Keywords
chronic calcific pancreatitis - tropical pancreatitis - mutation - computed tomography
- magnetic resonance imaging - pancreatic malignancy
Introduction
Tropical chronic pancreatitis (TCP) is a unique juvenile nonalcoholic form of chronic
pancreatitis prevalent in tropical developing countries. TCP is characterized by the
younger age of onset, rapid progression, higher prevalence of diabetes and pancreatic
calculi, and higher propensity to develop pancreatic malignancy. The usual clinical
scenario of TCP can be witnessed in a child, adolescent or young adult presented with
recurrent attacks of abdominal pain, steatorrhea, and diabetes which usually sets
in by the third decade. The diabetic stage of the disease is referred to as fibrocalculous
pancreatic diabetes. The diabetes is severe and requires high doses of insulin although
ketosis is uncommon. Demonstration of high blood sugar level and pancreatic calculi
on imaging confirms the diagnosis.[1]
[2] Zuidema from Indonesia was the first to describe a series of 45 cases of TCP.[3] Geevarghese et al reported the largest series of TCP in the world from the south-western
Indian state of Kerala.[4]
[5] The prevalence of chronic pancreatitis in the Western population is 10 to 15 per
100,000, which is considerably lesser compared with the prevalence of 120 to 200 per
100,000 in certain parts of south India.[1] TCP is unique compared with other forms of chronic pancreatitis in its etiology,
imaging features, and prognosis. In this article, we review the etiopathogenesis and
distinct imaging features and complications of TCP.
Etio-Pathogenesis
Malnutrition, consumption of cassava, viral infection, and familial and genetic factors
have been implicated in the causation of TCP. The main mechanism of pancreatic damage
(acinar cell injury) is autodigestion by trypsin. Mutations in genes that prevent
premature activation of trypsinogen to trypsin lead to pancreatitis. Mutations with
high prevalence in TCP are serine protease inhibitor (SPINK 1), cationic trypsinogen
gene (PRSS 1), and cystic fibrosis transmembrane conductance regulator (CFTR) gene.
A recent study from India showed a high association of tropical pancreatitis with
SPINK N34S mutation. These mutations are believed to lead toward sentinel pancreatitis,
and combined with other exogenous factors precipitate further recurrent episodes of
pancreatitis in predisposed patients ([Fig. 1]).[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
Fig. 1 Aetio-Pathogenesis of Tropical Chronic Pancreatitis.
Pathology
The morphological features of pancreas depend on the duration and severity of the
disease. Parenchymal atrophy is variable and the size of gland is inversely proportional
to duration. Fibrosis is the most important microscopic finding and also the main
cause of atrophy of the gland. In advanced stages, the gland is replaced by adipose
tissue. The pancreatic ducts show areas of stenosis and dilatation. The characteristic
intraductal calculi of varying size (millimetric to 5 cm) are observed. The core organic
matrix of calculi consists of desquamated epithelium, fibrin, mucin, and protein deposits.
Later, calcium (predominantly in form of calcium carbonate) deposits in the periphery
of this matrix.[15]
[16]
[17]
[18]
[19]
The characteristic microscopic finding in TCP is the periductular fibrosis, predominantly
involving the main duct and small ductules leading to marked dilatation of the ducts.[20] Immunohistochemistry has shown an overall decrease in the percent of α cells and
β cells. The decrease in insulin positivity in the islets is often inversely proportional
to the duration of diabetes.[21]
Imaging
Imaging and diagnosis of TCP are almost never made in the early stages, as the dominant
symptom of abdominal pain is non-specific. The imaging feature depends on the stage
of the disease. In the early stages, small calculi can be detected only on computed
tomography (CT) or ultrasound and can be easily missed on plain radiographs. Ultrasound
is a useful tool to regularly follow up these patients and to detect complications.[22]
[23]
[24]
[25] When the pancreatic parenchyma is completely replaced by the fat, the echogenic
fat on an ultrasound could mimic the normal pancreas ([Fig. 2]). CT is the modality of choice, as it allows complete visualization of the gland,
detection of calcifications, and identification of associated complications.[26]
[27] As the onset of TCP is at a younger age, these patients require frequent imaging
for early detection of the complications/neoplasm. Although CT is a sensitive tool,
the cumulative radiation dose is a cause for concern. Magnetic Resonance Imaging (MRI)
is an excellent modality to delineate the ductal anatomy and conduct follow-up imaging
of younger patients. However, when the ducts are packed with the calculi, visualization
of the ducts on magnetic resonance cholangiopancreatography (MRCP) is compromised
([Fig. 3]).
