**2. Functional anatomy of the pancreas**

This chapter is a brief review of human pancreas development and anatomy, with a special emphasis on the exocrine pancreas from both a physiological and a clinical point of view. In other words, this chapter presents developmental and structural basis to understanding pancreas physiology, its blood and lymphatic vasculature, innervation and the integrative regulation of its function, as well as the clinical symptoms and patterns of spreading in cases of malignancy.

#### **2.1. Embryological and ontogenetic development of the pancreas**

All parenchymal cell types of the pancreas (acinar, ductal and endocrine cells) are derived from primitive endodermal cells of the foregut [1, 2]. In humans, between the 26th and 28th day of gestation, two endodermal diverticula evaginate from the duodenum, thus forming the dorsal and the ventral pancreatic anlage [3–6]. The dorsal pancreatic bud lies in the dorsal mesentery opposite and above the liver bud. The ventral pancreatic bud develops in the ventral mesentery below the liver bud and connects with the bile duct. During further development, both the ventral bud and the bile duct rotate clockwise, as viewed in the craniocaudal direction, until they reach the dorsal pancreatic bud. Parenchyma of the two buds merges during the 7th week of gestation. The ventral pancreas gives rise to the ventral or lower part of the head of the pancreas that involves also the processus uncinatus, whereas the dorsal pancreas gives rise to the rest of the future pancreas, i.e. the dorsal or upper part of the head, the neck, the body and the tail [7]. Together with parenchyma, the ducts of the primitive pancreas also merge. Ducts of the ventral pancreas and the proximal part of the dorsal pancreas give rise to the main pancreatic duct (of Wirsung). The distal part of the duct of the dorsal pancreas may either obliterate or give rise to the accessory pancreatic duct (of Santorini). In the latter case, the accessory duct drains into the duodenum in the smaller papilla of Santorini that is located orally relative to the larger papilla of Vater [6].

During endoscopic retrograde cholangiopancreatography (ERCP), in approximately 3% of people the so-called anomalous pancreaticobiliary junction (APBJ) can be found. In this variation, the pancreatic duct joins the bile duct a few centimetres proximally from the duodenal wall. Due to a reflux and stasis of a mixture of bile and pancreatic juice in the bile duct and gallbladder, the incidence of gallbladder and bile duct carcinoma is increased in these people [8, 9]. In addition to APBJ, a number of other conditions result from defects in the embryological development of the pancreas, such as the annular pancreas and pancreas divisum, that are reviewed elsewhere [8]. The dual embryological origin of the pancreas also reflects in the smaller size and a tighter arrangement of the lobules in the ventral pancreas (lower head and the uncinate process), as well as a different cellular make-up of islets of Langerhans and vascular supply (see below) [10].

In newborns, the total weight of pancreas is around 3 g and the volume of the exocrine pancreas increases approximately linearly to 20 years of age [11–13]. During the period of 20–60 years of age, the volume remains stable and then decreases beyond 60 years of age [11] (**Figure 1**).

**Figure 1.** Embryonic development of the pancreas. (A) The position of the pancreatic buds in an embryo at the 5th week of development. (B) During development, the ventral pancreatic diverticulum rotates clockwise to reach its dorsal counterpart. (C) The ventral and dorsal bud as well as their duct merges during development of the gland.

#### **2.2. Macro- and microscopic anatomy of the pancreas**

and the regulation of exocrine secretion and with the role pancreas plays in intestinal digestion of nutrients. Together, these topics shall provide a solid ground to understand etiopathophysiology of the most common pancreatic diseases, their symptoms and crucial clinical character-

This chapter is a brief review of human pancreas development and anatomy, with a special emphasis on the exocrine pancreas from both a physiological and a clinical point of view. In other words, this chapter presents developmental and structural basis to understanding pancreas physiology, its blood and lymphatic vasculature, innervation and the integrative regulation of its function, as well as the clinical symptoms and patterns of spreading in cases

