Juan C. Manivel

Correlation of pancreatic histopathologic findings and islet yield in children with chronic pancreatitis undergoing total pancreatectomy and islet autotransplantation

Objectives: The probability of insulin independence after intraportal islet autotransplantation (IAT) for chronic pancreatitis (CP) treated by total pancreatectomy (TP) relates to the number of islets isolated from the excised pancreas. Our goal was to correlate the islet yield with the histopathologic findings and the clinical parameters in pediatric (age, <19 years) CP patients undergoing TP-IAT. Methods: Eighteen pediatric CP patients aged 5 to 18 years (median, 15.6 years) who underwent TP-IAT were studied. Demographics and clinical history came from medical records. Histopathologic specimens from the pancreas were evaluated for presence and severity of fibrosis, acinar cell atrophy, inflammation, and nesidioblastosis by a surgical pathologist blinded to clinical information. Results: Fibrosis and acinar atrophy negatively correlated with islet yield (P = 0.02, r = −0.50), particularly in hereditary CP (P = 0.01). Previous duct drainage surgeries also had a strong negative correlation (P = 0.01). Islet yield was better in younger (preteen) children (P = 0.02, r = −0.61) and in those with pancreatitis of shorter duration (P = 0.04, r = −0.39). Conclusions: For preserving beta cell mass, it is best to perform TP-IAT early in the course of CP in children, and prior drainage procedures should be avoided to maximize the number of islets available, especially in hereditary disease.

Correlation of histopathology, islet yield, and islet graft function after islet autotransplantation in chronic pancreatitis.

Objective: The number of islets available (yield) is an important predictor of insulin independence after islet autotransplantation (IAT) done at the time of total pancreatectomy to treat painful chronic pancreatitis. The aim of this study was to correlate histopathologic findings with islet yield and graft function. Methods: Pancreatic histopathology was examined in 105 adults who underwent pancreatectomy and IAT; postoperative insulin use was known in 53 cases. Histologic degree of fibrosis, acinar atrophy, inflammation, and nesidioblastosis were scored by a surgical pathologist. The correlation of histopathology with islet yield and graft function was evaluated. Results: Patients received a median of 2968 islet equivalents per kilogram. Fibrosis and acinar atrophy correlated negatively with islet yield (P < 0.001, r = −0.67), as did inflammation (P < 0.001, r = −0.43). There was a positive correlation of islet yield (P < 0.0001, r = 0.64) and a negative correlation of fibrosis (P = 0.006, r = −0.43) and acinar atrophy (P = 0.006, r = −0.42) with islet graft function. Conclusion: More severe histopathologic changes were associated with a lower islet yield and lower likelihood of insulin independence. Total pancreatectomy and IAT should not be delayed in patients with painful chronic pancreatitis refractory to medical therapy; otherwise progressive damage to the pancreas may limit islet yield and increase the risk of diabetes.Abbreviations: IAT - islet autotransplantation, CP - chronic pancreatitis

Opioids Induce Renal Abnormalities in Tumor-Bearing Mice

Background/Aims: The etiology of renal dysfunction in cancer patients is likely to be multifactorial. A large proportion of these patients receive opioid analgesics, but whether opioids contribute to renal dysfunction remains uncertain. In a murine cancer model, we examined the effects of chronic opioid administration on renal function and pathology, and the molecular mechanisms involved. Methods: C3H/HeJ mice implanted with 2472 tumor cells were treated with either morphine or hydromorphone in clinically relevant doses, or PBS (controls). Renal function was assessed by blood and urine chemistry as well as by measuring mean arterial pressure (MAP) and kidney perfusion. Pathological changes in the kidneys were examined by routine histology. Molecular changes were examined by assessing eNOS, iNOS, HO-1 and COX-2 expression in whole-kidney lysates by Western immunoblotting, and cellular colocalization of these enzymes was determined using immunofluorescence microscopy. Results:Three weeks of opioid treatment resulted in increased kidney weight, elevated BUN and proteinuria, and decreased MAP. This was accompanied by histological abnormalities including glomerular enlargement, hypercellularity, peritubular congestion, vasodilatation and tubular casts. The vasoregulatory molecules iNOS, eNOS, HO-1 and COX-2 were upregulated in the kidneys. The NOS inhibitor L-NAME prevented the morphine-induced increase in perfusion and kidney weight. Conclusions: The chronic use of clinically relevant doses of opioidsleads to structural kidney abnormalities, upregulates NOS, COX-2 and HO-1, and results in renal dysfunction in a murine model of cancer.

