Surgery_Schwartz

Surgery_Schwartz. of mesenteric and portal vein obstruction in chronic pancreatitis. Arch Surg. 1987;122:410-415. 205. Warshaw AL, Rattner DW. Timing of surgical drainage for pancreatic pseudocyst. Clinical and chemical criteria. Ann Surg. 1985;202:720-724. 206. Baron TH, Harewood GC, Morgan DE, et al. Outcome differences after endoscopic drainage of pancreatic necrosis, acute pancreatic pseudocysts, and chronic pancreatic pseudocysts. Gastrointest Endosc. 2002;56:7-17. 207. Kozarek RA, Brayko CM, Harlan J, et al. Endoscopic drainage of pancreatic pseudocysts. Gastrointest Endosc. 1985;31:322-327. 208. Bell RH, Jr. Atlas of pancreatic surgery. In: Bell RH, Jr, Rikkers LF, Mulholland MW, eds. Digestive Tract Surgery. A Text and Atlas. Philadelphia: Lippincott-Raven; 1996:963. 209. Park AE, Heniford BT. Therapeutic laparoscopy of the pancreas. Ann Surg. 2002;236:149-158. 210. Hawes RH. Endoscopic management of pseudocysts. Rev Gastroenterol Disord. 2003;3:135-141. 211. Heider R, Meyer AA, Galanko JA, et


Surgery_Schwartz

Surgery_Schwartz. laparoscopy of the pancreas. Ann Surg. 2002;236:149-158. 210. Hawes RH. Endoscopic management of pseudocysts. Rev Gastroenterol Disord. 2003;3:135-141. 211. Heider R, Meyer AA, Galanko JA, et al. Percutaneous drainage of pancreatic pseudocysts is associated with a higher failure rate than surgical treatment in unselected patients. Ann Surg. 1999;229:781-787. 212. Rao R, Fedorak I, Prinz RA. Effect of failed computed tomography-guided and endoscopic drainage on pancreatic pseudocyst management. Surgery. 1993;114:843-847, discussion 847-849. 213. Lipsett PA, Cameron JL. Internal pancreatic fistula. Am J Surg. 1992;163:216-220. 214. Uchiyama T, Suzuki T, Adachi A, et al. Pancreatic pleural effusion: case report and review of 113 cases in Japan. Am J Gastroenterol. 1992;87:387-391. 215. Lipsett PA, Cameron JL. Treatment of ascites and fistulas. In: Beger HG et al, eds. The Pancreas. London: Blackwell-Science; 1998:788. 216. Beger H, Schlosser W, Poch B, et al. Inflammatory mass in the


Surgery_Schwartz

Surgery_Schwartz. PA, Cameron JL. Treatment of ascites and fistulas. In: Beger HG et al, eds. The Pancreas. London: Blackwell-Science; 1998:788. 216. Beger H, Schlosser W, Poch B, et al. Inflammatory mass in the head of the pancreas. In: Beger HG et al, eds. The Pancreas. London: Blackwell-Science; 1998:757.Brunicardi_Ch33_p1429-p1516.indd 151001/03/19 6:47 PM 1511PANCREASCHAPTER 33 217. Friess H, Yamanaka Y, Buchler M, et al. A subgroup of patients with chronic pancreatitis overexpress the c-erb B-2 protooncogene. Ann Surg. 1994;220:183-192. 218. Sakorafas GH, Sarr MG, Farley DR, et al. The significance of sinistral portal hypertension complicating chronic pancreatitis. Am J Surg. 2000;179:129-133. 219. Amann ST, Toskes PP. Analgesic treatment. In: Beger HG et al, eds. The Pancreas. London: Blackwell-Science; 1998:766. 220. Forsmark CE. Management of chronic pancreatitis. Gastroenterol. 2013;144:1282-1291. 221. Halgreen H, Pedersen NT, Worning H. Symptomatic effect of pancreatic enzyme therapy in


Surgery_Schwartz

Surgery_Schwartz. 1998:766. 220. Forsmark CE. Management of chronic pancreatitis. Gastroenterol. 2013;144:1282-1291. 221. Halgreen H, Pedersen NT, Worning H. Symptomatic effect of pancreatic enzyme therapy in patients with chronic pancreatitis. Scand J Gastroenterol. 1986;21:104-108. 222. Hildebrand P, Ensinck JW, Gyr K, et al. Evidence for hormonal inhibition of exocrine pancreatic function by somatostatin 28 in humans. Gastroenterol. 1992;103:240-247. 223. Toskes PP, Forsmark CE, DeMeo MT, et al. A multicenter controlled trial of octreotide for pain of chronic pancreatitis. Pancreas. 1993;8:774. 224. Malfertheiner P, Mayer D, Buchler M, et al. Treatment of pain in chronic pancreatitis by inhibition of pancreatic secretion with octreotide. Gut. 1995;36:450-454. 225. Lieb JG, Shuster JJ, Theriaque D, et al. A pilot study of octreotide LAR vs. octreotide tid for pain and quality of life in chronic pancreatitis. J Pancreas. 2009;10:518-522. 226. Gress F, Schmitt C, Sherman S, et al. Endoscopic


Surgery_Schwartz

Surgery_Schwartz. D, et al. A pilot study of octreotide LAR vs. octreotide tid for pain and quality of life in chronic pancreatitis. J Pancreas. 2009;10:518-522. 226. Gress F, Schmitt C, Sherman S, et al. Endoscopic ultrasound-guided celiac plexus block for managing abdominal pain associated with chronic pancreatitis: a prospective single center experience. Am J Gastroenterol. 2001;96:409-416. 227. Jacob L, Geenen JE, Catalano MF, Geenen DJ. Prevention of pancreatitis in patients with idiopathic recurrent pancreatitis: aprospective nonblinded randomized study using endoscopic stents. Endoscopy. 2001;33:559-562. 228. Aizawa T, Ueno N. Stent placement in the pancreatic duct prevents pancreatitis after endoscopic sphincter dilation for removal of bile duct stones. Gastrointest Endosc. 2001;54:209-213. 229. Lau ST, Simchuk EJ, Kozarek RA, et al. A pancreatic ductal leak should be sought to direct treatment in patients with acute pancreatitis. Am J Surg. 2001;181:411-415. 230. Canty TG, Sr, Weinman D.


Surgery_Schwartz

Surgery_Schwartz. ST, Simchuk EJ, Kozarek RA, et al. A pancreatic ductal leak should be sought to direct treatment in patients with acute pancreatitis. Am J Surg. 2001;181:411-415. 230. Canty TG, Sr, Weinman D. Management of major pancreatic duct injuries in children. J Trauma. 2001;50:1001-1007. 231. Kim HS, Lee DK, Kim IW, et al. The role of endoscopic retrograde pancreatography in the treatment of traumatic pancreatic duct injury. Gastrointest Endosc. 2001;54:49-55. 232. Heyries L, Barthet M, Delvasto C, et al. Long-term results of endoscopic management of pancreas divisum with recurrent acute pancreatitis. Gastrointest Endosc. 2002;55:376-381. 233. Gabbrielli A, Mutignani M, Pandolfi M, et al. Endotherapy of early onset idiopathic chronic pancreatitis: results with long-term follow-up. Gastrointest Endosc. 2002;55:488-493. 234. Kozarek RA, Brandabur JJ, Ball TJ, et al. Clinical outcomes in patients who undergo extracorporeal shock wave lithotripsy for chronic calcific pancreatitis. Gastrointest


Surgery_Schwartz

Surgery_Schwartz. Endosc. 2002;55:488-493. 234. Kozarek RA, Brandabur JJ, Ball TJ, et al. Clinical outcomes in patients who undergo extracorporeal shock wave lithotripsy for chronic calcific pancreatitis. Gastrointest Endosc. 2002;56:496-500. 235. Nealon WH, Thompson JC. Progressive loss of pancreatic function in chronic pancreatitis is delayed by main pancreatic duct decompression. A longitudinal prospective analysis of the modified puestow procedure. Ann Surg. 1993;217:458-466; discussion 466-468. 236. Andersen DK, Frey CF. The evolution of the surgery for chronic pancreatitis. Ann Surg. 2010;251(1):18-32. 237. Link G. The treatment of chronic pancreatitis by pancreatostomy: a new operation. Ann Surg. 1911;53:768-782. 238. Link G. Long term outcome of pancreatostomy for chronic pancreatitis. Ann Surg. 1935;101:287. 239. Priestley JT, Comfort MW, Radcliffe J. Total pancreatectomy for hyperinsulinism due to an islet-cell adenoma: survival and cure at sixteen months after operation presentation of


Surgery_Schwartz

Surgery_Schwartz. 1935;101:287. 239. Priestley JT, Comfort MW, Radcliffe J. Total pancreatectomy for hyperinsulinism due to an islet-cell adenoma: survival and cure at sixteen months after operation presentation of metabolic studies. Ann Surg. 1944;119:211-221. 240. Whipple AO. Radical surgery for certain cases of pancreatic fibrosis associated with calcareous deposits. Ann Surg. 1946;124:991-1008. 241. Fry WJ, Child CG III. Ninety-five per cent distal pancreatectomy for chronic pancreatitis. Ann Surg. 1965;162:543-549. 242. Moody FG, Calabuig R, Vecchio R, et al. Stenosis of the sphincter of Oddi. Surg Clin North Am. 1990;70:1341-1354. 243. Cattell RB. Anastomosis of the duct of Wirsung in palliative operation for carcinoma of the head of the pancreas. Surg Clin North Am. 1947;27:636-643. 244. Duval MK, Jr. Caudal pancreatico-jejunostomy for chronic relapsing pancreatitis. Ann Surg. 1954;140:775-785. 245. Zollinger RM, Keith LM, Jr, Ellison EH. Pancreatitis. N Engl J Med.


Surgery_Schwartz

Surgery_Schwartz. MK, Jr. Caudal pancreatico-jejunostomy for chronic relapsing pancreatitis. Ann Surg. 1954;140:775-785. 245. Zollinger RM, Keith LM, Jr, Ellison EH. Pancreatitis. N Engl J Med. 1954;251:497-502. 246. Puestow CB, Gillesby WJ. Retrograde surgical drainage of pancreas for chronic relapsing pancreatitis. AMA Arch Surg. 1958;76:898-907. 247. Partington PF, Rochelle RE. Modified Puestow procedure for retrograde drainage of the pancreatic duct. Ann Surg. 1960;152:1037-1043. 248. Eleftheriadis N, Dinu F, Delhaye M. Long-term outcome after pancreatic stenting in severe chronic pancreatitis. Endoscopy. 2005;37:223-230. 249. Gabbrielli A, Pandolfi M, Mutignani M, et al. Efficacy of main pancreatic-duct endoscopic drainage in patients with chronic pancreatitis, continuous pain, and dilated duct. Gastrointest Endosc. 2009;61:576-581. 250. Morgan DE, Smith JK, Hawkins K, Wilcox CM. Endoscopic stent therapy in advanced chronic pancreatitis: relationships between ductal changes, clinical response, and


Surgery_Schwartz

Surgery_Schwartz. Endosc. 2009;61:576-581. 250. Morgan DE, Smith JK, Hawkins K, Wilcox CM. Endoscopic stent therapy in advanced chronic pancreatitis: relationships between ductal changes, clinical response, and stent patency. Am J Gastroenterol. 2003;98:821-826. 251. Rosch T, Daniel S, Scholz M, et al. Endoscopic treatment of chronic pancreatitis: a multicenter study of 1000 patients with long-term follow-up. Endoscopy. 2002;34:765-771. 252. Ponchon T, Bory RM, Hedelius F, et al. Endoscopic stenting for pain relief in chronic pancreatitis: results of a standardized protocol. Gastrointest Endosc. 1995;42:452-456. 253. Vitale GC, Cothron K, Vitale EA, et al. Role of pancreatic duct stenting in the treatment of chronic pancreatitis. Surg Endosc. 2004;18:1431-1434. 254. Bradley EL III. Long-term results of pancreatojejunostomy in patients with chronic pancreatitis. Am J Surg. 1987;153:207-213. 255. Cahen DL, Gouma DJ, Nio Y, et al. Endoscopic versus surgical drainage of the pancreatic duct in chronic


