Case Study
Inappropriate antidiuretic hormone secretion due to squamous cell lung cancer
Asian Cardiovascular & Thoracic Annals 2015, Vol. 23(5) 579–581 ß The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492314544128 aan.sagepub.com
Christophoros Kotoulas, Ioannis Panagiotou, Panteleimon Tsipas and Emmanouil Koutoulakis
Abstract The syndrome of inappropriate secretion of antidiuretic hormone is a disorder of impaired water excretion caused by the inability to suppress secretion of antidiuretic hormone. It has been commonly associated with small cell carcinoma. The association of this syndrome with squamous cell lung carcinoma has rarely been reported, with only 4 cases over the past two decades in the English literature. We describe the case of a 75-year-old Caucasian male who developed the syndrome after a right pneumonectomy for down-staged squamous cell lung cancer previously treated with neoadjuvant platinum-based chemotherapy and radiotherapy.
Keywords Carcinoma, non-small-cell lung, hyponatremia, inappropriate ADH syndrome, lung neoplasms, pneumonectomy, vasopressins
Introduction The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterized by excessive release of antidiuretic hormone, and the result is often dilutional hyponatremia in which the sodium level remains normal but total body fluid increases.1 The majority of tumor-related cases (70%) are linked to squamous-cell lung carcinoma, whilst SIADH is extremely rare in non-small-cell lung cancers (NSCLC).2 This case is unique in being one of SIADH development after curative resection for squamous-cell lung cancer in a patient previously treated with neoadjuvant chemotherapy and radiation therapy.
Case report A 75-year-old Caucasian male was referred to our department for resection of a down-staged squamouscell lung carcinoma. He was initially diagnosed with a cT3N2M0 centrally located tumor of the right lung, and he received 4 courses of platinum-based chemotherapy and radiotherapy. Positron emission tomography and computerized tomography (PET-CT) scan was
negative for both mediastinal and extrathoracic disease. The preoperative electrolyte panels were unremarkable with a serum sodium level of 135 mmol L 1. The patient underwent a right intrapericardial pneumonectomy and complete mediastinal lymph node dissection. The pathology report revealed a pT3N0M0 squamouscell lung carcinoma. The postoperative course was uneventful until the 6th postoperative day when paroxysmal atrial fibrillation was demonstrated despite normal electrolyte values, with the exception of mild hyponatremia (serum sodium 132 mmol L 1). Intravenous amiodarone administration resulted in control of the heart rate, although the rhythm remained irregular. On the 7th postoperative day, a marked decrease in serum sodium levels was noted (122 mmol L 1), but clinically, the patient was euvolemic,
Cardiothoracic Surgery and Cardiology Departments, Iaso General Hospital, Athens, Greece Corresponding author: Christophoros Kotoulas, PhD, FETCS, FCCP, Kifissias Ave 38, Ampelokipoi, Athens, 11526, Greece. Email: [email protected]
Downloaded from aan.sagepub.com at U.A.E University on November 13, 2015
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Asian Cardiovascular & Thoracic Annals 23(5)
hemodynamically stable, and asymptomatic. He was treated with intravenous sodium replacement but the serum sodium levels remained unchanged for the next two days. The antidiuretic hormone (ADH) level was 141 pg mL 1 (normal 0–8 pg mL 1) and the serum osmolality was low. These findings in combination with persistent hyponatremia, the euvolemic status with no diuretic use, and the absence of renal insufficiency or other metabolic disorder made the diagnosis of the syndrome clear. The patient was initially treated with fluid restriction and a mild increase in sodium levels was noted. Although the serum sodium levels remained low for the next 8 days, the patient displayed only transient and mild confusion. In addition, he was given oral demeclocycline in conjunction with intravenous furosemide and sodium replacement. He was finally discharged on the 21st postoperative day with normal serum levels. Unfortunately, he died 3 months later due to a respiratory tract infection.
