J Gastrointest Canc DOI 10.1007/s12029-015-9740-1
CASE REPORT
ACTH-Producing Pancreatic Neuroendocrine Tumor Presenting with Severe Hypokalemic Alkalosis: A Case Report Shirin Attarian 1 & Steven K. Libutti 2 & Jennifer Chuy 3
# Springer Science+Business Media New York 2015
Case Report A 66-year-old African American woman with a past medical history of hypertension, obesity, and heart failure with mildly reduced ejection fraction presented with increasing lower extremity edema, weight loss of 12 lb over the past 3 months, worsening glycemic control, and darkening of her fingers and facies. On laboratory evaluation, she was found to have hypokalemia with a potassium level of 2.4 mEq/L (normal 3.5– 5 mEq/L) and metabolic alkalosis with HCO3 of 42 mEq/L (normal 24–30 mEq/L), and pH of 7.54 (normal 7.35–7.45). The hypokalemia was initially attributed to the recent increase in the dose of her furosemide to manage her lower extremity edema. However, due to persistent hypokalemia despite significant potassium repletion and notable metabolic alkalosis, further work-up was undertaken. Cortisol level was 85 μg/dL (normal 5–25 μg/dL), ACTH was 580 pg/mL (normal 5–27 pg/mL), and 24-h urine cortisol was 3087 μg/mL (nl 5–50 μg/mL). The patient also demonstrated a lack of suppression of serum cortisol level after a 10mg dexamethasone suppression test, with a morning cortisol level of 73 μg/dL. This was highly suggestive of ectopic ACTH secretion.
To identify the source of ACTH secretion, computer tomography (CT) of the chest, abdomen, and pelvis with contrast was obtained. On imaging, she was noted to have a 3.8× 3.1-cm pancreatic tail mass with multiple hypoenhancing lesions in the liver with the largest one measuring 4 cm and bilateral adrenal hyperplasia (Figs. 1, 2, and 3). Octreotide scan was obtained as well, which was negative. Subsequently, she underwent a liver biopsy. Pathology showed a neuroendocrine tumor, and immunostain was positive for ACTH, chromogranin, synaptophysin, and CD56. Ki67 index was greater than 10 %, consistent with a grade 2 intermediate grade tumor. The patient was started on metyrapone to inhibit steroidogenesis. The cortisol level abruptly dropped from 91 to 24 μg/dL after initiation of metyrapone. Spironolactone and losartan were started to treat hypokalemia and hypertension. Of note, in her immunocompromised state, the patient developed health-care-associated pneumonia during the course of her hospitalization and was treated with broad-spectrum antibiotics and respiratory support. Following hospital discharge, she was enrolled in a clinical trial with temozolomide with or without capecitabine.
Discussion * Jennifer Chuy [email protected] 1
Department of Internal Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
2
Department of Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
3
Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, 1695 Eastchester Road, Bronx, NY 10461-2374, USA
Neuroendocrine tumors (NETs) show heterogeneity in morphology, function, and clinical features. The majority of patients with malignant pancreatic NETs (PNETs) present with advanced stage tumors, and 65 % of patients present with unresectable or metastatic disease [1]. WHO has suggested the classification of NETs according to criteria including the presence of metastases, the Ki-67/ MIB-1 index, the histological grade, vascular invasion, and tumor size. The WHO classification of NETs includes (1)
J Gastrointest Canc
Fig. 1 Sagittal computer tomography images with arterial phase contrast showing a mass in the tail of the pancreas
well-differentiated NETs, (2) well-differentiated neuroendocrine carcinomas, and (3) poorly differentiated neuroendocrine carcinomas. According to epidemiologic studies, the incidence of PNETs is rising, which may be due to an increase in the number of incidental diagnoses and advances in imaging or the aging population as the incidence of PNETs increases with age and peaks in the eighth decade. Although overall survival has remained relatively unchanged over the past several decades, outcomes may improve, as effective therapies were lacking until recently [2, 3]. PNETs are classified as functional and nonfunctioning, depending on the presence of an accompanying hormonal syndrome. The full spectrum of disease ranges from early-stage
Fig. 2 Axial computer tomography images with arterial phase contrast showing a mass in the tail of the pancreas
Fig. 3 Axial computer tomography image with arterial phase contrast showing two liver metastases