Surgery_Schwartz

Surgery_Schwartz. pancreatojejunostomy in patients with chronic pancreatitis. Am J Surg. 1987;153:207-213. 255. Cahen DL, Gouma DJ, Nio Y, et al. Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis. N Engl J Med. 2007;356:676-684. 256. Dite P, Ruzicka M, Zboril V, Novotny I. A prospective randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis. Endoscopy. 2003;35:553-558. 257. Aldridge MC, Williamson RC. Distal pancreatectomy with and without splenectomy. Br J Surg. 1991;78:976-979. 258. Khanna A, Koniaris LG, Nakeeb A, et al. Laparoscopic spleen-preserving distal pancreatectomy. J Gastrointest Surg. 2005;9:733-738. 259. Traverso LW, Longmire WP, Jr. Preservation of the pylorus in pancreaticoduodenectomy. Surg Gynecol Obstet. 1978; 146:959-962. 260. Huang JJ, Yeo CJ, Sohn TA, et al. Quality of life and outcomes after pancreaticoduodenectomy. Ann Surg. 2000;231:890-898. 261. Sakorafas GH, Farnell MB, Nagorney DM, et al. Pancreato-duodenectomy


Surgery_Schwartz

Surgery_Schwartz. JJ, Yeo CJ, Sohn TA, et al. Quality of life and outcomes after pancreaticoduodenectomy. Ann Surg. 2000;231:890-898. 261. Sakorafas GH, Farnell MB, Nagorney DM, et al. Pancreato-duodenectomy for chronic pancreatitis: long-term results in 105 patients. Arch Surg. 2000;135:517-522; discussion 523. 262. Jimenez RE, Fernandez-del Castillo C, Rattner DW, et al. Outcome of pancreaticoduodenectomy with pylorus Brunicardi_Ch33_p1429-p1516.indd 151101/03/19 6:47 PM 1512SPECIFIC CONSIDERATIONSPART IIpreservation or with antrectomy in the treatment of chronic pancreatitis. Ann Surg. 2000;231:293-300. 263. Mannell A, Adson MA, McIlrath DC, et al. Surgical management of chronic pancreatitis: long-term results in 141 patients. Br J Surg. 1988;75:467-472. 264. Gall FP, Muhe E, Gebhardt C. Results of partial and total pancreaticoduodenectomy in 117 patients with chronic pancreatitis. World J Surg. 1981;5:269-275. 265. Beger HG, Witte C, Krautzberger W, et al. Experiences with duodenum-sparing


Surgery_Schwartz

Surgery_Schwartz. of partial and total pancreaticoduodenectomy in 117 patients with chronic pancreatitis. World J Surg. 1981;5:269-275. 265. Beger HG, Witte C, Krautzberger W, et al. Experiences with duodenum-sparing pancreas head resection in chronic pancreatitis. Chirurg. 1980;51:303-307. 266. Beger HG, Krautzberger W, Bittner R, et al. Duodenum-preserving resection of the head of the pancreas in patients with severe chronic pancreatitis. Surgery. 1985;97:467. 267. Beger HG, Schlosser W, Friess HM, et al. Duodenum-preserving head resection in chronic pancreatitis changes the natural course of the disease: a single-center 26-year experience. Ann Surg. 1999;230:512-519; discussion 519. 268. Buchler MW, Friess H, Muller MW, et al. Randomized trial of duodenum-preserving pancreatic head resection versus pylorus-preserving Whipple in chronic pancreatitis. Am J Surg. 1995;169:65-69; discussion 69-70. 269. Frey CF, Smith GJ. Description and rationale of a new operation for chronic pancreatitis. Pancreas.


Surgery_Schwartz

Surgery_Schwartz. Whipple in chronic pancreatitis. Am J Surg. 1995;169:65-69; discussion 69-70. 269. Frey CF, Smith GJ. Description and rationale of a new operation for chronic pancreatitis. Pancreas. 1987;2:701-707. 270. Frey CF, Amikura K. Local resection of the head of the pancreas combined with longitudinal pancreaticojejunostomy in the management of patients with chronic pancreatitis. Ann Surg. 1994;220:492-504; discussion 504-507. 271. Andersen DK, Topazian MD. Pancreatic head excavation: a variation on the theme of duodenum-preserving pancreatic head resection. Arch Surg. 2004;139:375-379. 272. Izbicki JR, Strate T, Yekebas EE, et al. Chronic pancreatitis. In: Yeo CJ, Dempsey DT, Klein AS, et al, eds. Shackleford’s Surgery of the Alimentary Tract. 6th ed. New York: Saunders; 2007:1218. 273. Ho HS, Frey CF. The Frey procedure: combined local resection of the head of the pancreas with longitudinal pancreaticojeju-nostomy. Operat Tech Gen Surg. 2001;4:153-167. 274. Ho HS, Frey CF. The Frey


Surgery_Schwartz

Surgery_Schwartz. HS, Frey CF. The Frey procedure: combined local resection of the head of the pancreas with longitudinal pancreaticojeju-nostomy. Operat Tech Gen Surg. 2001;4:153-167. 274. Ho HS, Frey CF. The Frey procedure: local resection of pancreatic head combined with lateral pancreaticojejunostomy. Arch Surg. 2001;136:1353-1358. 275. Farkas G, Leindler L, Daroczi M, et al. Organ-preserving pancreatic head resection in chronic pancreatitis. Br J Surg. 2003;90:2-32. 276. Farkas G, Leindler L, Daroczi M, Farkas G, Jr. Prospective randomised comparison of organ-preserving pancreatic head resection with pylorus-preserving pancreaticoduodenectomy. Langenbecks Arch Surg. 2006;391:338-342. 277. Gloor B, Friess H, Uhl W, et al. A modified technique of the Beger and Frey procedure in patients with chronic pancreatitis. Dig Surg. 2001;18:21-25. 278. Koninger J, Seiler CM, Sauerland S, et al. Duodenum-preserving pancreatic head resection—a randomized controlled trial comparing the original Beger procedure


Surgery_Schwartz

Surgery_Schwartz. Dig Surg. 2001;18:21-25. 278. Koninger J, Seiler CM, Sauerland S, et al. Duodenum-preserving pancreatic head resection—a randomized controlled trial comparing the original Beger procedure with the Berne modification (ISRCTN No. 50638764). Surgery. 2008;143:490-498. 279. Izbicki JR, Bloechle C, Broering DC, et al. Extended drainage versus resection in surgery for chronic pancreatitis: a prospective randomized trial comparing the longitudinal pancreaticojejunostomy combined with local pancreatic head excision with the pylorus-preserving pancreatoduodenectomy. Ann Surg. 1998;228:771-779. 280. Strate T, Bachmann K, Busch P, et al. Resection vs. drainage in treatment of chronic pancreatitis: long-term results of a randomized trial. Gastroenterology. 2008;134:1406-1411. 281. Klempa I, Spatny M, Menzel J, et al. Pancreatic function and quality of life after resection of the head of the pancreas in chronic pancreatitis. A prospective, randomized comparative study after duodenum preserving


Surgery_Schwartz

Surgery_Schwartz. M, Menzel J, et al. Pancreatic function and quality of life after resection of the head of the pancreas in chronic pancreatitis. A prospective, randomized comparative study after duodenum preserving resection of the head of the pancreas versus Whipple’s operation. Chirurg. 1995;66:350-359. 282. Izbicki JR, Bloechle C, Knoefel WT, et al. Drainage versus resection in surgical therapy of chronic pancreatitis of the head of the pancreas: a randomized study. Der Cherurg. 1997;68:369-377. 283. Strate T, Taherpour Z, Bloechle C, et al. Long-term follow-up of a randomized trial comparing the Beger and Frey procedures for patients suffering from chronic pancreatitis. Ann Surg. 2005;241:591-598. 284. Keck T, Adam U, Makowiec F, et al. Shortand long-term results of duodenum preservation versus resection for the management of chronic pancreatitis: a prospective randomized study. Surg. 2012;152(3)suppl 1:S95-S102. 285. Bachmann K, Tomkoetter L, Kutup A, et al. Is the Whipple procedure harmful for


Surgery_Schwartz

Surgery_Schwartz. for the management of chronic pancreatitis: a prospective randomized study. Surg. 2012;152(3)suppl 1:S95-S102. 285. Bachmann K, Tomkoetter L, Kutup A, et al. Is the Whipple procedure harmful for long-term outcomes of chronic pancreatitis? 15 year follow-up comparing the outcome after PPPD and Frey procedures in chronic pancreatitis. Ann Surg. 2013;258:815-821. 286. Zheng Z, Xiang G, Tan C, et al. Pancreaticoduodenectomy vs. duodenum-preserving pancreatic head resection for the treatment of chronic pancreatitis. Pancreas. 2012;41:147-152. 287. Riediger H, Adam U, Fischer E, et al. Long-term outcome after resection for chronic pancreatitis in 224 patients. J Gastrointest Surg. 2007;11:949-959; discussion 959-960. 288. Buchler MW, Friess H, Bittner R, et al. Duodenum-preserving pancreatic head resection: long-term results. J Gastrointest Surg. 1997;1:13-19. 289. Ramesh H, Jacob G, Lekha V, Venugopal A. Ductal drainage with head coring in chronic pancreatitis with small-duct disease. J


Surgery_Schwartz

Surgery_Schwartz. head resection: long-term results. J Gastrointest Surg. 1997;1:13-19. 289. Ramesh H, Jacob G, Lekha V, Venugopal A. Ductal drainage with head coring in chronic pancreatitis with small-duct disease. J Hepatobiliary Pancreat Surg. 2003;10:366-372. 290. Shrikhande SV, Kleeff J, Friess H, et al. Management of pain in small duct chronic pancreatitis. J Gastrointest Surg. 2006;10:227-233. 291. Najarian JS, Sutherland DE, Baumgartner D, et al. Total or near total pancreatectomy and islet autotransplantation for treatment of chronic pancreatitis. Ann Surg. 1980;192:526-542. 292. Robertson RP, Lanz KJ, Sutherland DE, et al. Prevention of diabetes for up to 13 years by autoislet transplantation after pancreatectomy for chronic pancreatitis. Diabetes. 2001;50:47-50. 293. Sutherland DE, Radosevich DM, Bellin, MD, et al. Total pancreatectomy and islet autotransplantation for chronic pancreatits. J Am Coll Surg. 2012;214:409-426. 294. Rastellini C. Donor and recipient selection in pancreatic islet


Surgery_Schwartz

Surgery_Schwartz. Bellin, MD, et al. Total pancreatectomy and islet autotransplantation for chronic pancreatits. J Am Coll Surg. 2012;214:409-426. 294. Rastellini C. Donor and recipient selection in pancreatic islet transplantation. Curr Opin Organ Transplant. 2002;7:196-201. 295. Chinnakotla S, Beilman GJ, Dunn TB, et al. Factors predicting outcomes after a total pancreatectomy and auto-transplantation leesons learned from over 500 cases. Ann Surg. 2015; 262:610-622. 296. Chinnakotla S, Bellin MD, Schwarzenberg SJ, et al. Total pancreatectomy and islet autotransplantation in children for chronic pancreatitis: indication, surgical techniques, post-operative management, and long-term out-comes. Ann Surg. 2014;260:56-64. 297. Richards ML, Gauger PG, Thompson NW, Kloos RG, Giordano T. Pitfalls in the surgical treatment of insulinoma. Surgery. 2002;132:1040-1049; discussion 1049. 298. Howard TJ, Stabile BE, Zinner MJ, Chang S, Bhagavan BS, Passaro E, Jr. Anatomic distribution of pancreatic endocrine


Surgery_Schwartz

Surgery_Schwartz. treatment of insulinoma. Surgery. 2002;132:1040-1049; discussion 1049. 298. Howard TJ, Stabile BE, Zinner MJ, Chang S, Bhagavan BS, Passaro E, Jr. Anatomic distribution of pancreatic endocrine tumors. Am J Surg. 1990;159:258-264. 299. Service FJ, Natt N, Thompson GB, et al. Noninsulinoma pancreatogenous hypoglycemia: a novel syndrome of hyper-insulinemic hypoglycemia in adults independent of mutations in Kir6.2 and SUR1 genes. J Clin Endocrinol Metab. 1999;84: 1582-1589.Brunicardi_Ch33_p1429-p1516.indd 151201/03/19 6:47 PM 1513PANCREASCHAPTER 33 300. Cui YF, Elahi D, Andersen DK. Advances in the etiology and management of hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass. J Gastrointest Surg. 2011; 15(10):1879-1888. 301. Deol ZK, Frezza E, DeJong S, Pickleman J. Solitary hepatic gastrinoma treated with laparoscopic radiofrequency ablation. JSLS. 2003;7:285-289. 302. Case CC, Wirfel K, Vassilopoulou-Sellin R. Vasoactive intestinal polypeptide-secreting tumor (VIPoma)


Surgery_Schwartz

Surgery_Schwartz. hepatic gastrinoma treated with laparoscopic radiofrequency ablation. JSLS. 2003;7:285-289. 302. Case CC, Wirfel K, Vassilopoulou-Sellin R. Vasoactive intestinal polypeptide-secreting tumor (VIPoma) with liver metastases: dramatic and durable symptomatic benefit from hepatic artery embolization, a case report. Med Oncol. 2002;19:181-187. 303. Tanaka S, Yamasaki S, Matsushita H, et al. Duodenal somatostatinoma: a case report and review of 31 cases with special reference to the relationship between tumor size and metastasis. Pathol Int. 2000;50:146-152. 304. Falconi M, Bartsch DK, Eriksson B, et al. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors. Neuroendocrinology. 2012;95:120-134. 305. Mazzaglia PJ, Berber E, Milas M, et al. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival.


