JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
September 2018
D-M15

Signalment (AFIP 2760643):  3-year-old military working dog

HISTORY:  This dog presented with vomiting and abdominal pain.

HISTOPATHOLOGIC DESCRIPTION: 

1. Pancreas: Replacing over 50% of the pancreatic parenchyma and extending into the peripancreatic adipose tissue are multifocal to coalescing areas of lytic necrosis, characterized by loss of cellular architecture and replacement with eosinophilic karyorrectic debris, fibrin, hemorrhage, and edema which are rimmed by degenerate neutrophils and macrophages.  Within the adjacent parenchyma, acinar cells are degenerate with swollen pale vacuolated eosinophilic cytoplasm or necrotic with shrunken hypereosinophilic cytoplasm with pyknotic nuclei and loss of zymogen granules.  Multifocally, blood vessels are incorporated within these necrotic areas and the vascular tunics are transmurally expanded by small amounts of necrotic cell debris, fibrin, hemorrhage and edema (vasculitis); few vessels contain fibrin thrombi. Areas of necrosis, inflammation, and hemorrhage also extend into the peripancreatic adipose tissue, where adipocytes at the periphery exhibit loss of cellular detail (fat necrosis) and replacement by basophilic finely granular mineral and acicular cholesterol clefts (fat saponification).
2. Lymph node: Within the subcapsular and medullary sinuses, there is moderate draining hemorrhage and edema, and macrophages often contain light brown granular to globular intracytoplasmic pigment (hemosiderin). 

MORPHOLOGIC DIAGNOSIS: 

1. Pancreas:  Pancreatitis, necrotizing, acute, multifocal, moderate, with peripancreatic fat necrosis and saponification, breed not specified, canine. 
2. Lymph node: Draining hemorrhage, chronic-active, moderate.

ETIOLOGY:  Unknown

CONDITION:  Acute pancreatic necrosis

SYNONYMS: Acute pancreatitis, Pancreatitis

GENERAL DISCUSSION:

• Pancreatitis – term used with reference to both acute pancreatic necrosis and to diseases that are primarily inflammatory; however, these disorders have different causes, pathogenesis, and histologic characteristics
  • Both acute and chronic pancreatitis are considered different conditions from pancreatic necrosis:
    • Acute pancreatic necrosis is a life threatening condition that may become chronic or relapsing; the inciting cause is often unknown and initially includes mesenteric adipose tissue adjacent to the pancreas and acinar cells at the edge or margin of the pancreatic lobules
    • Acute pancreatitis may occur when there is inflammation with a centrilobular region or a periductal pattern, and may occur associated with reflux of digestive enzymes from the duodenum; when severe may include extensive hemorrhage and histiologic lesion may overlap with severe acute pancreatic necrosis
    • Chronic interstitial pancreatitis is a pattern more commonly observed in cats and arrises secondary to a process originating in the ducts
  • Most common of the pancreatic diseases in dogs and also occasionally occurs in cats
  • Acute and life-threatening syndrome or chronic relapsing syndrome that culminates in exocrine pancreatic insufficiency and diabetes mellitus (DM)
  • Only chronic pancreatitis and DM were correlated in recent studies in cats
  • Obese, sedentary bitches are predisposed; occurs in dogs more than cats, rare in other species (sporadic in horse associated with strongyle migration)
    • Cocker spaniels have increased incidence
  • Any acute cases may become chronic pancreatitis (especially duct obstruction), which is accompanied by fibrosis and atrophy
  • In cats, chronic pancreatitis almost always manifests as extensive fibrosis with little inflammation

PATHOGENESIS:

• 3 major mechanisms of pancreatitis
  • Obstruction of duct (calculi, parasites, neoplasia)
  • Direct injury to acinar cells (T-2 mycotoxin, zinc, sulfa drugs, or ischemia)
  • Disturbances of enzyme trafficking within acinar cells (aberrant transport of proenzymes as may occur with steroids)
• Common trigger of high fat meals in dogs has unclear specific pathogenesis
• Regardless of mechanism, all result in activated enzymes autodigesting the pancreas and peripancreatic fat
• Lysosomes and zymogen granules co-localize or fuse which is associated with increased intracellular calcium concentration which activates trypsin, primarily by cathepsin B
  • May represent the common pathway by which different mechanisms result in pancreatic necrosis
• Trypsin > activates enzymes (elastase and phospholipase A) > autodigestion, necrosis, vasculitis > vasoactive amine release > increased vascular permeability > edema, hemorrhage, thrombosis, ischemic necrosis
• Local activation of the complement cascade (activated prekallikrein) and cytokines (TNF-alpha, IL-1, IL-6, IL-8, and platelet activating factor)
• Leukocytes generate ROS and more cytokines which consume protease inhibitors (e.g. alpha 1- protease inhibitor and macroglobulin), which trigger DIC, SIRS, etc.
• One study suggests that dogs with acute necrotic pancreatitis leads to recruitment of pulmonary intravascular macrophages within the lungs, resulting in pulmonary complications

TYPICAL CLINICAL FINDINGS:

• Severe acute abdominal pain with anorexia, vomiting, lethargy
• Canine pancreatic lipase (cPL): Positive snap test is suggestive of pancreatitis
• Pancreatic lipase immunoreactivity (cPLI or fPL): Most sensitive test
• Serum amylase and lipase: Often used but not sensitive or specific
• Inflammatory leukogram: Neutrophilia with left shift and toxic neutrophils
• Liver involvement: Increased ALP and ALT, hyperglycemia, glucosuria
• Hypocalcemia (rare, severe cases): Tetany

TYPICAL GROSS FINDINGS:

• The duration of the disease influences the gross appearance of the  pancreas
• Early stage: Lesions observed appear as yellowish flecks or small plaques of necrosis and saponification of adipocytes in the tissue of the peripancreatic mesentery
  • Necrosis of marginal acinar cells
• End stage: Pancreas is absent or replaced by nodular remnants or atrophied pancreatic tissue
• Pancreatic edema with gray-white areas and hemorrhage
• Peritonitis with fibrinous adhesions to affected areas on pancreas
• Peritoneal fluid may be hemorrhagic and contain fat droplets
• Repeated acute episodes may lead to chronic fibrosing pancreatitis
• Portal vein thrombosis (Rule outs: IMHA, pancreatitis, protein losing nephropathy and enteropathy, peritonitis, corticosteroid administration, and neoplasia)
• Focal liver necrosis may be present
• A minority of dogs with pancreatic necrosis may develop multifocal necrotizing panniculitis.

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Coagulative or lytic necrosis of the peripancreatic adipose tissue and pancreatic parenchyma
• Edematous separation of the interstitium with mural necrosis
• Influx of leukocytes in varying degrees
• Focally extensive areas of hemorrhage and thrombosis of blood vessels
• Fibrinous exudates in the interlobular septa
• Saponification, necrosis and inflammation of fat characterized by acidophilic, opaque, amorphous, or lacy intracytoplasmic substance, or basophilic fibrillar or granular mineralized substance

ULTRASTRUCTURAL FINDINGS:

• Lysis of acinar cells
• Accumulation of large amounts of glycogen in a mononuclear cell

ADDITIONAL DIAGNOSTIC TESTS:

• Ultrasound: Enlarged, hypoechoic pancreas
• Radiography: Increased density in the right cranial quadrant (ground glass), left gastric displacement, right duodenal displacement, gas-filled duodenum/colon

DIFFERENTIAL DIAGNOSIS:

• Gross: Nodular exocrine hyperplasia, zinc toxicosis
• Histologically: Zinc toxicosis  
• Zinc toxicosis is a cause of pancreatic necrosis in dogs, calves, sheep, and waterfowl
• Exocrine pancreatic insufficiency (EPI): Low TLI

COMPARATIVE PATHOLOGY:

Causes of pancreatitis:

• Horses: Causes a chronic interstitial pancreatitis due to migrating strongyles
• Calves, sheep, dogs: Zinc toxicosis, pancreatic calculi
• Pigs: Cassia occidentalis (shrub in Southeastern US) intoxication; T-2 (trichothecene mycotoxin) toxicosis
• Non-human primates: Adenoviral pancreatitis has been reported in rhesus monkeys infected with simian immunodeficiency virus. Other causes include Trichospirura leptostoma found in pancreatic ducts.
• Avian:
  • Pancreatitis has been reported in turkeys with either highly pathogenic avian influenza (HPAI) or Turkey viral hepatitis
  • Pancreatic necrosis with birds affected by West Nile Virus
  • Exocrine pancreatic necrosis in chickens infected with 9a5b Newcastle Disease Virus
• Cats (types of pancreatitis):
  • Acute necrotizing form similar to dogs, with or without fibrosis
  • Suppurative pancreatitis involving inflammation rather than necrosis (likely due to ascending bacterial infection)
  • Chronic: Fibrosis, lymphocytes, cystic dilation
  • Acute: No fibrosis, neutrophils, and necrosis
  • Both: Lobulation, amyloid, periductular inflammation, atypical nodules
  • Chronic most often in cats WITHOUT GI disease
  • Very little involvement of pancreatic ducts
  • One report suggests association between pancreatitis and IMHA in cats
• Juvenile pancreatic atrophy in greyhounds:
  • Pancreatic atrophy, acinar cell apoptosis, zymogen granule loss, cytoplasmic clearing or vacuolar change, lobular atrophy, islet loss, lymphoplasmacytic inflammation BUT NOT duct involvement
  • German shepherd dogs don’t get islet loss
  • T-cells predominate

REFERENCES:

1. Boulianne M, Brash ML, Charlton BR, et al. Avian Diseases Manual. Jacksonville, FL: American Association of Avian Pathologists, Inc; 2013.
2. Brady AG, Carville Angela AL. Digestive System Diseases of Nonhuman Primates. In: Nonhuman Primates Biomedical Research: Diseases. Vol 2. 2nd ed. San Diego, CA: Academic Press; 2012:615.
3. Brenner K, Harkin KR, Andrews GA, Kennedy G. Juvenile Pancreatic Atrophy in Greyhounds: 12 Cases (1995-2000). J Vet Intern Med. 2009;23:67-71.
4. Brown DL, Van Wettere AJ, Cullen JM. Hepatobiliary system and exocrine pancreas. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:465-468.
5. El-Bahrawy A, Zaid A, Sunden Y,et al. Pathogenesis of Pancreatitis in Chickens after Experimental Infection with 9a5b Newcastle Disease Virus Mutant Isolate. J Comp Pathol. 2015 Nov;153(4):315-23.
6. Jubb KVF. Pancreas. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016:357-361.
7. Ruaux CG. Feline Pancreatitis: Diagnosis and Treatmen. In: Ettinger SJ, Felmen EC, Cote E eds. Textbook of Veterinary Internal Medicine. 8th ed. St. Louis, MO: Elsevier; 2017:1688-1693.
8. Steiner JM. Canine Pancreatitis: Diagnosis and Treatment. In: Ettinger SJ, Felmen EC, Cote E eds. Textbook of Veterinary Internal Medicine. 8th ed. St. Louis, MO: Elsevier; 2017:1683-1688.
9. Vrolyk V, Wobeser BK, Al-Dissi AN, Carr A, Singh B. Lung Inflammation Associated With Clinical Acute Necrotizing Pancreatitis in Dogs. Vet Pathol. 2017 Jan;54(1):129-140.
10. Zini E, Ferro S, Lunardi F, et al. Exocrine pancreas in cats with diabetes mellitus. Vet Pathol. 2016:53(1):145-152.
11. Zoia A, Drigo M. Association Between Pancreatitis and Immune-mediated Haemolytic Anemia in Cats: A Cross-sectional Study. J Comp Pathol. 2017 May;156(4):384-388.

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