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Chapter 17
pancreatic remnant. Given the dismal survival for those with invasive disease and lack of subsequent curative therapies, it is questionable whether this type of follow-up should be limited to those with dysplasia or PANIN at the margin, or for patients with invasive disease >
3 years from resection when the conditional survival is more favourable. In contrast, for those without high-grade dysplasia or malignancy at the margin, the AGA guidelines do not recommend ongoing surveillance (excluding mixed-type IPMN or family history of pancreatic cancer), again based on weak supporting evidence.
There is a lack of reliable evidence regarding recommended follow-up regimens. Both the IAP and AGA guidelines acknowledge this, but feel it is reasonable to perform cross-sectional imaging at a variable frequency (1–2yearly). tumour markers is currently not supported.
2,23
The routine use of
23
Given that recurrence would seem to occur most
commonly within the pancreatic remnant, Tomimaru et al. have proposed performing a pancreatico­gastrostomy to allow easy endoscopic follow-up of the duct.
38
Additionally, the association of IPMNs with other gastrointestinal malignancies should alert physicians to investigate new gastrointestinal symptoms promptly.
Pancreatic neuroendocrine tumours
Pancreatic neuroendocrine tumours (PNETs) are rare tumours with a reported incidence of 0.2–0.4 per 100 000, although post-mortem studies have reported PNETs in up to 10% of the population.39 Eighty-five per cent of PNETs are non-syndromic (non-functional), with the rest comprised of syndromic tumours which carcinoid, insulinoma and gastrinoma are the most common.
41
The aetiology is poorly understood and although the majority of tumours are sporadic, there are associations with several hereditary syndromes, including Von Hippel–Lindau, multiple endocrine neoplasia-1 (MEN-1), neurofibromatosis type 1 and tubular sclerosis.
42
Clinical presentation
The mode of presentation is dependent on the functional state of the tumour. Non-functioning tumours may present incidentally, whereas symptoms are usually related to mass effect or the presence of metastatic disease. For those tumours associated with a syndrome, this will be related to the specific hormone produced (Table17.2).
40
of
Investigations
The order of investigations will be dependent on presentation. The general principle for functional tumours is to confirm the diagnosis (biochemically) prior to localisation (radiologically).
Biochemical
Specific fasting gut hormones can be measured for functional tumours but testing is complex and subject to change, therefore it is recommended that when faced with the need to investigate such a patient current guidelines are reviewed and the recommended tests are performed in centres with significant experience. including those with non-functional tumours, serum chromogranin A (protein produced from cells arising from the neural crest) will be elevated. chromogranin A is sensitive, it is not highly specific and those interpreting the test must be aware of causes of false-positive results. chromogranin A has been shown to correlate with burden of disease (although not with gastrinomas), response to treatment and recurrence.
Other investigations, such as calcium, parathyroid hormone, calcitonin and thyroid function tests, should also be considered, particularly if there is a history that suggests MEN-1. a hereditary component is suspected, referral to an appropriate genetic service for further investigation should be initiated.
Radiology
For non-functioning tumours, where localisation is often not an issue, a high-quality arterial and portal venous phase CT will be sufficient to direct therapy, particularly in determining if surgery is indicated. Features suggestive of a PNET on CT include the presence of a hypervascular or hyperdense lesion within the pancreas; however, they can also appear cystic or contain calcifications. large incidental mass within the pancreas, particularly without vascular encasement or desmoplastic reaction, should also alert the clinician to the possibility of a PNET.
Although somatostatinomas, VIPomas and glucagonomas tend to be large and easily identified and staged by contrast-enhanced CT, this is often not the case for insulinomas and gastrinomas, unless there is widespread metastatic disease. Most insulinomas are < hypervascular (Fig.17.4) with either uniform or target enhancement; however, given that they are often non­contour-conforming, detection of the vascular blush is essential to localise them (the chance of detection can be maximised by timing the images 25 seconds after contrast injection).