All parenchymal cell types of the pancreas (acinar, ductal and endocrine cells) are derived from primitive endodermal cells of the foregut [1, 2]. In humans, between the 26th and 28th day of gestation, two endodermal diverticula evaginate from the duodenum, thus forming the dorsal and the ventral pancreatic anlage [3–6]. The dorsal pancreatic bud lies in the dorsal mesentery opposite and above the liver bud. The ventral pancreatic bud develops in the ventral mesentery below the liver bud and connects with the bile duct. During further development, both the ventral bud and the bile duct rotate clockwise, as viewed in the craniocaudal direction, until they reach the dorsal pancreatic bud. Parenchyma of the two buds merges during the 7th week of gestation. The ventral pancreas gives rise to the ventral or lower part of the head of the pancreas that involves also the processus uncinatus, whereas the dorsal pancreas gives rise to the rest of the future pancreas, i.e. the dorsal or upper part of the head, the neck, the body and the tail [7]. Together with parenchyma, the ducts of the primitive pancreas also merge. Ducts of the ventral pancreas and the proximal part of the dorsal pancreas give rise to the main pancreatic duct (of Wirsung). The distal part of the duct of the dorsal pancreas may either obliterate or give rise to the accessory pancreatic duct (of Santorini). In the latter case, the accessory duct drains into the duodenum in the smaller papilla of Santorini that is located

During endoscopic retrograde cholangiopancreatography (ERCP), in approximately 3% of people the so-called anomalous pancreaticobiliary junction (APBJ) can be found. In this variation, the pancreatic duct joins the bile duct a few centimetres proximally from the duodenal wall. Due to a reflux and stasis of a mixture of bile and pancreatic juice in the bile duct and gallbladder, the incidence of gallbladder and bile duct carcinoma is increased in these people [8, 9]. In addition to APBJ, a number of other conditions result from defects in the embryological development of the pancreas, such as the annular pancreas and pancreas divisum, that are reviewed elsewhere [8]. The dual embryological origin of the pancreas also reflects in the smaller size and a tighter arrangement of the lobules in the ventral pancreas

istics, as well as some key diagnostic and therapeutic principles.

**2.1. Embryological and ontogenetic development of the pancreas**

**2. Functional anatomy of the pancreas**

orally relative to the larger papilla of Vater [6].

of malignancy.

20 Challenges in Pancreatic Pathology

The human pancreas is a large solitary retroperitoneal organ with well-defined outer borders located at the level of the L1 and L2 vertebrae. The gland is 14–18 cm long, 2–9 cm wide and 2–3 cm thick, weighing 50–125 g [11, 14–17]. It is surrounded by a fibrous capsule from which connective tissue septa extend into the gland dividing its parenchyma into distinct lobes and lobules. In contrast to the outer borders, there are no clear-cut macroscopic borders between the major parts in which the pancreas is usually divided for descriptive purposes: the head, the body and the tail. Generally, the left border of the superior mesenteric vein (SMV) is regarded as the border between the C-shaped head aligned with the upper duodenum on the right and the body located underneath the stomach and extending roughly horizontally in the medial plane on the left. The mid-point of the body and tail combined is then arbitrarily defined as the border between the body and the tail, with the tail usually ranging 1.5–3.5 cm in length [14, 17, 18]. Some authors define a fourth and a fifth part, the inferomedial uncinate process that lies beneath the SMV and the superior mesenteric artery (SMA), and the isthmus or neck, which is an approximately 2 cm wide part of the pancreas situated anterior to the SMA and the point where the SMV and the splenic vein (SV) join to form the portal vein [14–17].