Surgery_Schwartz

Surgery_Schwartz. 2012;95:120-134. 305. Mazzaglia PJ, Berber E, Milas M, et al. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery. 2007;142:10-19. 306. Kotteas EA, Syrigos KN, Saif MW. Profile of capecitabine/temozolomide combination in the treatment of well-differentiated neuroendocrine tumors. Onco Targets Ther. 2016;9:699-704. 307. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2014. Bethesda, MD: National Cancer Institute. Available at: https://seer.cancer.gov/csr/1975_2014/. Accessed July 30, 2018. 308. Gold EB, Goldin SB. Epidemiology of and risk factors for pancreatic cancer. Surg Oncol Clin N Am. 1998;7:67-91. 309. Fisher WE. Diabetes. Risk factor for the development of pancreatic cancer or manifestation of the disease? World J Surg. 2001;25:503-508. 310. Jean M, Lowy A, Chiao P, et al. The Molecular Biology of Pancreatic Cancer. New York: Springer-Verlag; 2002. 311. Berger


Surgery_Schwartz

Surgery_Schwartz. cancer or manifestation of the disease? World J Surg. 2001;25:503-508. 310. Jean M, Lowy A, Chiao P, et al. The Molecular Biology of Pancreatic Cancer. New York: Springer-Verlag; 2002. 311. Berger D, Fisher W. Inherited Pancreatic Cancer Syndromes. New York: Springer-Verlag; 2002. 312. Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491(7424):399-405. 313. Biankin AV, Kench JG, Dijkman FP, et al. Molecular pathogenesis of precursor lesions of pancreatic ductal adenocarcinoma. Pathology. 2003;35(1):14-24. 314. Wilentz RE, Hruban RH. Pathology of cancer of the pancreas. Surg Oncol Clin N Am. 1998;7:43-65. 315. Ritts R, Pitt H. CA19-9 in pancreatic cancer. Surg Oncol Clin N Am. 1998;7:93-101. 316. Kung-Kai Kuo, Chao-Jen Kuo, Chiang-Yen Chiu, et al. Quantitative proteomic analysis of differentially expressed protein profiles involved in pancreatic ductal adenocarcinoma pancreas.


Surgery_Schwartz

Surgery_Schwartz. Kuo, Chao-Jen Kuo, Chiang-Yen Chiu, et al. Quantitative proteomic analysis of differentially expressed protein profiles involved in pancreatic ductal adenocarcinoma pancreas. 2016;45(1):71-83. 317. Shailesh V Shrikhande, Savio George Barreto, Mahesh Goel, Supreeta Arya. Multimodality imaging of pancreatic ductal adenocarcinoma: a review of the literature. HPB (Oxford). 2012;14(10):658-668. 318. Kim HJ, Conlon KC. Laparoscopic Staging. New York: Springer-Verlag; 2002. 319. Shah RJ, Howell DA, Desilets DJ, et al. Multicenter randomized trial of the spiral Z-stent compared with the Wallstent for malig-nant biliary obstruction. Gastrointest Endosc. 2003;57:830-836. 320. Lillemoe K, Cameron JL, Kaufman HS, Yeo CJ, Pitt HA, Sauter PK. Chemical splanchnicectomy in patients with unresectable pancreatic cancer. A prospective randomised trial. Ann Surg. 1993;217:447-455. 321. Singh SM, Reber HA. Surgical palliation for pancreatic cancer. Surg Clin North Am. 1989;69:599-611. 322. Nagaraja V,


Surgery_Schwartz

Surgery_Schwartz. cancer. A prospective randomised trial. Ann Surg. 1993;217:447-455. 321. Singh SM, Reber HA. Surgical palliation for pancreatic cancer. Surg Clin North Am. 1989;69:599-611. 322. Nagaraja V, Eslick GD, Cox MR. Endoscopic stenting versus operative gastrojejunostomy for malignant gastric outlet obstruction-a systematic review and meta-analysis of randomized and non-randomized trials. J Gastrointest Oncol. 2014;5(2):92-98. 323. Herman J, Chang D, Goodman K, et al. Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma. Cancer. 2015;121(7):1128-1137. 324. Casper ES, Green MR, Kelsen DP, et al. Phase II trial of gem-citabine (2,2’-difluorodeoxycytidine) in patients with adeno-carcinoma of the pancreas. Invest New Drugs. 1994;12:29-34. 325. Moore MJ, Goldstein D, Hamm J, et al. National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with


Surgery_Schwartz

Surgery_Schwartz. of the pancreas. Invest New Drugs. 1994;12:29-34. 325. Moore MJ, Goldstein D, Hamm J, et al. National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960-1966. 326. Conroy T, Desseigne F, Ychou M, et al. Folfirinox versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825. 327. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-1703. doi:10.1056/NEJMoa1304369 328. Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557. 329. Martin RC II,


Surgery_Schwartz

Surgery_Schwartz. folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557. 329. Martin RC II, McFarland K, Ellis S, et al. Irreversable electroporation therapy in the management of locally advanced pancreatic adenocarcinoma. J Am Coll Surg. 2012; 215:361-369. 330. Martin RC, Kwon D, Chalikonda S, et al. Treatment of 200 locally advanced (Stage III) pancreatic adenocarcinoma patients with irreversible electroporation: safety and efficacy. Ann Surg. 2015;262(3):486-494. 331. Chua TC, Saxena A. Extended pancreaticoduodenectomy with vascular resection for pancreatic cancer: a systematic review. J Gastrointest Surg. 2010;14:1442-1452. 332. Gong Y, Zhang L, He T, et al. Pancreaticoduodenectomy combined with vascular resection and reconstruction for patients with locally advanced pancreatic cancer: a multicenter, retrospective analysis. PLoS One. 2013;8(8):e70340.


Surgery_Schwartz

Surgery_Schwartz. Pancreaticoduodenectomy combined with vascular resection and reconstruction for patients with locally advanced pancreatic cancer: a multicenter, retrospective analysis. PLoS One. 2013;8(8):e70340. doi:10.1371/journal.pone.0070340 333. Castleberry AW, Ci MM, White RR, et al. The impact of vascular resection on early postoperative outcomes after pancreaticoduodenectomy: an analysis of the American College of Surgeons National Surgical Quality Improvement Program Database. Ann Surg Oncol. 2012;19:4068-4077. 334. Zureikat AH, Postlewait LM, Liu Y, et al. A multi-institutional comparison of perioperative outcomes of robotic and open pancreaticoduodenectomy. Ann Surg. 2016;264(4):640-649. 335. Yamaguchi K, Kishinaka M, Nagai E, et al. Pancreatoduo-denectomy for pancreatic head carcinoma with or with-out pylorus preservation. Hepatogastroenterol. 2001;48: 1479-1485. 336. Ohtsuka T, Yamaguchi K, Ohuchida J, et al. Comparison of quality of life after pylorus-preserving pancreatoduodenectomy


Surgery_Schwartz

Surgery_Schwartz. or with-out pylorus preservation. Hepatogastroenterol. 2001;48: 1479-1485. 336. Ohtsuka T, Yamaguchi K, Ohuchida J, et al. Comparison of quality of life after pylorus-preserving pancreatoduodenectomy and Whipple resection. Hepatogastroenterol. 2003; 50:846-850.Brunicardi_Ch33_p1429-p1516.indd 151301/03/19 6:47 PM 1514SPECIFIC CONSIDERATIONSPART II 337. Van Buren G, Bloomston M, Hughes SJ, et al. A ran-domized prospective multicenter trial of pancreatico-duodenectomy with and without routine intraperitoneal drainage. Ann Surg. 2014;259(4):605-612. doi: 10.1097/SLA.0000000000000460 338. Van Buren G, Bloomston M, Schmidt CR, et al. A prospective randomized multicenter trial of distal pancreatectomy with and without routine intraperitoneal drainage. Ann Surg. 2017;266(3):421-431. doi: 10.1097/SLA.0000000000002375 339. Bassi C1, Molinari E, Malleo G, et al. Early versus late drain removal after standard pancreatic resections: results of a prospective randomized trial. Ann Surg.


Surgery_Schwartz

Surgery_Schwartz. 10.1097/SLA.0000000000002375 339. Bassi C1, Molinari E, Malleo G, et al. Early versus late drain removal after standard pancreatic resections: results of a prospective randomized trial. Ann Surg. 2010;252(2):207-214. doi: 10.1097/SLA.0b013e3181e61e88 340. Keane FK, Wo JY, Ferrone CR, et al. Intraoperative radiotherapy in the era of intensive neoadjuvant chemotherapy and chemoradiotherapy for pancreatic adenocarcinoma. Am J Clin Oncol. Post Author Corrections: October 12, 2016. 341. Birkmeyer JD, Finlayson SR, Tosteson AN, et al. Effect of hospital volume on in-hospital mortality with pancreaticoduodenectomy. Surgery. 1999;125(3):250-256. 342. Gordon TA, Bowman HM, Tielsch JM, et al. Statewide regionalization of pancreaticoduodenectomy and its effect on in-hospital mortality. Ann Surg. 1998;228:71-78. 343. Buchler M, Friess H, Klempa I, et al. Role of octreotide in the prevention of postoperative complications following pancreatic resection. Am J Surg. 1992;163:125-130; discussion


Surgery_Schwartz

Surgery_Schwartz. 1998;228:71-78. 343. Buchler M, Friess H, Klempa I, et al. Role of octreotide in the prevention of postoperative complications following pancreatic resection. Am J Surg. 1992;163:125-130; discussion 130-131. 344. Montorsi M, Zago M, Mosca F, et al. Efficacy of octreotide in the prevention of pancreatic fistula after elective pancreatic resections: a prospective, controlled, randomized clinical trial. Surgery. 1995;117:26-31. 345. Pederzoli P, Bassi C, Falconi M, et al. Efficacy of octreotide in the prevention of complications of elective pancreatic surgery. Italian Study Group. Br J Surg. 1994;81:265-269. 346. Barnett SP, Hodul PJ, Creech S, et al. Octreotide does not prevent postoperative pancreatic fistula or mortality following pancreaticoduodenectomy. Am Surg. 2004;70:222-226; discussion 227. 347. Hesse UJ, DeDecker C, Houtmeyers P, et al. Prospectively randomized trial using perioperative low-dose octreotide to prevent organ-related and general complications after pancreatic


Surgery_Schwartz

Surgery_Schwartz. 227. 347. Hesse UJ, DeDecker C, Houtmeyers P, et al. Prospectively randomized trial using perioperative low-dose octreotide to prevent organ-related and general complications after pancreatic surgery and pancreatico-jejunostomy. World J Surg. 2005;29:1325-1328. 348. Lowy AM, Lee JE, Pisters PW, et al. Prospective, randomized trial of octreotide to prevent pancreatic fistula after pancreaticoduodenectomy for malignant disease. Ann Surg. 1997;226:632-641. 349. Suc B, Msika S, Piccinini M, et al. Octreotide in the prevention of intra-abdominal complications following elective pancreatic resection: a prospective, multicenter randomized controlled trial. Arch Surg. 2004;139:288-294; discussion 295. 350. Allen PJ, Mithat G, Brennan MF, et al. Pasireotide for postoperative pancreatic fistula. N Engl J Med. 2014;370: 2014-2022. doi:10.1056/NEJMoa1313688 351. Yeo CJ, Cameron JL, Maher MM, et al. A prospective ran-domized trial of pancreaticogastrostomy versus pancreati-cojejunostomy after


