Persistent hyperinsulinemic hypoglycemia in the newborn and infants

Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) is the most frequent cause of hypoglycaemia in infancy. Clinical presentation is heterogeneous, with variable onset of hypoglycaemia and response to diazoxide, and presence of sporadic or familial forms. Underlying histopathological lesions can be focal or diffuse. Focal lesions are characterised by focal hyperplasia of pancreatic islet-like cells, whereas diffuse lesions implicate the whole pancreas. The distinction between the two forms is important because surgical treatment and genetic counselling are radically different. Focal lesions correspond to somatic defects which are totally cured by limited pancreatic resection, whereas diffuse lesions require a subtotal pancreatectomy exposing to high risk of diabetes mellitus. Diffuse lesions are due to functional abnormalities involving several genes and different transmission forms. Recessively inherited PHHI have been attributed to homozygote mutations for the beta-cell sulfonylurea receptor (SUR1) or the inward-rectifying potassium-channel (Kir6.2) genes. Dominantly inherited PHHI can implicate the glucokinase gene, particularly when PHHI is associated with diabetes, the glutamate dehydrogenase gene when hyperammonaemia is associated, or another locus.     

Loss of functional KATP channels in pancreatic beta-cells causes persistent hyperinsulinemic hypoglycemia of infancy

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a disorder of childhood associated with inappropriate hypersecretion of insulin by the pancreas. The pathogenesis of the condition has hitherto remained controversial. We show here that insulin-secreting cells from a homogeneous group of five infants with PHHI lack ATP-sensitive K+ channel (KATP) activity. As a consequence, PHHI beta-cells are spontaneously electrically active with high basal cytosolic Ca2+ concentrations due to Ca2+ influx. Our findings define the pathogenesis of this disease as a novel K+ channel disorder.     

Pancreatic polypeptide immunoreactivity in sporadic gastrinoma: relationship to intraabdominal location

Sporadic gastrinoma is a pancreatic endocrine tumor whose ontogeny is unknown. The anatomic area where the vast majority of sporadic gastrinomas is found (pancreatic head region) corresponds topographically to the area traversed embryologically by the ventral pancreatic bud. Pancreatic polypeptide (PP), a 36-amino acid hormone, is secreted by pancreatic endocrine cells derived almost exclusively from the ventral pancreatic bud and is proposed as a marker for ventral bud derivation. Based on these observations we postulate that sporadic gastrinomas, found around the head of the pancreas, are derived from ventral bud tissue and should display a high incidence of PP immunoreactivity. Overall, we found PP immunoreactivity in 7 of 14 (50%) gastrinomas. Of those tumors located to the right of the superior mesenteric artery (SMA) (around the head of the pancreas), seven of nine (78%) contained PP, whereas no gastrinoma to the left of the SMA (n = 5) contained PP (p = 0.021; Fisher exact test). Only one other pancreatic endocrine or exocrine tumor, a glucagonoma located to the left of the SMA, stained positively for PP. We conclude that sporadic gastrinomas found around the head of the pancreas (to the right of the SMA) have a high incidence of PP immunoreactivity. These findings are consistent with our hypothesis that sporadic gastrinomas are derived from the ventral pancreatic bud.     

Hyperinsulinism in children: diagnostic value of pancreatic venous sampling correlated with clinical, pathological and surgical outcome in 25 cases

Neonatal hypoglycemia represents an emergency of heterogeneous etiology. The occurrence of persistent hypoglycemia caused by hyperinsulinism has not been well established. Some authors claim that it may be more common than previously suggested. The diagnostic goal is to distinguish hyperinsulinemia from other causes of hypoglycemia because management strategies differ. The diagnosis of persistent hypoglycemia attributable to hyperinsulinism is made when insulin secretion is excessive or inappropriate (> 10 microIU/ml). Medical management includes frequent feeding, high hydrocarbon intake, glucagon, diazoxide, somatostatin or steroid treatment. In case of resistance to medical intervention, surgery consisting of subtotal pancreatectomy is performed to avoid neurological sequelae. However, pediatric organic hypoglycemia secondary to hyperinsulinism can be caused by either diffuse or focal pancreatic lesions. Differentiation between these two types of lesion is necessary since partial pancreatectomy can prevent diabetes. In this prospective study, pancreatic venous sampling (PVS) was evaluated for the preoperative localization of lesions in 25 children with hyperinsulinism and correlated with surgical, pathological and clinical outcome. PVS is the most accurate preoperative technique for localizing focal lesions in children. Besides being safe and effective, it has the great advantage of detecting focal secretion, thus reducing the need for extensive surgery.     