Fig. 2 An 18-year-old male patient with tropical chronic pancreatitis (TCP) and diabetes
mellitus. Contrast CT axial images (A, B), Ultrasonography images (C, D) show pancreatic parenchyma completely replaced by fat (B, arrow). Echogenic fat on ultrasound can mimic normal pancreas (D, arrow). Note the dilated main pancreatic duct (MPD) with intraductal calculi (A, C arrow).
Fig. 3 A 20-year-old male patient with tropical chronic pancreatitis (TCP) and diabetes
mellitus. Contrast CT axial images (A), T2 weighted MR axial image (B), MRCP image (C) show dilated main pancreatic duct (MPD) packed with the calculi (A, arrow). Packed intraductal calculi cause difficulty in the visualization of the
pancreatic duct on MRI (B, arrow) and MRCP (C, arrow) images.
Pancreatic Parenchyma and Pancreatic Duct
Pancreatic size is inversely proportional to the duration of the disease. The degree
of duct dilatation also increases as the disease progresses. Diffuse and massive main
ductal dilatation is a common pattern ([Fig. 4]). However, focal dilatation involving either head, body, or tail region can also
be observed.
Fig. 4 A 25-year-old male patient with tropical chronic pancreatitis (TCP) and diabetes
mellitus. Axial images (A, B) of contrast CT shows completely atrophic pancreas (not visualized), hugely dilated
main pancreatic duct (A, arrow) and large intraductal calculi in the head region of the pancreas (B, arrow). Note absence of calculi in the body and tail region.
Pancreatic Calculi
Identifying the characteristic distribution of calculi is a crucial factor in establishing
the diagnosis of TCP. The stones range in size from small sand-like particles to 5
cm. Usually, the stones in the head region are larger and denser, whereas size and
density progressively decrease toward the tail region. The shape of calculi depends
on location and may be smooth elongated, rounded, or staghorn shape. Various distribution
patterns can be identified in TCP. The most common and characteristic pattern is diffusely
scattered large intraductal calculi throughout the head, body, and tail region ([Fig. 5]). The second pattern is large calculi distributed predominantly in the head region
of the pancreas ([Fig. 4]).[23]
[25]
[28]
[29] An uncommon pattern is numerous tiny calculi diffusely scattered throughout the
gland. This pattern is indistinguishable from alcoholic calcific pancreatitis, which
is the most common cause of chronic calcific pancreatitis worldwide. However, the
calculi in alcoholic pancreatitis are fine, speckled and have hazy margins, while
those in TCP are dense and discrete. The overlap of alcohol abuse in many patients
with TCP can make clinical and radiological diagnosis challenging ([Table 1]).[30] Another mimicker of TCP is hereditary pancreatitis, which is a rare autosomal dominant
disease occurring in children. The calculi in hereditary pancreatitis are similar
to alcoholic pancreatitis however ductal dilatation and pancreatic atrophy is less
in comparison to TCP.[31]
Fig. 5 A 20-year-old male patient with tropical chronic pancreatitis (TCP) and diabetes
mellitus. Plain radiograph (A), coronal (B, C) and axial (D–F) contrast computed tomography (CT) images show atrophic pancreas and uniform sized
large intraductal calculi distributed throughout the pancreas (A–F, arrow).
Table 1
Tropical chronic pancreatitis versus alcoholic pancreatitis
|
Tropical pancreatitis
|
Alcoholic pancreatitis
|
|
Geographic distribution
|
Tropical
|
Temparate
|
|
Age of onset
|
Young
|
Middle age
|
|
Cassava
|
High intake
|
No intake
|
|
Nutrition
|
Mal-nourished
|
Well-nourished
|
|
Alcoholism
|
Non-alcoholics
|
Alcoholics
|
|
Diabetes
|
70 to80%, before or with the onset of pain. Severe, insulin- dependant but ketosis
resistant
|
50%, after the onset of pain Mild diabetes
|
|
Pancreatic duct
|
Markedly dilated
|
Less dilated
|
|
Calculi
|
Dense,large,discrete, always large duct, seldom parenchymal
|
Fine, speckled, hazy margins, Parenchymal or small ducts Rarely large duct
|
|
Course of disease
|
Rapid progression
|
Slow progression
|
|
Malignancy
|
Common
|
Less common
|
Intraductal Papillary Mucinous Neoplasm (IPMN) of the pancreas can clinically present
itself as chronic pancreatitis. Moreover, irregular ductal dilatation and intraductal
mucin calcification in these patients can make it difficult to differentiate it from
TCP by imaging. Demonstration of the presence of intraductal papillary nodules or
intraductal mucin, projection of the papilla into the duodenal lumen by CT/MRI, and
endoscopy helps differentiate IPMN from TCP.[32]
[33]
[34]
[35]
Patients with hyperparathyroidism and hypercalcemia are at increased risk of developing
pancreatitis. The mechanism may involve deposition of calcium within the pancreatic
duct and excessive conversion of trypsinogen to trypsin catalyzed by calcium. Imaging
findings are indistinguishable from alcoholic pancreatitis, showing small pancreatic
calcification distributed throughout the pancreas. Lesser degree of ductal dilatation,
atrophy of gland, and small size of calcifications help in differentiating it from
TCP.[36]
[37]
[38]
Usually, patients with TCP require insulin for diabetes control.[39] In patients not responding to medical management, surgical management is indicated.
