Ann Otol Rhinol LaryngollOO:1991
SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION IN CANCER OF THE HEAD AND NECK YUVAL ZOHAR, MD YOAV
P. TALMI, MD
YEHUDA FINKELSTEIN, MD
MICHAEL NOBEL, MD
UZI GAFTER, MD PETAH-TIQVA, ISRAEL
The syndrome of inappropriate secretion of arginine vasopressin (AVP) known as the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterized by hyponatremia that results from water retention attributable to persistent AVP release. It may occur in a variety of malignant and nonmalignant lesions, with small cell or oat cell carcinoma of the lung by far responsible for the largest number of these cases. Cancer of the head and neck may be a rare cause of SIADH, and only a few such cases have been reported. We describe four patients with advanced cancer of the head and neck region with coexisting SIADH. Diagnosis and treatment are reported and the literature is reviewed. The possible occurrence of SIADH in the head and neck surgical practice should be kept in mind. Since SIADH is usually transient, water restriction and parenteral sodium chloride may be sufficient in overcoming the acute phase. KEY WORDS -
antidiuretic hormone, arginine vasopressin, head and neck cancer, SIADH.
Since first described by Schwartz et al" in 1957, SIADH was reported to occur with a variety of neoplastic and nonneoplastic lesions. Occurrence of SIADH in cancer of the head and neck is rare, and only a few such cases were reported. 2 •5 - u We report four patients with advanced recurrent carcinoma of the head and neck seen over a period of 10 years, with coexisting SIADH. The diagnosis and treatment are described.
INTRODUCTION
The biologically active form of antidiuretic hormone in humans is arginine vasopressin (AVP). The syndrome of inappropriate secretion of AVP known as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is characterized by hyponatremia that results from water retention attributable to persistent AVP release. These patients are unable to excrete a dilute urine, and retention of ingested fluids occurs with expansion of the extracellular fluid volume without edema. The syndrome may arise through three pathophysiologic mechanisms: 1) discharge of AVP synthesized in tumor tissue, 2) nontumorous lung tissue's acquiring the capacity to synthesize AVP, or its reduction of left atrial filling, stimulating central AVP release, or 3) release of AVP from the neurohypophysis due to neighboring lesions or drugs, independent of normal stimuli.
The files of 260 patients suffering from carcinoma of the head and neck seen in the years 1978 to 1988 were reviewed. Four patients with recurrent metastatic cancer of the larynx and pyriform sinus were found to have suffered from SIADH during this period. The patients were all men between the ages of 40 and 65 years (mean, 58 years). CASE REPORTS
Case 1. The patient, 62 years of age, underwent supraglottic laryngectomy and irradiation 10 years before his present admittance. He presented with T3N2MO squamous cell carcinoma of the glottis with unilateral neck metastases and underwent total laryngectomy and neck dissection. Residual local growth was seen 3 weeks thereafter. Further treatment with cisplatin, bleomycin sulfate, and methotrexate was given. Six weeks after cessation of treatment, routine blood tests showed a sodium level of 126 mEq/L, potassium 3.1 mEq/L, urea 26 mg/dL, uric acid 2.1 mg/dL, creatinine 0.9 mg/dL, and osmolality 237 mOsm/kg. Urine osmolality was 270 mOsm/kg. Serum glucose, chloride, and albumin were normal. Serum lipid levels and thyroid function test results were normal. Chest radio-
Patients with SIADH may present with weight gain, lethargy, weakness, and confusion. Convulsions and coma may occur in severe cases. Low serum sodium, blood urea nitrogen, uric acid, creatinine, and albumin levels, with plasma hyposmolality and inappropriately elevated urine osmolality, are characteristic. A urinary sodium concentration of more than 20 mEq/L is suggestive of the syndrome.':" To establish the diagnosis of SIADH it is essential to exclude 1) adrenal insufficiency, 2) hyponatremic edema states, 3) pseudohyponatremia associated with hyperlipidemia, 4) severe hyperglycemia, 5) hypothyroidism, 6) primary polydipsia, 7) essential hyponatremia (sick cell syndrome), and 8) renal failure. 2.3
From the Departments of Otolaryngology (Zohar, Talmi, Finkelstein), General Surgery (Nobel), and Nephrology (Gafter), Hasharon Hospital, Golda Medical Center, Tel-Aviv University Medical School, Petah- Tiqva, Israel.
