M. Rothmund

Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer

Objective: Familial pancreatic cancer (FPC) accounts for approximately 3% of all pancreatic cancer (PC) cases. It has been suggested that high-risk individuals (HRIs) should be offered a screening programme. Aim: To evaluate the diagnostic yield of a prospective screening programme in HRIs from families with FPC over a period of 5 years. Methods: HRIs of families with FPC of the National German Familial Pancreatic Cancer Registry (FaPaCa) were counselled and enrolled in a prospective, board-approved PC screening programme. Screening included clinical examination, laboratory tests, endoscopic ultrasound (EUS) and MRI with magnetic resonance cholangiopancreaticography (MRCP) and MR angiography. Results: Between June 2002 and December 2007, 76 HRIs of families with FPC took part in the screening programme with a total of 182 examination visits. Twenty-eight patients revealed abnormalities in EUS (n = 25) and/or MR/MRCP (n = 12). In 7 patients fine needle aspiration cytology was performed. Operative pancreatic explorations were performed in 7 individuals, resulting in limited resections in 6 cases. Histopathological examination of the resected specimens showed serous oligocystic adenomas (n = 3), pancreatic intraepithelial neoplasia 1 (PanIN1) lesions with lobular fibrosis (n = 1), PanIN2 lesions (n = 1) and PanIN1 lesion plus a gastric type intraductal papillary mucinous neoplasm (IPMN) (n = 1). Conclusions: In FPC an EUS/MR/MRCP-based screening programme leads to the detection of potential precursor lesions of PC. However, the yield of an extensive screening programme is low, especially since the tumourigenic value of low grade PanIN lesions is not yet defined. Taking into account the enormous psychological stress for the tested individual and the high costs, a general PC screening in HRIs is not justified.

Outcome of Duodenopancreatic Resections in Patients With Multiple Endocrine Neoplasia Type 1

Objective:To evaluate the outcome of an aggressive surgical approach for duodenopancreatic neuroendocrine tumors (PETs) associated with multiple endocrine neoplasia type 1 (MEN1). Summary Background Data:The management of PETs is still controversial in the setting of the autosomal dominant inherited MEN1 syndrome. Methods:MEN1 patients that had either biochemical evidence of functioning PETs or visualized nonfunctioning PETs larger than 1 cm in size on imaging were operated. Since 1997, patients were followed annually by biochemical testing and imaging studies. Results:Twenty-six genetically confirmed MEN1 patients underwent duodenopancreatic resection for functioning (n = 17) or nonfunctioning (n = 9) PETs. Ten (38%) patients had malignant PETs as characterized by the presence of lymph node (10 patients) and/or distant metastases (2 patients). The surgical approach was selected based on the type, location, and size of PETs. Four Zollinger-Ellison syndrome (ZES) patients required pylorus preserving pancreaticoduodenectomy (PPPD) as initial or redo procedure, 20 patients underwent other duodenopancreatic resections, and 2 patients had simple enucleations of PETs. After median 83 months (range, 5–241 months), 24 patients were alive and 2 patients died of an unrelated cause. All patients with insulinoma or vipoma and 7 of 11 patients with ZES were biochemically cured, including the ZES patients who underwent PPPD. However, 19 of 26 (73%) patients developed new small PETs (<1 cm) in the pancreatic remnant, but no patient had yet detectable metastases on imaging. Conclusions:Early and aggressive surgery of PETs in MEN1 patients prevents the development of liver metastases, which are the most life-threatening determinant. PPPD might be the procedure of choice for MEN1–ZES, which has to be proven in large scale studies.

An aggressive surgical approach leads to long-term survival in patients with pancreatic endocrine tumors.

Objective:To evaluate the outcome of reoperations in patients with duodenopancreatic neuroendocrine tumors (PETs) in a tertiary referral center. Summary Background Data:The management of reoperations in PETs is still controversial. Methods:A total of 125 patients with PETs that underwent surgery between 1987 and 2004 at our institution were retrospectively evaluated. The diagnosis of PETs was based on clinical symptoms, biochemical tests, and histopathology. Patients with at least one reoperation were analyzed regarding clinical characteristics, pathology, operations, and long-term follow-up. Results:A total of 33 patients with a median age of 42 years were identified for this study: 13 patients had gastrinomas, 12 patients had nonfunctional islet cell tumors, 6 patients had insulinomas, and 2 patients had vipomas; 24 patients had sporadic NETs, 9 patients had a MEN-1-syndrome; 27 patients had histologically verified malignant tumors; 33 initial operations and 50 reoperations were performed. The initial procedures comprised 27 resections of the primary tumor and 6 explorative laparotomies; 28 of all reoperations were resections of distant metastases, including 15 liver resections; 19 resections of the pancreas or duodenum were performed during reoperations. The overall morbidity and mortality was 45% and 4.8%, respectively. After a median follow-up of 124 months (range, 16–384 months), 27 of 33 patients are still alive, 12 without evidence of disease. All 6 patients with benign tumors are still alive. The 5-, 10-, and actuarial 25-year survival rate for patients with malignant tumors were 81%, 72%, and 36%, respectively. The survival rate was significantly related to the patients age at time of initial operation and better in patients younger than 50 years compared with patients older than 50 years (P = 0.0007), and the presence or development of metastases (none or lymph node metastases versus distant metastases: P = 0.01). Conclusion:We show that an aggressive surgical approach leads to long-term survival in patients with malignant PETs. Although long-term cure can only be achieved in a proportion of patients with malignant PETs, significant long-term palliation can be achieved.

