symptom of MTC is rare [11]. This is a rare case, with unusual presentation. Airway problems were not the presenting issue, and initial thoughts that skeletal dysplasia related-airway abnormality was responsible proved wrong. Instead, a second, rare pathology was discovered. The case illustrates how presentation is not always obvious, and the need to
P. Shah et al. / International Journal of Pediatric Otorhinolaryngology Extra 14 (2016) 1e3
3
Fig. 3. Revised ATA guidelines outlining the management of suspected MTC. Our patient fit into the metastatic MTC arm and therefore was started on tyrosine kinase inhibitor. Image taken from Wells SA Jr, Asa SL, Dralle H et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25:567.
consider a wide differential diagnosis to ensure that rare cases of cancer in childhood are identified. References [1] E. Kebebew, P.H. Ituarte, A.E. Siperstein, et al., Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems, Cancer 88 (2000) 1139. [2] S.A. Wells Jr., S.L. Asa, H. Dralle, et al., Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma, Thyroid 25 (2015) 567. [3] F. Pacini, M.G. Castagna, C. Cipri, M. Schlumberger, Medullary thyroid carcinoma, Clin. Oncol. R. Coll. Radiol. 22 (2010) 475. [4] M.J. Bugalho, J.R. Santos, L. Sobrinho, Preoperative diagnosis of medullary thyroid carcinoma: fine needle aspiration cytology as compared with serum calcitonin measurement, J. Surg. Oncol. 91 (2005) 56. [5] F. Raue, K. Frank-Raue, A. Grauer, Multiple endocrine neoplasia type 2. Clinical
features and screening, Endocrinol. Metab. Clin. North Am. 23 (1994) 137. [6] Brandi, et al., Guidelines for diagnosis and therapy of MEN type 1 and type 2, J. Clin. Endocrinol. Metab. 86 (12) (2001) 5658. [7] R.M. Hofstra, R.M. Landsvater, I. Ceccherini, et al., A mutation in the RET protooncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma, Nature 367 (1994) 375. [8] J. Smit, Treatment of advanced medullary thyroid cancer, Thyroid Res. 6 (Suppl 1) (2013) S7. [9] R. Elisei, et al., Cabozantinib in progressive medullary thyroid Cancer, J. Clin. Oncol. 31 (2013) 3639e3646. [10] P. Schoffski, et al., An international, double blind, randomized, placebocontrolled phase III trial (EXAM) of cabozantinib (XL-184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline, J. Clin. Oncol. 30 (15-Suppl5508) (2012). [11] P. Dharmshaktu, et al., MEN2B syndrome presenting as an acute respiratory emergency, BMJ Case Rep. (2013), http://dx.doi.org/10.1136/bcr-2013-201080 [Published Online].