A few animal studies have focused on radiation-induced vascular and ductal damage. The vascular and connective tissues appear to have similar radiosensitivity as tissues elsewhere in the body. Zook et al. observed moderate radiation-induced occlusive vascular disease in dogs receiving abdominal neutron or photon radiation and postulated that this phenomenon could contribute to acinar and duct cell changes (Zook et al. 1983). In another study, 80 Gy was delivered to rat abdomens and histological changes were observed at intervals following exposure (Kovacs 1976). In the acute phase of radiation injury during the first 2 weeks following radiation, most of the acini remain intact with rare small necrotic foci. Edema, inflammation, and dilatation of efferent ductules with stasis consequently leads to atrophy of the acini associated with the efferent ducts over the next several months. During this period, the number of capillaries diminishes, and the number of necrotic foci increase in areas where no capillaries are visible (Kovacs 1976). These progressive late structural changes are thought to contribute to functional changes over time.

Early radiation-induced pancreatic injury results in the decline in bicarbonate and enzyme secretion shortly following radiation to the pancreas in canines and other animals (Corring et al. 1975; Pieroni et al. 1976; Volk et al. 1966). One canine study utilizing intraoperative pancreatic radiation doses of 17.5–40 Gy resulted in a progressive decrease in exocrine pancreatic function, which was evaluated by measuring N-benzoyl-l-tyrosyl-para-aminobenzoic acid, which correlated with weight loss and percentage of normal appearing acinar cells (Ahmadu-Suka et al. 1988). Autopsies performed on the dogs at 135 days following radiation demonstrated a dose-dependent degree of pancreatic atrophy in the irradiated dogs (Ahmadu-Suka et al. 1988).

In contrast islet cell damage appears to be rapidly repaired without alterations in blood glucose levels (Sarri et al. 1991). Most investigators believe that islet cells are more resistant than the acinar tissue to radiation effects (Fajardo and Berthrong 1981; Cameron and Flecker 1925; Zook et al. 1983; Ahmadu-Suka et al. 1988; Spaulding and Lushbaugh 1955). One study demonstrated that degeneration of beta cells occurs approximately 1–4 days after a single large fraction of pancreatic radiation with complete regeneration at 18 days (Cameron and Flecker 1925). Another investigator delivered single large doses of radiation to monkey pancreas and found necrosis of islet cells at 8 h, with beta cells more resistant that alpha cells (Spaulding and Lushbaugh 1955). In both studies there were no morphologic changes noted in the acinar cells during a short follow-up period (Cameron and Flecker 1925; Spaulding and Lushbaugh 1955). In addition, data suggest that the insulin function of a pancreas in rats exposed to a single 4 Gy dose is maintained at a level sufficient for ensuring adequate regulation of glucose homeostasis and of carbohydrate metabolism (Shkumatov 2004).

Similar studies evaluating histological changes and endocrine function have been performed in primates who underwent irradiation in preparation for pancreatic transplantation. Eight or 10 Gy whole body radiation was delivered over 4–5 weeks, with a maximum of 2 Gy weekly. Although the animals remained normoglycemic, insulin release was significantly reduced in both groups during irradiation and was associated with mild glucose intolerance. Histological changes included necrosis of the islet cells and acinar tissue, and cytocavitary network changes of alpha and beta cells, including degranulation, vacuolization, mitochondrial destruction, and an increase in lysosomes (Du Toit et al. 1987).

Other animal studies utilizing fractionated or single doses of radiation have demonstrated acinar gland damage (Pieroni et al. 1976; Volk et al. 1966; Wellmann et al. 1966). Early ultrastructural changes include acinar cell degeneration, mitochondrial injury, and vesicles in endoplasmic reticulum cisternae, which are evident within 1 h following single dose radiation exposure (50–90 Gy) on electron microscopy and are associated with reduced enzyme secretion (Volk et al. 1966). After 8 days following radiation, numerous membrane-bound cytoplasmic bodies, endoplasmic reticulum containing entrapped degenerating mitochondria, and reduced zymogen granules are observed (Volk et al. 1966).

Acini exposed to radiation are known to exhibit increased autophagy, however, these changes do not appear to be related to radiation-induced lysosomal degradation of intracellular proteins (Somosy et al. 1996; Telbisz et al. 2002). Islet cells show similar degenerative organelle changes that are repaired efficiently and last up to 3 weeks, during which time there is no alteration in blood glucose levels (Cameron and Flecker 1925; Volk et al. 1966; Spaulding and Lushbaugh 1955). Longer follow-up demonstrates a recovery period from 3–5 weeks, consisting of increasing endoplasmic reticulum and gradual disappearance of autophagic remnants. After about 5–12 months, the ultrastructure of the cells returns to normal morphologic appearance with the exception of persistent interstitial fibrosis. Conversely, pancreatic function does not completely recover, and continues to exhibit a persistent decrease in enzyme production compared to pretreatment (Wellmann et al. 1966).

In another early study utilizing fractionated pancreatic radiation (45–50 Gy over 30 days) in nine dogs whose pancreas had been surgically mobilized in the abdomen, Archambeau et al. performed functional studies of blood glucose and pancreatic secretions obtained through fistulae (Archambeau et al. 1966). Samples of the pancreatic head and tail were also obtained at 2, 3, and 6 months after radiation demonstrated progressive interstitial fibrosis with distorted normal pancreatic architecture, and preserved acini and the islet morphology. No changes in secretory volume, serum, and pancreatic electrolytes or blood glucose were detected, but there was an initially elevated serum amylase, which declined progressively (Archambeau et al. 1966).