Surgical management for carcinoid tumors of small bowel, appendix, colon, and rectum

Abstract. Carcinoid tumors occur most frequently in the gastrointestinal tract. Despite their ability to produce hormones, most of the midgut and hindgut carcinoids covered in this study are clinically silent, and the diagnosis is often not made before emergency surgery or evaluation for liver metastases. Because the rate of lymph node involvement and the prognosis of carcinoid tumors depend on their site and size, surgery refers to these two factors too. Lymph node metastases are most commonly found with small bowel carcinoids (20–45%), providing the rationale for an extended resection including the adjacent lymph node drainage area. Carcinoid tumors of the appendix < 1 cm in diameter rarely metastasize, simply requiring appendectomy for treatment. Lesions > 2 cm should be treated by right hemicolectomy because of their approximately 30% risk of lymph node metastases. Resection should always be done for carcinoid tumors of the colon resection as for adenocarcinomas. Rectal carcinoids < 2 cm rarely metastasize, directing the conclusion that for these smaller lesions local excision is sufficient; for lesions >2 cm a standard cancer resection should be performed provided distant metastases are absent. In general, the younger the patient or the larger the primary tumor, the more aggressive the treatment should be.

Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors

Tumors of the endocrine pancreas are extremely rare, and molecular mechanisms leading to their development are not well understood. A candidate tumor suppressor gene, DPC4, located at 18q21, has recently been shown to be inactivated in half of pancreatic adenocarcinoma xenografts. The close anatomical relationship of the exocrine and endocrine pancreas prompted us to determine the role of DPC4 in the tumorigenesis of 25 pancreatic islet cell tumors (11 insulinomas, nine non-functioning endocrine carcinomas, three gastrinomas, two vipomas). A mutation screening of the highly conserved COOH-terminal domain of DPC4 (exons 8 – 11) was performed by single-strand conformational variant (SSCP) analysis and a PCR-based deletion assay. Five of nine (55%) non-functioning endocrine pancreatic carcinomas revealed either point mutations, small intragenic deletions or homozygous deletion of DPC4 sequences compared to none of the insulinomas, gastrinomas or vipomas. These results suggest that DPC4 is an important target gene promoting tumorigenesis of non-functioning neuroendocrine pancreatic carcinomas.

Adrenal involvement in multiple endocrine neoplasia type 1

Adrenal lesions belong to the spectrum of multiple endocrine neoplasia type 1 (MEN-1) syndrome. However, the prevalence of adrenal involvement, the characteristics, and the clinical management of adrenal lesions have not yet been clearly defined. A total of 66 patients with confirmed MEN1 germline mutations and 1 additional patient with typical manifestations in three organ systems were monitored in a regular screening program that included evaluation of the adrenals (median follow-up 96 months; range 12 to 300 months). Age at the diagnosis of MEN-1 and of adrenal tumors and the clinical characteristics, genotype, treatment, and follow-up of adrenal disease were analyzed. Adrenal lesions were identified in 18 of 67 (26.8%) MEN-1 patients and were diagnosed 5 years later than MEN-1. The median tumor diameter at diagnosis was 3.0 cm (range 1.2–15.0 cm), with most tumors being 3 cm or smaller. Eight patients had bilateral tumors. Ten patients had nonfunctional benign tumors, three had benign adrenal Cushing syndrome, and one patient had a pheochromocytoma. Four patients developed adrenocortical carcinomas (ACCs), three of which were functional. Nine adrenalectomies and one subtotal adrenalectomy were performed in six patients. Three patients with ACC died owing to the tumor. Patients with mutations in exons 2 and 10 developed adrenal tumors significantly more often than patients with other mutations (p <0.01). Adrenal tumors are a common feature of MEN-1 but occur later in the course of the disease. The lesions are often small and nonfunctional and can therefore be managed by close surveillance; others have significant malignant potential and should be considered for surgery when they are 3 cm or larger.