341
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Zohar et al, SIADH in Head & Neck Cancer
graphs demonstrated only mild cardiomegaly. A concurrent neurologic evaluation revealed no pathologic findings. The patient was treated by fluid restriction and a single 40-mg dose of furosemide. Increased urine levels and a return of serum and urine laboratory values to normal, except for mild hypoalbuminemia, were seen within 48 hours. No recurrence of SIADH was seen. The patient died several weeks later following rupture of the carotid artery. Case 2. The patient, 65 years of age, underwent partial laryngectomy and unilateral neck dissection for T2N1MO squamous cell cancer of the larynx and ipsilateral neck metastases. Three months later he presented with recurrent, poorly differentiated squamous cell tumor of the larynx with bilateral neck metastases. The patient was treated by radiotherapy and a subsequent partial chemotherapy course of cisplatin, bleomycin sulfate, and methotrexate, discontinued because of severe lymphocyte depletion. Five days later, a sudden decrease in urinary output was noted, accompanied by mild agitation. Serum sodium level was 120 mEq/L, chloride 79 mEq/L, potassium 3.1 mEq/L, and creatinine 0.8 mg/dL. Serum osmolality was 267 mOsm/kg, urine osmolality 304 mOsm/kg, and urine sodium 54 mEq/L. Serum glucose, calcium, and albumin were normal. Results of thyroid function tests and the serum lipidogram were normal. Chest radiographs were normal. The patient was initially treated with 150 mL of 5 % sodium chloride, followed by an 800-mL/d fluid restriction. He responded well after the first 24 hours, with a rise in serum sodium level to 126 mEq/L and increased urinary output. The following day, however, urine output dropped to 600 mL/d, with serum sodium and chloride levels being 118 mEq/L and 84 mEq/ L, respectively. The serum creatinine level was 0.9 mg/dL. Further treatment with furosemide and fluid restriction failed. The patient's condition further deteriorated and he died. Case 3. The patient, 40 years of age, presented with bilaterally enlarged cervical lymph nodes and was found to suffer from T2N3MO squamous cell carcinoma of the pyriform sinus. Radical neck dissection on one side and conservative neck dissection on the other side with partial pharyngectomy were done. The patient received 72 Gy postoperative irradiation, but recurrence of the tumor was seen soon thereafter. The patient received two courses of cisplatin and methotrexate without a significant effect. His condition further deteriorated. Five weeks later, routine laboratory tests showed a serum sodium level of 126 mEq/L, serum osmolality of 265 mOsm/kg, urine sodium of 104 mEq/L, and urine osmolality of 321 mOsm/kg. Creatinine clearance was 84, and serum glucose and lipid levels were normal. Thyroid and adrenal functions were within normal limits. Chest radiographs demonstrated no pulmonary disease. The patient was treated with
fluid restriction and his laboratory values returned to the normal range within 36 hours, during which time he presented with no symptoms attributable to SIADH. At this stage, massive neck disease was evident with apparent compression of the remaining jugular vein. The patient died a month later with no evident recurrence of SIADH. Case 4. The patient, 63 years of age, was hospitalized because of terminal T4N3MO squamous cell carcinoma of the larynx. The patient had been at home and had poor compliance, but occasional laboratory test results obtained over a 2-month period demonstrated constant hyponatremia of 121 to 130 mEq/L. Serum urea and uric acid recorded once during this period were 20 mg/dL and 3.2 mg/dL, respectively. An investigation done after this period revealed a serum sodium level of 123 mEq/L, potassium 3.3 mEq/L, urea 22 mg/dL, uric acid 2.4 mg/ dL, and creatinine 1.0 mg/dL. Serum osmolality was 201 mOsm/kg, urine osmolality 317 mOsm/kg, and urine sodium 23 mEq/L. Serum glucose, calcium, and