Surgical procedures such as Puestow procedure (longitudinal pancreaticojejunostomy),
Duval procedure (distal pancreaticojejunostomy), and subtotal pancreatectomy have
shown good results.[40] Most deaths in TCP are due to complications secondary to diabetes. Other causes
of mortality are severe infections, pancreatic cancer, and pancreatitis-related complications.[41]
Complications
Acute on Chronic Pancreatitis
Patients with TCP have recurrent episodes of acute exacerbations. CT is a useful modality
to detect early changes. The gland shows focal or diffuse enlargement in the background
of CCP. Increased density in the peripancreatic fat, thickening of fascial planes,
and fluid collection (intra-pancreatic, peripancreatic space, and lesser sac) indicates
acute exacerbation of the disease ([Fig. 6]).[42]
Fig. 6 A 30-year-old male patient with tropical chronic pancreatitis (TCP) presented with
acute pain abdomen. Axial plain images (A–C) and axial contrast images (D–F) of Computed tomography (CT) show atrophic pancreas and uniform sized large intraductal
calculi distributed throughout the pancreas (A–G arrow). Bulky head of the pancreas (D, arrowhead) with surrounding fat stranding (E, arrowhead) suggestive of acute on chronic pancreatitis.
Pseudocysts
Evolution of fluid collection into pseudocyst occurs over a period between 4 and 6
weeks. Pseudocysts are composed of a thick, well-defined capsule of dense fibrous
connective tissue ([Fig. 7]). Larger pseudocysts (>5 cm) usually do not undergo spontaneous resolution and require
intervention. Usually, pseudocysts possess water density attenuation content. Increase
in the density of pseudocyst content may be secondary to infection or hemorrhage (hemosucchus
pancreaticus). Although CT characterizes the collections/pseudocysts, sometimes MRI/MRCP
could be helpful in delineating the ductal communication with the pseudocysts.[43]
Fig. 7 A 35-year-old male patient with tropical chronic pancreatitis (TCP) with a recurrent
episode of acute pancreatitis. Axial contrast CT images show atrophic pancreas, dilated
main pancreatic duct (C, arrow), large intraductal calculi in the head (A, arrow), body region (B, arrow) and pseudocyst in the body region of the pancreas (C, arrowhead).
Biliary Obstruction
Biliary obstruction can be secondary to benign distal common bile duct (CBD) strictures
or pancreatic head malignancy. Benign strictures show a smooth narrowing of distal
CBD with low grade intrahepatic biliary dilatation, whereas pancreatic head malignancy
causes abrupt cut off of distal CBD with high grade intrahepatic biliary dilatation ([Fig. 8]).[44]
[45]
Fig. 8 A 39-year-old male patient with tropical chronic pancreatitis (TCP) with a recurrent
episode of acute pancreatitis. Axial (A–C) and coronal (D, E) Contrast CT images show irregular dilated main pancreatic duct (A, arrow) and calcifications in the head region (C, arrow). A hypodense mass in the head region (B, D arrow) causing smooth narrowing of distal CBD (E, arrow) with no significant biliary obstruction. EUS guided biopsy done from head
mass and histopathology report was non-malignant inflammatory mass.
