Benign Tumors of the Pancreas – Limited Local Surgical Treatment for Cystic Neoplasms and Neuroendocrine Tumors – an Overview

Введение. К доброкачественным опухолям поджелудочной железы (ПЖ) могут быть отнесены внутрипротоковые папиллярно-муцинозные опухоли, муцинозные кистозные опухоли, серозная цистаденома, солиднопсевдопапиллярная опухоль и нейроэндокринные опухоли (НЭО), чаще всего инсулиномы. Эволюция таких органосберегающих вмешательств, как энуклеация, центральная резекция (ЦР) ПЖ и дуоденумсохраняющая тотальная или частичная резекция головки ПЖ (ДСРГПЖ), демонстрирует их эффективность при доброкачественных опухолях ПЖ. Цель. Оценить возможности хирургического лечения доброкачественных опухолей ПЖ локальной резекцией, базируясь на существующих показаниях к оперативному лечению, анализе ранних послеоперационных осложнений и отдаленных результатов. Результаты. Энуклеация опухоли рекомендуется для всех манифестных нейроэндокринных новообразований размером до 3 см при отсутствии контакта с протоком поджелудочной железы. Этот метод применялся в основном при НЭО и реже при кистозных опухолях. Порядка 20% энуклеаций выполнены минимально инвазивным доступом. Тяжелые хирургические послеоперационные осложнения, потребовавшие повторных вмешательств, отмечены в 11% наблюдений, панкреатическая фистула – в 33% наблюдений, госпитальная летальность составила менее 1%. Основными преимуществами энуклеаций являются низкий уровень послеоперационных осложнений и очень низкая госпитальная летальность. Две трети ЦР выполнены пациентам с манифестными кистозными опухолями и 1/3 – при НЭО. Высокая частота панкреатических фистул и тяжелых послеоперационных осложнений связана с обработкой проксимальной культи ПЖ. Госпитальная летальность 0,8% является преимуществом этой операции. ДСРГПЖ в 50% наблюдений применена в виде тотальной резекции головки с сегментарной резекцией перипапиллярной зоны двенадцатиперстной кишки и интрапанкреатической части общего желчного протока. У 2/3 этих больных были манифестные или бессимптомные кистозные опухоли и у 10% – НЭО. Основным преимуществом этих операций по сравнению с панкреатодуоденальной резекцией (ПДР) является сохранение в большей степени экзои эндокринной функций и госпитальная летальность менее 0,5%. Уровень доказательности для энуклеаций и ЦР низкий в связи с ретроспективной оценкой данных и отсутствием результатов контрольных исследований. Преимущества ДСРГПЖ перед ПДР были показаны результатами 9 проспективных контролируемых исследований, 3 исследований “случай–контроль” и двумя ретроспективными контролируемыми исследованиями. Заключение. При использовании энуклеаций, ЦР, тотальных и частичных ДСРГПЖ отмечаются низкий уровень послеоперационных осложнений и очень низкая госпитальная летальность. Основным преимуществом ограниченных резекций является сохранение экзои эндокринной функций ПЖ и перипанкреатических тканей.

segment resection (CP) and duodenum-preserving total or partial pancreatic head resection (DPPHRt/p) shifted options of surgical treatment to application of local techniques.Objectives.Surgical treatment of benign cystic neoplasms and neuroendocrine tumors using local surgical extirpation techniques are evaluated based on present knowledge about indication to surgery, early postoperative complications and late outcome perspectives.Results.Tumor enucleation is recommended for all symptomatic neuroendocrine adenomas of a size up to 3 cm and non-adherence to pancreatic main ducts.EN was applied predominantly for neuroendocrine tumors and less frequently for cystic neoplasms.About 20% of enucleations are performed as minimal invasive procedures.Surgery-related severe postoperative complications with the need of reintervention are observed in 11%, pancreatic fistula in 33%, but hospital mortality was below 1%.Major advantages of EN are low procedure-related early postoperative morbidity and a very low hospital mortality.CP is applied in two thirds for symptomatic cystic neoplasms and in one third for neuroendocrine tumors.The high level of pancreatic fistula and severe postoperative complications are associated with management of the proximal pancreatic stump.Hospital mortality of 0.8% is a benefit of this procedure.DPPHRt/p has been applied in about 50% as total pancreatic head resection with segment resection of the peripapillary duodenum and the intrapancreatic common bile duct.Two thirds of patients suffered symptomatic or asymptomatic cystic neoplasms and 10% neuroendocrine tumors.Major advantages of local pancreatic head resection compared to Whipple type pancreatico duodenectomy are highly significant preservation of the exo-and endocrine functions and a low hospital mortality below 0.5%.The level of evidence for EN and CP is low, because of retrospective data evaluation and absence of results from controlled studies.For DPPHRt/p results of 9 prospective controlled studies, 3 case controlled studies and 2 retrospective controlled studies underline the advantages of DPPHRt/p compared to partial pancreaticoduoden ectomy.Conclusion.The application of tumor enucleation, pancreatic middle segment resection and duodenum-preserving total or partial pancreatic head resection are associated with low level of surgery-related early postoperative complications and a very low hospital mortality.The major advantages of the limited procedures are preservation of exo-and endocrine pancreatic functions and maintenance of peripancreatic GI-tract tissue.