43
In the majority of patients with PNETs,
41
Although
43
The degree of elevation of
43
41
For those in whom
44
The presence of a
44
2 cm and solitary. On CT they tend to be
44
MRI features include low
292
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Cystic and neuroendocrine tumours of the pancreas
Table17.2 • Presentation, diagnosis and initial medical management of functional pancreatic neuroendocrine tumours
Medical options for initial symptom
Tumour type Syndrome Symptoms Diagnosis
control
Insulinoma Whipple's triad Neuroglycaemic or
neurogenic symptoms relieved with eating
Gastrinoma Zollinger–Ellison Complicated peptic
ulceration or gastro­oesophageal reflux, diarrhoea, abdominal pain
Glucagonoma Glucagonoma syndrome Necrolytic migratory
erythema, weight loss, diabetes mellitus, stomatitis, diarrhoea, thromboembolism
VIPoma Verner–Morrison
syndrome
Profuse watery diarrhoea, hypokalaemia
Somatostatinoma Gallstones, steatorrhoea,
hypochlorhydria, glucose intolerance
Carcinoid Carcinoid syndrome Abdominal pain, if
metastases then flushing, palpitations, rhinorrhoea, diarrhoea, bronchospasm, pellagra
Insulin:glucose ratio >0.3 in presence of hypoglycaemia C-peptide suppression
Overnight feeding Diazoxide titrated to symptom resolution Somatostatin analogue
test Serum fasting gastrin
>
1000 pg/mL (if gastric
pH <2.5)
High-dose proton pump inhibition (may require up to 60 mg b.d.)
Secretin stimulation test
Plasma glucagon
>
1000 pg/mL
Somatostatin analogue, hyperalimentation, thrombosis prophylaxis
Plasma VIP >
1000 pg/
Somatostatin analogue
mL Raised plasma
somatostatin
24-hour urinary 5-HIAA Somatostatin analogue
signal intensity on T1-weighted images and they are particularly well seen on fat-suppressed (T1- and T2-weighted) images.
44
In contrast to insulinoma, gastrinoma can be multiple and extrapancreatic (located within the gastrinoma triangle; the junction between neck and body of the pancreas medially, the junction of the second and third parts of the duodenum inferiorly and the junction of the common bile duct and cystic duct superiorly). they tend to be less vascular than insulinoma. is a high rate (70–80%) of lymph node and hepatic metastases. of gastrinoma is related to size and can be as low as 30–50%.
44
The sensitivity of CT in the detection
45
Although slightly better figures have been
45
On radiological examination,
44
There
reported for insulinomas, this can be increased to 94% with the use of thin formats and, with the addition of endoscopic ultrasound, sensitivities of 100% have been reported.
45
Endoscopic ultrasound is particularly useful for imaging the duodenal wall, regional lymph nodes and the pancreatic head, and has reported sensitivities of 79–100%, but is operator-dependent.
45
Equally, the use of intraoperative ultrasound has also been shown to be useful, particularly in gastrinomas, by identifying
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occult multiple primaries or metastatic disease. The sensitivity for detecting small lesions in the pancreatic head is reported to be as high as 97%.
45
PNET hepatic metastases often appear as low­attenuation lesions on pre-contrast CT and hyper­vascular lesions on post-contrast imaging.45 It is, however, important to perform a hepatic arterial phase as they can be isointense with normal parenchyma on portal venous imaging. MRI appearances of hepatic metastases are usually of low signal intensity lesions on T1- and high signal intensity on T2-weighted images. Importantly, 15% of hepatic metastases were only seen on immediate post-gadolinium imaging.
In addition to standard radiological imaging, somatostatin receptor scintigraphy (SRS) is also very useful in the staging and treatment of PNETs (with the exception of insulinomas).
43
SRS works on the principle that PNETs express somatostatin receptors. The use of a somatostatin analogue labelled with a radioactive isotope (of which there are several) allows a functional image to be obtained but it requires somatostatin analogues to be stopped prior to the scan. As a single investigation, it is
293
Chapter 17
Figure17.4 • A 78-year-old man presented with neuroglycaemic symptoms. Biochemical testing confirmed an insulinoma.
Arterial phase computed tomography revealed a hypervascular lesion in the tail of the pancreas (black arrow). Laparoscopic spleen-preserving distal pancreatectomy was performed. Histology confirmed malignant, node-positive neuroendocrine tumour consistent with an insulinoma. After 4years with no symptoms the patient re-presented with symptoms of hypoglycaemia. Further investigation revealed an isolated nodal recurrence adjacent to the superior mesenteric artery. The patient underwent a completion radical antegrade modular distal pancreatico-splenectomy with resolution of hypoglycaemic symptoms.
probably the most sensitive for the detection of
Treatment
PNETs; however, equivalence can be achieved with a combined approach of standard radiology (particularly MRI and EUS), which has the advantage of providing a detailed anatomical analysis.
46
SRS does, however, offer the advantage of reflecting functionality, which is important if treatment doses of radiolabelled somatostatin analogues or meta-iodobenzylguanidine (MIBG) are to be used.
18
F-labelled deoxyglucose PET has not been shown to be useful for the majority of PNETs; however, the development of newer alternatives to
18
F-labelled deoxyglucose would appear to be promising. Invasive investigations such as selective arterial calcium (insulinoma) and secretin (gastrinoma) stimulation with hepatic/portal venous sampling are not used routinely and are undertaken only if there is a high suspicion but non-invasive imaging has failed to localise the tumour.