Together with the mesenchyma, the exocrine part of the parenchyma amounts to 96–99% of the total pancreas volume (TPV) [14–16]. Each lobe contains several smaller lobes called lobules. In humans, the lobules are 1–10 mm in diameter [19]. The borders between adjacent lobules are incomplete and thus the whole parenchyma is a continuous unit [20]. Each morphologically recognizable lobule is also a single-functional glandular unit draining into a single duct. In turn, each lobule is supplied by 2–9 arterioles, thus each glandular lobule comprises a few so-called vascular or primary lobules, each of which, by definition, receives

a single artery [20]. The remaining 1–4% of TPV contributes the endocrine parenchyma in the form of approximately a million islets of Langerhans, each of which measures around 100 μm and contains approximately a thousand endocrine cells of at least five different types [14].

From a pathophysiological point of view, as a basic microcirculatory unit the primary lobules resemble the liver units of Rappaport, in that different types of ischemic injuries involve different parts of primary lobules. In more proximal obstruction of a pancreatic artery (due to vasoconstriction in shock, for instance), the most peripheral parts of the primary lobule undergo necrosis, whereas in more distal obstruction (due to blockage of a terminal arteriole in malignant hypertension for instance) the most central parts of a lobule undergo necrosis [19, 21].

Finally, each lobule is composed of acini that are dome-shaped clusters of pyramid-shaped acinar cells. Exocrine secretions from apical poles of acinar cells flow into the lumen of the socalled intercalate duct. Intercalated ducts drain into intra-lobular ducts, these in turn into larger inter-lobular ducts and these finally converge into the main pancreatic duct. The main pancreatic duct empties into the duodenum together with the common bile duct. The end parts of both ducts constitute the so-called hepatopancreatic ampulla (of Vater). The ampulla communicates with the duodenal lumen via the major duodenal papilla (of Vater). The pancreas may have one accessory duct (of Santorini) that leads into the duodenum independently from the main duct and about 2 cm ventroproximally to it [8, 20, 22, 23]. Smooth muscle fibres in the wall of the distal part of the common bile duct, the main pancreatic duct and the papilla form a sphincter (of Oddi) [24], whether or not the smooth muscle fibres in the wall of the distal accessory duct form a functional sphincter remains a matter of debate [23].

Impaction of a gall stone in the ampulla is a specific cause of pancreatitis. Somewhat complimentary to the situation in APBJ, Opie proposed that the impaction creates a common channel between the pancreatic and the common bile duct and that the entry of bile into the pancreatic excretory system triggers the inflammation in pancreatitis [25].

#### **2.3. Vascular supply of the pancreas**

The regional blood flow to the pancreas approximates 1% of the cardiac output, 90% of which is directed to the exocrine part [26]. The arterial supply is derived from the celiac artery and the SMA [15, 27–30]. The neck, body and the tail of the pancreas (i.e. the major part of the dorsal pancreas) are irrigated by pancreatic branches of the splenic artery (SA) and by the dorsal pancreatic artery (DPA) that branches off near the origin of celiac, hepatic or splenic artery. DPA separates into two main branches: the right branch anastomoses with the anterior superior pancreaticoduodenal artery (PDA, see below) and the left branch gives rise to the transverse pancreatic artery (TPA, also termed the inferior pancreatic artery). TPA runs at the inferior border of the body and tail, usually anastomosing with the pancreatica magna artery, which is the largest pancreatic branch of the splenic artery [30, 31]. The head and the uncinate process are supplied by an anterior and a posterior arcade [32–35]. The anterior arcade is formed by the anterior superior PDA, and the posterior arcade is formed by the posterior superior PDA [33]. The anterior and posterior superior PDA anastomoses with the anterior and posterior inferior PDA, respectively, both stem from the SMA [34, 35]. The uncinate process and the lower head of the pancreas (i.e. the ventral pancreas) are thus supplied by the SMA.

a single artery [20]. The remaining 1–4% of TPV contributes the endocrine parenchyma in the form of approximately a million islets of Langerhans, each of which measures around 100 μm and contains approximately a thousand endocrine cells of at least five different types [14].