EFFECT OF SEROMUSCULAR COLOCYSTOPLASTY LINED WITH UROTHELIUM AND PARTIAL DETRUSORECTOMY ON A NEW CANINE MODEL OF REDUCED BLADDER CAPACITY

We developed a canine model of reduced bladder capacity by spraying talc on the outer surface of the detrusor after peeling the peritoneum from the bladder. This method was effective to reduce bladder capacity to almost a third of normal and this reduction persisted for the 6-month followup. On this model we performed detrusorectomy (auto-augmentation) and seromuscular colocystoplasty, and compared the results. Following detrusorectomy in talc bladder dogs bladder capacity failed to increase significantly at 3 months and 6 months. In contrast, seromuscular colocystoplasty caused a significant increase in bladder capacity in talc bladder dogs that was sustained for the 6-month followup. We also performed detrusorectomy in dogs with normal bladders and observed a progressive decrease in bladder capacity, which became significant at 6 months. Histology of the bladders after sacrifice revealed that talc induces a desmoplastic reaction around the detrusor that limits bladder distensibility and reduces its capacity. With detrusorectomy the perivesical fibrotic layer induced by talc and the detrusor were effectively removed but a thin layer of fibrosis developed between the bladder mucosa and the peritoneum that may account for the lack of improvement in bladder capacity. Identical observations were made after detrusorectomy in normal bladders. In contrast, following seromuscular colocystoplasty the bladder mucosa was adjacent to the submucosa of the colonic patch without fibrosis, a finding that may account for the restoration of bladder capacity. These experiments confirm previous experimental and clinical observations about seromuscular colocystoplasty, and suggest that it may result in better long-term results than simple auto-augmentation.

Sarcoidosis presenting with hearing loss and granulomatous interstitial nephritis in an adolescent.

Granulomatous interstitial nephritis is an uncommon finding in a kidney biopsy. The differential diagnosis is broad and includes infections, drug exposure, and sarcoidosis. Sarcoidosis, a systemic disorder of unknown etiology characterized by the presence of noncaseating granulomata in affected organs, is rare in children. We discuss an adolescent boy with the unusual presentation of granulomatous interstitial nephritis and acute deafness. Sarcoidosis should be considered as part of the differential diagnosis for children and adolescents with hearing loss and kidney disease.