Surgery_Schwartz

Surgery_Schwartz. N Engl J Med. 2014;370: 2014-2022. doi:10.1056/NEJMoa1313688 351. Yeo CJ, Cameron JL, Maher MM, et al. A prospective ran-domized trial of pancreaticogastrostomy versus pancreati-cojejunostomy after pancreaticoduodenectomy. Ann Surg. 1995;222(4):580-588; discussion 588-592. 352. Wente MN, Shrikhande SV, Muller MW, et al. Pancreaticojejunostomy vs. pancreaticogastrostomy: systematic review and meta-analysis. Am J Surg. 2007;193:171-183. 353. Suzuki Y, Fujino Y, Tanioka Y, et al. Selection of pancreaticojejunostomy techniques according to pancreatic texture and duct size. Arch Surg. 2002;137:1044-1047; discussion 1048. 354. Reid-Lombardo KM, Farnell MB, Crippa S, et al. Pancreatic anastomotic leakage after pancreaticoduodenectomy in 1,507 patients: a report from the Pancreatic Anastomotic Leak Study Group. J Gastrointest Surg. 2007;11:1451-1458. 355. Dong Z, Xu J, Wang Z, Petrov MS. Stents for the prevention of pancreatic fistula following pancreaticoduodenectomy. Cochrane Database Syst


Surgery_Schwartz

Surgery_Schwartz. Study Group. J Gastrointest Surg. 2007;11:1451-1458. 355. Dong Z, Xu J, Wang Z, Petrov MS. Stents for the prevention of pancreatic fistula following pancreaticoduodenectomy. Cochrane Database Syst Rev. 2016;(5):CD008914. doi: 10.1002/14651858.CD008914.pub3 356. Jang JY, Chang YR, Kim SW, et al. Randomized multicentre trial comparing external and internal pancreatic stenting during pancreaticoduodenectomy. Br J Surg. 2016;103(6):668-675. doi: 10.1002/bjs.10160. 357. Sutton CD, Garcea G, White SA, et al. Isolated Roux-loop pancreaticojejunostomy: a series of 61 patients with zero postoperative pancreaticoenteric leaks. J Gastrointest Surg. 2004;8:701-705. 358. Yang YM, Tian XD, Zhuang Y, et al. Risk factors of pancreatic leakage after pancreaticoduodenectomy. World J Gastroenterol. 2005;11:2456-2461. 359. Di Carlo V, Chiesa R, Pontiroli AE, et al. Pancreatoduodenectomy with occlusion of the residual stump by Neoprene injection. World J Surg. 1989;13:105-110; discussion


Surgery_Schwartz

Surgery_Schwartz. 2005;11:2456-2461. 359. Di Carlo V, Chiesa R, Pontiroli AE, et al. Pancreatoduodenectomy with occlusion of the residual stump by Neoprene injection. World J Surg. 1989;13:105-110; discussion 110-111. 360. Tran K, Van Eijck C, Di Carlo V, et al. Occlusion of the pancreatic duct versus pancreaticojejunostomy: a prospective randomized trial. Ann Surg. 2002;236:422-428, discussion 428. 361. Fisher WE, Chai C, Hodges SE, Wu MF, Hilsenbeck SG, Brunicardi FC. Effect of BioGlue on the incidence of pancreatic fistula following pancreas resection. J Gastrointest Surg. 2008;12:882-890. 362. Lillemoe KD, Cameron JL, Kim MP, et al. Does fibrin glue sealant decrease the rate of pancreatic fistula after pancreaticoduodenectomy? Results of a prospective randomized trial. J Gastrointest Surg. 2004;8:766-772, discussion 772-774. 363. Kazanjian KK, Hines OJ, Eibl G, Reber HA. Management of pancreatic fistulas after pancreaticoduodenectomy: results in 437 consecutive patients. Arch Surg.


Surgery_Schwartz

Surgery_Schwartz. 2004;8:766-772, discussion 772-774. 363. Kazanjian KK, Hines OJ, Eibl G, Reber HA. Management of pancreatic fistulas after pancreaticoduodenectomy: results in 437 consecutive patients. Arch Surg. 2005;140:849-854, discussion 854-856. 364. Bilimoria KY, Bentrem DJ, Ko CY, et al. National failure to operate on early stage pancreatic cancer. Ann Surg. 2007;246(2):173-180. doi: 10.1097/SLA.0b013e3180691579 365. Group GTS. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer. 1997;59:2006-2010. 366. Neoptolemos JP, Dunn JA, Stocken DD, et al. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001;358:1576-1585. 367. Rocha FG1, Hashimoto Y, Traverso LW, et al. Interferon-based adjuvant chemoradiation for resected pancreatic head cancer: long-term follow-up of the Virginia Mason Protocol. Ann Surg. 2016;263(2):376-384. doi:


Surgery_Schwartz

Surgery_Schwartz. Hashimoto Y, Traverso LW, et al. Interferon-based adjuvant chemoradiation for resected pancreatic head cancer: long-term follow-up of the Virginia Mason Protocol. Ann Surg. 2016;263(2):376-384. doi: 10.1097/SLA.0000000000001190 368. Russo S, Saif MW. Neoadjuvant therapy for pancreatic cancer: an ongoing debate. Therap Adv Gastroenterol. 2016;9(4):429-436. 369. Tachezy M, Gebauer F, Petersen C, et al. Sequential neoadjuvant chemoradiotherapy (CRT) followed by curative surgery vs. primary surgery alone for resectable, non-metastasized pancreatic adenocarcinoma: NEOPA—a randomized multicenter phase III study (NCT01900327, DRKS00003893, ISRCTN82191749). BMC Cancer. 2014;14:411. 370. Gingras MC, Covington KR, Chang DK, et al. Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation. Cell Rep. 2016;14(4):907-919. 371. Laffan TA, Horton KM, Klein AP, et al. Prevalence of unsuspected pancreatic cysts on MDCT. AJR Am J Roentgenol.


Surgery_Schwartz

Surgery_Schwartz. mutations and exhibit frequent WNT dysregulation. Cell Rep. 2016;14(4):907-919. 371. Laffan TA, Horton KM, Klein AP, et al. Prevalence of unsuspected pancreatic cysts on MDCT. AJR Am J Roentgenol. 2008;191(3):802-807. doi: 10.2214/AJR.07.3340 372. Tanaka M, Adsay V, Chari S, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pacreatology. 2012(12):183-197.Brunicardi_Ch33_p1429-p1516.indd 151401/03/19 6:47 PM 1515PANCREASCHAPTER 33 373. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology. 2004;126:1330-1336. 374. Khalid A, Zahid M, Finkelstein SD, et al. Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study. Gastrointest Endosc. 2009;69:1095-1102. 375. Yoon WJ, Brugge WR. Pancreatic cystic neoplasms: diagnosis and management. Gastroenterol Clin North Am.


Surgery_Schwartz

Surgery_Schwartz. pancreatic cysts: a report of the PANDA study. Gastrointest Endosc. 2009;69:1095-1102. 375. Yoon WJ, Brugge WR. Pancreatic cystic neoplasms: diagnosis and management. Gastroenterol Clin North Am. 2012;41(1):103-118. 376. Furukawa T, Hatori T, Fujita I, et al. Prognostic relevance of morphological types of intraductal papillary mucinous neoplasms of the pancreas. Gut. 2011;60(4):509-516. 377. Brugge WR. Management and outcomes of pancreatic cystic lesions. Dig Liver Dis. 2008;40(11):854-859. 378. Boni L, Benevento A, Dionigi G, Cabrini L, Dionigi R. Primary pancreatic lymphoma. Surg Endosc. 2002;16:1107-1108.Brunicardi_Ch33_p1429-p1516.indd 151501/03/19 6:47 PM


Surgery_Schwartz

Surgery_Schwartz. Brunicardi_Ch33_p1429-p1516.indd 151601/03/19 6:47 PMThis page intentionally left blank


Surgery_Schwartz

Surgery_Schwartz. The SpleenAdrian E. Park, Eduardo M. Targarona, Adam S. Weltz, and Carlos Rodriguez-Otero Luppi 34chapterHISTORICAL BACKGROUNDThe spleen has been the subject of man’s musings since almost the establishment of the written word. It has been largely mis-understood, often maligned, and certainly underappreciated as a major organ for more than two millennia. The ancients, pre-sumably through patient observation and occasional anatomic exploration, often consigned the spleen to a vestigial role.Our current understanding of the central role played by the spleen in regulating the immune system and influencing meta-bolic and endocrine functions has been built upon knowledge gleaned only over the past few decades. Our early notions of the spleen as a dispensable filter of blood or seat of emotion have been dispelled as our understanding of its structure and function has evolved, informing our surgical approach to this worthy and fascinating organ. Many of the “founding fathers of medicine”


Surgery_Schwartz

Surgery_Schwartz. have been dispelled as our understanding of its structure and function has evolved, informing our surgical approach to this worthy and fascinating organ. Many of the “founding fathers of medicine” have weighed in on the anatomy and function of the spleen over the centuries. Hippocrates in the fourth century BC was one of the first to write on the spleen.1-3 He taught broadly on the need for balance and equilibrium between the patient and his environment. Illness arose from disharmony in nature, particularly among the patient’s four humors: blood, phlegm, black bile (melancholia), and yellow bile. Hippocrates wrote of a direct connection between the brain and spleen and its particu-lar association with the black bile. These ideas would influence thinking about the role of the spleen for more than 1000 years.2Aristotle, later in the same era, famously stated that, “Nature makes nothing in vain,” yet held the spleen to be an organ of minor importance whose main role was to


Surgery_Schwartz

Surgery_Schwartz. spleen for more than 1000 years.2Aristotle, later in the same era, famously stated that, “Nature makes nothing in vain,” yet held the spleen to be an organ of minor importance whose main role was to counterbal-ance the liver.4 He also described how the “hot character” of the spleen aided in digestion.Galen, in the second century AD, engaged in more seri-ous anatomic investigation espousing the early belief that func-tion followed structure. His investigations, though pioneering, lacked sufficient rigor, evidenced by his contention that black bile or melancholia flowed from the liver to the spleen and then through the short gastric vessels into the stomach to be excreted. The influence of Galen’s teaching endured for more than 1200 years. All the more remarkable considering the cur-rent hallowed measure of influence of surgical publication, the impact factor, which is most commonly calculated using a 2-year frame of reference.5,6In the early 17th century, several physician scientists,


Surgery_Schwartz

Surgery_Schwartz. measure of influence of surgical publication, the impact factor, which is most commonly calculated using a 2-year frame of reference.5,6In the early 17th century, several physician scientists, Mal-pighi being the most prominent, began testing hypotheses on splenic function by splenectomizing dogs. He reportedly fol-lowed several dogs 5 years postoperatively, noting their healthy survival though apparent ravenous hunger and enhanced sexual appetites. The spleen, still in the era of “balanced humors,” was thus felt to play a role in balancing various appetites as well. In addition to melancholy, the spleen became associated with anger and, paradoxically, was also seen as the “seat of laughter.”7The claim for the first human splenectomy may have pre-dated that of canine splenectomy. Andriano Zaccavello was credited in 1549 with having performed a splenectomy on a middle-aged woman. This claim remains shrouded in contro-versy, and the indication for the surgery and whether in fact


Surgery_Schwartz

Surgery_Schwartz. Zaccavello was credited in 1549 with having performed a splenectomy on a middle-aged woman. This claim remains shrouded in contro-versy, and the indication for the surgery and whether in fact splenectomy was performed have been called into question. The patient apparently survived, but may in fact have under-gone resection of an ovarian cyst rather than her spleen!8 Most patients who underwent splenectomy in the three centuries that followed fared badly. The vast majority of splenectomies per-formed were partial. Most of these patients required surgery for Historical Background 1517Embryology and Anatomy 1518Physiology and Pathophysiology 1520Indications for Splenectomy 1522Benign Disorders / 1524Malignant Conditions / 1527Miscellaneous Disorders and Lesions / 1529Imaging for Evaluation of Size and Pathology 1532Preoperative Considerations 1532Vaccination and Patient Education / 1532Deep Vein Thrombosis Prophylaxis / 1533Splenectomy Techniques 1533Patient Preparation / 1533Open