43
Once the diagnosis of a functioning tumour is established, control of the hormonal excess is the first priority in minimising symptoms and complications. Medications used for each individual tumour are shown in Table 17.2. Somatostatin analogue infusions are recommended pre- and intraoperatively for carcinoid tumours to prevent carcinoid crisis.
41
Surgery offers the only chance of cure for those with localised disease. The approach is dependent on tumour type and the presence or
46
absence of an inherited syndrome.
43
The specific management of hereditary PNETs is beyond the remit of this chapter and readers are referred to more detailed reviews for an in-depth discussion.
Over 80% of localised sporadic insulinomas are
solitary, benign and <
2 cm in size, making them ideal
for consideration of enucleation and laparoscopic
42,47,48
294
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Cystic and neuroendocrine tumours of the pancreas
resection.43 Enucleation is considered possible if the lesion can be clearly localised pre- or intraoperatively and if the relationship to the pancreatic duct has been clearly identified. has been shown to be particularly valuable in helping to assess these factors. histological confirmation of the benign nature must be established. tumours where malignancy is suspected (hard, infiltrating tumour, duct obstruction or lymph node involvement), if there is major vascular involvement or the tumour is large. for resection as for any pancreatic tumour. However, if a distal pancreatectomy is being performed, attempts to preserve the spleen should be made. Blind pancreatic resection should be avoided. Ablative therapies may also be appropriate in selected patients.
For localised sporadic gastrinoma, surgery
has been shown to increase survival.
Duodenotomy and intraoperative ultrasound com bined with palpation (sensitivity 91–95%) are the key to successful intraoperative localisation.49 For duodenal gastrinomas, small tumours (< can be enucleated from the submucosa while larger tumours require full-thickness excision. pancreatic gastrinomas, intraoperative assessment regarding the suitability for enucleation (similar to that described above for insulinomas) should be performed. However, if the tumour is not suitable, a formal pancreatic resection (pancreatico­duodenectomy) should be performed. It is now recommend that formal oncological lymph node dissection be performed due to high rates of involvement and possible survival benefit.
Most localised non-functioning tumours are detected at such a size that enucleation is not feasible, but given the increasing use of cross­sectional imaging and the earlier detection of smaller lesions, enucleation is likely to become a more frequent possibility. For asymptomatic suspected benign, non-functioning PNETs, it has been recommended that tumours < safely observed.43 The risk of malignancy is related
harbour malignant potential (Fig.17.5).50 Currently, patients should be assessed regarding fitness for surgery and an informed decision made with the patient regarding resection or observation. Central pancreatectomy has also been shown to be feasible for selected tumours and has the advantage of reducing the risk of postoperative diabetes. formal resection with lymphadenectomy should be performed for suspected malignant tumours as lymph node metastases are common (27–83%).
43
Intraoperative ultrasound
47
Postoperatively,
41
Resection is required for
47
Patients should be assessed
43
48
47
47
5 mm)
49
For
43
2 cm can be
51
A
50
Figure17.5 • A 30-year-old female with Von Hippel–
Lindau disease underwent pancreatic screening. Radiological imaging revealed five neuroendocrine tumours within the pancreatic head. Pancreatico­duodenectomy was performed. Pathological sectioning of the pancreatic head revealed multiple neuroendocrine tumours (PNET), including at least one well-differentiated pancreatic endocrine carcinoma (node-positive) and a well-differentiated duodenal endocrine carcinoma (DC). All tumours were between 12 and 18 mm diameter. An incidental serous cyst adenoma (SCA) was also identified.
Resection is the treatment of choice for symptomatic
patients with localised disease.
50
The median survival following resection was reported as significantly longer than for patients with metastatic or locally advanced unresectable disease (7.2 years vs 2.1 vs
5.2 years).50 Importantly, however, 48% of patients who underwent resection for localised disease developed recurrence at a median follow-up of
2.7 years.50 Because of the long natural history of these tumours and given that many are symptomatic and difficult to palliate without resection (e.g. tumour bleeding), the criteria for what determines unresectable disease may not be the same as those for adenocarcinoma of the pancreas. The MD Anderson experience would suggest that, in high-volume centres, major venous reconstruction can be performed safely, but only rarely should arterial reconstruction (isolated hepatic artery involvement) or upper abdominal exenteration be performed, due to the associated high long-term morbidity.
50
In addition, a recent report has also indicated that an incomplete resection (R2) is associated with a high perioperative mortality and may in fact be detrimental to the patient's survival.
