Terrell E Jones1, Melena D Bellin2, Dhiraj Yadav3, Martin L Freeman4, Sarah J Schwarzenberg5, Adam Slivka3, Jennifer S Chennat3, Gregory J Beilman6, Srinath Chinnakotla6, Timothy L Pruett6, Varvara Kirchner6, Abhinav Humar7, Martin Wijkstrom7, Amer H Zureikat7, Marina N Nikiforova1, Abigail I Wald1, David C Whitcomb3, Aatur D Singhi8. 1. Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. 2. Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA; Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA. 3. Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. 4. Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA. 5. Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA. 6. Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA. 7. Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. 8. Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Electronic address: singhiad@upmc.edu.
Abstract
BACKGROUND: The identification of genetic risk factors for chronic pancreatitis, such as PRSS1, CFTR and SPINK1, provides the opportunity to define key pathologic hallmarks and etiologic-specific changes. For example, pancreata from PRSS1 and CFTR patients exhibit progressive lipomatous atrophy without significant fibrosis. Considering the pathology of SPINK1-associated pancreatitis is ill-defined, we examined the pancreata of SPINK1 patients with chronic pancreatitis. METHODS: Histologic sections after total pancreatectomy with islet autotransplantation and associated clinicopathologic data were collected from 28 patients with SPINK1 germline alterations. Clinical findings, germline data, anatomic anomalies and pathologic findings were descriptively evaluated. RESULTS: Patients ranged in age from 5 to 48 years (median, 21.6 years) with abdominal pain between 2 and 25 years (median, 5.8 years). Most patients were SPINK1 heterozygous and 14 (50%) had co-occurring CFTR (n = 12) and CTRC (n = 2) mutations. Other pancreatitis risk factors included anatomic anomalies (n = 9) and tobacco use (n = 1). Overall, 24 (86%) patients had additional pancreatitis-associated germline alterations, SPINK1 homozygosity, anatomic anomalies or environmental factors. Examination of pancreata revealed a sequential pattern of exocrine parenchymal loss and replacement by prominent fibrosis, dependent on the duration of abdominal pain. No malignancies were identified, but low-grade pancreatic intraepithelial neoplasia was present for 2 cases. CONCLUSIONS: Within this descriptive study, SPINK1-associated pancreatitis is characterized by parenchymal fibrosis and suggests divergent pathophysiologic mechanisms from PRSS1 and CFTR-associated pancreatitis. Moreover, SPINK1 patients frequently had additional etiologic factors that did not impact the development of pancreatic fibrosis and may implicate SPINK1 as a disease modifier gene.
BACKGROUND: The identification of genetic risk factors for chronic pancreatitis, such as PRSS1, CFTR and SPINK1, provides the opportunity to define key pathologic hallmarks and etiologic-specific changes. For example, pancreata from PRSS1 and CFTRpatients exhibit progressive lipomatous atrophy without significant fibrosis. Considering the pathology of SPINK1-associated pancreatitis is ill-defined, we examined the pancreata of SPINK1patients with chronic pancreatitis. METHODS: Histologic sections after total pancreatectomy with islet autotransplantation and associated clinicopathologic data were collected from 28 patients with SPINK1 germline alterations. Clinical findings, germline data, anatomic anomalies and pathologic findings were descriptively evaluated. RESULTS:Patients ranged in age from 5 to 48 years (median, 21.6 years) with abdominal pain between 2 and 25 years (median, 5.8 years). Most patients were SPINK1 heterozygous and 14 (50%) had co-occurring CFTR (n = 12) and CTRC (n = 2) mutations. Other pancreatitis risk factors included anatomic anomalies (n = 9) and tobacco use (n = 1). Overall, 24 (86%) patients had additional pancreatitis-associated germline alterations, SPINK1 homozygosity, anatomic anomalies or environmental factors. Examination of pancreata revealed a sequential pattern of exocrine parenchymal loss and replacement by prominent fibrosis, dependent on the duration of abdominal pain. No malignancies were identified, but low-grade pancreatic intraepithelial neoplasia was present for 2 cases. CONCLUSIONS: Within this descriptive study, SPINK1-associated pancreatitis is characterized by parenchymal fibrosis and suggests divergent pathophysiologic mechanisms from PRSS1 and CFTR-associated pancreatitis. Moreover, SPINK1patients frequently had additional etiologic factors that did not impact the development of pancreatic fibrosis and may implicate SPINK1 as a disease modifier gene.
Authors: R H Pfützer; M M Barmada; A P Brunskill; R Finch; P S Hart; J Neoptolemos; W F Furey; D C Whitcomb Journal: Gastroenterology Date: 2000-09 Impact factor: 22.682
Authors: J Threadgold; W Greenhalf; I Ellis; N Howes; M M Lerch; P Simon; J Jansen; R Charnley; R Laugier; L Frulloni; A Oláh; M Delhaye; I Ihse; O B Schaffalitzky de Muckadell; A Andrén-Sandberg; C W Imrie; J Martinek; T M Gress; R Mountford; D Whitcomb; J P Neoptolemos Journal: Gut Date: 2002-05 Impact factor: 23.059
Authors: Aatur D Singhi; Reetesh K Pai; Jeffrey A Kant; Tanner L Bartholow; Herbert J Zeh; Kenneth K Lee; Martin Wijkstrom; Dhiraj Yadav; Rita Bottino; Randall E Brand; Jennifer S Chennat; Mark E Lowe; Georgios I Papachristou; Adam Slivka; David C Whitcomb; Abhinav Humar Journal: Am J Surg Pathol Date: 2014-03 Impact factor: 6.394