Surgery_Schwartz

Surgery_Schwartz. of Size and Pathology 1532Preoperative Considerations 1532Vaccination and Patient Education / 1532Deep Vein Thrombosis Prophylaxis / 1533Splenectomy Techniques 1533Patient Preparation / 1533Open Splenectomy / 1533Laparoscopic Splenectomy / 1534Hand-Assisted Splenectomy / 1534Single-Incision Laparoscopic Surgery Splenectomy / 1535Robotic Splenectomy / 1536Partial Splenectomy / 1536Inadvertent Intraoperative Splenic Injury / 1538Preoperative Grading Score to Predict Technical Difficulty in Laparoscopic Splenectomy / 1536Splenectomy Outcomes 1538Overwhelming Postsplenectomy Infection / 1538Complications / 1539Hematologic Outcomes / 1539Cancer / 1539Ultrasound / 1540Computed Tomography / 1540Plain Radiography / 1540Magnetic Resonance Imaging / 1540Angiography / 1541Nuclear Imaging / 1541Brunicardi_Ch34_p1517-p1548.indd 151723/02/19 2:36 PM 1518left upper quadrant stab wounds sustained in battles or duels resulting in partial or complete splenic prolapse.9It was in the early 18th


Surgery_Schwartz

Surgery_Schwartz. 151723/02/19 2:36 PM 1518left upper quadrant stab wounds sustained in battles or duels resulting in partial or complete splenic prolapse.9It was in the early 18th century that the growing body of anatomic microstructural knowledge began to turn the tide on the long-held theory of health and disease deriving from a balance of the four humors. William Henson believed the spleen to be a ductless vascular gland similar to the thyroid and adrenals. In 1777, he wrote of the lymphatic nature of the spleen and its filtering function and even suggested its role in hematopoiesis.10Rudolf Virchow, one of the first to discover leukemia, implicated the spleen as figuring prominently in all leukemia patients. He suspected that the spleen was responsible for gen-erating the leukocytes in large quantities in these patients. There soon followed an enthusiastic effort by surgeons to cure leu-kemia by splenectomy. Dr. Thomas Bryant performed the first splenectomy in 1866 in a patient with leukemia.


Surgery_Schwartz

Surgery_Schwartz. in these patients. There soon followed an enthusiastic effort by surgeons to cure leu-kemia by splenectomy. Dr. Thomas Bryant performed the first splenectomy in 1866 in a patient with leukemia. The patient died, as did all 14 patients who underwent splenectomy for leukemia over the next 15 years. After his second consecutive mortality in this setting, Bryant declared that “the operation is physiologically unsound & surgically unsafe for leukemia and should not be performed.”11 In 1908, Johnson reported a series of 99 splenectomies for leukemia with an 85% mortality rate. Unfortunately, it took several decades for his words to be heeded.In 1916, a medical student from Prague named Paul Kaznelson wrote on the key role played by the spleen in the destruction of platelets leading to the first reported (and success-ful) splenectomy for a patient with idiopathic thrombocytopenia purpura.2As surgeons’ experience with the procedure grew, the associated morbidity and mortality decreased. By


Surgery_Schwartz

Surgery_Schwartz. reported (and success-ful) splenectomy for a patient with idiopathic thrombocytopenia purpura.2As surgeons’ experience with the procedure grew, the associated morbidity and mortality decreased. By 1920, the Mayo Clinic reported that splenectomy had a reduced mortality rate of 11%.1O’Donnell in 1929 was the first to describe fatal post-splenectomy sepsis in a child who had undergone the sur-gery for hemolytic anemia.3 It took Springer’s 1973 review of almost 2800 postsplenectomy patients and the 2.5% inci-dence of sepsis-induced mortality (vs. 0.01% in the general population) to reorient surgeons to more conservative splenic procedures.2,3The advent of minimally invasive surgery and laparo-scopic splenectomy in the early 1990s represented a clear advance, benefitting the patient through this evolution of sur-gical technique. Most large series of laparoscopic splenectomy for benign and malignant indication now report a mortality rate of <1%.12,13 As even more contemporary research


Surgery_Schwartz

Surgery_Schwartz. this evolution of sur-gical technique. Most large series of laparoscopic splenectomy for benign and malignant indication now report a mortality rate of <1%.12,13 As even more contemporary research reveals the spleen to play a central role in immune, metabolic, and endocrine function, it follows that the surgeon’s role going forward will be to preserve this organ and its functions when-ever possible.EMBRYOLOGY AND ANATOMYConsisting of an encapsulated mass of vascular and lymphoid tissue, the spleen is the largest reticuloendothelial organ in the body. Arising from the primitive mesoderm as an outgrowth of the left side of the dorsal mesogastrium, by the fifth week of gestation, the spleen is evident in an embryo 8 mm long.Development begins through the formation of the splanch-nic mesodermal plate, derived from the mesoderm, at embryonic day 12. The embryonic spleen is first colonized by erythroid and myeloid progenitor cells at 2 weeks of gestation. Follow-ing soon thereafter, the


Surgery_Schwartz

Surgery_Schwartz. plate, derived from the mesoderm, at embryonic day 12. The embryonic spleen is first colonized by erythroid and myeloid progenitor cells at 2 weeks of gestation. Follow-ing soon thereafter, the hematopoietic stem cells take up resi-dence in the forming spleen.14 The spleen assumes an important hematopoietic role until the fifth month of gestation. After birth, splenic erythropoietic function may persist in some hematologic disorders.15Key Points1 The human spleen plays a key immunologic role in defense against a number of organisms, particularly encapsulated bacteria.2 The spleen can cause significant morbidity and/or hema-tologic disturbance if it becomes hyperfunctioning (hyper-splenism) or hypertrophied (splenomegaly).3 There is a broad spectrum of nontraumatic diseases for which elective splenectomy can be curative or palliative. They can be broadly categorized as red blood cell disor-ders and hemoglobinopathies, white blood cell disorders, platelet disorders, bone marrow


Surgery_Schwartz

Surgery_Schwartz. elective splenectomy can be curative or palliative. They can be broadly categorized as red blood cell disor-ders and hemoglobinopathies, white blood cell disorders, platelet disorders, bone marrow disorders, infections and abscesses, cysts and tumors, storage diseases and infiltra-tive disorders, and miscellaneous conditions.4 Inadvertent intraoperative splenic injury is a scenario for which every abdominal surgeon should be prepared. Avail-ability of a predetermined algorithm, with emphasis on the patient’s condition, facilitates intraoperative decision making.5 Partial splenectomy may be a suitable alternative to total splenectomy for certain conditions of hypersplen-ism or splenomegaly, particularly in children in whom preservation of splenic immunologic function is especially important.6 Preoperative splenic artery embolization for elective sple-nectomy has benefits and disadvantages. It may be most suitable in cases of enlarged spleen. Conclusive evidence is lacking.7 Vaccination


Surgery_Schwartz

Surgery_Schwartz. splenic artery embolization for elective sple-nectomy has benefits and disadvantages. It may be most suitable in cases of enlarged spleen. Conclusive evidence is lacking.7 Vaccination of the splenectomized patient remains the most effective prevention strategy against OPSI. Preopera-tive vaccination before elective splenectomy is most prudent.8 Laparoscopic splenectomy provides equal hematologic outcomes with decreased morbidity compared with the open operation. The laparoscopic approach has emerged as the standard for elective, nontraumatic splenectomy.9 Overwhelming postsplenectomy infection (OPSI) is an uncommon but potentially grave disease. Children and those undergoing splenectomy for hematologic malig-nancy are at elevated risk.10 Antibiotic prophylactic strategies against OPSI vary widely. Data regarding their use are lacking.Brunicardi_Ch34_p1517-p1548.indd 151823/02/19 2:36 PM 1519THE SPLEENCHAPTER 34The organ continues its differentiation and migration to the left upper


Surgery_Schwartz

Surgery_Schwartz. widely. Data regarding their use are lacking.Brunicardi_Ch34_p1517-p1548.indd 151823/02/19 2:36 PM 1519THE SPLEENCHAPTER 34The organ continues its differentiation and migration to the left upper quadrant, where it comes to rest with its smooth, diaphragmatic surface facing posterosuperiorly.16The most common anomaly of splenic embryology is the accessory spleen. Present in up to 20% of the population, one or more accessory spleens may also occur in up to 30% of patients with hematologic disease. Over 80% of accessory spleens are found in the region of the splenic hilum and vascu-lar pedicle. Other locations for accessory spleens in descending order of frequency are the gastrocolic ligament, the pancreas tail, the greater omentum, the stomach’s greater curve, the splenocolic ligament, the small and large bowel mesentery, the left broad ligament in women, and the left spermatic cord in men (Fig. 34-1).10,16The abdominal surface of the diaphragm separates the spleen from the lower


Surgery_Schwartz

Surgery_Schwartz. the small and large bowel mesentery, the left broad ligament in women, and the left spermatic cord in men (Fig. 34-1).10,16The abdominal surface of the diaphragm separates the spleen from the lower left lung and pleura and the ninth to eleventh ribs. The visceral surface faces the abdominal cavity and contains gastric, colic, renal, and pancreatic impressions. Spleen size and weight vary with age, with both diminishing in the elderly and in those with underlying pathologic conditions. The average adult spleen is 7 to 11 cm in length and weighs 150 g (range, 70–250 g).The spleen’s superior border separates the diaphragmatic surface from the gastric impression of the visceral surface and often contains one or two notches, which are particularly pro-nounced when the spleen is greatly enlarged.Of particular clinical relevance, the spleen is suspended in position by several ligaments and peritoneal folds to the colon (splenocolic ligament), the stomach (gastrosplenic liga-ment), the


Surgery_Schwartz

Surgery_Schwartz. particular clinical relevance, the spleen is suspended in position by several ligaments and peritoneal folds to the colon (splenocolic ligament), the stomach (gastrosplenic liga-ment), the diaphragm (phrenosplenic ligament), and the kidney, ABCDEFGFigure 34-1. Sites where accessory spleens are found in order of importance. A. Hilar region, 54%; B. pedicle, 25%; C. tail of pan-creas, 6%; D. splenocolic ligament, 2%; E. greater omentum, 12%; F. mesentery, 0.5%; G. left ovary, 0.5%.Gastrosplenic ligamentLesser sacGreater omentumSplenocolic ligamentSustentaculum lienisPhrenicocolic ligamentFigure 34-2. Suspensory ligaments of the spleen.adrenal gland, and tail of the pancreas (splenorenal ligament) (Fig. 34-2). In a related historical footnote it was widely held less than 200 years ago that a “wandering spleen” led women to experience hypochondria. Dietl in 1863 finally clarified that “it was not a patient’s temperament but rather relaxation, exten-sion or the hypoplasia of splenic


Surgery_Schwartz

Surgery_Schwartz. that a “wandering spleen” led women to experience hypochondria. Dietl in 1863 finally clarified that “it was not a patient’s temperament but rather relaxation, exten-sion or the hypoplasia of splenic ligaments that made a spleen wander.”17 The gastrosplenic ligament contains the short gas-tric vessels; the remaining ligaments are avascular, with rare exceptions, such as in patients with portal hypertension. The relationship of the pancreas to the spleen also has important clinical implications. In cadaveric anatomic series, the tail of the pancreas has been demonstrated to lie within 1 cm of the splenic hilum 75% of the time and to actually abut the spleen in 30% of patients.2The spleen derives most of its blood from the splenic artery, the longest and most tortuous of the three main branches of the celiac artery. The splenic artery can be characterized by the pattern of its terminal branches. The distributed type of splenic artery is the most common (70%) and is distinguished by a