Discussion Many disorders such as tumors of the lung and brain, central nervous system disturbances, adrenocorticotropic hormone deficiency, and several drugs including chemotherapeutics may cause SIADH. SIADH was first associated with malignancy when described in two patients with bronchogenic carcinoma in 1967.7 Nowadays, it is known as a paraneoplastic phenomenon, and 70% of malignancy-related cases are the result of small-cell lung carcinoma.2 In contrast, NSCLC is a very rare cause of SIADH. There have been only 4 reported cases over the past two decades.3–6 In one large case series of 427 patients with NSCLC, only 3 (0.7%) were diagnosed with SIADH.8 In 2004, Lee and colleagues9 suggested that squamouscell carcinoma produced neuropeptide Y in the hypothalamus, which stimulated the production of endogenous ADH, contrary to the direct ectopic production of ADH in small-cell lung carcinoma. A variety of chemotherapeutic agents may lead to SIADH. The mechanism of this effect may be an abnormal release of ADH or that the drug makes existing ADH work in a stronger fashion than usual. Cisplatin might induce an unknown factor which acts on the hypothalamicpituitary axis to affect the release of ADH.10 Our case is unique because the development of SIADH happened after curative resection of a squamous-cell lung carcinoma previously treated with neoadjuvant platinumbased chemotherapy plus radiation therapy. We assume that chemotherapy was not responsible for the development of SIADH because the patient presented with normal serum electrolytes on admission. He had undergone PET-CT scan preoperatively, which was negative for mediastinal and extrathoracic disease.
Thus the scenario of a latent metastasis producing an ADH-like hormone is almost impossible. We hypothesize 2 possible causes for the development of SIADH to our patient. The first is related to intraoperative manipulation of the tumor. We hypothesize that the tumor which was located centrally and near the lower pulmonary vein released some unknown hormone-like substance that eventually stimulated ADH secretion. The second hypothesis is related to amiodarone administration; this is a rare but potentially lethal adverse effect of this drug. It is speculated that amiodarone might induce SIADH by its channel-modulating properties on either renal or neural tissues. Age and sex may be contributing factors to amiodarone-induced SIADH. The elderly appear to be particularly at risk of drug-induced SIADH. It appears that amiodaroneinduced SIADH is more prevalent after a loading dose of the drug. However, because of the long half-life of amiodarone, the cumulative effect on the development of SIADH remains undefined.11 Patients with severe hyponatremia incur higher mortality, especially the elderly.12 Asymptomatic patients, as in our case, have a lower risk of neurologic sequela but can still develop osmotic demyelination if rapidly corrected.10 Restriction of water intake, eradication of the underlying cause, intravenous administration of diuretics and concentrated salt solutions along with demeclocycline have been described as the treatment of choice.13 The mechanism by which patients with squamous cell carcinoma develop SIADH is still unknown. To the best of our knowledge, the case we have described is the first report of SIADH development after curative resection of a squamous-cell lung cancer previously treated with neoadjuvant chemotherapy and radiation therapy. We suggest that tumor manipulation during surgery and postoperative amiodarone administration could be possible causes of SIADH development. Funding This research received no specific grant from any funding agency in the public, commerical, or not-for-profit sectors.
Conflict of interest statement None declared.
References 1. Rose BD and Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed. New York: McGrawHill, 2001:703. 2. Vanhees SL, Paridaens R and Vansteenkiste JF. Syndrome of inappropriate antidiuretic hormone associated with chemotherapy-induced tumour lysis in small-cell lung cancer: case report and literature review. Ann Oncol 2000; 11: 1061–1065.