Introduction
Cystic neoplastic lesions of the pancreas, first histologically identified 1978 by Compagno and Oertel [1], who separated mucinous cystic neoplasms from serous cystic adenomas and 1989 by a clinicopathologic definition of intraductal papillary mucinous neoplasms of the pancreas [2], are detected frequently.Applying multislice CT, the prevalence of cystic neoplasms of the pancreas was 2.6%, MRI 13.5% and MRCP 44.7% [3].Intraductal mucinous neoplasia (IPMN) and mucinous cystic neoplasia (MCN) are the most challenging pancreatic benign tumors, because they inherit a high risk for malignant transformation [4].Serous cyst adenoma (SCA) and solid pseudopapillary neoplasia (SPN) have a much lower risk of malignancy (Table 1).
Pancreatic neuroendocrine tumors (PanNETs) are relatively rare tumors, accounting for 2% of all pancreatic neoplasms and affecting 1 to 2 individuals per 100,000 population per year.With improving imaging technologies, more cases are found as incidentalomas.Endocrine tumors involving the pancreas may be either functioning or nonfunctioning.Non-functioning endocrine tumors are reported in 15% to 53% of clinical series [5].Adenomas are classified as functioning , when patients suffer clinical symptoms due to hormonal hyperfunction.The most frequent endocrine tumors are insulinomas; 5 to 10% of them are islet cell cancers.Gastrinomas are 30 % of all malignant hormone active neuroendocrine tumors.Most of the vipomas, somatostatinomas and glucagonomas are in 40 to 80% malignant lesions.0.2 to 1% of 100,000 individuals p.a. suffer multiple endocrine tumors, most frequently identified as multiple endocrine neoplasia (MEN 1) syndrome, Hibbel-Lindau syndrome (VHL) or neurofibromatosis type 1 (NF1).The grading of PanNETs is based on calculations of counting mitoses and by Ki67 labelling index [6].

