JPC SYSTEMIC PATHOLOGY

HEMOLYMPHATIC SYSTEM

April 2024

H-P08

 

Signalment (JPC #2247995): Young adult female cynomolgus monkey (Macaca fascicularis).     

 

HISTORY: This monkey was wild-caught in Southeast Asia or the Philippines and was a control animal on a 14-week study. She was in apparently good health when euthanized.

 

HISTOPATHOLOGIC DESCRIPTION: Lymph node: Multifocally, paracortical areas, medullary cords, and medullary sinuses contain up to 1 mm diameter, poorly organized, coalescing, eosinophilic granulomas composed of a central core of intrahistiocytic and/or extracellular trematode eggs surrounded by concentric layers of numerous multinucleated giant cell macrophages (Langhans and foreign body type) and epithelioid macrophages that are further surrounded by numerous eosinophils, fewer lymphocytes and plasma cells, and occasional layers of hypertrophied fibroblasts. Eggs are 40 x 50 µm and have a yellow-brown, 2-3 µm thick refractile shell; prominent lateral spines; and a central 30-40 µm-wide, irregular, eosinophilic miracidium with numerous 3 um-diameter basophilic nuclei. Remaining medullary sinuses, and occasional subcapsular sinuses, are diffusely filled with many macrophages, eosinophils, fewer neutrophils, lymphocytes, plasma cells, and are expanded by eosinophilic proteinaceous fluid or clear space (edema). Lymphoid follicles are diffusely increased in number and size and have prominent germinal centers (secondary follicles) and mantle zones, and there is expansion of paracortical areas (lymphoid hyperplasia), with increased numbers of tingible body macrophages.  

 

Liver: Multifocally expanding portal and periportal areas, replacing hepatocytes, and compressing surrounding cords and sinusoids are coalescing, up to 1 mm, eosinophilic granulomas centered on schistosome eggs as previously described. Focally, the tunica media of one vessel wall within a portal area is expanded and effaced by variable numbers of eosinophils, lymphocytes, and fibrin which partially occlude the vessel lumen. Diffusely, portal areas are expanded by moderate amounts of fibrous connective tissue and moderate numbers of eosinophils, lymphocytes, plasma cells, and fewer macrophages. Biliary duct profiles are increased (ductular reaction). Sinusoids directly surrounding the granulomas contain low to moderate numbers of similar inflammatory cells, with small numbers of brown pigment-laden Kupffer cells.  

 

MORPHOLOGIC DIAGNOSIS: 1. Lymph node: Lymphadenitis, granulomatous and eosinophilic, multifocal to coalescing, moderate, with numerous trematode eggs and moderate diffuse lymphoid hyperplasia, Cynomolgus monkey (Macaca fascicularis), nonhuman primate.

2. Liver: Hepatitis, portal and periportal, granulomatous and eosinophilic, multifocal, moderate, with numerous trematode eggs.

 

ETIOLOGIC DIAGNOSIS: Lymph node and hepatic schistosomiasis

 

CAUSE: Flukes of the family Schistosomatidae 

 

CONDITION: Schistosomiasis, bilharziasis

 

GENERAL DISCUSSION:

• Schistosomiasis is a snail-borne “blood fluke” infection, which typically do not cause clinical disease
• Damage and clinical effects are the result of adult flukes and their eggs in blood vessels of the liver, lungs, alimentary and urogenital tracts, and the nasal cavity; extrusion of the eggs causes the most damage 
• Genera that parasitize mammals: Schistosoma, Heterobilharzia, Orientobilharzia
  1. All flukes have specific intermediate hosts, which determines their geographic distribution, but typically have a variety of definitive hosts
  2. Mixed infections and hybridization between schistosome flukes may occur 
  3. Not zoonotic, but do infect humans (cause of “swimmer’s itch”)
• Several species of schistosomatid flukes infect non-human primates naturally and are typically incidental; fluke eggs may be found almost anywhere in the body:
  1. Schistosoma mansoni – new world monkeys (squirrel monkeys), old world monkeys (mangabeys, patas monkeys, guenons, baboons), and great apes (chimpanzees)
  2. Schistosoma haematobium – old world monkeys (mangabeys, guenons, baboons) and great apes (chimpanzees)
  3. Schistosoma mattheei – baboons 