Vascular Complications
The incidence of pseudoaneurysm of visceral arteries in chronic pancreatitis is 7
to 10%, greater than in acute pancreatitis (1–6%).[46]
[47] Various mechanisms of pseudoaneurysm formation are as follows: enzymatic autodigestion
of arterial wall leading to pseudoaneurysm formation, visceral artery eroding into
pseudocyst converting pseudocyst into a pseudoaneurysm, and pseudocyst eroding into
bowel wall with bleeding from the mucosal surface ([Fig. 9]). TCP frequently causes thrombosis of the splenic vein.[46]
[48] Multiphase CT detects the site and cause of the bleed with good sensitivity. It
also provides a good vascular roadmap for surgery or embolization.[49]
[50]
Fig. 9 A 32-year-old male patient with tropical chronic pancreatitis (TCP) with haematemesis.
Contrast CT (A) and DSA (B, C) images show calcifications in the head region (A, arrowhead) and pseudoaneurysm from gastroduodenal artery branch (A, yellow arrow; B arrow). Isolation of pseudoaneurysm achieved by coil trapping technique (C, arrow).
Malignant versus Inflammatory Masses
Various studies have shown that 7 to 10% of patients with TCP develop pancreatic carcinoma.
Compared with other forms of chronic pancreatitis, malignancy complicating TCP occurs
at a much younger age and has a worse prognosis. TCP patients have a hundredfold increased
risk of developing pancreatic cancer than controls.[50]
[51] A common problem faced in imaging of patients with TCP is to differentiate between
the inflammatory mass (pseudotumor) and the pancreatic carcinoma. The shrunken and
atrophic pancreas is the most frequent finding in TCP. However, the focal inflammatory
process may mimic carcinoma ([Fig. 8]).[52]
[53]
[54] With advances in CT and MRI, various investigators have attempted to differentiate
inflammatory mass from carcinoma. Studies show that both inflammatory mass and carcinoma
histologically consist of abundant fibrosis, and show hypoenhancement in contrast-enhanced
CT or MRI images. Johnson PT et al observed that masses, due to chronic pancreatitis
and pancreatic carcinoma, show delayed progressive enhancement on dynamic contrast
MRI and attributed this to the abundant fibrosis within these masses.[55] Kumaresan S et al studied the utility of diffusion-weighted imaging (DWI) in differentiating
inflammatory mass from carcinoma and concluded that DWI does not add any additional
value with regard to differentiating between the two.[56] Secondary signs which can point toward malignancy are metastases, the abrupt cutoff
of CBD, and vascular invasion ([Fig. 10]).[44]
[45] Any soft tissue appearing in a completely atrophic gland on follow-up imaging should
be treated with high suspicion. Although endoscopic ultrasound (EUS) has high resolution,
studies have shown its limited role in differentiating inflammatory mass from carcinoma.
EUS provides good guidance for fine needle aspiration (FNA) or biopsy. However, the
sensitivity of EUS-FNA for malignancy in parenchymal masses with features of TCP is
low (54–74%).[57]
[58]
[59]
[60]
[61] The only reliable method of confirming malignancy is histopathology of the surgical
specimen.
Fig. 10 A 38-year-old female patient with tropical chronic pancreatitis (TCP). Axial (A–C) and coronal (D–F) Contrast CT images show, atrophic pancreas, dilated main pancreatic duct (MPD) (A,
arrowhead) with multiple intraductal calculi (A, D arrow). An irregular hypodense mass (B, arrow) in pancreatic body region with encasement and narrowing of celiac artery
(C, arrow), hepatic artery (E, arrowhead), SMA (F, arrow) and occlusion of main portal vein (E, arrow) with multiple collaterals at hilum (D, arrowhead). Histopathology report was adenocarcinoma.
Changing Trends in TCP
Balakrishna et al have extensively studied TCP over a period of 30 years and have
observed the changing trends in the TCP. The disease now occurs in older individuals,
who have milder diabetes which can be controlled using oral hypoglycemic agents. TCP
is now a more heterogeneous disease, sometimes presenting itself in classical form
and often resembling idiopathic or alcoholic chronic pancreatitis. In a particular
patient, more than one etiological factor may be operating in tandem and their relative
contributions determine the manifestations of TCP.[1]
Conclusion
TCP is a unique, rapidly progressing calcific pancreatitis occurring among younger
non-alcoholic patients. It has a higher propensity to develop malignancy at a younger
age with a worse prognosis. TCP is also showing a change in pattern, with cases reported
from the temperate region and from those afflicted with milder diabetes. The typical
imaging features of this condition helps in differentiating it from other forms of
calcific pancreatitis. Awareness of this unique pathogenetic entity will enable the
radiologist to recognize it early. Intervention at an early stage, using newer therapeutic
approaches, could help to ensure better survival and prognosis. Population-wide genetic
studies could help in the prevention of this condition in the future.