Conventional bilateral cervical exploration versus open minimally invasive parathyroidectomy under local anaesthesia for primary hyperparathyroidism

Minimally invasive parathyroidectomy (MIP) has been introduced for the treatment of patients with primary hyperparathyroidism (pHPT). Thus far, only one randomized trial has compared video‐assisted MIP with conventional bilateral cervical exploration (BCE). The value of open MIP is therefore not known.

Prospective Evaluation of Imaging Procedures for the Detection of Pancreaticoduodenal Endocrine Tumors in Patients with Multiple Endocrine Neoplasia Type 1

Early identification of pancreaticoduodenal endocrine tumors (PETs) in multiple endocrine neoplasia type 1 (MEN-1) is mandatory, because these tumors represent the most common cause of death within the syndrome. The diagnostic value of imaging procedures has therefore been evaluated in a prospective observational study. Between December 1997 and June 2003 twenty-two MEN-1 patients with genetically confirmed disease were followed for PETs using a standardized screening program with serum hormone measurements, endoscopic ultrasonography (EUS), computed tomography (CT), and somatostatin-receptor scintigraphy (SRS). Results could be validated by surgery and histopathology in 13 patients during 18 operations. In 12 asymptomatic patients with tumors measuring 10 mm or less, who have not yet undergone operation, PETs were detected by EUS in 12/12, by CT in 1/12, and by SRS in 2/11 cases. In 13 patients who have undergone surgical exploration EUS, CT, and SRS were true positive in 12 of 16, 7 of 13, and 12 of 17 cases, respectively, although the number of tumors detected by each imaging procedure alone was lower than the number detected intraoperatively and histopathologically in almost every case. A solitary liver metastasis in one patient and a nonfunctioning PET recurrence in another were identified only by SRS. Endoscopic untrasonography is the most sensitive imaging procedure for the detection of small (≤ 10 mm) PETs in MEN-1, whereas SRS is the procedure of choice for the identification of metastases of MEN-1 PETs—i.e., for staging. Detection of PETs at an early stage by an aggressive screening program using EUS may lead to prompt surgical intervention and improved prognosis of MEN-1 PETs.

Surgical treatment of pheochromocytomas : Laparoscopic or conventional?

AbstractBackground: The use of minimally invasive techniques in the surgical treatment of pheochromocytoma is controversial because of possible intraoperative excessive hormone release resulting in cardiovascular instabilities. Methods: Laparoscopic adrenalectomy was performed in nine patients with a total of 10 pheochromocytomas. Conversion was required in two cases. The relevant data were prospectively documented and compared with a historical group of nine patients who had undergone conventional transabdominal adrenalectomy for unilateral pheochromocytoma. Results: The laparoscopic operations lasted significantly longer than the conventional procedures (median 243 min vs. 100 min, p < 0.01). Intraoperative cardiovascular instabilities (tachycardia, hypertension) occurred in seven laparoscopically and eight conventionally treated patients. All were easily controlled. Blood transfusions were necessary in four patients in the conventional and one patient in the laparoscopic group. Postoperative hospital stay and duration of analgetic treatment were significantly shorter after laparoscopic adrenalectomy. Conclusions: Laparoscopic adrenalectomy is a safe procedure for patients with pheochromocytoma.

Ultrasonography in the diagnosis of acute appendicitis: A prospective study

The diagnostic accuracy and practical impact of high-resolution sonography were prospectively studied in 523 consecutive patients admitted to the hospital with suspected appendicitis. The criteria for ultrasound diagnosis of acute appendicitis included visualization of a noncompressible aperistaltic appendix, with a targetlike appearance in transverse view and a diameter greater than or equal to 7 mm. In 115 of 130 patients with proven appendicitis the inflamed appendix or appendiceal abscess could be visualized, giving a sensitivity of 88.5%. The mean diameter of ultrasonically visible appendices was 11.4 +/- 3.2 mm. The overall accuracy and specificity of sonography in the diagnosis of acute appendicitis were 95.7% and 98%, respectively. The predictive value of a positive test was 94.5% and that of a negative result 96.3%. In a separate analysis of the results in 121 women of childbearing age, who have a high risk of preoperative misdiagnosis, the overall accuracy was found to be 96.7%, with 82.6% sensitivity and 100% specificity. Twenty-four (89%) of the 27 patients with appendiceal rupture (incidence 20.8%) were correctly diagnosed with ultrasound. The other 3 cases (11%) were missed. Routine use of ultrasonography has significantly improved the diagnostic accuracy in patients with suspected appendicitis and has reduced the negative laparotomy rate from 22.9% to 13.2%.