Surgery_Schwartz

Surgery_Schwartz. of the celiac artery. The splenic artery can be characterized by the pattern of its terminal branches. The distributed type of splenic artery is the most common (70%) and is distinguished by a short trunk with many long branches entering over three-fourths of the spleen’s medial surface. The less common magis-tral type of splenic artery (30%) has a long main trunk dividing near the hilum into short terminal branches, and these enter over 25% to 30% of the spleen’s medial surface. The spleen also receives some of its blood supply from the short gastric vessels that branch from the left gastroepiploic artery running within the gastrosplenic ligament. The splenic vein joins the superior mesenteric vein to form the portal vein and accommodates the major venous drainage of the spleen.When a normal, freshly excised spleen is sectioned, the cut surface is finely granular and predominantly dark red with whit-ish nodules distributed liberally across its expanse. This gross observation reflects


Surgery_Schwartz

Surgery_Schwartz. freshly excised spleen is sectioned, the cut surface is finely granular and predominantly dark red with whit-ish nodules distributed liberally across its expanse. This gross observation reflects the spleen’s microstructure. The splenic parenchyma is composed of two main elements: the red pulp, constituting approximately 75% of total splenic volume, and the white pulp (Fig. 34-3). At the interface between the red and white pulp is the narrow marginal zone.Brunicardi_Ch34_p1517-p1548.indd 151923/02/19 2:36 PM 1520SPECIFIC CONSIDERATIONSPART IIBlood enters the red pulp through cords comprised of fibro-blasts and reticular fibers, which contain many macrophages and lack an endothelial lining. The blood then passes from these “open” cords to venous sinuses, which are surrounded and sepa-rated by the same reticulum, and ultimately drains into tributar-ies of the splenic vein. An understanding of the microanatomy of these sinuses has elucidated the mechanical filtration function of the


Surgery_Schwartz

Surgery_Schwartz. by the same reticulum, and ultimately drains into tributar-ies of the splenic vein. An understanding of the microanatomy of these sinuses has elucidated the mechanical filtration function of the spleen. Unlike the cords of the red pulp, the sinuses of the red pulp are lined by endothelial cells. These cells contain unique stress fibers that connect the endothelial cells and that contain actin and myosin–like filaments capable of producing a sliding action. When activated, these filaments can create slits or gaps between the endothelial cells through which blood can then pass from the cords.14 Aging erythrocytes with stiffer mem-branes get stuck trying to pass into the sinus and are phagocy-tized by macrophages within the red pulp.15The red pulp thus serves as a dynamic filtration system, enabling macrophages to remove microorganisms, cellular debris, antigen-antibody complexes, and senescent erythrocytes from the circulation.Around the terminal millimeters of splenic arterioles, a


Surgery_Schwartz

Surgery_Schwartz. enabling macrophages to remove microorganisms, cellular debris, antigen-antibody complexes, and senescent erythrocytes from the circulation.Around the terminal millimeters of splenic arterioles, a periarticular lymphatic sheath replaces the native adventitia of the vessel. The sheath is comprised of T lymphocytes and intermittent aggregations of B lymphocytes or lymphoid fol-licles. When antigenically stimulated, the follicles, serving as centers of lymphocyte proliferation, develop germinal centers, which regress as the stimulus or infection subsides. This white pulp consists of nodules that normally are ≤1 mm in size but can increase to several centimeters when nodules coalesce, as occurs in certain lymphoproliferative disorders. At the junction between the white and red pulp is the marginal zone, where lymphocytes are more loosely aggregated.As well as serving as a transit area, the marginal zone is home to its own unique population of cells. Notably two spe-cific types of


Surgery_Schwartz

Surgery_Schwartz. the marginal zone, where lymphocytes are more loosely aggregated.As well as serving as a transit area, the marginal zone is home to its own unique population of cells. Notably two spe-cific types of macrophages reside there, marginal zone macro-phages and marginal zone metallophilic macrophages. The former play an important role in the targeting and clearance of certain bacterial pathogens. The latter have been shown to be the main producers of interferons A and B in response to a viral challenge.14PHYSIOLOGY AND PATHOPHYSIOLOGYThe spleen is contained by a 1to 2-mm thick capsule. In humans, the capsule is rich in collagen and contains some elas-tin fibers. Many mammals have splenic capsules and trabecu-lae with abundant smooth muscle cells, which upon autonomic stimulation contract to expel large volumes of stored blood into the general circulation. The human splenic capsule and trabecu-lae, by contrast, contain few or no smooth muscle cells.Total splenic inflow of blood is


Surgery_Schwartz

Surgery_Schwartz. to expel large volumes of stored blood into the general circulation. The human splenic capsule and trabecu-lae, by contrast, contain few or no smooth muscle cells.Total splenic inflow of blood is approximately 250 to 300 mL/min. Blood flows through successively tapering arteries to arterioles, traverses the white pulp, crosses the marginal zone, and enters the red pulp. From that entry, the flow rate through the spleen may vary greatly. Animal studies measuring the tran-sit times of isotopically labeled blood through the spleen have revealed three distinct velocities of flow. Humans have long been recognized to have both a fast or closed circulation—with blood passing directly from arterioles into venous sinuses—and a slower or open circulation. Most of the spleen’s filtration func-tion occurs via the slower circulation. During open circulation, blood percolates through the reticular space and splenic cords, thus gaining access through gaps or slits in the endothelial cell lining to


Surgery_Schwartz

Surgery_Schwartz. occurs via the slower circulation. During open circulation, blood percolates through the reticular space and splenic cords, thus gaining access through gaps or slits in the endothelial cell lining to the sinuses as previously described. Flowing into and out of the venous sinuses through these gaps, the blood is exposed to extensive contact with splenic macrophages. These are responsible for the innate immune response of the spleen, which occurs largely within the marginal zone. The white pulp, by contrast, is involved only in adaptive immunity. In addition, because the passage of plasma through these spaces does not slow in a similar manner, a temporary and unique adhesive con-tact between blood cells and components of the splenic cord may occur. That there is a selective slowing of blood cell flow versus plasma flow is further evidenced by the fact that within the spleen, the erythrocyte concentration (hematocrit) is twice that of the general circulation. During this contact with


Surgery_Schwartz

Surgery_Schwartz. cell flow versus plasma flow is further evidenced by the fact that within the spleen, the erythrocyte concentration (hematocrit) is twice that of the general circulation. During this contact with splenic macrophages, it is likely that the removal of both cellular debris and senescent blood cells occurs.18The process by which the spleen removes erythrocyte inclusions, such as Heinz bodies (intracellular altered hemo-globin), without cell lysis while red blood cells travel through the spleen is not well understood. The spleen acts as the major site for clearance from the blood of damaged or aged red blood cells and, in addition, has a part in the removal of abnormal white blood cells and platelets. A minimum of 2 days of the erythrocyte’s 120-day life cycle is spent sequestered in the spleen. Daily, approximately 20 mL of aged red blood cells are removed. Evidence suggests that, as erythrocytes age, previ-ously undetected antigens on their surfaces may attach to auto-antibodies in the


Surgery_Schwartz

Surgery_Schwartz. Daily, approximately 20 mL of aged red blood cells are removed. Evidence suggests that, as erythrocytes age, previ-ously undetected antigens on their surfaces may attach to auto-antibodies in the circulation; then macrophages may bind to the antibodies and initiate phagocytosis. It is probable that the erythrocyte is damaged over time by multiple passages through the spleen as well as delayed transit through the congested and relatively hypoxic and acidotic environment of the splenic cords.The spleen can also serve as an extra medullary site for hematopoiesis, if required. Another role played by the spleen is in recycling iron. Erythrocytes in large numbers are destroyed intravascularly throughout the body. The released hemoglobin is then bound to haptoglobin, which is ultimately scav-enged from the circulation in the spleen.191Trabeculae (depicted as both capsular and white lined material)Splenic capsuleRed pulpWhite pulpFigure 34-3. Splenic architecture. (Used with permission from


Surgery_Schwartz

Surgery_Schwartz. from the circulation in the spleen.191Trabeculae (depicted as both capsular and white lined material)Splenic capsuleRed pulpWhite pulpFigure 34-3. Splenic architecture. (Used with permission from Ivan George, University of Maryland School of Medicine.)Brunicardi_Ch34_p1517-p1548.indd 152023/02/19 2:36 PM 1521THE SPLEENCHAPTER 34The spleen plays a vital, although not indispensable, role in host defense evidenced by the healthy survival of splenec-tomized patients. Both innate and adaptive immune responses (historically categorized as cell-mediated and humoral immu-nity) occur within the spleen.In addition to the previously noted activities of the mar-ginal zone macrophages, marginal zone B cells serve to detect circulating pathogens and respond quickly to either differenti-ate into immunoglobulin M (IgM)–producing plasma cells or to function as antigen-presenting cells (APCs), which facilitate pathogen removal and destruction.It is APC entry in the white pulp in particular that is


Surgery_Schwartz

Surgery_Schwartz. M (IgM)–producing plasma cells or to function as antigen-presenting cells (APCs), which facilitate pathogen removal and destruction.It is APC entry in the white pulp in particular that is key to the initiation of the adaptive immune response. Antigens are thus presented to immunocompetent centers within the lymphoid follicles. This gives rise to the elaboration of immunoglobulins (predominantly IgM). After an antigen challenge, such an acute IgM response results in the release of opsonic antibodies from the white pulp of the spleen. Antigen clearance is then facilitated by the splenic and hepatic reticuloendothelial systems.The structure and immunophysiology of the white pulp is very similar to that of lymph nodes, with the notable difference being that material enters the lymph node in the lymph whereas it is delivered to the white pulp in the blood.20The spleen also produces opsonins, tuftsin, and proper-din. Circulating monocytes are converted within the red pulp into fixed


Surgery_Schwartz

Surgery_Schwartz. in the lymph whereas it is delivered to the white pulp in the blood.20The spleen also produces opsonins, tuftsin, and proper-din. Circulating monocytes are converted within the red pulp into fixed macrophages that account for the spleen’s remarkable phagocytic activity.The spleen also appears to be a major source of the protein properdin, important in the initiation of the alternate pathway of complement activation. The splenic reticuloendothelial system is better able to clear bacteria that are poorly or inadequately opsonized from the circulation than is the hepatic reticuloendo-thelial system. Encapsulated bacteria generally fit such a pro-file, hence the risk posed by pneumococcus and Haemophilus influenzae to an asplenic patient. There appears to be sufficient physiologic capacity within the complement cascade to with-stand the loss of tuftsin and properdin production without an increase in patient vulnerability after splenectomy.21-23In patients with chronic hemolytic disorders,


Surgery_Schwartz

Surgery_Schwartz. the complement cascade to with-stand the loss of tuftsin and properdin production without an increase in patient vulnerability after splenectomy.21-23In patients with chronic hemolytic disorders, splenic tissue may become permanently hypertrophied. The reticular spaces of the red pulp become distended with macrophages engorged with the products of erythrocyte breakdown, and splenomegaly can result. It is important to distinguish between splenomegaly and hypersplenism, two similar but distinct terms that are critical to understand when discussing splenic pathology. Splenomegaly refers simply to abnormal enlargement of the spleen. Splenomeg-aly is described variably within the surgical literature as moderate, massive, and hyper, which reflects a lack of con-sensus. Most would agree, however, that splenomegaly applies to organs weighing ≥500 g and/or averaging ≥15 cm in length.Massive splenomegaly similarly lacks a consensus defini-tion but has been described variably as spleens >1 kg in


Surgery_Schwartz

Surgery_Schwartz. that splenomegaly applies to organs weighing ≥500 g and/or averaging ≥15 cm in length.Massive splenomegaly similarly lacks a consensus defini-tion but has been described variably as spleens >1 kg in mass or >22 cm in length (Fig. 34-4).9 Spleens palpable below the left costal margin are thought to be at least double normal size, with an estimated weight of ≥750 g.24There is not a single, universally accepted standard, but most would agree that an ex vivo mass of >1 kg or a pole-to-pole length of >15 cm generally qualifies as splenomegaly. Hypersplenism often is found in association with splenomegaly but is not synonymous with it. Hypersplenism is defined as the presence of one or more cytopenias in the context of a normally functioning bone marrow.2ABCFigure 34-4. Splenomegaly. A. Computed tomography (CT) scan. B. Three-dimensional reconstruction of CT scan. C. Postoperative specimen.Brunicardi_Ch34_p1517-p1548.indd 152123/02/19 2:36 PM 1522SPECIFIC CONSIDERATIONSPART IIDisorders