From a pathophysiological point of view, as a basic microcirculatory unit the primary lobules resemble the liver units of Rappaport, in that different types of ischemic injuries involve different parts of primary lobules. In more proximal obstruction of a pancreatic artery (due to vasoconstriction in shock, for instance), the most peripheral parts of the primary lobule undergo necrosis, whereas in more distal obstruction (due to blockage of a terminal arteriole in malignant hypertension for instance) the most central parts of a lobule undergo necrosis [19,

Finally, each lobule is composed of acini that are dome-shaped clusters of pyramid-shaped acinar cells. Exocrine secretions from apical poles of acinar cells flow into the lumen of the socalled intercalate duct. Intercalated ducts drain into intra-lobular ducts, these in turn into larger inter-lobular ducts and these finally converge into the main pancreatic duct. The main pancreatic duct empties into the duodenum together with the common bile duct. The end parts of both ducts constitute the so-called hepatopancreatic ampulla (of Vater). The ampulla communicates with the duodenal lumen via the major duodenal papilla (of Vater). The pancreas may have one accessory duct (of Santorini) that leads into the duodenum independently from the main duct and about 2 cm ventroproximally to it [8, 20, 22, 23]. Smooth muscle fibres in the wall of the distal part of the common bile duct, the main pancreatic duct and the papilla form a sphincter (of Oddi) [24], whether or not the smooth muscle fibres in the wall of

the distal accessory duct form a functional sphincter remains a matter of debate [23].

excretory system triggers the inflammation in pancreatitis [25].

**2.3. Vascular supply of the pancreas**

Impaction of a gall stone in the ampulla is a specific cause of pancreatitis. Somewhat complimentary to the situation in APBJ, Opie proposed that the impaction creates a common channel between the pancreatic and the common bile duct and that the entry of bile into the pancreatic

The regional blood flow to the pancreas approximates 1% of the cardiac output, 90% of which is directed to the exocrine part [26]. The arterial supply is derived from the celiac artery and the SMA [15, 27–30]. The neck, body and the tail of the pancreas (i.e. the major part of the dorsal pancreas) are irrigated by pancreatic branches of the splenic artery (SA) and by the dorsal pancreatic artery (DPA) that branches off near the origin of celiac, hepatic or splenic artery. DPA separates into two main branches: the right branch anastomoses with the anterior superior pancreaticoduodenal artery (PDA, see below) and the left branch gives rise to the transverse pancreatic artery (TPA, also termed the inferior pancreatic artery). TPA runs at the inferior border of the body and tail, usually anastomosing with the pancreatica magna artery, which is the largest pancreatic branch of the splenic artery [30, 31]. The head and the uncinate process are supplied by an anterior and a posterior arcade [32–35]. The anterior arcade is

21].

22 Challenges in Pancreatic Pathology

The venous drainage is anatomically less constant and roughly follows the arterial pattern. The splenic vein collects blood from the neck, the body and the tail via multiple small braches [17, 29]. The blood from the head of the pancreas is drained via two arcades. The anterior venous arcade is formed by the anterior superior and inferior pancreaticoduodenal veins (PDV) draining into the superior mesenteric vein. The posterior arcade consists of the posterior superior and inferior PDV. The posterior inferior PDV drains blood into the superior mesenteric vein, whereas the posterior superior PDV drains directly into the portal vein [15, 28, 29]. A number of anastomoses connect the veins and are typically more irregular than arterial anastomoses [15].

The smallest intra-lobular vessels are collectively termed the microvasculature of the pancreas [36]. A physiologically important relationship exists between the endocrine and exocrine tissue at the level of the microvasculature. In the human pancreas, the majority of islets of Langerhans are situated within exocrine lobules and the islet capillaries lead blood to a second capillary network surrounding acini. This arrangement of the two capillary networks in series is named the insulo-acinar portal system and forms an important basis for endocrine influences upon the exocrine pancreas [37–41]. The venous blood from inter-lobular islets flows directly into the inter-lobular veins and this type of flow is named the insulo-venous system. Noteworthy, from both the insulo-venous and -acinar system, the venous blood is ultimately passed to the portal vein [27, 42] (**Figure 2**).