Intraductal papillary mucinous neoplasia
IPMN are predominantly located in the pancreatic head and more frequently found in male patients, whereas MCN are located in the left pancreas and frequently found in female patients.IPMN are classified into subtypes based on the histomorphology [7].The subtypes show additionally different mucin expression patterns MUC 1, MUC 2 and MUC 5 AC [8].
In terms of the origin of the lesion, IPMN representa heterogeneous group of neoplasms.The classification into main duct (MD-IPMN) and branch duct IPMN (BD-IPMN) remains challenging since an additional subgroup referred as mixed type includes either combination of main duct and branch duct neoplasia.Histologically, a subclassification in tubular, gastrointestinal and biliopancreatic type has been established.The histologic subtypes have different rates of developing malignant transformation towards invasive cancer.MD-IPMN originate in tissue of the main pancreatic duct.Patients are predominantly male;up to 70% involve the head of the pancreas.Up to 50% of the patients are asymptomatic; however, malignancy has developed by the time of diagnosis in up to 72% [9].The reported rates of malignancy of MD-and BD-IPMN range from 35.7-72% and 6.3-51% respectively (Table 2).According to international guidelines published 2012, resection should be the treatment of choice for all surgical fit patients suffering MD-IPMN to avoid development of an invasive carcinoma from the primary benign lesion.However, the need for surgical resection in patients with BD-IPMN is controversial because of the lower rate of malignancy [18,19].
Surgical treatment of MD-IPMN effects a 5-year overall survival of above 90 % in cases with low and intermediate grade dysplasia and between 45 and 55% for advanced cancer.In terms of the histological subtype, patients with colloid carcinoma have a better prognosis than the non-intestinal cancers [24].Tubular carcinoma arising from IPMN with predominant involvement of the main pancreatic duct have the worst overall and disease specific survival [23,24].Minimally invasive carcinoma, defined as invasion less than 5 mm, represent a special feature of the IPMN.Minimal invasive IPMN carcinoma have a 5-year survival rate twice that of carcinoma with microscopic massive invasion in surrounding tissues [17] (Table 3).Branch Duct IPMN.For branch duct IPMN controversial positions are publisheddue to the lower rate of malignancy.The international consensus guidelines, recently published [15,29] defined highrisk criteria for branch duct IPMN: presence of solid components in CT and main pancreatic duct dilation > 10 mm.Furthermore, a status of worrisome features has been established as cyst > 3 cm, thickening/ enhancing cyst wall, MPD 5-9 mm, mural nodules and abrupt changes in the MPD caliber.Investigation of a large cohort group with branch duct IPMN revealed a CA 19-9 cutoff level of > 13 U/ml as a signof risk for malignant transformation.The combination of history of acute pancreatitis, serum CA 19-9 level > 13 U/ml and the presence of mural nodules are useful criteria for predicting minimal invasive carcinoma, respectively high-grade dysplasia IPMN [30].Surgical resection should be considered, when a patient with branch duct IPMN presents with two of these three factors.

Mucinous Cystic Neoplasia
MCNs are defined as tumors with mucin producing columnar epithelium occurring preferentially in the body and tail of the pancreas in pre-menopausal women.MCNs are histologically defined as well-demarcated cysts lined up by a mucin producing columnar epithelium surrounded by ovarian type stroma.Regardless of the epithelial differentiation, mucinous cystic neoplasia are classified as precancerous lesion.MCNs do not generally communicate with the pancreatic ducts, although duct connections of the lesion are observed.According to the current World Health Organization classification [31] low-grade MCNs are generally regarded to be at risk for progression to higher grade adenoma and to invasive carcinoma.Invasive carcinoma deriving from mucinous cyst adenoma are usually from a tubular type, however, colloid carcinoma are reported to derive sometimes from MCNs.According to international guidelines, MCNs should be operated if the patient is fit for surgery.In operative specimens low-grade dysplasia has been found in 31-72% and high-grade dysplasia in 3.9-14.4%,frequently in association with an invasive carcinoma.The prognosis of patients after complete resection of a non-invasive MCN is excellent.However, the 5-year survival rate for invasive carcinoma after R0 resection is still only 33-56% [32][33][34][35].

Serous Cyst Adenomas
Serous cyst adenomas constitute 10-15% of all cystic masses of the pancreas and 1-2% of pancreatic neoplasms.The cysts are well loculated, filled with mucine-free serous fluid and are surrounded by cuboidal or flattened epithelium.SCNs are usually multi-lobular cystic tumors consisting of small cysts, some millimeters in diameter (microcystic type) and show a thin capsule, well demarcated from pancreatic tissue.Some of the cysts are large, (macro cystic type).The cysts are located in about 1/3 in the pancreatic head and 2/3 in body and tail.The neoplasm shows a predilection of the middle-aged women.Symptoms are frequently nonspecific, abdominal pain is the most common clinical compliance.However, many of the lesions are asymptomatic, detected by chance.The risk of malignancy is with 3-5% very low [10,12,13].Large serous cyst adenomas are more likely to be symptomatic.Long-term observation of serous cyst adenomas have revealed a median growth rate of only 0.6 cm per year [15].

