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Successful surgical treatment of a primary liver gastrinoma during pregnancy: A case report
American Journal of Obstetrics and Gynecology (2004) 191, 1716e8
www.ajog.org
Successful surgical treatment of a primary liver gastrinoma during pregnancy: A case report Jorge Delgado, MD,a,* Bertha Delgado, MD,b Ami D. Sperber, MD, MSPH,a Alex Fich, MDa Department of Gastroenterologya and Department of Pathology,b Soroka Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel Received for publication October 15, 2003; revised February 21, 2004; accepted March 9, 2004
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– KEY WORDS Primary Liver Gastrinoma Zollinger-Ellison syndrome Pregnancy Surgery
Primary neuroendocrine tumors of the liver, particularly gastrinomas, are exceptionally rare. We present a case of a sporadic primary liver gastrinoma in a young woman in whom the definitive diagnosis was reached, and surgical therapy was performed during pregnancy. Ó 2004 Elsevier Inc. All rights reserved.
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
Gastrinomas are rare neuroendocrine tumors with an incidence of 1 to 4 cases per/million per year.1,2 These tumors secrete a large amount of gastrin, which typically results in the development of an acid hypersecretory state, the Zollinger-Ellison syndrome (ZES).1,2 Approximately 80% of patients have the sporadic form, 60% to 90% of the tumors are malignant with a slow growth rate, and most are located at the gastrinoma triangle, which is delineated by the cystic duct, the border of the second and third parts of the duodenum, and the junction of the neck with the body of the pancreas.1,2 Surgery is the only effective treatment.1,2 A few anecdotal reports of primary liver gastrinoma (PLG) have been reported in the medical literature,1,2 but little is known about the proper management of PLG or any other gastrinoma during pregnancy.1-3 There have been no
* Reprint requests: Jorge Delgado, MD, Department of Gastroenterology, Soroka Medical Center, Beer-Sheva 84101, Israel. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.03.024
reports of successful curative treatment of PLG during pregnancy.
Case report A 29-year-old woman was referred to the Department of Gastroenterology of the Soroka University Medical Center in June 2000 complaining of increasingly severe and recurrent diffuse abdominal pain, chronic diarrhea, and moderate weight loss over the 3-year period before admission. Two months before, the patient had been operated on urgently because of an acute surgical abdomen resulting from a ‘‘spontaneous’’ perforation of the jejunum. Her family history was unremarkable. The workup included a gastroscopy, which demonstrated esophagitis and postbulbar duodenitis with a normal duodenal biopsy, a gastric pH of 1, and a negative rapid urease test. A small bowel follow-through x-ray showed a nonspecific malabsorption pattern. Colonoscopy, including intubation of the terminal ileum, was normal. The
Delgado et al
Figure 1 Contrast-enhanced thoracic-abdominal CT, showing a single solid, well-demarcated lesion (6 cm in diameter) in the left hepatic lobe.
fasting serum gastrin level was 1149 pg/mL (normal %115 pg/mL). At that point the working diagnosis was ZES. A contrast-enhanced thoracic-abdominal CT showed a single, solid, well-demarcated lesion (6 cm in diameter) in the left hepatic lobe. The pancreas and all other abdominal organs were normal (Figure 1). A somatostatin-receptor scintigraphy with octreotride (SRS) revealed uptake by an isolated, well-defined hepatic mass in the same location (Figure 2). Endoscopic ultrasonography (EUS) showed a normal duodenum and pancreas tissue, and a fine-needle aspiration (FNA) biopsy of the 6-cm liver mass confirmed the diagnosis of a neuroendocrine tumor of uncertain malignant potential. None of the tests (CT, SRS, and EUS) showed evidence of other tumors or of metastastic spread of the gastrinoma. There was no clinical, laboratory, or radiologic evidence of multiple endocrine neoplasia type I (MEN I), which includes primary hyperparathyroidism and pituitary tumors together with enteropancreatic tumors such as gastrinoma. High-dose lansoprazole therapy (90 mg/day) was initiated with symptomatic improvement in the diarrhea and abdominal pain. In the meantime, the patient became pregnant and an abdominal ultrasound exam performed in August 2000 revealed a pregnancy of 12 weeks. No change was made in the lansoprazole therapy, which is graded by the FDA as a category B drug that can be prescribed in pregnancy with the aim of relieving the symptoms caused by hypersecretion because the patient remained symptomatic throughout the first 20 weeks of gestation. A multidisciplinary consultation was convened in October 2000, at
1717
Figure 2 Somatostatin-receptor scintigraphy (SRS) showing octreotride uptake by an isolated, well-defined hepatic mass.
