JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
AUGUST 2022
I-B04

 

Signalment (JPC# 1662297):  6-year-old male chimpanzee (Pan troglodytes)

 

HISTOPATHOLOGIC DESCRIPTION:  Slide A:  Haired skin:  Diffusely expanding the dermis, elevating the epidermis, widely separating collagen bundles, and extending to surgical margins are numerous histiocytes and fewer lymphocytes, plasma cells, and fibroblasts arranged in variably sized nodular aggregates and multifocally infiltrating peripheral nerves.  Histiocytes either have abundant, microvacuolated, eosinophilic cytoplasm or a variably sized (up to 50µm in diameter), clear, cytoplasmic vacuole with clumped aggregates of intracytoplasmic, amphophilic to lightly basophilic, fibrillar material (lepra cells).  Dermal collagen is often fragmented and hypereosinophilic (collagenolysis).  Small vessels within the granulomatous nodules are lined by hypertrophied, reactive endothelium.  Multifocally, the epidermis is mildly hyperplastic with acanthosis and moderate orthokeratotic hyperkeratosis.

 

Peripheral nerve:  Diffusely expanding and infiltrating into the nerve fascicles and expanding and elevating the perineurium and epineurium are abundant inflammatory infiltrates as previously described.  Cytoplasmic vacuoles within lepra cells are up to 100um in diameter.  There are multifocal areas of mild perineural fibrosis admixed with numerous lymphocytes and fewer plasma cells.

 

Liver:  Multifocally and randomly, there are variably sized nodular aggregates of the previously described histiocytes with large, clear cytoplasmic vacuoles (lepra cells) multifocally admixed with variable numbers of viable and degenerate neutrophils.  Multifocally, hepatocytes contain numerous, variably sized, intracytoplasmic, clear vacuoles (vacuolar change) and there are occasionally few periportal lymphocytes and fewer macrophages and plasma cells.

 

Slide B:  Acid-fast stain:  Haired skin, liver, and peripheral nerve:  Vacuoles within histiocytes contain numerous acid-fast, 2-3 µm x 1 µm bacilli, occurring singly and in long, beaded chains up to 8-10 µm in length.

 

MORPHOLOGIC DIAGNOSIS: 

1. Haired skin:  Dermatitis and neuritis, granulomatous, diffuse, severe, with intrahistiocytic acid-fast bacilli, chimpanzee (Pan troglodytes), nonhuman primate.

2. Peripheral nerve: Neuritis, granulomatous, diffuse, severe and intrahistiocytic acid-fast bacilli.

3. Liver: Hepatitis, histiocytic and neutrophilic, multifocal, random, mild, with intrahistiocytic acid-fast bacilli.

 

ETIOLOGIC DIAGNOSIS:  Mycobacterial dermatitis, neuritis, and hepatitis

 

CAUSE:  Mycobacterium leprae

 

CONDITION:  Lepromatous leprosy

 

SYNONYMS:  Leprosy; Hansen’s disease

 

GENERAL DISCUSSION:

• Mycobacterium leprae is an acid-fast, obligate intracellular organism that causes a chronic, zoonotic, granulomatous disease in humans and non-human primates (known as leprosy)
• Armadillos are a natural reservoir and likely a source of human leprae infection
• Primarily affects cooler areas of skin (upper respiratory tract mucosa, digits, hands, nose, ears, tail, and scrotum) and peripheral nerves of humans and non-human primates (leprosy); nerve involvement is a unique feature
• Principally encountered in tropical climates

 

PATHOGENESIS:

• Organism transmitted via inhalation > phagocytized by alveolar macrophages > systemic dissemination > cooler areas of body (i.e. skin and extremities)
• M. leprae causes two different types of disease; the host T-helper (Th) lymphocyte response determines if the patient develops lepromatous or tuberculoid leprosy
  • Lepromatous leprosy: Typically indicates a poor host immune response and is more severe
  • Develops in hosts with a dominant CD4+/Th2 response, or a weak CD4+/Th1 response (CD4+ Th2 cells release IL-4, IL-5, IL-10à suppresses macrophage activation)
    • IL-4 inhibits the Th1 response allowing the Th2 response to dominate
    • B cell antibody production is not protective and may lead to antigen-antibody complexes, resulting in vasculitis and glomerulonephritis
• Tuberculoid leprosy
  • Mediated by CD4+/Th1 cell response and production of IL-2 and IFN-γ; γ/δ receptor T-cell lymphocytes are also present and produce IFN-γ; macrophages produce IL-12 (critical for a Th1 response)