albumin were normal. Results of thyroid function tests, adrenal function, and the serum lipidogram were normal. Chest radiographs and brain computed tomograms were normal. The patient evaded treatment and apparently was symptom-free apart from periods of lethargy perhaps attributable to his deteriorating general condition. Another series of tests taken a week before his death demonstrated a serum sodium level of 119 mEq/L, potassium of 4.2 mEq/L, urea of 26 mg/dL, and uric acid of 1.8 mg/dL. Serum osmolality was 181 mOsm/kg and urine osmolality 207 mOsm/kg. This documents an untreated case of chronic SIADH of over 3 months' duration. No marked symptoms were evident when the patient was seen by us, and although no form of treatment was initiated because of his near-complete lack of compliance, no severe effects were noted. DISCUSSION
In the present series, four patients with advanced metastatic squamous cell carcinoma of the head and neck region developed hyponatremia 3 to 11 months after undergoing a surgical procedure. This hyponatremia was found by clinical and biochemical criteria to be part of SIADH. In three patients, the syndrome was transient and responded to dehydration treatment within 24 to 48 hours. The fourth patient presented with chronic SIADH that lasted for 3 months until his death and did not necessitate any treatment. The cause for SIADH in these patients has not been established, but several pathophysiologic mechanisms may be considered. 1. Occurrence may be related to ectopic excretion of AVP or an AVP-like substance by the tumor, as was shown by Osterman et al." Tumor resection re-
Downloaded from aor.sagepub.com at Harvard Libraries on April 28, 2015
Zohar et al, SIADH in Head & Neck Cancer
versed SIADH in other cases but AVP or an AVPlike substance was not detected in the tumoral tissue,5,10 or was slightly above normal in the serum and negligible in tumoral tissue extract. It is noteworthy that Odell and Wolfson;' reporting on their previous experience, found elevated AVP levels in 41 % of patients with carcinoma of the lung and 43% of patients with carcinoma of the colon when compared to normal subjects after 12 hours' dehydration. These patients had no clinical evidence for SIADH at that time, but presumably would manifest it if given excess water. 2. Secretion of a neurotransmitter or releasing factor for AVP by the tumor is another possibility. 12 Hayes et al" describe two patients with SIADH following induction chemotherapy for squamous cell carcinoma of the oropharynx and oral cavity. Although immunoperoxidase staining of the original biopsy specimens in the two patients was negative for AVP, these authors propose that a substance producing SIADH was released from the malignant cells during the rapid cytolytic phase of tumor destruction. In these two cases, SIADH was related to the administration of cisplatin and not to the existence of the tumor. Their patients developed their disorder after days 6 and 7 of their chemotherapy course. In our case 2, SIADH developed on the fifth day following termination of a partial chemotherapeutic course, and a possible connection cannot be ruled out. 3. Another mechanism was described by McQuarrie et al ;" who have demonstrated an increased effect of AVP in patients after bilateral simultaneous neck dissection. They have experimentally shown a transient increase in the cerebral venous pressure apparently causing release of AVP and leading to renal water retention and concurrent blood volume expansion. This effect causing transient SIADH may be encountered in head and neck surgery practice and can perhaps account for the findings in patient 3, although it cannot explain our other cases or those reported in the literature. 4. Finally, invasion of the vagus nerve leading to baroreceptor denervation may lead to hyponatremia." According to the literature, SIADH is rarely en-
343
PATIENTS WITH SIADH ASSOCIATED WITH CANCER OF THE HEAD AND NECK
Author
Year
No.