which time a decision was reached to excise the tumor, despite the gestation, taking into account that the focal symptomatic neuroendocrine liver tumor was clearly defined, with more than 3 cm in diameter, and had an uncertain malignant metastatic potential. There is no mention in the literature of the potential ill effects of PLG to the fetus. Regarding the mother, complete surgical resection of the tumor, as soon as possible improves the chance of cure and eliminates the risk of other complications of ZES, such as peptic ulcer, perforation, bleeding, and malabsorption. At the gestational age of 20 weeks, an exploratory laparotomy by midline incision with left hepatectomy and resection of the tumor was performed under general anesthesia at the Hopitaux de Paris, Groupe Hospitalier Bichat-Claude Bernard, Paris, France. In addition, the gastrinoma triangle was assessed, and intraoperative ultrasonography and endoscopic duodenal transillumination were carried out. Tocolytics were not administered during the operation. Parietal cell vagotomy was unnecessary in light of the good control of gastric output that was achieved with lansoprazole. The tumor size was 7 ! 6 ! 3 cm. There was no intraoperative evidence of other pancreatic or duodenal tumors. The fetal heart rate was monitored continuously throughout the operation, and uterine activity was monitored by tocodynamometer during the postoperative period. The histopathologic, immunohistochemical, and electron microscopic examinations of the liver specimen documented a well-differentiated gastrinoma with highly positive gastrin and chromogranin stains, and negative insulin and serotonin stains.
1718 After surgery, the patient was asymptomatic and the serum gastrin level returned immediately to the normal range. The immediate postsurgical course was uncomplicated, with no fetal complications. The pregnancy culminated at 42 weeks through a vaginal delivery with induction of labor. A healthy male baby, with Apgar score 9/9, birth weight of 3500 g, and no congenital malformations, was delivered. The patient was followed by gastrin level, abdominal CT, MRI, EUS, and SRS at 3, 6, and 12 months after surgery, and at yearly intervals thereafter. At 3-year follow-up the patient is asymptomatic with a normal serum gastrin level. There is no evidence of tumor recurrence by EUS, SRS, or MRI, and there has been no need for antisecretory therapy.
Comment There are only isolated reports of PLG, probably arising from neuroendocrine-like cells within the intrahepatic biliary tree,1,2 with scant information in the medical literature on the management of ZES during pregnancy, without mention to a definitive surgery approach during gestation.3 We report a unique case of liver gastrinoma with typical clinical features of ZES, such as recurrent abdominal pain, chronic diarrhea, and weight loss in a pregnant patient. The results of the extensive pre-, intra-, and postoperative work-up provided clear evidence that the tumor was a PLG. This is supported by the 3-year follow-up, in which the patient has been asymptomatic, with no evidence of any other tumor, and a nor-
Delgado et al mal serum gastrin level. Although a tiny gastrinoma at another site could not be recognized, the complete resolution of symptoms after left hepatectomy with tumor excision, the prompt normalization of the serum gastrin level, and the absence of other tumor tissue on follow-up SRS, EUS, and CT (combined specificity rate of 90% for gastrinoma liver metastasis),1,2 provide strong support for our diagnosis of isolated PLG. As discussed previously, surgery was the treatment of choice in this case, despite the pregnancy, because of the focal character of the PLG with a well-defined metastatic potential and the absence of other tumors. Occasional discussions on the management of the ZES in pregnancy have been published, referring primarily to curative therapy before conception or control of gastric acid hypersecretion during pregnancy.3 To our knowledge, this is the only report of definitive, surgical treatment of PLG during the course of pregnancy. The outcome, as reflected in the 3-year follow-up, has been highly satisfactory.