An Unusual Lesion Presenting as Cholangiopathy

Division of Gastroenterology, Department of Medicine, University of Michigan, Ann Arbor, Michigan; Department of Pathology, University of Minnesota and Minneapolis Veterans Affairs Medical Center, Minneapolis, Minneapolis 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 Question: A 75-year-old man presented with gradual-onset painless jaundice and right upper quadrant pain for 3 weeks. He was afebrile, with mild right upper quadrant tenderness, without Murphy’s sign. Laboratory tests were pertinent for an aspartate aminotransferase of 142 U/L, an alanine aminotransferase of 142 U/L, alkaline phosphatase of 461 U/L, and direct/total bilirubin of 3.5/9.3 mg/dL. Magnetic resonance cholangiopancreatography showed intrahepatic biliary dilatation with right hepatic duct strictures and nonvisualization of the proximal common hepatic and central common bile ducts, replaced with vague enhancement (Figure A, arrow shows right hepatic duct strictures). Further investigations were significant for negative CA 19-9, CA-125 of 125 U/mL (normal, 0-30), and normal gamma immunoglobulin subclasses. Endoscopic ultrasonography showed marked thickening of the extrahepatic bile duct up to the hilum without definite mass lesion. Endoscopic retrograde cholangiopancreatography (ERCP) revealed a very small distal bile duct (Figure B), about 4 mm, with diffuse stenosis from the upper common duct, extending into the right hepatic duct. Left duct system was mildly dilated. This was treated with plastic biliary stent to the segment III (Figure C). Biopsies (Figure D) of the ampulla and the bile duct showed frequent immunoglobulin (Ig)G4-positive plasma cells (30 cells per high-power field). Steroid was initiated for possible IgG4-associated cholangitis (IAC). At 10 days after the index ERCP, he had worsening nausea and vomiting without worsening laboratory tests. ERCP and esophagogastroduodenoscopy showed narrowing of the duodenal bulb and the proximal second portion of the duodenum. Biopsies of the duodenum and the bile duct showed nonspecific inflammatory changes without evidence of

Penile Cancer in a Man With Netherton Syndrome

Netherton syndrome (NS) is a rare autosomal recessive skin disease with severe skin inflammation and scaling, a specific hair shaft defect (trichorrhexis invaginata or bamboo hair), and severe atopic manifestations including atopic dermatitis and hay fever with high serum immunoglobulin E levels and hypereosinophilia. NS is caused by loss-of-function mutations in serine protease inhibitor of Kazal-type 5 (SPINK5) encoding lympho-epithelial Kazal-type-related inhibitor (LEKTI) expressed in the stratified epithelia. We report the first case of penile squamous cell carcinoma in a patient with NS.

Intracytoplasmic basophilic bodies in leukocytes in an HIV patient with pleural and pericardial effusion led to unexpected diagnosis

Human immunodeficiency virus (HIV) infections are declining worldwide; however, there are still >1.2 million HIV-infected people in the USA and ~6700 deaths/year can be directly attributed to HIV-related diseases. Opportunistic infections, Kaposi sarcoma, and non-Hodgkin lymphomas are always high in the differential diagnosis of HIV patients with systemic symptoms; however, causes of morbidity and mortality in HIV patients on highly active antiretroviral therapy are now approaching those of the general population. We present a case of an HIV patient who presented with B symptoms and body effusions. Diagnostic work-up geared towards infectious and neoplastic diseases led to the identification of intra- and extracellular rounded basophilic bodies in bone marrow and pleural effusion that were recognized as LE cells and allowed the diagnosis of systemic lupus erythematosus (SLE). We discuss the historical aspects of LE cell discovery, recent advances about their nature, ramifications of concurrent HIV-infection, and SLE and provide reference images of a finding that was originally described in bone marrow biopsies, but that nowadays has been nearly forgotten due to the development of alternative diagnostic tests.

Acquired adenomatous hyperplasia of the rete testis: an immunohistochemical study of its pathogenesis

Adenomatous hyperplasia of the rete testis (AHRT) is an uncommon abnormality first described by Nistal and Paniagua in 1988. Congenital and acquired forms of AHRT are recognized. We present a case of AHRT in a patient who underwent bilateral orchiectomy for penile carcinoma; he had received chemotherapy for Hodgkin lymphoma 18 years prior. Proposed causes for this disorder include developmental, hormonal, and paracrine induction by adjacent testicular tumors and exposure to chemicals, based on clinical contexts but without experimental support. We performed immunohistochemical studies using markers of cell cycle (cyclin D1, p16), proliferation (Ki-67), apoptosis (bcl2), senescence (γ-H2AX), and androgen receptors to try to provide scientific support for or refute existing hypotheses. Our results indicate that, in this case of acquired AHRT after chemotherapy, the process is neither adenomatous nor hyperplastic but rather represents abnormal accumulation of rete testis cells with acquired senescence.