Metastatic disease
Only 10% of patients with hepatic metastases will be suitable for potentially curative resection. However, it would appear that although recurrence rates are high, a survival advantage can be achieved, although randomised data are lacking. Synchronous cholecystectomy should be performed
52
41
53
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295
Chapter 17
to reduce complications from adjuvant therapy such as somatostatin analogues and hepatic artery embolisation.
53
For patients with non-functioning unresectable metastatic disease, there is no evidence to support palliative or ‘debulking’ resections, with possibly the only exceptions being those who have significant local symptoms from the primary and low-volume hepatic metastases.
50
For those with obstruction of the gastrointestinal or biliary tract, surgical bypass should be the first-line treatment in those with well-differentiated disease, given the indolent nature of the disease.
A cytoreductive approach (surgery or ablative therapies) has been advocated in patients with hormonal excess and hepatic metastases if 90% of tumour bulk can be removed, although randomised trials are lacking. documented in the UK and European guidelines on the management of metastatic PNETs included somatostatin analogues (short- and long-acting), interferon-α, hepatic artery embolisation, radiolabelled analogues (MIBG and somatostatin), liver transplantation and radiofrequency ablation.
41,43
Other options assessed
53
41,54
Systemic chemotherapy for PNETs has been based
around streptozocin and 5-fluorouracil after a randomised trial in 1979 showed a survival advantage for patients with metastatic carcinoid tumours receiving combination chemotherapy.
55
However, given the side-effects and variable behaviour of PNETs, it has not been widely accepted into clinical practice. More recently there is increased interest in the use of temozolomide-based chemotherapy.
Two recent placebo-controlled randomised trials using the novel agents sunitinib56 and everolimus57 have shown an increase in overall and progression-free survival, respectively. In addition, a placebo-controlled trial of lanreotide in patients with enteropancreatic NETs has shown evidence of antiproliferative activity.58 Thus, the results of these three trials would suggest these treatments should represent the standard of care.
The therapeutic options for patients with metastatic disease continue to evolve. It is clear that decision­making is complex and dependent on tumour and patient factors. It is strongly recommended that management decisions for these patients are made in a multidisciplinary forum.
54
Pathology and outcome
PNETs are classified into four groups based on a combination of clinical, histological and molecular features. classified as well-differentiated endocrine tumours
41
Tumours confined to the pancreas are
that can be subdivided into those of benign behaviour
2 cm size, <2 mitoses per 10 high-power fields
(< (HPFs), Ki67 index <2% and no vascular invasion) or uncertain behaviour (if the above criteria are not met). Tumours not confined to the pancreas (gross local invasion or metastases) or that exhibit evidence of small-cell carcinoma are considered endocrine carcinoma, which are further subdivided into well-differentiated (well to moderately differentiated (mitotic rate 2–10 per 10 HPFs, Ki67 index >5%) or poorly differentiated (small-cell carcinoma, necrosis, >10 mitoses per 10 HPFs, Ki67 index >15%, prominent vascular and perineural invasion). Importantly, the diagnosis of functional tumours is not made histologically but clinically, as immunohistochemical staining of specific hormones does not correlate with the clinical picture.
41
In 2010, the seventh edition of the American Joint Committee on Cancer (AJCC) published its first TNM staging classification for PNETs. et al. retrospectively applied the staging system to a dataset of 425 patients with PNETs.
59
Using this, Strosberg
60
Five-year overall survival for stages I–IV was 92%, 84%, 81% and 57%, respectively, thus indicating the proposed system is a useful adjunct for classifying PNETs.
Other tumours
The other two main types of cystic neoplasms are serous (SCA) and mucinous (MCN) cystic neoplasms. Because of the difference in malignant potential, the management of these two tumours differs, yet clinically and radiologically there is considerable overlap. It is therefore useful to contrast and compare them. The exact incidence of serous and mucinous cystic tumours is unknown; however, in a retrospective review of 24 039 patients undergoing radiological imaging, 0.7% had pancreatic cystic neoplasms. Of the 49 (0.2%) who underwent surgery, 10 and 16 patients had a final diagnosis of SCA and MCN, respectively. retrospective study reported on 2622 patients with
62
The median age at diagnosis was 58years,
SCA. with 74% occurring in women. Sixty-one percent of patients were asymptomatic. SCA were evenly distributed throughout the pancreas. In contrast, MCNs are almost exclusively found in women, with a peak incidence in the fifth decade, and are more likely to be located within the tail. also commonly associated with Von Hippel–Lindau syndrome
42
(Fig.17.5), and young patients presenting with multiple cystic lesions involving the pancreas and kidneys should be genetically assessed.