Downloaded from aan.sagepub.com at U.A.E University on November 13, 2015
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3. McDonald P, Lane C, Rojas GE and Masood A. Syndrome of inappropriate anti-diuretic hormone in non-small cell lung carcinoma: a case report. Ecancermedicalscience 2012; 6: 279. 4. Katsuragi N, Shiraishi Y, Nakajima Y, Kurai M, Takahashi N and Tanaka S. Squamous cell bronchogenic carcinoma with syndrome of inappropriate secretion of antidiuretic hormone. Kyobu Geka 2004; 57: 847–850. 5. Monsieur I, Meysman M, Noppen M, et al. Non-small cell lung cancer with multiple paraneoplastic syndromes. Eur Respir J 1995; 8: 1231–1234. 6. Tho LM and Ferry DR. Is the paraneoplastic syndrome of inappropriate antidiuretic hormone secretion in lung cancer always attributable to the small cell variety? Postgrad Med J 2005; 81: e17. 7. Bartter FC and Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone [Review]. Am J Med 1967; 42: 790–806. 8. Sausville E, Carney D and Battey J. The human vasopressin gene is linked to the oxytocin gene and is selectively
9.
10. 11. 12.
13.
expressed in a cultured lung cancer cell line. J Biol Chem 1985; 260: 10236–10241. Lee JH, Cha MJ, Choi SH, Hwang SJ, Kim DG and Jahng JW. Neuropeptide Y immunoreactivity and corticotropin-releasing hormone mRNA level are increased in the hypothalamus of mouse bearing a human oral squamous cell carcinoma. Neuropeptides 2004; 38: 345–350. Ellison DH and Berl T. The syndrome of inappropriate diuresis. N Engl J Med 2007; 356: 2064–2072. Shavit E and Sherer Y. Hyponatremia induced by amiodarone therapy. Isr Med Assoc J 2007; 9: 564–565. Sherlock M and Thompson CJ. The syndrome of inappropriate antidiuretic hormone: current and future management options. Eur J Endocrinol 2010; 162(Suppl 1): S13–S18. Pillai BP, Unnikrishnan AG and Pavithran PV. Syndrome of inappropriate antidiuretic hormone secretion: revisiting a classical endocrine disorder. Indian J Endocr Metab 2011; 15(Suppl 3): S208–S215.
Downloaded from aan.sagepub.com at U.A.E University on November 13, 2015
Inappropriate antidiuretic hormone secretion due to squamous cell lung cancer
Asian Cardiovascular & Thoracic Annals 2015, Vol. 23(5) 579–581 ß The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492314544128 aan.sagepub.com
Christophoros Kotoulas, Ioannis Panagiotou, Panteleimon Tsipas and Emmanouil Koutoulakis
Abstract The syndrome of inappropriate secretion of antidiuretic hormone is a disorder of impaired water excretion caused by the inability to suppress secretion of antidiuretic hormone. It has been commonly associated with small cell carcinoma. The association of this syndrome with squamous cell lung carcinoma has rarely been reported, with only 4 cases over the past two decades in the English literature. We describe the case of a 75-year-old Caucasian male who developed the syndrome after a right pneumonectomy for down-staged squamous cell lung cancer previously treated with neoadjuvant platinum-based chemotherapy and radiotherapy.
Keywords Carcinoma, non-small-cell lung, hyponatremia, inappropriate ADH syndrome, lung neoplasms, pneumonectomy, vasopressins
Introduction The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterized by excessive release of antidiuretic hormone, and the result is often dilutional hyponatremia in which the sodium level remains normal but total body fluid increases.1 The majority of tumor-related cases (70%) are linked to squamous-cell lung carcinoma, whilst SIADH is extremely rare in non-small-cell lung cancers (NSCLC).2 This case is unique in being one of SIADH development after curative resection for squamous-cell lung cancer in a patient previously treated with neoadjuvant chemotherapy and radiation therapy.