Tumor Location
Moses et all Forrest et al" Srigley et al'" Hayes et al" Osterman et al" Kandylis et al" o kutomi et alii Abdi and Bishop' Present study
1976 1978 1983 1986 1986 1986 1987 1988 1989
2 1 1 2 1 1 1 1 4
Larynx Tongue Olfactory neuroblastoma Pharynx, oral cavity Olfactory neuroblastoma Pyriform sinus Floor of mouth Tongue Larynx (3), pyriform sinus (1)
countered in the practice of head and neck surgery. A review of the literature summarized in the Table 2 •S - 11 revealed only 10 cases, most of which were associated with squamous cell carcinoma. The four additional cases reported herein, found over a period of 10 years, suggest that SIADH may occur more frequently than previously noted. Nevertheless, as most cases of SIADH are due to small cell and oat cell carcinomas of the lung,1-3.7,9 a thorough examination should be done to rule out the possibility of a second neoplasm actually causing this disorder. Treatment of SIADH caused by excretion of AVP or an AVP-like substance requires removal or destruction of the involved tumorous tissue.v'" With the necessity of tumor removal notwithstanding, patients with mild to moderate symptoms should be treated primarily by fluid restriction. Intravenous administration of 3 % to 5 % sodium chloride and furosemide may supplement treatment. In more severe SIADH cases or prior to surgical resection, treatment with demeclocycline (600 to 1,200 mg daily) should be given. Demeclocycline, a tetracycline effective in interfering with the renal action of AVP, was found to be superior to lithium in SIADH patients." Although diagnosis can be established by the patient's symptoms, serum and urine laboratory values, and response to treatment, serum AVP levels should be recorded where possible, and tumor specimens should be evaluated by immunohistochemical staining when available. Although not always clinically evident, the possibility of occurrence of SIADH in such cases should be remembered, and early treatment initiated to prevent further morbidity in these compromised patients.
REFERENCES 1. Odell WD, Wolfson AR. Humoral syndromes associated with cancer. Annu Rev Med 1978;29:379-406. 2. Moses AM, Miller M, Streeten DHP. Pathophysiologic and pharmacologic alterations in the release and action of ADH. Metabolism 1976;25:697-721. 3. Zerbe R, Stropes L, Robertson G. Vasopressin function in the syndrome of inappropriate antidiuresis. Annu Rev Med 1980; 31:315-27.
4. Schwartz WB, Warren B, Curelop S, Bartter FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med
1957;23:529-42.
5. Hayes DF, Lechan RM, Posner MR, Weichselbaum RR, Miller D, Ervin T. The syndrome of inappropriate antidiuretic hormone secretion associated with induction chemotherapy for squamous cell carcinoma of the head and neck. J Surg Oncol 1986;32: 150-2. 6. Osterman M, Calhoun A, Dunham M, et al. Chronic syndrome of inappropriate antidiuretic hormone secretion and hypertension in a patient with olfactory neuroblastoma. Arch Intern Med 1986;146:1731-5.
7. Abdi EA, Bishop S. The syndrome of inappropriate anti-
Downloaded from aor.sagepub.com at Harvard Libraries on April 28, 2015
344
Zohar et al, SIADH in Head & Neck Cancer
diuretic hormone secretion with carcinoma of the tongue. Med Pediatr OncoI1988;16:210-5. 8. Kandylis KV, Vasilomanolakis M, Efremides AD. Syndrome of inappropriate antidiuretic hormone secretion in pyriform sinus squamous cell carcinoma [Letter]. Am J Med 1986;81: 946. 9. Forrest IN, Cox M, Hong C, Morrison G, Bia M, Singer I. Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med 1978;298:173-7. 10. Srigley JR, Dayal VS, Gregor RT, Love R, van Nostrand AWP. Hyponatremia secondary to olfactory neuroblastoma. Arch
Otolaryngol 1983;109:559-62. 11. Okutomi T, Sakata S, Tatematsu N, Oka N. Squamous cell carcinoma of tongue and floor of mouth associated. with syndrome of inappropriate secretion of antidiuretic hormone. J Oral Maxillofac Surg 1987;45:447-9. 12. Robertson GL. Cancer and inappropriate antidiuresis. In: Ruddon RW, ed. Biological markers of neoplasia: basic and applied aspects. New York, NY: Elsevier North-Holland, 1978: 277-93. 13. McQuarrie DC, Mayberg M, Ferguson M, Shons AR. A physiologic approach to the problems of simultaneous bilateral neck dissection. Am J Surg 1977;134:455-60.
FIRST INTERNATIONAL CONFERENCE ON ACOUSTIC NEUROMA The First International Conference on Acoustic Neuroma will be held Aug 25-29, 1991, in Copenhagen, Denmark. For further information, contact Copenhagen Acoustic Neuroma Conference, Secretariate, ENT Department, Gentofte University Hospital, DK-2900 Hellerup, Copenhagen, Denmark.