On cross-sectional imaging, the four typical appearances of SCA were microcystic (45%; multiple <2-cm cysts), macrocystic (32%; multiple >2-cm cysts), mixed type (18%; variable-sized cysts) and solid
61
A recent large multinational
63
SCAs are
64
296
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Cystic and neuroendocrine tumours of the pancreas
(5%; no cysts visible on cross sectional imaging).62 Central calcification (so-called sunburst calcification) occurred in 15%. When the classic features are present, differentiation from other tumours is not difficult; however, the presence of a uni- or oligolocular macrocystic (>
2 cm) lesion is more difficult to diagnose and a wide differential exists. Both SCAs (oligocystic type) and MCNs can fall into this group, although MCNs are less likely to be multilocular and, if calcification occurs, it does so peripherally and may be a marker of underlying malignancy.
65
The presence of solid components within a cystic lesion indicates the presence of, or high-risk of, malignancy and therefore surgical resection should be considered.
65
Included within this differential would be PNET, solid pseudopapillary neoplasm (young women) or mucinous cyst adenocarcinoma. for either SCAs or MCNs to communicate with the pancreatic duct, but it has been reported.
65
It is unusual
65
The ability of non-interventional imaging to obtain an accurate diagnosis is limited. In a report of 100 SCAs from Bassi etal., the correct diagnosis was achieved in 53%, 54% and 76% by ultrasound (US), CT and MRI, respectively.
66
An incorrect diagnosis was made in 31%, 34% and 26%, and the investigation was non-diagnostic in 16%, 12% and 0% with US, CT and MRI, respectively.
In a study of solitary cystic (IPMNs were excluded) neoplasms, 71 patients underwent EUS and fluid aspiration (for mucin, viscosity, amylase, lipase, CEA, CA19-9, cytology) followed by surgery to assess its accuracy.
67
The authors concluded that an accurate algorithm using measurement of viscosity, lipase and CEA can be used to determine the diagnosis of cystic lesions. A viscosity of 1.6 indicates an MCN and the patient should be offered resection. If it is <1.6 and the lipase is <
6000 U/mL, this indicates an SCA. If the viscosity is <1.6 and lipase is > 6000 U/ mL, then a CEA measurement should be performed, and if this value is less than 480 U/mL the diagnosis
is a pseudocyst. If it is >480 U/mL, a repeat EUS and fine-needle aspiration should be performed in 3–6 months. Using this algorithm, only 2 of 71 patients that underwent resection for suspected MCN had a final histology revealing a pseudocyst.
The management of SCAs and MCNs differs based on their malignant potential. SCAs rarely undergo malignant transformation and if asymptomatic, no intervention is required.62 Patients with significant symptoms may be offered resection.62 Until recently it was recommended that all suspected MCNs undergo resection because of their malignant potential.2 However, more recent series shown that it is safe to observe lesions less than 3 cm without mural nodules, thus aligning management with BD-IPMN.
68,69
have
Pathologically, SCAs demonstrate monomorphous
cuboidal-shaped epithelium. The cells are glycogen­rich with cellular cytoplasm and small regular nuclei. There is a lack of mitotic activity. The cysts appear ‘empty’ on microscopy. In contrast, the cyst content of MCNs is turbid and tenacious,
64
and microscopically (unlike SCAs) the cyst lining can be highly variable. The cells are mucin-producing, which can be a single cell layer of flattened cuboidal epithelium or contain papillary tufting.
64
The tumours are classified as benign, borderline or malignant depending on the nuclear features of the cells. tumour as malignant invasion can occur without the presence of a mass.
64
It is important to examine the whole
64
The unique feature of MCNs, however, is the presence of ovarian stroma (highly cellular, densely packed, plump spindle cells). Current recommendations require the presence of this for a tumour to be classified as a MCN. particularly important when the differential includes IPMN, in which this type of stroma is not seen.
2
This is
2
Key points
As the use of cross-sectional imaging has become more frequent, there has been an increase in the
diagnosis of cystic neoplasms within the pancreas.
Main-duct IPMNs should be resected due to the high incidence of underlying malignancy; however,
a selective approach to intervention for side-branch IPMNs should be taken (dependent on the presence of symptoms, tumour markers and tumour characteristics).
Investigation and follow-up of cystic lesions of the pancreas requires a multimodal approach, of
which endoscopic ultrasound with biopsy is becoming an increasingly important component.
While asymptomatic SCAs do not require intervention, some MCNs should be resected due to their
underlying malignant potential.
The management of PNETs will be dependent on the presence or absence of an underlying genetic
syndrome, whether the tumour is hormonally active, and stage of disease.
New adjuvant therapies have been shown to increase progression-free survival in patients with
advanced neuroendocrine tumours.