References 1. Azimuddin K, Chamberlain RS. The surgical management of pancreatic neuroendocrine tumors. Surg Clin North Am 2001;81: 511-25. 2. Roy PK, Venzon DJ, Shojamanesh H, Abou-Saif A, Peghini P, Doppman JL, et al. Zollinger-Ellison syndrome. Clinical presentation in 261 patients. Medicine (Baltimore) 2000;79:379-411. 3. Stewart CA, Termanini B, Sutliff VE, Corleto VD, Weber HC, Gibril F, et al. Management of the Zollinger-Ellison syndrome in pregnancy. Am J Obstet Gynecol 1997;176:224-33.
www.ajog.org
Successful surgical treatment of a primary liver gastrinoma during pregnancy: A case report Jorge Delgado, MD,a,* Bertha Delgado, MD,b Ami D. Sperber, MD, MSPH,a Alex Fich, MDa Department of Gastroenterologya and Department of Pathology,b Soroka Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel Received for publication October 15, 2003; revised February 21, 2004; accepted March 9, 2004
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– KEY WORDS Primary Liver Gastrinoma Zollinger-Ellison syndrome Pregnancy Surgery
Primary neuroendocrine tumors of the liver, particularly gastrinomas, are exceptionally rare. We present a case of a sporadic primary liver gastrinoma in a young woman in whom the definitive diagnosis was reached, and surgical therapy was performed during pregnancy. Ó 2004 Elsevier Inc. All rights reserved.
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
Gastrinomas are rare neuroendocrine tumors with an incidence of 1 to 4 cases per/million per year.1,2 These tumors secrete a large amount of gastrin, which typically results in the development of an acid hypersecretory state, the Zollinger-Ellison syndrome (ZES).1,2 Approximately 80% of patients have the sporadic form, 60% to 90% of the tumors are malignant with a slow growth rate, and most are located at the gastrinoma triangle, which is delineated by the cystic duct, the border of the second and third parts of the duodenum, and the junction of the neck with the body of the pancreas.1,2 Surgery is the only effective treatment.1,2 A few anecdotal reports of primary liver gastrinoma (PLG) have been reported in the medical literature,1,2 but little is known about the proper management of PLG or any other gastrinoma during pregnancy.1-3 There have been no
* Reprint requests: Jorge Delgado, MD, Department of Gastroenterology, Soroka Medical Center, Beer-Sheva 84101, Israel. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.03.024
reports of successful curative treatment of PLG during pregnancy.
Case report A 29-year-old woman was referred to the Department of Gastroenterology of the Soroka University Medical Center in June 2000 complaining of increasingly severe and recurrent diffuse abdominal pain, chronic diarrhea, and moderate weight loss over the 3-year period before admission. Two months before, the patient had been operated on urgently because of an acute surgical abdomen resulting from a ‘‘spontaneous’’ perforation of the jejunum. Her family history was unremarkable. The workup included a gastroscopy, which demonstrated esophagitis and postbulbar duodenitis with a normal duodenal biopsy, a gastric pH of 1, and a negative rapid urease test. A small bowel follow-through x-ray showed a nonspecific malabsorption pattern. Colonoscopy, including intubation of the terminal ileum, was normal. The
Delgado et al
Figure 1 Contrast-enhanced thoracic-abdominal CT, showing a single solid, well-demarcated lesion (6 cm in diameter) in the left hepatic lobe.
fasting serum gastrin level was 1149 pg/mL (normal %115 pg/mL). At that point the working diagnosis was ZES. A contrast-enhanced thoracic-abdominal CT showed a single, solid, well-demarcated lesion (6 cm in diameter) in the left hepatic lobe. The pancreas and all other abdominal organs were normal (Figure 1). A somatostatin-receptor scintigraphy with octreotride (SRS) revealed uptake by an isolated, well-defined hepatic mass in the same location (Figure 2). Endoscopic ultrasonography (EUS) showed a normal duodenum and pancreas tissue, and a fine-needle aspiration (FNA) biopsy of the 6-cm liver mass confirmed the diagnosis of a neuroendocrine tumor of uncertain malignant potential. None of the tests (CT, SRS, and EUS) showed evidence of other tumors or of metastastic spread of the gastrinoma. There was no clinical, laboratory, or radiologic evidence of multiple endocrine neoplasia type I (MEN I), which includes primary hyperparathyroidism and pituitary tumors together with enteropancreatic tumors such as gastrinoma. High-dose lansoprazole therapy (90 mg/day) was initiated with symptomatic improvement in the diarrhea and abdominal pain. In the meantime, the patient became pregnant and an abdominal ultrasound exam performed in August 2000 revealed a pregnancy of 12 weeks. No change was made in the lansoprazole therapy, which is graded by the FDA as a category B drug that can be prescribed in pregnancy with the aim of relieving the symptoms caused by hypersecretion because the patient remained symptomatic throughout the first 20 weeks of gestation. A multidisciplinary consultation was convened in October 2000, at
1717
Figure 2 Somatostatin-receptor scintigraphy (SRS) showing octreotride uptake by an isolated, well-defined hepatic mass.