Solid Pseudopapillary Neoplasia
Solid pseudopapillary adenomas (SPN) of the pancreas are rare tumors, representing 1-3% of all pancreatic tumors and 10 -15 % of cystic tumors of the pancreas.Franz published the first description of SPN in 1959 [36].The neoplasm is characterized by uniform cells with ovoid nuclei and eosinophilic granules arranged in sheets with pseudopapillary architecture.SPNs predominantly affect female patients during their reproductive phase.About 30-40% of SPN develop in the head and 60-70% in the left pancreas.The tumor appears demarcated from the pancreatic tissue, surrounded by a fibrous pseudocapsule.It exhibits a relatively indolent biological behavior with a favorable long-term prognosis.At the time of surgical treatment, about 20% are in the stage of an advanced pancreatic cancer, frequently with metastases in lymph nodes and liver.The overall mortality of solid pseudopapillary tumors is about 2%; the recurrence rate after surgery 10-15%.Patients, who are surgically treated in status of a benign lesion, are cured; > 90 % survive after 5 years [37,38].

Pancreatic Neuroendocrine Tumors (PanNETs)
PanNETs are 10% of all benign tumorous lesions of the pancreas.They develop hormonal active or inactive -from cellular compartments of islet cell Table 3. IPMN -Adenom-Carcinom Sequence [16,17,26,27] Adenom → Dysplasia → Carcinoma in situ 5-7 years → → Minimal invasive → Advanced cancer Risk (actual) since beginning of symptoms: MD-IPMN: 2 years -58% 5 years -63% BD-IPMN: 2 years -9% 5 years -15% parenchyma which constitutes 2-10% of the pancreatic tissue.In contrast to hormonal active PanNETs, functional inactive tumors produce late in the course clinical signs, which are mostly unspecific.Apart from well-established radiological investigations and EUS, measurement of specific hormones in the peripheral blood, somatostatine receptors sintigraphy and PET are diagnostic measures, which establish in most patients a diagnosis of type and location of the tumor respectively.Multifocality of PanNETs is well known, particularly in cases of hereditary syndromes like MEN1.The use of highly sensitive imaging techniques for diagnosis enables an identification of endocrine tumors below 1 cm in an asymptomatic stage.Up to 70% of all PanNETs are insulinoma, which most frequently show functional activity.90% of insulinoma are benign, independently of the degree of clinical symptoms.Usually 30-50% of all PanNET sarefunctional inactive.All gastropancreatic neuroendocrine tumors are considered potentially malignant [5,6,39].The risk of malignancy of tumors less than 2 cm in size, which show low degree of proliferation and have a tumor marker Ki67/MIB 1 positivity index of < 3 %, have a benign clinical course.PanNETs, which are histologically well differentiated, but associated with a Ki67/MIB 1 positivity index between 2 and 20 % are considered to have a distinctly higher risk for malignancy [7,39].The vast majority of gastrinoma, glucagonoma, vipoma and ACTH PanNETS are malignant.6-7% of all PanNETs are low differentiated neuroendocrine cancers [6,[40][41][42].

Indication to surgical extirpation of cystic neoplasms
Patients suffering symptomatic or asymptomatic main duct IPMN should have operative treatment in any case, when they are surgically fit according to consensus guidelines of international experts, published in 2006 and 2012 [15,29].For branch duct IPMN with tumor size above 4-5 cm or showing growth of the neoplasm and developing signs of malignancy, a change from surveillance to surgery is recommended.The development or presence of mural nodules, a pancreatic main duct dilation above 5 to 9 mm and wall thickening are signs of a malignant transformation and indicators to surgical extirpation.Tumor size is discussed as being a misleading criteria for surveillance, as it was recently documented in a large series of BD-IPMN, which showed in 17 % cancerous lesions in tumors below 2 cm [44] (Table 4).Multifocality, respectively the incidence of synchronous and metachronous multifocal IPMN are observed in up to 28% of IPMN [30,45].Surveillance of asymptomatic BD-IPMN is recommended for tumors up to a size of 3 cm [43].In terms of decision-making to operate for MCNs the borderline tumor size is considered to be 5 cm.Observation of asymptomatic SCA is recom-mended for tumor size of up to 4 cm by yearly investigations.For SCN, surgical treatment has been established for all patients, after diagnosis because of the risk of overlooking an invasive cancer, which isdocumented in up to 25% of all resected patients.