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297
Chapter 17
Recommended videos:
• Laparoscopic radical antegrade pancreatosplenectomy – https://tinyurl.com/yc3jgg9k (IHPBA members only)
• Laparoscopic pancreaticojejunostomy during laparoscopic pancreaticoduodenectomy –https://
tinyurl.com/y9gtsmwn
• University of Toronto video atlas of pancreatic techniques and procedures – https://tinyurl.com/
ya96srgv
Full references available at http://expertconsult.
inkling.com
Key references
2. TanakaM, Fernandez-del CastilloC, AdsayV, etal. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2012;12:183–97. PMID: 22687371.
This international guideline outlines a detailed management strategy for the IPMN and MCN of the pancreas. Importantly it differs in its recommendations from the AGA guidelines.
23. Vege SS, Ziring B, Jain R, et al. and Clinical Guidelines Committee. AGA Institute guideline on the diagnosis and management of asymptomatic neoplastic cysts. Gastroenterology 2015;148:819–
22. PMID: 25805375.
This highly controversial paper presents a sound methodological approach to the available evidence for the management of incidental pancreatic cystic neoplasms. It recommends a conservative approach to investigation and follow-up with stopping points due to the lack of supporting evidence and potential to do harm.
28. Falconi M, CrippaS, ChariS, etal. Quality and assessment of the guidelines on cystic neoplasms of the pancreas. Pancreatology 2015;15:463–9.
PMID: 26100659.
This paper examines the quality of the published guidelines on pancreatic cystic neoplasms. It highlights the deficits of the current literature and tries to achieve expert consensus on clinically important questions.
48. NortonJA, FrakerDL, AlexanderHR, etal. Surgery increases survival in patients with gastrinoma. Ann Surg 2006;244:410–9. PMID: 16926567.
In a study of 160 patients with gastrinomas, 35 patients (with similar staged localised disease) who did not undergo resection were compared to those who underwent resection. After 12 years' follow-up, 29% of those who did not undergo surgery had developed hepatic metastases compared to 5% in the resected group (P <0.001).
56. RaymondE, DahanL, RaoulJL, etal. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011;364:501–13. PMID:
21306237.
One hundred and seventy-one patients with advanced and progressive PNETs were randomised in double­blind fashion to placebo or sunitinib. The trial was stopped early due to increased complications and death in the placebo group. An improved progression­free survival (11.5 vs 5.5 months, P <0.001) and reduced risk of death (105 vs 255, P treatment group.
= 0.02) were seen in the
57. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumours. N Engl J Med 2011;364:514–23. PMID: 21306238.
In a placebo-controlled randomised crossover design trial, 410 patients with advanced and progressive PNETs were enrolled to placebo or everolimus. In those patients who received everolimus there was a 65% reduction in risk of progression (median progression­free survival was 11months vs 4.6 months) as compared to placebo. In addition, tolerance was high.
62. Jais B, Rebours V, Malleo G, et al. SCN of the pancreas: a multinational study of 2622 patients. Gut 2016;65:305–12. PMID: 26045140.
This large multinational study reported on 2622 patients with serous cystadenomas accumulated over three decades. The key points were: asymptomatic patients do not need resection and disease-specific mortality is extremely rare.
298
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18

Hepatobiliary and pancreatic trauma

Adam Brooks Alex P. Navarro
Introduction
Hepatobiliary and pancreatic trauma represents one of the most challenging scenarios faced by specialist surgeons. Equally, the non-specialist will find such situations daunting due to the anatomical complexity of the region. Despite this, with a modern approach excellent outcomes are achievable in nearly all grades of hepato-pancreato-biliary (HPB) organ injury. The key factors required are meticulously accurate assessment of injury through imaging or at initial laparotomy, basic damage control manoeuvres performed with anatomical respect and understanding, and finally, definitive surgery undertaken by specialist HPB surgeons in complex cases.
This chapter will address the presentation, initial assessment and management of patients with liver, biliary and pancreatic injuries. The selection criteria for non-operative management will be discussed together with the indications for operative intervention. The factors guiding surgical options and decision-making will be examined. The spectrum of complications and likely outcomes following trauma will also be reviewed. The American Association for the Surgery of Trauma Organ Injury Scale (OIS) provides a description of the injury categorised from minor injury (grade
1) to severe injury (grade 6). The primary concern of the surgical team managing a trauma patient is the patient’s physiological status and this will determine surgical management; however, the OIS allows guidance based on available evidence for the management of liver, biliary and pancreas injuries.