FIRST INTERNATIONAL SKULL BASE CONGRESS The First International Skull Base Congress will be held June 14-20, 1992, in Hanover, Germany. For further information, contact Madjid Samii, MD, Professor and Chairman of Neurosurgery, Medical School Hanover, Neurosurgical Clinic, Hospital Nordstadt, Haltenhoffstr 41, D-3000 Hanover 1, Germany; phone 0049-(0)511-7638245 or 623151, FAX 0049-(0)511-7638606.
Downloaded from aor.sagepub.com at Harvard Libraries on April 28, 2015
SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION IN CANCER OF THE HEAD AND NECK YUVAL ZOHAR, MD YOAV
P. TALMI, MD
YEHUDA FINKELSTEIN, MD
MICHAEL NOBEL, MD
UZI GAFTER, MD PETAH-TIQVA, ISRAEL
The syndrome of inappropriate secretion of arginine vasopressin (AVP) known as the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterized by hyponatremia that results from water retention attributable to persistent AVP release. It may occur in a variety of malignant and nonmalignant lesions, with small cell or oat cell carcinoma of the lung by far responsible for the largest number of these cases. Cancer of the head and neck may be a rare cause of SIADH, and only a few such cases have been reported. We describe four patients with advanced cancer of the head and neck region with coexisting SIADH. Diagnosis and treatment are reported and the literature is reviewed. The possible occurrence of SIADH in the head and neck surgical practice should be kept in mind. Since SIADH is usually transient, water restriction and parenteral sodium chloride may be sufficient in overcoming the acute phase. KEY WORDS -
antidiuretic hormone, arginine vasopressin, head and neck cancer, SIADH.
Since first described by Schwartz et al" in 1957, SIADH was reported to occur with a variety of neoplastic and nonneoplastic lesions. Occurrence of SIADH in cancer of the head and neck is rare, and only a few such cases were reported. 2 •5 - u We report four patients with advanced recurrent carcinoma of the head and neck seen over a period of 10 years, with coexisting SIADH. The diagnosis and treatment are described.
INTRODUCTION
The biologically active form of antidiuretic hormone in humans is arginine vasopressin (AVP). The syndrome of inappropriate secretion of AVP known as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is characterized by hyponatremia that results from water retention attributable to persistent AVP release. These patients are unable to excrete a dilute urine, and retention of ingested fluids occurs with expansion of the extracellular fluid volume without edema. The syndrome may arise through three pathophysiologic mechanisms: 1) discharge of AVP synthesized in tumor tissue, 2) nontumorous lung tissue's acquiring the capacity to synthesize AVP, or its reduction of left atrial filling, stimulating central AVP release, or 3) release of AVP from the neurohypophysis due to neighboring lesions or drugs, independent of normal stimuli.
The files of 260 patients suffering from carcinoma of the head and neck seen in the years 1978 to 1988 were reviewed. Four patients with recurrent metastatic cancer of the larynx and pyriform sinus were found to have suffered from SIADH during this period. The patients were all men between the ages of 40 and 65 years (mean, 58 years). CASE REPORTS
Case 1. The patient, 62 years of age, underwent supraglottic laryngectomy and irradiation 10 years before his present admittance. He presented with T3N2MO squamous cell carcinoma of the glottis with unilateral neck metastases and underwent total laryngectomy and neck dissection. Residual local growth was seen 3 weeks thereafter. Further treatment with cisplatin, bleomycin sulfate, and methotrexate was given. Six weeks after cessation of treatment, routine blood tests showed a sodium level of 126 mEq/L, potassium 3.1 mEq/L, urea 26 mg/dL, uric acid 2.1 mg/dL, creatinine 0.9 mg/dL, and osmolality 237 mOsm/kg. Urine osmolality was 270 mOsm/kg. Serum glucose, chloride, and albumin were normal. Serum lipid levels and thyroid function test results were normal. Chest radio-
Patients with SIADH may present with weight gain, lethargy, weakness, and confusion. Convulsions and coma may occur in severe cases. Low serum sodium, blood urea nitrogen, uric acid, creatinine, and albumin levels, with plasma hyposmolality and inappropriately elevated urine osmolality, are characteristic. A urinary sodium concentration of more than 20 mEq/L is suggestive of the syndrome.':" To establish the diagnosis of SIADH it is essential to exclude 1) adrenal insufficiency, 2) hyponatremic edema states, 3) pseudohyponatremia associated with hyperlipidemia, 4) severe hyperglycemia, 5) hypothyroidism, 6) primary polydipsia, 7) essential hyponatremia (sick cell syndrome), and 8) renal failure. 2.3
From the Departments of Otolaryngology (Zohar, Talmi, Finkelstein), General Surgery (Nobel), and Nephrology (Gafter), Hasharon Hospital, Golda Medical Center, Tel-Aviv University Medical School, Petah- Tiqva, Israel.