which time a decision was reached to excise the tumor, despite the gestation, taking into account that the focal symptomatic neuroendocrine liver tumor was clearly defined, with more than 3 cm in diameter, and had an uncertain malignant metastatic potential. There is no mention in the literature of the potential ill effects of PLG to the fetus. Regarding the mother, complete surgical resection of the tumor, as soon as possible improves the chance of cure and eliminates the risk of other complications of ZES, such as peptic ulcer, perforation, bleeding, and malabsorption. At the gestational age of 20 weeks, an exploratory laparotomy by midline incision with left hepatectomy and resection of the tumor was performed under general anesthesia at the Hopitaux de Paris, Groupe Hospitalier Bichat-Claude Bernard, Paris, France. In addition, the gastrinoma triangle was assessed, and intraoperative ultrasonography and endoscopic duodenal transillumination were carried out. Tocolytics were not administered during the operation. Parietal cell vagotomy was unnecessary in light of the good control of gastric output that was achieved with lansoprazole. The tumor size was 7 ! 6 ! 3 cm. There was no intraoperative evidence of other pancreatic or duodenal tumors. The fetal heart rate was monitored continuously throughout the operation, and uterine activity was monitored by tocodynamometer during the postoperative period. The histopathologic, immunohistochemical, and electron microscopic examinations of the liver specimen documented a well-differentiated gastrinoma with highly positive gastrin and chromogranin stains, and negative insulin and serotonin stains.
1718 After surgery, the patient was asymptomatic and the serum gastrin level returned immediately to the normal range. The immediate postsurgical course was uncomplicated, with no fetal complications. The pregnancy culminated at 42 weeks through a vaginal delivery with induction of labor. A healthy male baby, with Apgar score 9/9, birth weight of 3500 g, and no congenital malformations, was delivered. The patient was followed by gastrin level, abdominal CT, MRI, EUS, and SRS at 3, 6, and 12 months after surgery, and at yearly intervals thereafter. At 3-year follow-up the patient is asymptomatic with a normal serum gastrin level. There is no evidence of tumor recurrence by EUS, SRS, or MRI, and there has been no need for antisecretory therapy.
Comment There are only isolated reports of PLG, probably arising from neuroendocrine-like cells within the intrahepatic biliary tree,1,2 with scant information in the medical literature on the management of ZES during pregnancy, without mention to a definitive surgery approach during gestation.3 We report a unique case of liver gastrinoma with typical clinical features of ZES, such as recurrent abdominal pain, chronic diarrhea, and weight loss in a pregnant patient. The results of the extensive pre-, intra-, and postoperative work-up provided clear evidence that the tumor was a PLG. This is supported by the 3-year follow-up, in which the patient has been asymptomatic, with no evidence of any other tumor, and a nor-
Delgado et al mal serum gastrin level. Although a tiny gastrinoma at another site could not be recognized, the complete resolution of symptoms after left hepatectomy with tumor excision, the prompt normalization of the serum gastrin level, and the absence of other tumor tissue on follow-up SRS, EUS, and CT (combined specificity rate of 90% for gastrinoma liver metastasis),1,2 provide strong support for our diagnosis of isolated PLG. As discussed previously, surgery was the treatment of choice in this case, despite the pregnancy, because of the focal character of the PLG with a well-defined metastatic potential and the absence of other tumors. Occasional discussions on the management of the ZES in pregnancy have been published, referring primarily to curative therapy before conception or control of gastric acid hypersecretion during pregnancy.3 To our knowledge, this is the only report of definitive, surgical treatment of PLG during the course of pregnancy. The outcome, as reflected in the 3-year follow-up, has been highly satisfactory.
References 1. Azimuddin K, Chamberlain RS. The surgical management of pancreatic neuroendocrine tumors. Surg Clin North Am 2001;81: 511-25. 2. Roy PK, Venzon DJ, Shojamanesh H, Abou-Saif A, Peghini P, Doppman JL, et al. Zollinger-Ellison syndrome. Clinical presentation in 261 patients. Medicine (Baltimore) 2000;79:379-411. 3. Stewart CA, Termanini B, Sutliff VE, Corleto VD, Weber HC, Gibril F, et al. Management of the Zollinger-Ellison syndrome in pregnancy. Am J Obstet Gynecol 1997;176:224-33.