Liver trauma
The liver is the most frequently injured organ in abdominal trauma. injuries was noted by J. Hogarth Pringle in his seminal monograph published in 1908, where he commented ‘Rupture of the liver is fortunately an accident not often met with, but one which may be associated with a condition of the patient as serious as any one can meet with in surgical practice’. capacity for torrential haemorrhage from the liver means that the patient can quickly enter a vicious cycle of physiological derangements consisting of coagulopathy, hypothermia and metabolic acidosis, rapidly leading to death. severe hepatic injury by Asensio exsanguination accounted for 54% of deaths.
Mechanisms of liver injury
The liver can be injured by two principal injury mechanisms: blunt and penetrating trauma. Motor vehicle crashes account for the majority of blunt injuries, whereas gunshot wounds and stabbings constitute the major cause of penetrating injuries. A 2017 review of 10years of outcomes for hepatic trauma in the UK showed that, of 4368 cases of hepatic trauma, 81% were caused by blunt injuries with 19% due to penetrating trauma. typical for other European centres, the experience in South Africa, where penetrating injuries account for 66% of liver trauma, North America, where up to 86% of liver injuries are penetrating wounds.
1
The serious nature of liver
2
The
3
A review of 7454 cases of
4
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in 1990 found that
5
6
it differs from
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Chapter 18
Blunt liver trauma may be divided accord ing to the mechansism of injury: deceleration (shearing) and crush injury. Deceleration injuries tend to occur in road traffic crashes and falls from a height where there is rapid forceful movement of the liver relative to its fixed diaphragmatic attachments.
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Crush injuries are caused by direct trauma to the liver area. The two types of injury may coexist, but tend to produce somewhat different types of liver injury. Deceleration or shearing injuries create lacerations in the hepatic parenchyma, typically between the right posterior section (segments 6 and 7), the right anterior section (segments 5 and 8), and the right/left liver plane (segments 5/8 vs segment 4A/4B) which can extend to involve major vessels. In contrast, a direct blow to the abdomen may lead to a crush injury, with damage to the central portion of the liver (segments 4, 5 and 8). Compression between the right lower ribs and the spine may also cause bleeding from the caudate lobe (segment 1). Blunt trauma can rupture Glisson's capsule and can also lead to subcapsular or intraparenchymal haematoma formation.
Penetrating injuries are usually associated with gunshot or stab wounds, with the former usually resulting in more tissue damage due to the cavitation effect as the bullet traverses the liver substance.
Injury to the hepatic veins and juxtahepatic vena cava can occur as a result of shearing stress in blunt trauma. Typically such injuries are associated with rapid pre-hospital death. However, it is worth noting that there may not be initial exsanguinating haemorrhage if the weight of the liver provides sufficient compression against the retroperitoneum allowing tamponade.
Classification of liver injury
The severity of liver trauma ranges from a minor capsular tear, with or without parenchymal injury, to extensive disruption involving both lobes of the liver with associated hepatic vein or vena caval injury. The American Association for the Surgery of Trauma has adopted for general use the classification of liver injury described initially in 1989 by Moore and colleagues, and revised subsequently in 1994 injury grade is calculated from assessment of the liver injury using information derived from radiological study, operative findings or autopsy report. Where there are multiple injuries to the liver, the grade is advanced by one stage. As stated previously, it is the physiological status of the patient rather than the anatomical grade of injury that dictates management. Grade I–III injuries are considered minor; they represent 80–90% of all cases and the majority can be managed non­operatively. Grade IV–V injuries are considered severe injuries and non-operative management or surgical intervention can be applied depending on the patient’s physiology and clinical progression. Grade VI lesions are generally regarded as incompatible with survival.
The initial assessment of an injured patient should be performed according to Advanced Trauma Life Support (ATLS) protocols developed by the American College of Surgeons Committee on Trauma. A rapid primary survey should be completed to identify immediately life-threatening injuries that require emergency intervention. Simultaneously, adequate intravenous access should be established to allow resuscitation to begin.
11
(Table 18.1). The hepatic
Table18.1 • Hepatic injury scale used by the American Association for the Surgery of Trauma
Grade* Description
I Haematoma Subcapsular, <10% surface area Laceration Capsular tear, <
1 cm parenchymal depth II Haematoma Subcapsular, 10–50% of surface area Laceration Intraparenchymal <
10 cm in diameter, 1–3 cm parenchymal depth, <10 cm in length
III Haematoma Subcapsular, >50% surface area or expanding; ruptured subcapsular or parenchymal haematoma;
intraparenchymal haematoma >
10 cm or expanding Laceration >3 cm parenchymal depth IV Laceration Parenchymal disruption involving 25–75% of hepatic lobe or 1–3 Couinaud segments within a
single lobe
V Laceration Parenchymal disruption involving >75% of hepatic lobe or >3 Couinaud segments within a
single lobe Vascular Juxtahepatic venous injuries – retrohepatic cava, major hepatic veins VI Vascular Hepatic avulsion
*Advance one grade for multiple injuries up to grade II.