Occurrence of human pancreatic polypeptide in pancreatic endocrine tumors. Possible implication in the watery diarrhea syndrome

Eighteen endocrine pancreatic tumors were examined for the occurrence of cells producing insulin, glucagon, gastrin, human pancreatic polypeptide (HPP), and vasoactive intestinal polypeptide (VIP) and for A1 cells. More than half of the tumors were mixed, i.e., they contained more than one type of hormone-producing cell. The clinical symptoms were attributable only to one of the hormones produced by the mixed tumors. Three of four tumors causing the watery diarrhea syndrome contained both VIP and HPP cells. In one such tumor there was a strong predominance of HPP cells; the serum HPP levels of this patient were a thousandfold elevated, whereas her VIP levels were within the normal range. Several lines of evidence point to HPP as a possible agent causing the watery diarrhea syndrome. In many of our patients, HPP cells hyperplasia was present in the extratumoral pancreas. Such hyperplasia may give rise to the raised serum HPP levels seen in many patients having endocrine pancreatic tumors.     

Diagnosis of carcinoma in situ of the pancreas by peroral pancreatoscopy and pancreatoscopic cytology

BACKGROUND: Most pancreatic carcinomas are unresectable at the time of diagnosis, but recently the diagnosis of carcinoma in situ of the pancreas has become possible. This diagnosis can be made by the detection of cancer cells in pancreatic juice and the radiographically demonstrated lack of a mass lesion. It has greatly improved the effectiveness of surgery. Carcinoma in situ remains within the pancreatic ductal epithelium and has not yet invaded the parenchyma. However, it has often been difficult to locate carcinoma in situ by conventional diagnostic methods, such as ultrasonography, endoscopic ultrasonography, computed tomography, and endoscopic retrograde pancreatography. METHODS: Peroral pancreatoscopy and a new method of cytodiagnosis, pancreatoscopic cytology, were used to analyze 11 patients with carcinoma in situ of the pancreas, 10 with disease in the main duct of the pancreas and 1 with disease in the branch ducts. The results of pancreatoscopic cytology were compared with those of conventional pancreatic juice cytology. RESULTS: Under peroral pancreatoscopy, carcinoma in situ of the pancreas in the main duct appeared as papillary mucosa, irregular mucosa, or nodular mucosa. Using pancreatoscopic cytology, cancer cells were obtained from all the lesions, allowing a more thorough analysis than pancreatic juice cytology. CONCLUSIONS: Peroral pancreatoscopy and pancreatoscopic cytology are useful for locating and diagnosing carcinoma in situ of the pancreas.     

Focal nodular hyperplasia of the liver: a clinicopathologic study and review of the literature

We received the clinical records and pathologic material of 20 patients with biopsy proven hepatic focal nodular hyperplasia. The majority of the patients were females of child bearing age, five of whom had a history of oral use of contraceptives. In every instance focal nodular hyperplasia was an incidental finding; liver function tests were always normal. Focal nodular hyperplasia is a distinct histopathologic entity, distinguishable from liver cell adenoma. Specifically it consists of nodular aggregates of cytologically normal hepatocytes with foci of intranodular bile duct proliferation. Focal nodular hyperplasia appears to be a benign entity, even in patients in whom the lesion was not excised. The association between focal nodular hyperplasia and oral use of contraceptives may be coincidental, although hormonally related vascular changes may be responsible for rupture of the lesion.     