341
Downloaded from aor.sagepub.com at Harvard Libraries on April 28, 2015
342
Zohar et al, SIADH in Head & Neck Cancer
graphs demonstrated only mild cardiomegaly. A concurrent neurologic evaluation revealed no pathologic findings. The patient was treated by fluid restriction and a single 40-mg dose of furosemide. Increased urine levels and a return of serum and urine laboratory values to normal, except for mild hypoalbuminemia, were seen within 48 hours. No recurrence of SIADH was seen. The patient died several weeks later following rupture of the carotid artery. Case 2. The patient, 65 years of age, underwent partial laryngectomy and unilateral neck dissection for T2N1MO squamous cell cancer of the larynx and ipsilateral neck metastases. Three months later he presented with recurrent, poorly differentiated squamous cell tumor of the larynx with bilateral neck metastases. The patient was treated by radiotherapy and a subsequent partial chemotherapy course of cisplatin, bleomycin sulfate, and methotrexate, discontinued because of severe lymphocyte depletion. Five days later, a sudden decrease in urinary output was noted, accompanied by mild agitation. Serum sodium level was 120 mEq/L, chloride 79 mEq/L, potassium 3.1 mEq/L, and creatinine 0.8 mg/dL. Serum osmolality was 267 mOsm/kg, urine osmolality 304 mOsm/kg, and urine sodium 54 mEq/L. Serum glucose, calcium, and albumin were normal. Results of thyroid function tests and the serum lipidogram were normal. Chest radiographs were normal. The patient was initially treated with 150 mL of 5 % sodium chloride, followed by an 800-mL/d fluid restriction. He responded well after the first 24 hours, with a rise in serum sodium level to 126 mEq/L and increased urinary output. The following day, however, urine output dropped to 600 mL/d, with serum sodium and chloride levels being 118 mEq/L and 84 mEq/ L, respectively. The serum creatinine level was 0.9 mg/dL. Further treatment with furosemide and fluid restriction failed. The patient's condition further deteriorated and he died. Case 3. The patient, 40 years of age, presented with bilaterally enlarged cervical lymph nodes and was found to suffer from T2N3MO squamous cell carcinoma of the pyriform sinus. Radical neck dissection on one side and conservative neck dissection on the other side with partial pharyngectomy were done. The patient received 72 Gy postoperative irradiation, but recurrence of the tumor was seen soon thereafter. The patient received two courses of cisplatin and methotrexate without a significant effect. His condition further deteriorated. Five weeks later, routine laboratory tests showed a serum sodium level of 126 mEq/L, serum osmolality of 265 mOsm/kg, urine sodium of 104 mEq/L, and urine osmolality of 321 mOsm/kg. Creatinine clearance was 84, and serum glucose and lipid levels were normal. Thyroid and adrenal functions were within normal limits. Chest radiographs demonstrated no pulmonary disease. The patient was treated with
fluid restriction and his laboratory values returned to the normal range within 36 hours, during which time he presented with no symptoms attributable to SIADH. At this stage, massive neck disease was evident with apparent compression of the remaining jugular vein. The patient died a month later with no evident recurrence of SIADH. Case 4. The patient, 63 years of age, was hospitalized because of terminal T4N3MO squamous cell carcinoma of the larynx. The patient had been at home and had poor compliance, but occasional laboratory test results obtained over a 2-month period demonstrated constant hyponatremia of 121 to 130 mEq/L. Serum urea and uric acid recorded once during this period were 20 mg/dL and 3.2 mg/dL, respectively. An investigation done after this period revealed a serum sodium level of 123 mEq/L, potassium 3.3 mEq/L, urea 22 mg/dL, uric acid 2.4 mg/ dL, and creatinine 1.0 mg/dL. Serum osmolality was 201 mOsm/kg, urine osmolality 317 mOsm/kg, and urine sodium 23 mEq/L. Serum