Case report A 75-year-old Caucasian male was referred to our department for resection of a down-staged squamouscell lung carcinoma. He was initially diagnosed with a cT3N2M0 centrally located tumor of the right lung, and he received 4 courses of platinum-based chemotherapy and radiotherapy. Positron emission tomography and computerized tomography (PET-CT) scan was
negative for both mediastinal and extrathoracic disease. The preoperative electrolyte panels were unremarkable with a serum sodium level of 135 mmol L 1. The patient underwent a right intrapericardial pneumonectomy and complete mediastinal lymph node dissection. The pathology report revealed a pT3N0M0 squamouscell lung carcinoma. The postoperative course was uneventful until the 6th postoperative day when paroxysmal atrial fibrillation was demonstrated despite normal electrolyte values, with the exception of mild hyponatremia (serum sodium 132 mmol L 1). Intravenous amiodarone administration resulted in control of the heart rate, although the rhythm remained irregular. On the 7th postoperative day, a marked decrease in serum sodium levels was noted (122 mmol L 1), but clinically, the patient was euvolemic,
Cardiothoracic Surgery and Cardiology Departments, Iaso General Hospital, Athens, Greece Corresponding author: Christophoros Kotoulas, PhD, FETCS, FCCP, Kifissias Ave 38, Ampelokipoi, Athens, 11526, Greece. Email: [email protected]
Downloaded from aan.sagepub.com at U.A.E University on November 13, 2015
580
Asian Cardiovascular & Thoracic Annals 23(5)
hemodynamically stable, and asymptomatic. He was treated with intravenous sodium replacement but the serum sodium levels remained unchanged for the next two days. The antidiuretic hormone (ADH) level was 141 pg mL 1 (normal 0–8 pg mL 1) and the serum osmolality was low. These findings in combination with persistent hyponatremia, the euvolemic status with no diuretic use, and the absence of renal insufficiency or other metabolic disorder made the diagnosis of the syndrome clear. The patient was initially treated with fluid restriction and a mild increase in sodium levels was noted. Although the serum sodium levels remained low for the next 8 days, the patient displayed only transient and mild confusion. In addition, he was given oral demeclocycline in conjunction with intravenous furosemide and sodium replacement. He was finally discharged on the 21st postoperative day with normal serum levels. Unfortunately, he died 3 months later due to a respiratory tract infection.
Discussion Many disorders such as tumors of the lung and brain, central nervous system disturbances, adrenocorticotropic hormone deficiency, and several drugs including chemotherapeutics may cause SIADH. SIADH was first associated with malignancy when described in two patients with bronchogenic carcinoma in 1967.7 Nowadays, it is known as a paraneoplastic phenomenon, and 70% of malignancy-related cases are the result of small-cell lung carcinoma.2 In contrast, NSCLC is a very rare cause of SIADH. There have been only 4 reported cases over the past two decades.3–6 In one large case series of 427 patients with NSCLC, only 3 (0.7%) were diagnosed with SIADH.8 In 2004, Lee and colleagues9 suggested that squamouscell carcinoma produced neuropeptide Y in the hypothalamus, which stimulated the production of endogenous ADH, contrary to the direct ectopic production of ADH in small-cell lung carcinoma. A variety of chemotherapeutic agents may lead to SIADH. The mechanism of this effect may be an abnormal release of ADH or that the drug makes existing ADH work in a stronger fashion than usual. Cisplatin might induce an unknown factor which acts on the hypothalamicpituitary axis to affect the release of ADH.10 Our case is unique because the development of SIADH happened after curative resection of a squamous-cell lung carcinoma previously treated with neoadjuvant platinumbased chemotherapy plus radiation therapy. We assume that chemotherapy was not responsible for the development of SIADH because the patient presented with normal serum electrolytes on admission. He had undergone PET-CT scan preoperatively, which was negative for mediastinal and extrathoracic disease.