Injury to small- and medium-sized ducts resulting in occlusion of the lumen by cell debris has been demonstrated after 50 Gy fractionated radiation combined with 25 Gy intraoperative radiation to the pancreas in dogs. Over time, severe interstitial fibrosis was observed and by 135 days small- to medium-sized arteries and veins were narrowed with medial and adventitial fibrosis (Ahmadu-Suka et al. 1988). Others have demonstrated that local radiation impairs microcirculatory blood flow in healthy pancreas in a rat ductal pancreatic tumor model. A single fraction of 15 Gy resulted in increased tumor apoptosis but no change in tumor blood flow, whereas blood flow and functional capillary density in the normal pancreas was impaired 5 days after radiation, resulting in hypoperfusion (Ryschich et al. 2003). These changes are thought to contribute significantly to decline in pancreatic exocrine dysfunction and late parenchymal structural damage.

There is even less data describing radiation damage in humans following radiation to the pancreas. As mentioned earlier, Case and Warthin described atrophy of the acinae and degeneration and necrosis of pancreatic ducts in 3 patients with radiation-induced hepatitis (Case and Warthin 1924). Subsequently, in 1955, Brick observed pancreatic fibrosis during autopsies of three men who received radiation to the para-aortic lymph nodes for testicular cancer (Brick 1955). In another report, autopsies of patients treated with abdominal radiation for lymphoma demonstrated peripancreatic stromal fibrosis, sometimes severe, with myointimal proliferation in arteries. The authors described the appearance as similar to chronic pancreatitis with lack of active inflammation and necrosis (Fajardo 1982). Woodruff et al. performed postmortem studies of 22 patients who received radiation for pancreatic cancer using 50–60 Gy over 30 fractions delivered with helium ions. After a median of 9 months following radiation, approximately 85 % of patients demonstrated radiation injury in the nontumor bearing pancreas consisting of dense fibrosis, mainly located in the exocrine parenchyma. They reported that no patient died of pancreatic insufficiency and only one patient developed hyperglycemia (Cohen et al. 1985; Woodruff et al. 1984).

Because of the paucity of human specimens, very little is known regarding early radiation injury to the human pancreas and we predict early radiation damage by extrapolating from the animal studies previously described. After about 10–20 Gy, acinar injury is observed, similar to animal studies. Inflammatory cells are abundant and the number of secretory granules is reduced and the cytoplasm becomes vacuolated. Similar to other tissues, the amount of cellular damage increases with increasing fraction size. Zonal necrosis and ductule degeneration are observed at 60 Gy. Although larger ducts may only demonstrate mild cell changes and enlargement, smaller ducts develop distended lumens and plugging by cellular debris. Acute injury to arterioles and venules may also be present and associated with edema of the stroma and acute inflammation in regions of early parenchymal necrosis. In contrast, islet capillaries show relatively normal anatomical structure during the early injury phase without endothelial enlargement or fibrin thrombi, and islets of Langerhans appear normal (Fajardo et al. 2001).

Pathologic examination of patient pancreas specimens examined at 6 months or more after treatment with radiation demonstrate shrunken, fibrotic pancreas with thickening of the fibrous capsule and adhesions to the surrounding tissues grossly. Lobulation becomes less prominent, and large ducts may be dilated (Fajardo et al. 2001). Microscopic examination of irradiated pancreas at the same time interval demonstrate fibrotic parenchyma with severe acinar cell loss, abundant collagen, hyaline, and atypical fibroblasts similar in appearance to chronic pancreatitis. Despite these structural changes, islet cells appear normal. Occasionally fat necrosis and calcifications may be found (Case and Warthin 1924; Levy et al. 1993). At this time point, very little inflammation is found with the exception of small collections of lymphocytes trapped within the dense fibrous connective tissue. Arteriole walls are thickened with fibrosis of the intima and narrowed lumens while smaller arteries and veins demonstrate fibrous intimal plaques comprised of foam cells (Berthrong 1986). The number of ductules are reduced or atrophied, and plugged with cellular debris while larger ducts are dilated with enlarged nuclei (Fajardo et al. 2001).

Others have studied pancreatic function following abdominal radiation. In one study, the early and late effects of intraoperative radiation on the exocrine and endocrine functions of the residual pancreas were examined in 54 patients with pancreatic head resection, 20 whom underwent intraoperative radiation, and 34 who did not (Yamaguchi et al. 2000). Fasting blood sugar levels and glucose tolerance tests demonstrated no change at 2 months, but at 6 months the glucose tolerance was compromised compared to the preoperative baselines in both groups, while fasting blood sugar levels remained normal. The total amount of pancreatic juice drainage in the irradiated patients was about half as much as that in nonirradiated group. In addition, univariate and multivariate regression analyses demonstrated that intraoperative radiation was a significant independent factor in the decline of pancreatic exocrine function (N-benzol-L-tyrosyl-p-aminobenzoic acid excretion) in the early postoperative period (Yamaguchi et al. 2000).