**Figure 2.** Blood vessels and lymph nodes of the pancreas. The main arteries (red) and veins (blue) supplying pancreas, as well as the main lymph nodes (green), indexed according to the numerical system (see text for details).

The lymphatic system of the pancreas is usually divided into an internal and an external system [43]. The former has been described to some extent only in rodents and is reviewed in detail elsewhere [14, 43]. In brief, the internal lymphatic system arises in the form of blindbeginning intra-lobular vessels distributed in intra-lobular septa, close by smallest blood vessels and ducts, but at a certain distance from acinar cells, with every lobule possessing many such vessels [43, 44]. Intra-lobular vessels drain into inter-lobular vessels running close by inter-lobular blood vessels and ducts in inter-lobular septa. The largest inter-lobular vessels, also called collecting vessels, reach the surface of the gland and drain into the external system [43].

An insufficient removal of extracellular fluid and pancreatic enzymes by the lymphatic overflow system from the interstitium may play an etiological role in pancreatitis. The interstitium and the lymphatic vessels are involved in the inflammatory damage and fibrosis, further hampering the lymphatic drainage and initiating a vicious cycle [43, 44].

The external system consists of large surface lymphatic vessels and regional lymph nodes. Due to the clinical importance of the external system, especially in carcinoma, it has been studied extensively in humans [17, 43, 45–50]. The external lymphatic vessels can be grouped into roughly seven different groups, each of which is associated with a corresponding group of blood vessels. The superior vessels close by the splenic artery and the inferior vessels close by the TPA drain the tail and the left part of the body. The anterosuperior, posterosuperior, anteroinferior and posteroinferior pancreaticoduodenal vessels (close by the arteries of the same name), as well as the gastroduodenal vessels, drain the head of the pancreas and the right part of the body. In general, authors also agree on the anatomical position of the lymph nodes to which the aforementioned vessels drain and on which nodes are most commonly affected in carcinoma of different parts of the pancreas. In contrast, there is much confusion with regard to the nomenclature of the nodes, with a descriptive [17, 46, 51] and a numerical system [49, 52]. In brief, the main groups (with their notation according to the numerical system in parentheses) that collect lymph from the tail and the body are the splenic and gastrosplenic nodes that lie within and superior to the splenic hilum (10), as well as the suprapancreatic (11) and infrapancreatic (18) nodes that lie close by the splenic and inferior pancreatic artery, respectively. The main groups that collect lymph from the head are the hepatic (8) and hepatoduodenal (12), as well as the superior anterior (17a), superior posterior (13a), inferior anterior (17b) and inferior posterior (13b) pancreaticoduodenal nodes. In addition to these nodes that encircle the pancreas, the paraaortic (16), celiac (9), superior mesenteric (14) and the middle colic nodes (15) lie close by the abdominal aorta and its trunks [43, 53]. The nodes tightly surrounding the pancreas and the nodes around the aorta probably do not correspond to first and second barriers of spread, respectively, since they both receive lymph directly from the pancreas as well as from other nodes [43]. Nodes indexed by numbers 1–7 probably do not drain the pancreas [53]. Noteworthy, the centrifugal path from the aforementioned nodes is via cisterna chyli and the thoracic duct [15].