Thus the scenario of a latent metastasis producing an ADH-like hormone is almost impossible. We hypothesize 2 possible causes for the development of SIADH to our patient. The first is related to intraoperative manipulation of the tumor. We hypothesize that the tumor which was located centrally and near the lower pulmonary vein released some unknown hormone-like substance that eventually stimulated ADH secretion. The second hypothesis is related to amiodarone administration; this is a rare but potentially lethal adverse effect of this drug. It is speculated that amiodarone might induce SIADH by its channel-modulating properties on either renal or neural tissues. Age and sex may be contributing factors to amiodarone-induced SIADH. The elderly appear to be particularly at risk of drug-induced SIADH. It appears that amiodaroneinduced SIADH is more prevalent after a loading dose of the drug. However, because of the long half-life of amiodarone, the cumulative effect on the development of SIADH remains undefined.11 Patients with severe hyponatremia incur higher mortality, especially the elderly.12 Asymptomatic patients, as in our case, have a lower risk of neurologic sequela but can still develop osmotic demyelination if rapidly corrected.10 Restriction of water intake, eradication of the underlying cause, intravenous administration of diuretics and concentrated salt solutions along with demeclocycline have been described as the treatment of choice.13 The mechanism by which patients with squamous cell carcinoma develop SIADH is still unknown. To the best of our knowledge, the case we have described is the first report of SIADH development after curative resection of a squamous-cell lung cancer previously treated with neoadjuvant chemotherapy and radiation therapy. We suggest that tumor manipulation during surgery and postoperative amiodarone administration could be possible causes of SIADH development. Funding This research received no specific grant from any funding agency in the public, commerical, or not-for-profit sectors.
Conflict of interest statement None declared.
References 1. Rose BD and Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed. New York: McGrawHill, 2001:703. 2. Vanhees SL, Paridaens R and Vansteenkiste JF. Syndrome of inappropriate antidiuretic hormone associated with chemotherapy-induced tumour lysis in small-cell lung cancer: case report and literature review. Ann Oncol 2000; 11: 1061–1065.
Downloaded from aan.sagepub.com at U.A.E University on November 13, 2015
Kotoulas et al.
581
3. McDonald P, Lane C, Rojas GE and Masood A. Syndrome of inappropriate anti-diuretic hormone in non-small cell lung carcinoma: a case report. Ecancermedicalscience 2012; 6: 279. 4. Katsuragi N, Shiraishi Y, Nakajima Y, Kurai M, Takahashi N and Tanaka S. Squamous cell bronchogenic carcinoma with syndrome of inappropriate secretion of antidiuretic hormone. Kyobu Geka 2004; 57: 847–850. 5. Monsieur I, Meysman M, Noppen M, et al. Non-small cell lung cancer with multiple paraneoplastic syndromes. Eur Respir J 1995; 8: 1231–1234. 6. Tho LM and Ferry DR. Is the paraneoplastic syndrome of inappropriate antidiuretic hormone secretion in lung cancer always attributable to the small cell variety? Postgrad Med J 2005; 81: e17. 7. Bartter FC and Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone [Review]. Am J Med 1967; 42: 790–806. 8. Sausville E, Carney D and Battey J. The human vasopressin gene is linked to the oxytocin gene and is selectively
9.
10. 11. 12.
13.
expressed in a cultured lung cancer cell line. J Biol Chem 1985; 260: 10236–10241. Lee JH, Cha MJ, Choi SH, Hwang SJ, Kim DG and Jahng JW. Neuropeptide Y immunoreactivity and corticotropin-releasing hormone mRNA level are increased in the hypothalamus of mouse bearing a human oral squamous cell carcinoma. Neuropeptides 2004; 38: 345–350. Ellison DH and Berl T. The syndrome of inappropriate diuresis. N Engl J Med 2007; 356: 2064–2072. Shavit E and Sherer Y. Hyponatremia induced by amiodarone therapy. Isr Med Assoc J 2007; 9: 564–565. Sherlock M and Thompson CJ. The syndrome of inappropriate antidiuretic hormone: current and future management options. Eur J Endocrinol 2010; 162(Suppl 1): S13–S18. Pillai BP, Unnikrishnan AG and Pavithran PV. Syndrome of inappropriate antidiuretic hormone secretion: revisiting a classical endocrine disorder. Indian J Endocr Metab 2011; 15(Suppl 3): S208–S215.
Downloaded from aan.sagepub.com at U.A.E University on November 13, 2015