 

PATHOGENESIS:

• Most damage is caused by oviposition and extrusion of eggs through the tissues and mucous membranes with hallmark granulomatous inflammation and fibrosis 
• Mated schistosomes move out into the smallest venous radicles, and eggs are deposited first in the lumen of the vessel; eggs adhere to and are eventually covered by the endothelium (hyperplasia)
• Eggs of some species have spines which facilitate passive migration; the developing miracidium secretes compounds (e.g. proteolytic enzymes) that diffuse through the shell and aid in active migration
• As eggs are deposited in deeper veins, the antigens released by miracidia induce a delayed hypersensitivity response and formation of small granulomas (“pseudotubercles”)
• Eggs may “backwash” into portal system, leading to dissemination to aberrant organs (e.g. liver)

 

LIFE CYCLE:

• Indirect lifecycle with a snail intermediate host
• Eggs containing miracidia laid in vessels inhabited by adults (usually mesenteric veins) > eggs migrate through tissues to and through mucous membranes of intestine or urinary bladder > expelled in feces or urine > eggs hatch in water, releasing miracidia > miracidia actively penetrate soft tissues of aquatic snails > emerge from snail as cercariae (infective stage) > cercariae enter the definitive host by burrowing through the skin > cercariae lose their tails and become schistosomula > enter venules in dermis and are conveyed passively in blood, through the lungs, and into systemic circulation > those that arrive at correct final habitat (typically portal vein) develop further and those that arrive at other organs die > mature adults migrate into mesenteric veins  
  1. Exceptions include S. nasale which targets the veins of the nasal mucosa and S. mattheei which also targets veins of the urinary bladder
  2. Eggs may “backwash” into portal system or enter lymphatics > disseminate through body (especially to liver and regional lymph nodes)
• Prepatent period = 30-77 days

 

TYPICAL CLINICAL FINDINGS:

• Typically subclinical, but may see pyrexia, hemorrhagic diarrhea, hematuria, anemia (from hemorrhage), hypoproteinemia (from protein losing enteropathy), intrahepatic portal hypertension, and/or ascites, depending on type of schistosome, parasitic burden, and organs affected
• Less commonly: Cutaneous lesions (tiny petechiated nodules) due to penetration of the skin that are in contact with infected water or pneumonia from passage of large numbers of flukes through the lungs 
• May cause hemolytic anemia due to mechanical fragmentation of the RBCs; will see schistocytes (specific for mechanical fragmentation)  
• May be followed by spontaneous recovery in the absence of re-infection (immune response of host eliminates the parasites and suppresses the egg laying of survivors)

 

TYPICAL GROSS FINDINGS:

• Thickening of intestines (mostly the large bowel) or urinary bladder wall 
• Microgranulomas in liver +/- brain, spleen, intestines, urinary bladder, others
• Chronic, continued infection may result in GI or urinary stenosis and cirrhosis
• Adult flukes: 1-3cm long, intravascular; both sexes usually present, are sexually dimorphic and in constant copulation with long, slender, sylindrical female in the sex/gynecophoric canal of the short, leaf-like, muscular male
  1. S. mansoni and S. mattheei are in the mesenteric veins 
  2. S. haematobium are in the pelvic or portal veins

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Hallmark: Granulomatous response (+/- Splendore Hoeppli material) to eggs entrapped in host tissues
• Intestines: Transmural thickening by inflammation, fibrosis, and small granulomas and lymphoid nodules; mucosa may have polypoid or papillary proliferations; extends out into mesentery and mesenteric lymph nodes 
• Mesenteric and portal veins: Eosinophilic endophlebitis with irregular intimal proliferation, adult schistosomes, +/- thrombi; chronically, replaced by lymphocytic inflammation; may see similar effects in veins of pancreas, mesenteric and portal lymph nodes, and pulmonary arterioles 
• Liver: Bridging fibrosis, particularly around portal vessels; lobular collapse, nodular regeneration, bile duct hyperplasia, cholestasis
• Parasite:
  • Adults: Eosinophilic tegument, loose mesenchymal parenchyma, oral and acetabular suckers, paired ceca, NOT hermaphroditic (unlike other flukes); intravascular location 
  • Eggs: Elongated/ovoid; yellow-brown; rounded at both ends and a lateral spine (S mansoni) or rounded at only the anterior end and a posterior terminal spine (S haematobium); may have developing miracidium; NO operculum  