Lymph node involvement is associated with a poor prognosis and is present in approximately four out of five patients with pancreatic cancer [17, 53]. The largely asymptomatic nature of cancer growth, with jaundice, duodenal obstruction and pain as the most common symptoms appearing late in the course of the disease, probably contributes to the fact that the tumours are detected at an advanced stage. Due to the numerous anastomoses between lymphatic vessels and the fact that obstruction of lymphatic vessels brought about by cancer growth and spread may further alter the already unpredictable routes of drainage, it is extremely difficult to exactly predict the spreading pattern of pancreatic cancer [17, 43, 49]. Tumours originating in the tail and the body most frequently spread to nodes 8, 11, 16 and 18 and only nodes 17 have not been involved in any of the cases [53, 54]. Tumours from the head of the pancreas most frequently spread to nodes 13, 17, 14 and 16, with only nodes 10 and 15 being spared in all cases [49, 50, 53]. It seems that the dual embryological origin of pancreas also influences the spreading pattern of cancer of the head. Tumours from the lower (ventral) head spread to nodes around the SMA (14), in contrast tumours from the upper (dorsal) head spread to nodes around the common hepatic artery (8) and in the hepatoduodenal ligament (12), which is in accordance with the arterial supply (see above) [55].

#### **2.4. Innervation of the pancreas**

The lymphatic system of the pancreas is usually divided into an internal and an external system [43]. The former has been described to some extent only in rodents and is reviewed in detail elsewhere [14, 43]. In brief, the internal lymphatic system arises in the form of blindbeginning intra-lobular vessels distributed in intra-lobular septa, close by smallest blood vessels and ducts, but at a certain distance from acinar cells, with every lobule possessing many such vessels [43, 44]. Intra-lobular vessels drain into inter-lobular vessels running close by inter-lobular blood vessels and ducts in inter-lobular septa. The largest inter-lobular vessels, also called collecting vessels, reach the surface of the gland and drain into the external system

An insufficient removal of extracellular fluid and pancreatic enzymes by the lymphatic overflow system from the interstitium may play an etiological role in pancreatitis. The interstitium and the lymphatic vessels are involved in the inflammatory damage and fibrosis,

The external system consists of large surface lymphatic vessels and regional lymph nodes. Due to the clinical importance of the external system, especially in carcinoma, it has been studied extensively in humans [17, 43, 45–50]. The external lymphatic vessels can be grouped into roughly seven different groups, each of which is associated with a corresponding group of blood vessels. The superior vessels close by the splenic artery and the inferior vessels close by the TPA drain the tail and the left part of the body. The anterosuperior, posterosuperior, anteroinferior and posteroinferior pancreaticoduodenal vessels (close by the arteries of the same name), as well as the gastroduodenal vessels, drain the head of the pancreas and the right part of the body. In general, authors also agree on the anatomical position of the lymph nodes to which the aforementioned vessels drain and on which nodes are most commonly affected in carcinoma of different parts of the pancreas. In contrast, there is much confusion with regard to the nomenclature of the nodes, with a descriptive [17, 46, 51] and a numerical system [49, 52]. In brief, the main groups (with their notation according to the numerical system in parentheses) that collect lymph from the tail and the body are the splenic and gastrosplenic nodes that lie within and superior to the splenic hilum (10), as well as the suprapancreatic (11) and infrapancreatic (18) nodes that lie close by the splenic and inferior pancreatic artery, respectively. The main groups that collect lymph from the head are the hepatic (8) and hepatoduodenal (12), as well as the superior anterior (17a), superior posterior (13a), inferior anterior (17b) and inferior posterior (13b) pancreaticoduodenal nodes. In addition to these nodes that encircle the pancreas, the paraaortic (16), celiac (9), superior mesenteric (14) and the middle colic nodes (15) lie close by the abdominal aorta and its trunks [43, 53]. The nodes tightly surrounding the pancreas and the nodes around the aorta probably do not correspond to first and second barriers of spread, respectively, since they both receive lymph directly from the pancreas as well as from other nodes [43]. Nodes indexed by numbers 1–7 probably do not drain the pancreas [53]. Noteworthy, the centrifugal path from the aforementioned nodes is

Lymph node involvement is associated with a poor prognosis and is present in approximately four out of five patients with pancreatic cancer [17, 53]. The largely asymptomatic nature of

further hampering the lymphatic drainage and initiating a vicious cycle [43, 44].

via cisterna chyli and the thoracic duct [15].

[43].