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Hepatobiliary and pancreatic trauma
Current resuscitation strategies advocate haemostatic resuscitation and the transfusion of 1:1:1 blood, fresh frozen plasma and platelets. protocols based on ‘Damage control’ principles are encouraged.
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12
Techniques and
Diagnosis of liver injury
In penetrating abdominal trauma, hepatic injury should be considered in any patient with a wound to the abdomen. Hepatic injury should also be considered in patients with penetrating low thoracic wounds (it is important to be aware that the liver anteriorly is situated at the level of the nipple) and also in posterior penetrating wounds below a coronal plane at the tips of the scapulae.
Patients with major hepatic injury may present with profound clinical shock and abdominal distension. Hypotension resistant to fluid resuscitation combined with gross abdominal distension remains an indication for immediate laparotomy. The operative management options for patients in this situation will be discussed in detail subsequently. Emergency room thoracotomy with cross-clamping of the descending thoracic aorta is a dramatic but sometimes necessary intervention for exsanguinating abdominal haemorrhage.
The Eastern Association for the Surgery of Trauma (EAST) published practice guidelines for Emergency Department thoracotomy in 2015, meta-analysis of 72 studies that included 10 238 patients. This EAST study showed that overall survival rate for patients with penetrating thoracic trauma and signs of life on arrival at hospital was
21.3%, with a neurological intact survival of 11.7%. In patients with penetrating thoracic trauma with no signs of life on arrival at hospital, the survival rate was 8.3%, with a lower neurologically intact survival rate of 3.9%.
The outcomes for blunt injuries are worse. The survival rate of blunt trauma patients with signs of life on arrival at hospital is 4.6% and a neurological intact survival rate of 2.4%. Blunt trauma patients with no signs of life on arrival have an extremely poor survival rate of 0.7%. In the EAST analysis, one patient survived neurologically intact to discharge after blunt injury traumatic arrest with no signs of life out of 825 patients who underwent resuscitative thoracotomy in the Emergency Department.
REBOA (Resuscitative Endovascular Balloon Occlusion of the Aorta) is a technique where a balloon catheter is inserted into the femoral artery and the balloon inflated within the aorta to control distal bleeding. Relatively limited data exist to support its widespread deployment in the exsanguinating trauma patient; however, the technique is rapidly gaining interest.
14
based on a
14
15,16
Emergency room thoracotomy remains a potentially life-saving manoeuvre in patients with significant injury. However, these patients are better served by rapid transport to the operating theatre.
Patients who are haemodynamically stable or
respond to resuscitation should undergo appropriate imaging to determine the nature and extent of their injuries. Collateral history from the emergency services is invaluable – photos of the scene give information regarding the mechanism and likely injury pattern. Conscious patients may complain of abdominal pain. Shoulder tip pain may arise from blood in the subdiaphragmatic space causing phrenic nerve irritation.
Clinical signs may be detected during the initial
examination including anterior abdominal wall bruising, which may indicate compression from a seatbelt, and flank bruising, which may indicate retroperitoneal extravasation of blood. Signs of localised or generalised peritonitis are recorded in the conscious patient. Baseline investigations consist of a full blood count (for haemoglobin and haematocrit), serum urea and electrolytes, liver function tests, a coagulation screen, and blood for crossmatching. It will often be necessary to activate local Major Transfusion Protocols. Following initial assessment, patients who are conscious but have haemodynamic instability with clinical signs of peritonitis should undergo laparotomy. In patients who are haemodynamically stable and have suspected liver injury, further diagnostic tests may be undertaken at this stage to define the nature of the injuries. An ideal test will establish the presence and extent of any liver injury together with providing information on concomitant visceral injury.
Formerly, diagnostic peritoneal lavage (DPL) was
the procedure of choice for the quick diagnosis of haemoperitoneum, particularly in patients with an impaired level of consciousness and equivocal physical signs. However, DPL is invasive and a positive result for blood provides no information regarding either the site or the nature of the injury, and in the context of liver injury may lead to patients undergoing surgery where they may be better treated non-operatively.
An alternative investigation advocated in initial
trauma evaluation is Focused Assessment with Sonography for Trauma (FAST).
17
This involves ultrasonographic assessment of the pericardium, right upper quadrant including Morrison's pouch, left upper quadrant and pelvis. This evaluation is not designed to identify the degree of organ injury, but rather the presence of blood. A large meta-analysis of the use of emergency ultrasonography for blunt abdominal
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