Surgery_Schwartz

Surgery_Schwartz. tomography (CT) scan. B. Three-dimensional reconstruction of CT scan. C. Postoperative specimen.Brunicardi_Ch34_p1517-p1548.indd 152123/02/19 2:36 PM 1522SPECIFIC CONSIDERATIONSPART IIDisorders causing hypersplenism can be categorized as either (a) those in which increased destruction of abnormal blood cells occurs in an intrinsically normal spleen (e.g., hemolytic anemias) or (b) primary disorders of the spleen resulting in increased sequestration and destruction of normal blood cells (e.g., infiltrative disorders).The life cycles of cellular elements vary widely in human blood. A neutrophil in circulation has a normal half-life of approximately 6 hours. The spleen’s role in the normal clearance of neutrophils is not well established. It is clear that hypersplen-ism may result in neutropenia through sequestration of normal white blood cells or the removal of abnormal ones. Platelets, on the other hand, generally survive in the circulation for 10 days. Under normal circumstances,


Surgery_Schwartz

Surgery_Schwartz. through sequestration of normal white blood cells or the removal of abnormal ones. Platelets, on the other hand, generally survive in the circulation for 10 days. Under normal circumstances, a third of the total platelet pool is sequestered in the spleen. Thrombocytopenia may result from excessive sequestration of platelets as well as accelerated platelet destruction in the spleen. Splenomegaly may result in sequestration of up to 80% of the platelet pool. The spleen may also contribute to the immunologic alteration of platelets, which leads to thrombocytopenia in the absence of splenomegaly (e.g., idiopathic thrombocytopenic purpura [ITP]).25The immunologic functions of the spleen are consistent with those of other lymphoid organs. It is a site of bloodborne antigen presentation and the initiation of Tand B-lymphocyte activities involved in humoral and cellular immune responses. Alteration of splenic immune function often gives rise to anti-body production, which results in blood


Surgery_Schwartz

Surgery_Schwartz. initiation of Tand B-lymphocyte activities involved in humoral and cellular immune responses. Alteration of splenic immune function often gives rise to anti-body production, which results in blood cell destruction.Although the spleen contributes to the process of eryth-rocyte maturation, in adult humans there is little evidence of normal hematopoietic function. The spleen does have a minor role in hematopoiesis in the fourth month in the human fetus, and reactivation can occur in childhood if the bone marrow fails to meet the hematologic needs. Splenic hematopoiesis giving rise to abnormal red blood cells is seen in adults with myelopro-liferative disorders. In addition, in response to some anemias, elements of the red pulp may revert to hematopoiesis.INDICATIONS FOR SPLENECTOMYGenerally speaking, splenectomy is performed for the purposes of cure or palliation of hematological disease including condi-tions of hypersplenism, to relieve the mass effect and symptoms associated with


Surgery_Schwartz

Surgery_Schwartz. speaking, splenectomy is performed for the purposes of cure or palliation of hematological disease including condi-tions of hypersplenism, to relieve the mass effect and symptoms associated with splenomegaly, to control infection or hemorrhage and finally to diagnose splenic pathology. For the purposes of this chapter, we will divide these indications into the following categories: (a) benign conditions, including red blood cell disor-ders, hemoglobinopathies, and platelet disorders (Table 34-1a); (b) malignant conditions, including white blood cell disorders, bone marrow disorders (myeloproliferative disorders) and tumors of the spleen (Table 34-1b); and (c) miscellaneous conditions and lesions of the spleen including infections and abscesses, cysts, vascular anomalies, and more (Table 34-1c). We will conclude this chapter with a brief discussion on splenic salvage.Overall, the most common indication for splenectomy is trauma to the spleen, whether external trauma (blunt or


Surgery_Schwartz

Surgery_Schwartz. (Table 34-1c). We will conclude this chapter with a brief discussion on splenic salvage.Overall, the most common indication for splenectomy is trauma to the spleen, whether external trauma (blunt or penetrat-ing) or iatrogenic injury (e.g., at the time of other operations). Inadvertent intraoperative injury to the spleen, necessitating removal, also called “incidental splenectomy” is discussed in a 3Table 34-1aIndications for and expected response to splenectomy in various benign diseases, including red blood cell disorders, hemoglobinopathies, and platelet disordersDISEASE/CONDITIONINDICATIONS FOR SPLENECTOMYRESPONSE TO SPLENECTOMYEssential thrombocythemiaOnly for advanced disease (i.e., transformation to myeloid metaplasia or AML) with severe symptomatic splenomegalyRelief of abdominal pain and early satietyGlucose-6-phosphate dehydrogenase deficiency (G6PD)Excessive transfusion requirements; failure of medical therapy (controversial)May be curativeHereditary spherocytosisHemolytic


Surgery_Schwartz

Surgery_Schwartz. pain and early satietyGlucose-6-phosphate dehydrogenase deficiency (G6PD)Excessive transfusion requirements; failure of medical therapy (controversial)May be curativeHereditary spherocytosisHemolytic anemia, recurrent transfusions, intractable leg ulcersImproves or eliminates anemiaIdiopathic thrombocytopenic purpura (ITP)Failure of medical therapy, recurrent disease75%–85% rate of long-term responsePolycythemia veraOnly for advanced disease (i.e., transformation to myeloid metaplasia or AML) with severe symptomatic splenomegalyRelief of abdominal pain and early satietyPyruvate kinase deficiencyOnly in severe cases, recurrent transfusionsDecreased transfusion requirement, palliative onlySickle cell diseaseHistory of acute sequestration crisis, splenic symptoms, or infarction (consider concomitant cholecystectomy)Palliative, variable responseThalassemiaExcessive transfusion requirements, symptomatic splenomegaly, infarction, or hypersplenismDiminished transfusion requirements, relief


Surgery_Schwartz

Surgery_Schwartz. cholecystectomy)Palliative, variable responseThalassemiaExcessive transfusion requirements, symptomatic splenomegaly, infarction, or hypersplenismDiminished transfusion requirements, relief of symptomsThrombotic thrombocytopenic purpura (TTP)Excessive plasma exchange requirementTypically curativeWarm-antibody autoimmune hemolytic anemiaFailure of medical (steroid) therapy60%–80% response rate, recurrences commonBrunicardi_Ch34_p1517-p1548.indd 152223/02/19 2:36 PM 1523THE SPLEENCHAPTER 34Table 34-1bIndications for and expected response to splenectomy in various malignant diseases, including white blood cell disorders, myeloproliferative disorders, and nonhematologic tumors of the spleenDISEASE/CONDITIONINDICATIONS FOR SPLENECTOMYRESPONSE TO SPLENECTOMYAcute myeloid leukemia (AML)Intolerable symptomatic splenomegalyRelief of abdominal pain and early satietyChronic lymphocytic leukemia (CLL)Cytopenias and anemia75% response rateChronic myelogenous leukemia (CML)Symptomatic


Surgery_Schwartz

Surgery_Schwartz. symptomatic splenomegalyRelief of abdominal pain and early satietyChronic lymphocytic leukemia (CLL)Cytopenias and anemia75% response rateChronic myelogenous leukemia (CML)Symptomatic splenomegalyRelief of abdominal pain and early satietyChronic myelomonocytic leukemia (CMML)Symptomatic splenomegalyRelief of abdominal pain and early satietyMyelofibrosis (agnogenic myeloid metaplasia)Severe symptomatic splenomegaly76% clinical response at 1 y, high risk of hemorrhagic, thrombotic, and infectious complications (26%)Hairy cell leukemiaSevere symptomatic splenomegaly, severe transfusion requirements; failure of medical therapyCurativeHodgkin’s lymphomaSurgical staging in selected casesVariedNon-Hodgkin’s lymphomaCytopenias, symptomatic splenomegalyImproved complete blood count values, relief of symptomsMetastatic tumor of the spleen (most commonly breast, lung, and melanoma)If symptomatic, or as part of cancer treatmentVariedPrimary tumor of the spleenFor diagnosis and treatment of


Surgery_Schwartz

Surgery_Schwartz. of symptomsMetastatic tumor of the spleen (most commonly breast, lung, and melanoma)If symptomatic, or as part of cancer treatmentVariedPrimary tumor of the spleenFor diagnosis and treatment of cancerVariedTable 34-1cIndications for and expected response to splenectomy in various miscellaneous conditionsDISEASE/CONDITIONINDICATIONS FOR SPLENECTOMYRESPONSE TO SPLENECTOMYAbscess of the spleenMultiloculated, or failure of conservative measures for unilocularCurativeAmyloidosisSymptomatic splenomegalyImproves symptoms; does not correct underlying diseaseFelty’s syndromeNeutropenia80% durable response rateGaucher’s diseaseHypersplenismImproves cytopenias; does not correct underlying diseaseNiemann-Pick diseaseSymptomatic splenomegalyImproves symptoms; does not correct underlying diseasePortal/sinistral hypertensionSplenic vein thrombosis, symptomatic splenomegalyPalliativeSarcoidosisHypersplenism or symptomatic splenomegalyImproves symptoms and cytopenias; does not correct underlying


Surgery_Schwartz

Surgery_Schwartz. hypertensionSplenic vein thrombosis, symptomatic splenomegalyPalliativeSarcoidosisHypersplenism or symptomatic splenomegalyImproves symptoms and cytopenias; does not correct underlying diseaseSplenic artery aneurysmBest for distal lesions near splenic hilumCurativeSymptomatic nonparasitic cystsPartial splenectomy for small cysts; unroofing for large cystsCurativeSymptomatic parasitic cystsTherapy of choiceCurative; exercise caution not to spill cyst contentsWandering spleenAbdominal pain or splenomegaly (venous congestion)CurativeTraumatic ruptureGrades 4/5, or failure of conservative management of lower gradesCurativeBrunicardi_Ch34_p1517-p1548.indd 152323/02/19 2:36 PM 1524SPECIFIC CONSIDERATIONSPART IIlater section. Management of splenic injury in the trauma patient is also beyond the scope of this chapter and discussed else-where. The most common indications for elective splenec-tomy are malignancy and hematologic autoimmune disorders, principally, idiopathic thrombocytopenic


Surgery_Schwartz

Surgery_Schwartz. the scope of this chapter and discussed else-where. The most common indications for elective splenec-tomy are malignancy and hematologic autoimmune disorders, principally, idiopathic thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA).Benign DisordersRed Blood Cell Disorders Congenital Hereditary Spherocytosis. Hereditary spherocytosis (HS) is the most common type of hemolytic anemia for which splenectomy is indicated and the third most common type of congenital hemo-lytic anemia overall.26 HS results from an inherited dysfunction or deficiency in one of the erythrocyte membrane proteins (alpha or beta spectrin, ankyrin, band 3 protein, or protein 4.2). The result-ing destabilization of the membrane lipid bilayer allows a patho-logic release of membrane lipids. The red blood cell assumes a more spherical, less deformable shape, and the spherocytic eryth-rocytes are sequestered and destroyed in the spleen and hemolytic anemia ensues. HS is inherited primarily (70–80%


Surgery_Schwartz

Surgery_Schwartz. cell assumes a more spherical, less deformable shape, and the spherocytic eryth-rocytes are sequestered and destroyed in the spleen and hemolytic anemia ensues. HS is inherited primarily (70–80% of the time) in an autosomal dominant fashion; the estimated prevalence in Western populations is roughly 1 in 2000.26Patients with typical HS forms may have mild jaundice. Splenomegaly usually is palpable on physical examination. Laboratory examination reveals varying degrees of anemia: patients with mild forms of the disease may not have anemia; patients with moderate to severe forms may have hemoglobin levels as low as 4 to 6 g/dL. The mean corpuscular volume is typically low to normal or slightly decreased. For screening, a combined elevated mean corpuscular hemoglobin concentra-tion and an elevated erythrocyte distribution width are an excel-lent predictor. Other laboratory indicators of HS include those providing evidence of rapid red blood cell destruction, includ-ing elevated


Surgery_Schwartz

Surgery_Schwartz. and an elevated erythrocyte distribution width are an excel-lent predictor. Other laboratory indicators of HS include those providing evidence of rapid red blood cell destruction, includ-ing elevated reticulocyte count, elevated lactate dehydrogenase level, and increased level of unconjugated bilirubin. Sphero-cytes are readily apparent on peripheral blood film.Risks and benefits should be assessed carefully before splenectomy and cholecystectomy are performed for HS.27 The main indications are moderate to severe symptomatic hemo-lytic anemia, growth retardation, skeletal changes, leg ulcers, and extramedullary hemopoietic tumors in young patients.26,28 If gallstones coexist with spherocytosis, the gallbladder should be removed, but prophylactic cholecystectomy without gall-stones is controversial. Near total splenectomy is advocated in children. Dramatic clinical improvement—despite persistent hemolysis—usually occurs after splenectomy in patients with moderate to severe disease.