Indication to surgical treatments of PanNETs
Candidates for surgical treatment are patients with sporadic endocrine tumors, which are clinically active lesions.A surveillance program is recommended for patients with asymptomatic PanNETs below size of 1 cm [39].Pathomorphologically, PanNETs demon strate occasionally cystic changes, calcifications and intralesional bleeding.The most important criteria for decision-making are clinical symptoms, tumor size above 2 cm and an increased level of cell proliferation [5,40].Tumorous lesions below 2 cm in diameter, which have a low proliferation index, are mostly of benign nature; but endocrine neoplasms exhibiting a cell grading G2 and a proliferation index Ki67/MIB1 > 3-20% are considered to be a malignant process, as it is for PanNETs of tumor size > 2 cm, G1 cell grading and no signs of angioinvasion.PanNETs < 2 cm, which have histological grading G2 and Ki67/MIB1 index > 20%, have a high probability to develop a neuroendocrine cancer [39].Irrespective of tumor size, sporadic gastrinoma, glucagonoma and vipoma of the pancreas are considered a malignant lesion in about 50-80%.Surgery is recommended in any tumor size of these rare endocrine neoplasms [46,47].

Options for surgical treatment
Standard surgical treatment for benign cystic neoplasm and endocrine tumors of the pancreas are worldwide oncologic multiorgan resections for tumors (Table 5).For lesions in the pancreatic head, a Kausch-Whipple type resection and for tumors in body and tail of the pancreas, a spleen preserving pancreatic left resection is established in most surgical institutions worldwide.However, major surgical procedures are burdened with additional sacrifice of normal functional pancreatic and extrapancreatic tissues and a considerable high level of severe postoperative complications with a substantial risk of mortality.Even in high volume centers, hospital mortality has been reported between 4 and 7% in large series after a Kausch-Whipple resection.In the  [15] • PMD: Duct dilatation > 1 cm (>6 mm) [15] • TM size > 2 cm (>3 cm) [15] • Mural nodule size > 0.5 cm [15] • CEA > 110 mg/ml in fluid of cyst.late outcome after a Whipple-type resection, procedure-related late morbidity show an increase in exocrine insufficiency, a dysfunction of the glucose metabolism, respective new onset of insulin dependent diabetes mellitus in about 20% [48,49].Episodes of cholangitis in the long-term course after duodenopancreatectomy are more frequent than thought.Pancreatic left resection for benign tumors of the body and tail of the pancreas is performed in about 50% with additional splenectomy and a higher percentage of patients suffer permanent dysfunctions of glucose metabolism.
The recent evolution of limited surgical procedures established local resective techniques.However, local tumor extirpation is not yet used as standard surgical treatment for benign pancreatic neoplasms.Tumor enucleation, pancreatic middle segment resection and local extirpation of tumors in the pancreatic head applying duodenum-preserving total or partial pancreatic head resection, have the potential of a local tumor extirpation, associated with alow procedure-related postoperative morbidity and preservation of the exo-and endocrine pancreatic functions, compared to preoperative status, respectively to results after Kausch-Whipple resection for head tumor and compared to pancreatic left resection (Table 6).