glucose, calcium, and albumin were normal. Results of thyroid function tests, adrenal function, and the serum lipidogram were normal. Chest radiographs and brain computed tomograms were normal. The patient evaded treatment and apparently was symptom-free apart from periods of lethargy perhaps attributable to his deteriorating general condition. Another series of tests taken a week before his death demonstrated a serum sodium level of 119 mEq/L, potassium of 4.2 mEq/L, urea of 26 mg/dL, and uric acid of 1.8 mg/dL. Serum osmolality was 181 mOsm/kg and urine osmolality 207 mOsm/kg. This documents an untreated case of chronic SIADH of over 3 months' duration. No marked symptoms were evident when the patient was seen by us, and although no form of treatment was initiated because of his near-complete lack of compliance, no severe effects were noted. DISCUSSION
In the present series, four patients with advanced metastatic squamous cell carcinoma of the head and neck region developed hyponatremia 3 to 11 months after undergoing a surgical procedure. This hyponatremia was found by clinical and biochemical criteria to be part of SIADH. In three patients, the syndrome was transient and responded to dehydration treatment within 24 to 48 hours. The fourth patient presented with chronic SIADH that lasted for 3 months until his death and did not necessitate any treatment. The cause for SIADH in these patients has not been established, but several pathophysiologic mechanisms may be considered. 1. Occurrence may be related to ectopic excretion of AVP or an AVP-like substance by the tumor, as was shown by Osterman et al." Tumor resection re-
Downloaded from aor.sagepub.com at Harvard Libraries on April 28, 2015
Zohar et al, SIADH in Head & Neck Cancer
versed SIADH in other cases but AVP or an AVPlike substance was not detected in the tumoral tissue,5,10 or was slightly above normal in the serum and negligible in tumoral tissue extract. It is noteworthy that Odell and Wolfson;' reporting on their previous experience, found elevated AVP levels in 41 % of patients with carcinoma of the lung and 43% of patients with carcinoma of the colon when compared to normal subjects after 12 hours' dehydration. These patients had no clinical evidence for SIADH at that time, but presumably would manifest it if given excess water. 2. Secretion of a neurotransmitter or releasing factor for AVP by the tumor is another possibility. 12 Hayes et al" describe two patients with SIADH following induction chemotherapy for squamous cell carcinoma of the oropharynx and oral cavity. Although immunoperoxidase staining of the original biopsy specimens in the two patients was negative for AVP, these authors propose that a substance producing SIADH was released from the malignant cells during the rapid cytolytic phase of tumor destruction. In these two cases, SIADH was related to the administration of cisplatin and not to the existence of the tumor. Their patients developed their disorder after days 6 and 7 of their chemotherapy course. In our case 2, SIADH developed on the fifth day following termination of a partial chemotherapeutic course, and a possible connection cannot be ruled out. 3. Another mechanism was described by McQuarrie et al ;" who have demonstrated an increased effect of AVP in patients after bilateral simultaneous neck dissection. They have experimentally shown a transient increase in the cerebral venous pressure apparently causing release of AVP and leading to renal water retention and concurrent blood volume expansion. This effect causing transient SIADH may be encountered in head and neck surgery practice and can perhaps account for the findings in patient 3, although it cannot explain our other cases or those reported in the literature. 4. Finally, invasion of the vagus nerve leading to baroreceptor denervation may lead to hyponatremia." According to the literature, SIADH is rarely en-
343
PATIENTS WITH SIADH ASSOCIATED WITH CANCER OF THE HEAD AND NECK
Author
Year
No.