24 Challenges in Pancreatic Pathology

The pancreas is innervated by sympathetic, parasympathetic and afferent nerve fibres that enter and exit the pancreas together with vessels and follow them also within the pancreatic tissue [36, 56–59]. The somata of preganglionic sympathetic neurons innervating the pancreas reside in the lateral horn of the C8-L3 spinal cord segments and project to paravertebral sympathetic ganglia. Alternatively, some axons do not terminate at synapses within the paravertebral ganglia but continue within splanchnic nerves to synapse within the celiac ganglia and the superior mesenteric ganglion [36, 56, 57]. The tail and the body of the pancreas are supplied by nerve fibres that originate in the celiac plexus and follow the splenic artery and TPA [60]. The majority of nerve fibres to the pancreas supply the head [61]. They originate in the anterior and posterior hepatic plexus. The fibres that enter the uncinate process originate in the superior mesenteric ganglion [60].

As already mentioned, lymph node involvement is one of the most important prognostic factors in pancreaticobiliary tract carcinomas. In general, lymph node metastasis is established by lymphatic invasion; however, tumour cells were shown to be able to spread into the hilum of lymph nodes via neural invasion. The knowledge of patterns of neural architecture may improve curative procedures [62]. Moreover, embryological development of the pancreas served as a useful template for patterns of extrapancreatic nerve plexus invasion of pancreatic head carcinoma [63].

The efferent autonomous nerves in the pancreas have release sites that are not in close contact with cells and thus probably influence many targets at a time [58, 64]. In the exocrine pancreas, the sympathetic terminals contact predominantly the intra-pancreatic ganglia, blood vessels and ducts. Stimulation of sympathetic fibres indirectly inhibits the exocrine secretion by inhibiting intra-pancreatic ganglia and by decreasing supply of fluid via vasoconstriction [36]. The somata of the parasympathetic preganglionic neurons reside in the dorsal motor nucleus of vagus and the nucleus ambiguus [36, 56]. The majority of their axons join the vagus and some the splanchnic nerves and reach the neural plexuses around arteries where they intermingle with sympathetic fibres [61]. The preganglionic parasympathetic neurons finally reach intra-pancreatic ganglia together with vessels supplying them [36, 56]. The parasympathetic ganglia that reside within the inter-lobular septa, lobules and also close to islets receive input not only from parasympathetic preganglionic fibres, but also from other pancreatic ganglia, sympathetic fibres (see above), the myenteric plexus, as well as the sensory fibres (see below) [36]. Postganglionic fibres innervate acinar and ductal epithelial cells, ductal smooth muscle cells and vascular plexuses, as well as other ganglia. These fibres mediate parasympathetic stimulation of secretion from acinar and ductal cells, constriction of ducts, as well as an increase in fluid supply by vasodilation [36, 61].

In the pancreas, sympathetic and parasympathetic afferent fibres can also be found. They contain substance P (SP) or calcitonin gene-related product (CGRP) as neurotransmitters. Sympathetic afferents that innervate both the exocrine and the endocrine tissue join the sympathetic splanchnic nerves and transmit noci- and mechano-receptive sensory information to somata within the dorsal root ganglia and further on to preganglionic sympathetic neurons in the lateral horn of the spinal medulla and probably higher centres [36].

Pancreatic sympathetic innervation is altered in chronic pancreatitis and pancreatic cancer and may contribute to the neuropathic pain and visceral neuropathy in these states [65, 66]. Dorsal root ganglion sympathetic afferent neurons send collaterals to efferent ganglia, representing a neuroanatomical substrate for intrapancreatic monosynaptic vegetative reflexes. For example, SP and CGRP released at intra-pancreatic ganglia inhibit exocrine secretion. Intrapancreatic ganglia are also contacted by vagal afferents [36].

Somata of vagal afferent neurons reside within the nodose ganglia. They innervate the blood vessels, ducts, acini and islets. However, their centripetal pathways are not well known [36].