benign hyperplasia or adenoma and localized welldifferentiated neuroendocrine tumors to more advanced metastatic or poorly differentiated neuroendocrine carcinomas [3]. Nonfunctioning PNETs represent 60–80 % of all PNETs. Among functional PNETs, insulin and gastrin production are most frequent (17 and 15 %, respectively). ACTH production can cause ectopic adrenocorticotropin syndrome (EAS) [4, 5]. It is estimated that EAS represents about 20 % of ACTHdependent and 10–15 % of all types of Cushing’s syndrome. The most common forms of ACTH-producing tumors are small cell lung cancer, carcinoid tumors, thymomas, pancreatic islet cell tumors, and medullary carcinomas of the thyroid [5, 6]. Ectopic ACTH syndrome due to a PNET is very rare. Patients with this tumor usually develop early metastases, even prior to symptoms, and have a poor prognosis [4]. EAS can follow an acute or chronic course. The acute syndrome is associated with rapid onset of hypertension, weakness, edema, hypokalemia, glucose intolerance, anorexia, and weight loss. The chronic syndrome often presents with plethora, truncal obesity, buffalo hump, and red striae [7]. The prognosis of patients with EAS is influenced by tumor histology and severity of hypercortisolemia since they both affect mortality and morbidity. Tumor histology and the presence of non-lymph node metastases are the most important prognostic factors predicting overall survival. In a large institutional database, the median survival for metastatic pancreatic neuroendocrine carcinomas was 70 months, and the 5-year survival rate was 56 %. Age, sex, and tumor type (functional vs. nonfunctional) did not impact prognosis. Tumor grade, however, was highly prognostic for survival [8].
J Gastrointest Canc
Hypercortisolemia is associated with systemic infections, cardiac failure, and pulmonary embolism, and this underlines the necessity for rapid control of hypercortisolemia and prophylaxis against its complications [6]. The approach to treatment is management of hormonal hypersecretion and surgical resection when feasible. Unfortunately, PNETs are often detected at advanced stages when complete surgical removal is not feasible. Systemic therapies such as somatostatin analogues (SAs) and chemotherapy and newer targeted therapies including everolimus and sunitinib are available options. Somatostatin analogues exhibit antiproliferative activity and help control symptoms for patients with hormone secretion [8]. The CLARINET study recently showed that patients with metastatic, well- or moderately differentiated, nonfunctioning, and somatostatin-receptor-positive neuroendocrine tumors had significantly prolonged progression-free survival with lanreotide, a long-acting somatostatin analogue, compared to placebo (median not reached vs. median of 18.0 months respectively, p
CASE REPORT
ACTH-Producing Pancreatic Neuroendocrine Tumor Presenting with Severe Hypokalemic Alkalosis: A Case Report Shirin Attarian 1 & Steven K. Libutti 2 & Jennifer Chuy 3
# Springer Science+Business Media New York 2015
Case Report A 66-year-old African American woman with a past medical history of hypertension, obesity, and heart failure with mildly reduced ejection fraction presented with increasing lower extremity edema, weight loss of 12 lb over the past 3 months, worsening glycemic control, and darkening of her fingers and facies. On laboratory evaluation, she was found to have hypokalemia with a potassium level of 2.4 mEq/L (normal 3.5– 5 mEq/L) and metabolic alkalosis with HCO3 of 42 mEq/L (normal 24–30 mEq/L), and pH of 7.54 (normal 7.35–7.45). The hypokalemia was initially attributed to the recent increase in the dose of her furosemide to manage her lower extremity edema. However, due to persistent hypokalemia despite significant potassium repletion and notable metabolic alkalosis, further work-up was undertaken. Cortisol level was 85 μg/dL (normal 5–25 μg/dL), ACTH was 580 pg/mL (normal 5–27 pg/mL), and 24-h urine cortisol was 3087 μg/mL (nl 5–50 μg/mL). The patient also demonstrated a lack of suppression of serum cortisol level after a 10mg dexamethasone suppression test, with a morning cortisol level of 73 μg/dL. This was highly suggestive of ectopic ACTH secretion.
To identify the source of ACTH secretion, computer tomography (CT) of the chest, abdomen, and pelvis with contrast was obtained. On imaging, she was noted to have a 3.8× 3.1-cm pancreatic tail mass with multiple hypoenhancing lesions in the liver with the largest one measuring 4 cm and bilateral adrenal hyperplasia (Figs. 1, 2, and 3). Octreotide scan was obtained as well, which was negative. Subsequently, she underwent a liver biopsy. Pathology showed a neuroendocrine tumor, and immunostain was positive for ACTH, chromogranin, synaptophysin, and CD56. Ki67 index was greater than 10 %, consistent with a grade 2 intermediate grade tumor. The patient was started on metyrapone to inhibit steroidogenesis. The cortisol level abruptly dropped from 91 to 24 μg/dL after initiation of metyrapone. Spironolactone and losartan were started to treat hypokalemia and hypertension. Of note, in her immunocompromised state, the patient developed health-care-associated pneumonia during the course of her hospitalization and was treated with broad-spectrum antibiotics and respiratory support. Following hospital discharge, she was enrolled in a clinical trial with temozolomide with or without capecitabine.