The use of spiral computerized tomography in the study of pancreatic insulinoma: preliminary results

Insulinomas are usually benign tumors originating in the pancreatic islets: since they are biologically active tumors, insulinomas present at clinics with hypoglycemia caused by increased insulin production. We examined 7 patients with clinically suspected insulinomas with spiral CT to investigate its capabilities in identifying and characterizing this type of lesion. Four patients had abnormal spiral CT findings (true positives); the diagnosis was confirmed at surgery in 3 patients and at instrumental follow-up in the other. The tumors were 12.2 mm in average diameter. CT showed no tumor mass in 3 cases, which was confirmed at angiography and MRI (true negatives). We observed a typical contrast pattern in 50% of cases, namely a ring-like enhancement changing into homogeneous enhancement. Multiplanar and 3D reconstructions were not necessary for lesion identification, but we used them for regional vascular mapping. In our experience, which is limited to few cases and dose not allow any statistically significant conclusion, spiral CT exhibited high sensitivity in the detection and characterization of pancreatic insulinomas which permits to reduce the resort to more invasive angiographic techniques.     

Ultrasound guided percutaneous fine needle aspiration cytology of pancreas: a review of 61 cases

The study includes 61 cases which were subjected to ultrasound (US) guided fine needle aspiration cytology (FNAC) to find out the utility of this technique in the diagnosis of pancreatic lesions. Age of the patients ranged from 23 to 85 years with a median of 50 years. Male to female ratio was 36:25. One or more clinical diagnoses were offered in 16 and in 9 of these, the disease was related to pancreas. Subsequent to US, the lesions were localized to pancreas in 57 and the nature of pathology in the pancreatic lesion could be diagnosed in 31. By FNAC, 31 cases (50.8%) were diagnosed to have pancreatic malignancy which included adenocarcinoma (23 cases), papillary cystic tumour (1), muco-epidermoid carcinoma (1), acinic cell carcinoma (1), islet cell tumor (1), and non Hodgkin lymphoma (4). FNAC of liver in 2 cases and retroperitoneal lymph node in a case of pancreatic adenocarcinoma revealed metastasis. During follow up, 1 case of non Hodgkin's lymphoma showed CSF involvement. Three cases (4.9%) were suspected to have epithelial malignancy of which one was confirmed as an adenocarcinoma following surgery and histology. Four (6.6%) were benign lesions which included nonspecific inflammation (2 cases), tuberculous pancreatitis (1) and pseudopancreatic cyst (1). The remaining 23 cases (37.7%) had normal or inadequate cytology. Of these, FNAC of liver showed metastasis in 2 cases and one case each were diagnosed as adenocarcinoma and pseudopancreatic cyst respectively following surgery. None of the patients had any complication following FNAC. We recommend US guided FNAC to be routinely used for diagnosis of pancreatic lesion.     

Pyloric gland adenoma of the main pancreatic duct

A case of a pyloric gland type adenoma of the main pancreatic duct in a 69-year-old woman is reported. The tumor led to occlusion and cystic dilatation of the main duct in the pancreatic tail. The surgical resection specimen disclosed a polypoid, bilobed mass attached to the wall of the main pancreatic duct by a thin fibrous stalk. Light-microscopic examination revealed a well-demarcated nodule composed of closely packed tubular glands lined by columnar, mucin-secreting cells with abundant clear cytoplasm and basally oriented nuclei. Focal, mild cytologic atypia was seen. Pyloric metaplasia and focal papillary hyperplasia was present in the adjacent ductal epithelium. Periodic acid-Schiff reactions, with and without diastase predigestion, showed reactivity in the tubular glands, whereas alcian blue (pH 2.5) was negative. Immunohistochemical stains for chromogranin, serotonin, somatostatin, and gastrin failed to detect the respective antigens. Genetic analysis using polymerase chain reaction with mutant enrichment and allele specific oligonucleotide hybridization detected a single mutation at codon 12 of K-ras, which changed the wild-type glycine to arginine. This mutation is commonly found in invasive pancreatic ductal carcinomas. Although tumors with microscopic and immunohistochemical features consistent with pyloric gland adenoma have been described in the gallbladder, to our knowledge, this is the first reported case within the pancreatic ductal system. The finding of a K-ras, codon 12 mutation and the presence of focal dysplasia may denote neoplastic potential in association with this lesion.     