Surgery_Schwartz

Surgery_Schwartz. Near total splenectomy is advocated in children. Dramatic clinical improvement—despite persistent hemolysis—usually occurs after splenectomy in patients with moderate to severe disease. Because children can be affected with HS, the timing of splenectomy is important and is aimed at reducing the diminutive possibility of overwhelming postsple-nectomy sepsis. Delaying such an operation until the patient is between the ages of 4 and 6—unless the anemia and hemolysis accelerate—is recommended by most experts.29Red Blood Cell Enzyme Deficiencies. Red blood cell enzyme deficiencies associated with hemolytic anemia may be classified into two groups: deficiencies of enzymes involved in glycolytic pathways, such as pyruvate kinase deficiency, and deficien-cies of enzymes needed to maintain a high ratio of reduced to oxidized glutathione in the red blood cell, protecting it from oxidative damage, such as glucose-6-phosphate dehydrogenase (G6PD) deficiency.304Pyruvate Kinase Deficiency Pyruvate


Surgery_Schwartz

Surgery_Schwartz. ratio of reduced to oxidized glutathione in the red blood cell, protecting it from oxidative damage, such as glucose-6-phosphate dehydrogenase (G6PD) deficiency.304Pyruvate Kinase Deficiency Pyruvate kinase (PK) deficiency is the most common glycolytic defect causing congenital nons-pherocytic hemolytic anemia.31 Since its first description in the early 1960s, vast amounts of information have been elucidated about the genetic diversity of the disease, red blood cell clear-ance, long-term complications and treatment options includ-ing transfusion and splenectomy. PK deficiency affects people worldwide, with a slight preponderance among those of Northern European or Chinese descent. Its estimated prevalence in the Caucasian population is 51 per million.32,33 Clinical manifesta-tions of the disease vary widely, from transfusion-dependent severe anemia in early childhood to well-compensated mild ane-mia in adolescents or adults. Prenatal hydrops fetalis has also been reported.31 Pyruvate


Surgery_Schwartz

Surgery_Schwartz. disease vary widely, from transfusion-dependent severe anemia in early childhood to well-compensated mild ane-mia in adolescents or adults. Prenatal hydrops fetalis has also been reported.31 Pyruvate kinase enzyme activity is the gold standard for initial diagnostic testing or by detection of spe-cific mutations at the complementary DNA or genomic level. Splenomegaly is common, and in severe cases, splenectomy can alleviate transfusion requirements.31 As with other disorders that cause hemolytic anemia in children, splenectomy should be delayed if possible to at least 4 years of age to reduce the risk of postsplenectomy infection.Glucose-6-Phosphate Dehydrogenase Deficiency The most common red blood cell enzyme deficiency overall is G6PD deficiency. It is far more prevalent than PK deficiency with more than 400 million people affected worldwide, although most experience only moderate health risks and no longevity reduction.34 Clinical manifestations—chronic hemolytic ane-mia, acute


Surgery_Schwartz

Surgery_Schwartz. with more than 400 million people affected worldwide, although most experience only moderate health risks and no longevity reduction.34 Clinical manifestations—chronic hemolytic ane-mia, acute intermittent hemolytic episodes, or no hemolysis—depend on the variant of G6PD deficiency. The mainstay of therapy is avoidance of drugs known to precipitate hemolysis in patients with G6PD deficiency. Transfusions are given in cases of symptomatic anemia. Conventional wisdom is that splenectomy is not indicated in this disease, and certainly the overwhelming majority of patients with G6PD deficiency will neither require nor benefit from splenectomy. However, one report described a small case series of six symptomatic G6PD deficiency patients who had severe hemolytic anemia and required transfusion, all of whom were identified to share a common mutation at exon 10. All underwent splenectomy. A complete response occurred in four patients (transfusion requirement eliminated), and a partial


Surgery_Schwartz

Surgery_Schwartz. all of whom were identified to share a common mutation at exon 10. All underwent splenectomy. A complete response occurred in four patients (transfusion requirement eliminated), and a partial response occurred in one patient (transfusion requirement reduced); no follow-up data were provided for the remaining patient. This study indi-cates that for a carefully select group of patients with severe hemolytic anemia attributable to G6PD deficiency, splenec-tomy may be of benefit, although more data is needed before strong recommendation can be made.34Acquired Warm-Antibody Autoimmune Hemolytic Anemia. Autoim-mune hemolytic anemias (AIHAs) are characterized by the destruction of red blood cells, whose erythrocyte life span is diminished by autoantibodies leveled against antigens. AIHA is classified as either primary or secondary, depending on whether an underlying cause, such as a disease or toxin, is iden-tified. AIHA is also divided into “warm” and “cold” catego-ries, based on the


Surgery_Schwartz

Surgery_Schwartz. classified as either primary or secondary, depending on whether an underlying cause, such as a disease or toxin, is iden-tified. AIHA is also divided into “warm” and “cold” catego-ries, based on the temperature at which the autoantibodies exert their effect.35 In cold-agglutinin disease, severe symptoms are uncommon and splenectomy is almost never indicated; there-fore, this entity is not discussed further in this section. However, warm-antibody AIHA has clinical consequences with which the surgeon should be familiar.Brunicardi_Ch34_p1517-p1548.indd 152423/02/19 2:36 PM 1525THE SPLEENCHAPTER 34Warm-antibody AIHA, although occurring primarily in midlife, can affect individuals at all ages. The disorder is more common among women, and fully half of warm-antibody AIHA cases are idiopathic. Clinical presentation may be acute or gradual. Findings include mild jaundice and symptoms and signs of anemia. One-third to one-half of patients present with splenomegaly. Sometimes in such cases


Surgery_Schwartz

Surgery_Schwartz. Clinical presentation may be acute or gradual. Findings include mild jaundice and symptoms and signs of anemia. One-third to one-half of patients present with splenomegaly. Sometimes in such cases the spleen is palpable on physical examination. The diagnosis relies on demonstrat-ing hemolysis as indicated by anemia, reticulocytosis, and/or products of red blood cell destruction, including bilirubin, in the blood, urine, and stool. A positive result on direct Coombs’ test confirms the AIHA diagnosis by distinguishing autoimmune from other forms of hemolytic anemia.Treatment of AIHA depends on the severity of the disease and whether it is primary or secondary. Severe symptomatic anemia demands prompt attention, often requiring red blood cell transfusion. The mainstay treatment for both primary and secondary forms of symptomatic, unstable AIHA remains longterm corticosteroid administration.36 Therapy should continue until a response is noted by a rise in hematocrit and fall in


Surgery_Schwartz

Surgery_Schwartz. both primary and secondary forms of symptomatic, unstable AIHA remains longterm corticosteroid administration.36 Therapy should continue until a response is noted by a rise in hematocrit and fall in reticu-locyte count, which generally occurs within 3 weeks.Clinical response to splenectomy for AIHA varies, and the evidence from a number of small case series is conflicting. For example, one 2004 series reported a favorable response to splenectomy in patients with AIHA secondary to chronic lym-phocytic leukemia, whereas more recent series found no benefit from splenectomy in patients with AIHA secondary to systemic lupus erythematosus or inflammatory bowel disease.37,38Favorable responses to splenectomy have been reported in patients with warm-antibody AIHA, with a recent series show-ing complete remission of refractory AIHA following lapa-roscopic splenectomy at 35-month follow-up in patients over 60 years old.36 Transient responses are more common, how-ever, and many patients


Surgery_Schwartz

Surgery_Schwartz. complete remission of refractory AIHA following lapa-roscopic splenectomy at 35-month follow-up in patients over 60 years old.36 Transient responses are more common, how-ever, and many patients eventually experience hemolysis again despite splenectomy.37,38 The decision regarding splenectomy in the case of AIHA should be individualized based on careful consideration of the clinical history and frank discussion with the patient. It is considered as a third-line therapy after failure of steroids or anti-CD20 antibody administration.39Hemoglobinopathies. Sickle cell disease is an inherited chronic hemolytic anemia that results from the mutant sickle cell hemoglobin (HbS) within the red blood cell and is inher-ited in an autosomal dominant fashion. Persons who inherit an HbS gene from one parent (heterozygous) are carriers; those who inherit an HbS gene from both parents (homozygous) have sickle cell anemia.40In sickle cell disease, the underlying abnormality is the mutation of adenine to


Surgery_Schwartz

Surgery_Schwartz. (heterozygous) are carriers; those who inherit an HbS gene from both parents (homozygous) have sickle cell anemia.40In sickle cell disease, the underlying abnormality is the mutation of adenine to thymine in the sixth codon of the β-globin gene, which results in the substitution of valine for glutamic acid as the sixth amino acid of the β-globin chain. Mutant β chains included in the hemoglobin tetramer create HbS. Deoxy-genated HbS is insoluble and becomes polymerized and sickled. The subsequent lack of deformability of the red blood cell, in addition to other processes, results in microvascular congestion, which may lead to thrombosis, ischemia, and tissue necrosis. The disorder is characterized by painful intermittent episodes.Sequestration occurs in the spleen, with splenomegaly resulting early in the disease course. In most patients, subse-quent infarction of the spleen and autosplenectomy occur at some later time. The most frequent indications for splenectomy in sickle cell


Surgery_Schwartz

Surgery_Schwartz. early in the disease course. In most patients, subse-quent infarction of the spleen and autosplenectomy occur at some later time. The most frequent indications for splenectomy in sickle cell disease are recurrent acute sequestration crises, hypersplenism, and splenic abscess. The occurrence of one major acute sequestration crisis, characterized by rapid painful enlargement of the spleen and circulatory collapse, generally is considered sufficient grounds for splenectomy. Both partial and total splenectomy have been shown to control clinical symp-toms in children but may not change hematologic parameters.41 Preoperative preparation should include special attention to adequate hydration and avoidance of hypothermia.Transfusions are often indicated for anemia, for mod-erately severe episodes of acute chest syndrome (i.e., a new infiltrate on chest radiograph associated with new symptoms, such as fever, cough, sputum production, or hypoxia), and pre-operatively before splenectomy.


Surgery_Schwartz

Surgery_Schwartz. of acute chest syndrome (i.e., a new infiltrate on chest radiograph associated with new symptoms, such as fever, cough, sputum production, or hypoxia), and pre-operatively before splenectomy. Patients experiencing stroke or a severe crisis may require hydration and an exchange trans-fusion, which may be performed manually or with automated apheresis equipment. Hydroxyurea is an oral chemotherapeutic agent that upregulates fetal hemoglobin, which interferes with polymerization of HbS and thus reduces the sickling process.42Thalassemia. Thalassemia is the term for a group of inherited disorders of hemoglobin synthesis prevalent among people of Mediterranean extraction and classified according to the hemo-globin chain (α, β, or γ) affected. As a group, the thalassemias are the most common genetic diseases known to arise from a single gene defect.43,44 Most forms of this disorder are inherited in Mendelian recessive fashion from asymptomatic carrier par-ents. In the so-called thalassemia


Surgery_Schwartz

Surgery_Schwartz. diseases known to arise from a single gene defect.43,44 Most forms of this disorder are inherited in Mendelian recessive fashion from asymptomatic carrier par-ents. In the so-called thalassemia belt that extends throughout the shores of the Mediterranean as well as through the Arabian Peninsula, Turkey, Iran, India, and southeastern Asia, the inci-dence of thalassemia is between 2.5% and 15%. However, thal-assemias have been found in people of all ethnic origins.44In all forms of thalassemia, the primary defect is absent or reduced production of hemoglobin chains. From this abnormal-ity, two significant consequences arise: (a) reduced functioning of hemoglobin tetramers, yielding hypochromia and microcy-tosis; and (b) unbalanced biosynthesis of individual α and β subunits, which results in insoluble red blood cells that cannot release oxygen normally and may precipitate with cell aging. Both underproduction of hemoglobin and excess production of unpaired hemoglobin subunits contribute