Tumor Location
Moses et all Forrest et al" Srigley et al'" Hayes et al" Osterman et al" Kandylis et al" o kutomi et alii Abdi and Bishop' Present study
1976 1978 1983 1986 1986 1986 1987 1988 1989
2 1 1 2 1 1 1 1 4
Larynx Tongue Olfactory neuroblastoma Pharynx, oral cavity Olfactory neuroblastoma Pyriform sinus Floor of mouth Tongue Larynx (3), pyriform sinus (1)
countered in the practice of head and neck surgery. A review of the literature summarized in the Table 2 •S - 11 revealed only 10 cases, most of which were associated with squamous cell carcinoma. The four additional cases reported herein, found over a period of 10 years, suggest that SIADH may occur more frequently than previously noted. Nevertheless, as most cases of SIADH are due to small cell and oat cell carcinomas of the lung,1-3.7,9 a thorough examination should be done to rule out the possibility of a second neoplasm actually causing this disorder. Treatment of SIADH caused by excretion of AVP or an AVP-like substance requires removal or destruction of the involved tumorous tissue.v'" With the necessity of tumor removal notwithstanding, patients with mild to moderate symptoms should be treated primarily by fluid restriction. Intravenous administration of 3 % to 5 % sodium chloride and furosemide may supplement treatment. In more severe SIADH cases or prior to surgical resection, treatment with demeclocycline (600 to 1,200 mg daily) should be given. Demeclocycline, a tetracycline effective in interfering with the renal action of AVP, was found to be superior to lithium in SIADH patients." Although diagnosis can be established by the patient's symptoms, serum and urine laboratory values, and response to treatment, serum AVP levels should be recorded where possible, and tumor specimens should be evaluated by immunohistochemical staining when available. Although not always clinically evident, the possibility of occurrence of SIADH in such cases should be remembered, and early treatment initiated to prevent further morbidity in these compromised patients.
REFERENCES 1. Odell WD, Wolfson AR. Humoral syndromes associated with cancer. Annu Rev Med 1978;29:379-406. 2. Moses AM, Miller M, Streeten DHP. Pathophysiologic and pharmacologic alterations in the release and action of ADH. Metabolism 1976;25:697-721. 3. Zerbe R, Stropes L, Robertson G. Vasopressin function in the syndrome of inappropriate antidiuresis. Annu Rev Med 1980; 31:315-27.
4. Schwartz WB, Warren B, Curelop S, Bartter FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med
1957;23:529-42.
5. Hayes DF, Lechan RM, Posner MR, Weichselbaum RR, Miller D, Ervin T. The syndrome of inappropriate antidiuretic hormone secretion associated with induction chemotherapy for squamous cell carcinoma of the head and neck. J Surg Oncol 1986;32: 150-2. 6. Osterman M, Calhoun A, Dunham M, et al. Chronic syndrome of inappropriate antidiuretic hormone secretion and hypertension in a patient with olfactory neuroblastoma. Arch Intern Med 1986;146:1731-5.
7. Abdi EA, Bishop S. The syndrome of inappropriate anti-
Downloaded from aor.sagepub.com at Harvard Libraries on April 28, 2015
344
Zohar et al, SIADH in Head & Neck Cancer
diuretic hormone secretion with carcinoma of the tongue. Med Pediatr OncoI1988;16:210-5. 8. Kandylis KV, Vasilomanolakis M, Efremides AD. Syndrome of inappropriate antidiuretic hormone secretion in pyriform sinus squamous cell carcinoma [Letter]. Am J Med 1986;81: 946. 9. Forrest IN, Cox M, Hong C, Morrison G, Bia M, Singer I. Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med 1978;298:173-7. 10. Srigley JR, Dayal VS, Gregor RT, Love R, van Nostrand AWP. Hyponatremia secondary to olfactory neuroblastoma. Arch
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FIRST INTERNATIONAL CONFERENCE ON ACOUSTIC NEUROMA The First International Conference on Acoustic Neuroma will be held Aug 25-29, 1991, in Copenhagen, Denmark. For further information, contact Copenhagen Acoustic Neuroma Conference, Secretariate, ENT Department, Gentofte University Hospital, DK-2900 Hellerup, Copenhagen, Denmark.
FIRST INTERNATIONAL SKULL BASE CONGRESS The First International Skull Base Congress will be held June 14-20, 1992, in Hanover, Germany. For further information, contact Madjid Samii, MD, Professor and Chairman of Neurosurgery, Medical School Hanover, Neurosurgical Clinic, Hospital Nordstadt, Haltenhoffstr 41, D-3000 Hanover 1, Germany; phone 0049-(0)511-7638245 or 623151, FAX 0049-(0)511-7638606.
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