Allelic deletions on chromosome 11q13 in multiple endocrine neoplasia type 1-associated and sporadic gastrinomas and pancreatic endocrine tumors

Endocrine tumors (ETs) of pancreas and duodenum occur sporadically and as a part of multiple endocrine neoplasia type 1 (MEN1). The MEN1 tumor suppressor gene has been localized to chromosome 11q13 by linkage analysis but has not yet isolated. Previous allelic deletion studies in enteropancreatic ETs suggested MEN1 gene involvement in tumorigenesis of familial pancreatic ETs (nongastrinomas) and sporadic gastrinomas. However, only a few MEN1-associated duodenal gastrinomas and sporadic pancreatic nongastrinomas have been investigated. We used tissue microdissection to analyze 95 archival pancreatic and duodenal ETs and metastases from 50 patients for loss of heterozygosity (LOH) on 11q13 with 10 polymorphic markers spanning the area of the putative MEN1 gene. Chromosome 11q13 LOH was detected in 23 of 27 (85%) MEN1-associated pancreatic ETs (nongastrinomas), 14 of 34 (41%) MEN1-associated gastrinomas, 3 of 16 (19%) sporadic insulinomas, and 8 of 18 (44%) sporadic gastrinomas. Analysis of LOH on 11q13 showed different deletion patterns in ETs from different MEN1 patients and in multiple tumors from individual MEN1 patients. The present results suggest that the MEN1 gene plays a role in all four tumor types. The lower rate of 11q13 LOH in MEN1-associated and sporadic gastrinomas and sporadic insulinomas as compared to MEN1 nongastrinomas may reflect alternative genetic pathways for the development of these tumors or mechanisms of the MEN1 gene inactivation that do not involve large deletions. The isolation of the MEN1 gene is necessary to further define its role in pathogenesis of pancreatic and duodenal ETs.     

A study of light-initiated currents in Limulus lateral eye retinular cells

In a series of 18 patients with focal nodular hyperplasia of the liver characteristic histological changes were found in the lesion of 5 patients receiving female reproductive steroids, e.g, four women taking oral contraceptives for several years, and one man treated with synthetic estrogenic compound for carcinoma of the prostate. These lesions contained young, connective tissue septa with abundant proliferation of bile ducts, piecemeal necroses and lymphocytic infiltration. Much less or no activity, was found in the lesion of 11 women and 2 men without hormone treatment. Possible mechanisms for this activity are discussed, and it is proposed that focal nodular hyperplasia represents a congenital malformation, possibly a hamartoma, the liver cells of which may suffer from enzymatic defects, which may render them especially vulnerable to female sex hormones.     

Effects of eating on plasma hyaluronan in patients with cirrhosis: its mechanism and influence on clinical interpretation

Intraoperative hormonal measurements have been used successfully to guide the surgical treatment of various endocrine diseases. In this study, we report the results of intraoperative insulin measurement (IIM) in patients with organic hypoglycemia. IIMs were performed during 52 operations in 51 patients. Hyperinsulinism was secondary to a sporadic insulinoma (M = 40), a type I multiple endocrine neoplasia (MEN-I) (M = 8), an insulin-secreting carcinoma (M = 1), or pancreatic nesidioblastosis (M = 2). The insulin was measured with a radioimmunologic assay in blood samples simultaneously drawn from a peripheral vein and the portal vein at the beginning of the operation (T1) and 20 minutes after tumor removal (T2). Normoglycemia was achieved after surgery in 50 cases (96%). Systemic and portal insulin levels were normal at T1 in eight patients, precluding any further interpretation of the test. Completeness of surgery was confirmed by normalization of both systemic and portal insulin levels at T2 in 36 patients. In seven cases the systemic or portal insulin levels (or both) remained elevated at T2 despite a favorable outcome after surgery. Failure of the surgical procedure was predicted in two patients by the persistence of high levels of insulin at T2. In patients with initially elevated serum insulin levels, the positive predictive value and the specificity of intraoperative insulin measurement for completeness of surgery were both 100%. The sensitivity was 84%, the negative predictive value 22%, and the accuracy of the test 84%. We concluded that IIM is a simple, highly reliable tool for predicting the completeness of surgery in patients with organic hypoglycemia. IIM appears to be a valuable addendum to the surgical armamentarium against insulinoma especially for patients with atypical causes, such as MEN, insulin-secreting carcinoma, or pancreatic nesidioblastosis.     