 

ADDITIONAL DIAGNOSTIC TESTS:

• Demonstration of the ova in feces or urine
• PCR of feces, fresh or formalin fixed tissue  
• Nasal swab cytology
• Western blot 

 

DIFFERENTIAL DIAGNOSIS:

Eggs in nonhuman primate liver:

• Fasciola hepatica – Operculum  
• Athesmia foxi and A. heterolecithoides – Flukes found in bile ducts of New World monkeys 
• Capillaria hepatica – Bipolar plugs

 

COMPARATIVE PATHOLOGY:

• Schistosoma japonicum group
  • S. japonicum- All domestic animals in Far East; most pathogenic schistosome of cattle and sheep
  • S. mekongi- Dogs in Southeast Asia
• Schistosoma mansoni group
  • S. rodhaini in dogs and carnivores in Africa
• Schistosoma hematobium group
  • S. bovis in portal and mesenteric veins of ruminants, horses, camels, and pigs in southern Europe, Africa, and Asia
  • S. mattheei in portal and mesenteric veins, plus veins of urogenital tract and stomach of ruminants in Africa; migration of eggs into urine results in granulomatous cystitis, ureteritis, and occasionally renal pyelitis 
  • S. curassoni in ruminants in Africa
  • S. margrebowiei & S. leiperi in wild artiodactyls in Africa
• Schistosoma indicum group – India and Asia
  • S. spindale in mesenteric veins of ruminants, horses, and dogs
  • S. nasale in nasal mucosal veins of cattle, goats, and horses; proliferative granulomatous nasal lesions; animals dyspneic with open mouth breathing
  • S. indicum in portal and mesenteric veins of herbivores
  • S. incognitum in pigs and dogs
• Orientobilharzia genus: 
  • Orientobilharzia turkestanicum – Mesenteric veins of herbivores and cats in Russia, China, and Mongolia 
  • Orientobilharzia dattai, O. bomfordi – Artiodactyls in India
• Heterobilharzia americana (canine schistosomiasis) – southern USA; definitive host = racoons (primarily), but may accidentally infect dogs, horses, MANY other mammals; intermediate host = freshwater snail Bakerilymnaea cubensis or Pseudosuccinea columnella; immature flukes migrate to lung and liver (mostly);  mature adults migrate to mesenteric and intrahepatic portal veins
  • Dogs: classic multifocal to diffuse eosinophilic and granulomatous enterocolitis +/- transmural eggs, dystrophic mineralization, and/or similar inflammation in pancreas, lungs, liver; 50% of cases have hypercalcemia (from granulomatous inflammation)  
  • Horses: subclinical hepatic granulomas 
• Birds (mostly waterfowl, but reported in many others) – various schistosome trematode species (Allobilharzia, Austrobilharzia, Bilharziella, Dendritobilharzia, Gigantobilharzia, Trichobilharzia, Ornithobilharzia); may result in emaciation, dehydration, and pectoral muscle atrophy in aberrant hosts; associated with thrombosis of caudal mesenteric vein, fibrinohemorrhagic colitis, hepatomegaly, pulmonary congestion, or incidental findings such as focal myositis; eggs and/or adults surrounded by lymphoplasmacytic to granulomatous inflammation and Splendore-Hoeppli material 
  1. Ducks: Nasal schistosomes (T regenti) – penetrate skin à peripheral nerves à spinal chord and brain à eventually enters meningeal veins à mature in nasal cavity; leaves necrosis and lymphocytic inflammation in migration tracts
• Chelonids: Spirorchiid trematodes, one of the most common cardiovascular parasites worldwide in chelonids; stranding and mortality; found in cardiac chambers and great vessels
  1. Endocarditis, arteritis, thickening of tunica muscularis, mural mineralization, intimal nodular proliferation, thrombosis, aneurysms
  2. Ova are 500x100µm and often associated with granulomatous inflammation found in various sites (spleen, lungs and GI common)

 

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