Limitations of local surgical procedures for extirpation of benign tumors
Tumor enucleation is applied more frequently for endocrine tumors.21% of 838 patients, who had enucleation between 1993 and 2013, suffered cystic neoplasms and 73% pancreatic neuroendocrine tumors; 60% of adenomas were located in the head and neck and 40% in the body and tail of the pancreas.The overall postoperative morbidity was 41%; however, about 10% suffered severe complications.Minimal invasive enucleation technique has been applied in 22% of patients.The in-hospital mortality was 0.95%.The institutions of most of the reported series applied intraoperative ultrasonography detection of the tumor and during enucleation, controlling the proximity to the pancreatic main duct.37% of the patients developed postoperative pancreatic fistula.Apart from the minimal tissue trauma of the pancreas, an additional benefit of enucleation is the use of laparoscopic techniques.The major risk of tumor enucleation of benign tumors is the frequent development of pancreatic fistula.Severe type of pancreatic fistula type B and C has been observed in 16%.The limitation of the use of enucleation is the size of the lesion and tumor proximity to the pancreatic main duct.In case of tumor wall adherence to the pancreatic main duct, injuring of the duct by the enucleation technique increases the risk for pancreatic fistula [50,51].To avoid pancreatic fistula caused by enucleation technique, tumor size above 3 cm in diameter is a limiting criteria [52,53] (Table 7).
Pancreatic middle segment resection is applied in 63% for cystic neoplasms and in 31% for pancreatic neuroendocrine tumors.Pancreatic middle segment resection effects two resection surfaces of the pancreatic body.Resecting a cystic neoplasm of size 5-6 cm requires in most cases additional tumor dissection close to walls of the splenic vessels.IPMN and MCN tumors are surrounded by a wall of inflammatory tissue, which frequently extends to the wall of the splenic vein or artery.Tumor encasement of vessels is associated with a higher risk of blood loss during surgery and in the early or late postoperative course.The frequency of severe postoperative complications of 18% and a total fistula rate of 35%, of them 23% fistula grade B and C, are sequelae of the management of the pancreatic stumps (Table 7).The crucial point of CP is the surgical handling of the proximal pancreatic stump.Whereas the pancreatic tail is anastomosed by pancreaticojejunostomosis or more elegantly by pancreaticogastrostomosis, the proximal pancreatic stump is mostly handled by simple closure using mechanical devices or by U-suturing of the tissue with isolated closure of the pancreatic main duct [55][56].However, simple closure causes rather than prevents local complications like fistula or peripancreatic fluid collections and abscesses as well.However, the hospital mortality was with 0.8% very low.After extended middle segment resection of a large pancreatic segment, endocrine insufficiency in the long-term outcome was observed in up to 12% [57,58] (Table 8).

Duodenum-preserving total and partial pancreatic head resection
For benign tumors of the pancreatic head, a total or partial pancreatic head resection has been introduced in clinical practice between 1986 and 1994 [59][60][61][62].The location of the tumor within the pancreatic head and the size of the lesion determine the application of a partial or total head resection.Up to present times, the overall surgical experience using duodenum-preserving total pancreatic head resectionis limited.A total pancreatic head resection are performed in 75% of the patients either with additional resection of the peripapillary segment of the duodenum and resection of the intrapancreatic segment of the common bile duct or preservation of duodenum and common bile duct.In 70%, a DPPHRt/p applied for cystic neoplasms and in 10% for neuroendocrine tumors.In the postoperative course, severe morbidity occurred in 12%.The frequency of reoperation was 2.4%, of pancreatic fistula 20%, of them grade B and C 9%, and of hospital mortality 0.46%.Surgical techniques of total pancreatic head resection with dissection of the pancreatic head from peripapillary duodenum and preservation of the posterior pancreaticoduodenal arcades, deriving from the gastroduodenal artery, respectively inferior pancreaticoduodenal artery, are well established.A major advantage of DPPHRt/p is preservation of exo-and endocrine functions compared to the preoperative level [63][64][65][66][67][68][69].In prospective controlled trials, comparing duodenum- preserving total head resection with the Kausch-Whipple pancreaticoduodenectomy, the metabolic functions after DPPHRt were significantly better preserved.An additional advantage of this technique is tailoring the partial head resection maintaining neck of the pancreas or uncinate process or parts of the dorsal pancreatic head segment and preservation of the stomach.

Summary
Benign cystic neoplasms and neuroendocrine tumors of the pancreas are frequently found.The risk of malignant transformation is a substantial indicator for surgical treatment of IPMN.Patients suffering MCN, SPN and neuroendocrine tumors of the pancreas > 2 cm are candidates for surgery.Tumor enucleation, pancreatic middle segment resection and duodenum-preserving total or partial resection of the pancreatic head are local extirpation techniques of tumors, which provide major advantages in terms of maintenance of the exo-und endocrine pancreatic functions, preservation of GI-tract tissue and low level of surgery related postoperative complications and a very low hospital mortality.

Fig. 2 .
Multifocal IPMN lesion in the body and tail of the pancreas.

Table 1 .
Cystic Neoplasia and Neuroendocrine Tumors of the Pancreas

Table 2 .
Cystic Neoplasm of the Pancreas.Risk of Malignant Transformation

Table 4 .
IPMT -Clinical Signs for Malignant Tumor of

Table 5 .
Options for Surgical Treatment of Benign Cystic and Neuro-Endocrine Neoplasm of the Pancreas