Lymphoepithelial cysts of the pancreas: demonstration of lipid component using CT and MRI

We present two cases of surgically proven lymphoepithelial cyst (LEC) of the pancreas that had a lipid component visualized by CT and MRI. Identification of this component in a pancreatic cystic lesion is a key to favor the diagnosis of LEC or splenic epidermoid cyst over other cystic lesions when the lesion is noted in an elderly patient.     

Characteristics and treatment of mucin-producing tumor of the pancreas

BACKGROUND/AIMS: There has been no thorough clinicopathological analysis of a large number of cases with mucin-producing tumor of the pancreas. The aim of this study was to investigate the clinicopathological features of and therapeutic strategy for this ailment. METHODOLOGY: Two hundred and fifty-nine cases of mucin-producing tumor of the pancreas were analyzed clinicopathologically. RESULTS: Mucin-producing tumor of the pancreas was found in 177 males and 82 females (M:F=2.2:1). The mean age was 65.5 years. Jaundice, diabetes mellitus and a past history of pancreatitis were found in 15-19% of the cases. The tumor was most frequently (62%) found in the head of the pancreas. Pathologically, hyperplasia or adenoma was found in 58 cases, and adenocarcinoma in 160 cases. Five-year survival rate by the Kaplan-Meier method was 82.6% in all of the cases, and the post-operative survival curve was much better in cases with this type of carcinoma than in cases with ordinary pancreatic duct cell carcinoma (5-year survival rate: 17.3%). Organ-function preserving procedures, such as duodenum preserving subtotal resection of the head of the pancreas or spleen preserving distal pancreatectomy, might be recommended for this disease without infiltration. CONCLUSIONS: Mucin-producing tumor has unique clinicopathological characteristics, such as the dilated main pancreatic duct or branches, dilatation of the orifice of the papilla of Vater, or a good prognosis. Organ-function preserving procedures should be recommended in some cases with this ailment.     

Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas

BACKGROUND: Osteochondroma most frequently arises sporadically and as a solitary lesion, but also may arise as multiple lesions characterizing the autosomal dominant disorder hereditary multiple exostoses (HME) and the contiguous gene syndromes Langer-Giedion and DEFECT-11 syndromes. HME is genetically heterogeneous with association of three loci including 8q24.1 (EXT1), 11p11-12 (EXT2), and 19p (EXT3). Constitutional chromosomal microdeletions of 8q24.1 and 11p11-12 are features of the Langer-Giedion and DEFECT-11 syndromes, respectively. Cytogenetic studies of osteochondroma are rare. METHODS: Cytogenetic analysis was performed on 34 osteochondroma specimens from 22 patients with sporadic lesions and 4 patients with HME utilizing standard methodologies. Fluorescence in situ hybridization with chromosome specific probes was performed on three cases to define structural rearrangements further. RESULTS: Clonal abnormalities were detected in ten cases. Notably, deletion of 11p11-13 was observed in one case (a sporadic tumor) and loss or rearrangement of 8q22-24.1 in eight cases (seven sporadic and one hereditary tumor). CONCLUSIONS: These findings: 1) confirm previous observations of 8q24.1 karyotypic anomalies in sporadic osteochondroma, 2) reveal the presence of somatic chromosomal anomalies in hereditary osteochondromata, 3) suggest that similar to hereditary lesions, sporadic osteochondromas also are genetically heterogeneic (involvement of both 8q24.1 and 11p11-12), and 4) support the hypothesis that loss or mutation of EXT1 and EXT2, two putative tumor suppressor genes, may be important in the pathogenesis of sporadic as well as hereditary osteochondromata.     

Management of the pancreatic metastases from renal cell carcinoma: report of four resected cases

The pancreas is an uncommon site for metastasis from renal cell carcinoma. In most cases, pancreatic metastases occur as part of widespread nodal and visceral involvement, and there is thus evidence of metastatic disease elsewhere in the body. We present 4 cases with resectable pancreatic metastases arising from renal cell tumors without involvement of the regional lymph nodes at the operation. Three cases out of 4 were asymptomatic and the pancreatic metastases were detected by routine follow-up examination of renal cell carcinoma. Aggressive surgical treatment for the solitary metastatic lesion is advocated. Spread of renal cell carcinoma to the pancreas is, however, via the hematogenous route, and even solitary pancreatic metastasis may be one of the manifestations of the systemic metastasis of renal cell carcinoma. No pancreatic regional lymph nodes metastases were noted. Pancreatectomy should be undertaken to remove the tumor with adequate resection margins while preserving as much of the gland as possible. The prognosis of pancreatic metastases arising from a renal cell carcinoma is discussed with a review of the literature. Adjuvant chemo- and endocrine therapy should also be considered in these cases.     

Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma

Pancreatic adenocarcinomas are known to have a high incidence of K-ras gene mutations. Differential diagnosis of pancreatic cancer and chronic pancreatitis sometimes presents a clinical dilemma. We recently developed a highly sensitive and specific polymerase chain reaction capable of detecting 3-30 copies of mutant K-ras genes harboring codon 12 single base changes in the presence of 300,000 normal copies. Mutant ras genes were detected in DNA purified from pancreatic juice from all 6 cases of pancreatic adenocarcinoma and 1 case of intraductal papillary neoplasms of the pancreas. In 2 of 6 other cases with pancreatic adenocarcinoma, circulating metastatic cells were detected in DNA purified from peripheral blood. Activated ras genes were not found in pancreatic juice of three control cases (chronic pancreatitis and choledocholithiasis) or in the peripheral blood of two patients with insulinomas. Notable conclusions of this study are that there can be significant levels of shed tumor cells in peripheral blood and an even higher number in pancreatic juice. In addition, two different K-ras mutations were found in some patients.     

Detection of K-ras gene mutations at codon 12 in the pancreatic juice of patients with intraductal papillary mucinous tumors of the pancreas

BACKGROUND: The authors previously found specific mutations of the K-ras gene at codon 12 in the pancreatic juice of 67% of patients (6 of 9) with pancreatic ductal carcinoma, and the detection of these mutations was useful for diagnosis. This study was performed to detect and evaluate K-ras mutations in pancreatic juice from patients with intraductal papillary mucinous tumor of the pancreas, which is considered a low grade malignancy. The results were interpreted from the viewpoint of clinical significance. METHODS: K-ras mutations were examined using seminested polymerase chain reaction analysis combined with restriction enzyme digestion, followed by nonradioisotopic single strand DNA conformation polymorphism. RESULTS: Twelve of thirteen cases (92%) of intraductal papillary mucinous tumor of the pancreas, confirmed histologically (9 adenomas and 4 carcinomas), and 26 of 43 cases (60%) of ductal carcinoma showed specific K-ras gene mutations in the pancreatic juice. Furthermore, 4 of 22 patients (18%) with chronic pancreatitis, followed for more than 1 year without a sign of pancreatic tumor, showed K-ras mutations. In contrast, no mutations of the K-ras gene were detected in the pancreatic juice from 28 normal controls. CONCLUSIONS: K-ras mutations were found in the pancreatic juice of all but one patient with intraductal papillary mucinous tumor of the pancreas, but they were not useful for distinguishing carcinoma from adenoma. The authors concluded that K-ras mutations are not a specific marker for pancreatic neoplasms because similar mutations were detected in the pancreatic juice from patients with chronic pancreatitis. At the present time, the detection of K-ras mutations in pancreatic juice should be used clinically as an adjunct diagnostic modality for pancreatic diseases.     

Neonatal hyperinsulinism--surgical and pathologic considerations

Hyperinsulinism in infancy is most often associated with a diffuse pancreatic lesion designated islet-cell dysmaturation syndrome. This disease is commonly associated with persistent hypoglycemia which usually results from inappropriate secretion of insulin. Urgent medical therapy consisting of hypertonic glucose infusion, frequent feeding, and diazoxide is mandatory in order to prevent central nervous system damage. Where medical means of therapy are not effective, an early 85% subtotal pancreatectomy with preservation of the spleen, is indicated. Nine infants who suffered from hyperinsulinism are reported. In two, medical measures were sufficient to control the disease. One of these patients in whom treatment was started late, remained slightly mentally retarded. Seven patients underwent 85% pancreatectomy. In one of these, an additional 7.5% of the pancreas had to be removed and in a second patient total pancreatectomy was performed in order to control the disease. One patient died on the eighth postoperative day after acute gastric perforation. There was no evidence of residual brain damage in the patients who underwent subtotal pancreatectomy.