Discussion * Jennifer Chuy [email protected] 1
Department of Internal Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
2
Department of Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
3
Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, 1695 Eastchester Road, Bronx, NY 10461-2374, USA
Neuroendocrine tumors (NETs) show heterogeneity in morphology, function, and clinical features. The majority of patients with malignant pancreatic NETs (PNETs) present with advanced stage tumors, and 65 % of patients present with unresectable or metastatic disease [1]. WHO has suggested the classification of NETs according to criteria including the presence of metastases, the Ki-67/ MIB-1 index, the histological grade, vascular invasion, and tumor size. The WHO classification of NETs includes (1)
J Gastrointest Canc
Fig. 1 Sagittal computer tomography images with arterial phase contrast showing a mass in the tail of the pancreas
well-differentiated NETs, (2) well-differentiated neuroendocrine carcinomas, and (3) poorly differentiated neuroendocrine carcinomas. According to epidemiologic studies, the incidence of PNETs is rising, which may be due to an increase in the number of incidental diagnoses and advances in imaging or the aging population as the incidence of PNETs increases with age and peaks in the eighth decade. Although overall survival has remained relatively unchanged over the past several decades, outcomes may improve, as effective therapies were lacking until recently [2, 3]. PNETs are classified as functional and nonfunctioning, depending on the presence of an accompanying hormonal syndrome. The full spectrum of disease ranges from early-stage
Fig. 2 Axial computer tomography images with arterial phase contrast showing a mass in the tail of the pancreas
Fig. 3 Axial computer tomography image with arterial phase contrast showing two liver metastases
benign hyperplasia or adenoma and localized welldifferentiated neuroendocrine tumors to more advanced metastatic or poorly differentiated neuroendocrine carcinomas [3]. Nonfunctioning PNETs represent 60–80 % of all PNETs. Among functional PNETs, insulin and gastrin production are most frequent (17 and 15 %, respectively). ACTH production can cause ectopic adrenocorticotropin syndrome (EAS) [4, 5]. It is estimated that EAS represents about 20 % of ACTHdependent and 10–15 % of all types of Cushing’s syndrome. The most common forms of ACTH-producing tumors are small cell lung cancer, carcinoid tumors, thymomas, pancreatic islet cell tumors, and medullary carcinomas of the thyroid [5, 6]. Ectopic ACTH syndrome due to a PNET is very rare. Patients with this tumor usually develop early metastases, even prior to symptoms, and have a poor prognosis [4]. EAS can follow an acute or chronic course. The acute syndrome is associated with rapid onset of hypertension, weakness, edema, hypokalemia, glucose intolerance, anorexia, and weight loss. The chronic syndrome often presents with plethora, truncal obesity, buffalo hump, and red striae [7]. The prognosis of patients with EAS is influenced by tumor histology and severity of hypercortisolemia since they both affect mortality and morbidity. Tumor histology and the presence of non-lymph node metastases are the most important prognostic factors predicting overall survival. In a large institutional database, the median survival for metastatic pancreatic neuroendocrine carcinomas was 70 months, and the 5-year survival rate was 56 %. Age, sex, and tumor type (functional vs. nonfunctional) did not impact prognosis. Tumor grade, however, was highly prognostic for survival [8].
J Gastrointest Canc
Hypercortisolemia is associated with systemic infections, cardiac failure, and pulmonary embolism, and this underlines the necessity for rapid control of hypercortisolemia and prophylaxis against its complications [6]. The approach to treatment is management of hormonal hypersecretion and surgical resection when feasible. Unfortunately, PNETs are often detected at advanced stages when complete surgical removal is not feasible. Systemic therapies such as somatostatin analogues (SAs) and chemotherapy and newer targeted therapies including everolimus and sunitinib are available options. Somatostatin analogues exhibit antiproliferative activity and help control symptoms for patients with hormone secretion [8]. The CLARINET study recently showed that patients with metastatic, well- or moderately differentiated, nonfunctioning, and somatostatin-receptor-positive neuroendocrine tumors had significantly prolonged progression-free survival with lanreotide, a long-acting somatostatin analogue, compared to placebo (median not reached vs. median of 18.0 months respectively, p