 

TYPICAL CLINICAL FINDINGS:

• Lepromatous form: Involves the skin, peripheral nerves, eye, upper airways, testes, hands, and feet, with rare involvement of vital organs and CNS, and associated hypo- or anesthesia; ulnar and peroneal nerves often and symmetrically affected; involvement of testes can lead to sterility
• Tuberculoid form (less severe): Skin disease progresses with neuronal involvement, leads to hypoesthetic skin with loss of sensation and muscle atrophy; nerve damage leads to trophic changes and paralytic deformities in extremities; prolonged course of clinical disease

 

TYPICAL GROSS FINDINGS:

• Lepromatous form: Skin lesions begin as plaque-like, erythematous lesions with hyperpigmented, elevated margins and depressed centers
• Tuberculoid form: Macular, nodular, and papular lesions in cooler areas (e.g. face, ears, distal extremities, scrotum, upper airways, anterior chamber of eye); trauma often results in ulceration; contractures, paralysis, and autoamputation of fingers or toes; keratitis and corneal ulceration from facial nerve paralysis

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Lepromatous form: Nodular to diffuse, dermal to subcutaneous, granulomatous inflammation composed of abundant epithelioid macrophages in solid sheets, multinucleated histiocytic giant cells, variable perivascular lymphoplasmacytic inflammation, without necrosis, and abundant intracellular acid-fast bacilli (multibacillary)
• Tubercular form: Distinct dermal to subcutaneous granulomas with a central core of necrosis, often surrounded by lymphocytes and variable numbers of perivascular lymphocytes; few acid-fast bacilli (paucibacillary), typically found in necrotic regions
• Presence of lepra cells (encapsulated amphophilic masses of bacilli found within macrophages)

 

ULTRASTRUCTURAL FINDINGS:

• Histiocytes with extensively interdigitating plasma membranes and multiple electron-lucent cytoplasmic vacuoles of variable size, with dense round structures considered to be the acid-fast bacilli

 

ADDITIONAL DIAGNOSTIC TESTS:

• Grows slowly and poorly in culture, although it has been experimentally grown in animals (armadillo, non-human primates, and rodents)
• Stains more consistently with Fite-­Faraco (modified) acid fast method than with Ziehl-Nielsen (standard acid fast method); +/- silver stains
• In humans, detectable by skin testing with lepromin, a10 kD heat shock protein of leprae, with a negative tuberculin skin test
• PCR (especially for paucibacillary forms)

 

DIFFERENTIAL DIAGNOSIS:

• Lepromatous form: Xanthoma/xanthogranuloma (I-M03; also contains foamy macrophages)
• Other causes of granulomatous dermatitis: Fungal, protozoal

 

COMPARATIVE PATHOLOGY:

• Mycobacteria, leprosy group (obligate pathogens):
• Occurs spontaneously in the nine-banded armadillo (Dasypus novemcinctus) due to their low normal core temperature (important animal model)
  • Feline leprosy (I-B03): Rare disease caused by mycobacteria that cannot be cultured by standard mycobacteriologic methods; not zoonotic; occurs worldwide; cutaneous granulomas are most commonly caused by lepraemurium and M. visibile
  • Non-human primates: Reported in sooty mangabey (Cercocebus torquatus), chimpanzee, Cynomolgus macaque (Macaca fascicularis), white-handed gibbon (Hylobates lar), rhesus macaque (Macaca mulatta), and African green monkeys (Cercopithecus aethiops)
  • Rats and mice (murine leprosy): Leprosy-like disease caused by lepraemurium; primarily viscera and skin (rarely peripheral nerves)
  • Red squirrels: lepramatosis has been identified in Isle of Wright red squirrels
• Mycobacteria, tuberculosis group (obligate pathogens): tuberculosis, M. bovis, M. microti; often pulmonary (see N-B06 and P-B10)
• Mycobacteria, slow-growing (opportunistic): avium-intracellulare complex (MAC, see D-B10): M. avium avium (important in poultry), M. avium hominissuis (swine), M. avium silvaticum (rarely birds) and M. avium paratuberculosis (cows and birds, see below); M. kansasii, M. ulcerans
  • Cattle:
    • Farcy: Caused by senegalense and M. farcinogenes organisms that enter through skin wounds, tick bites; occurs in tropical and subtropical regions of the Caribbean, Latin America, Africa, and Asia; skin lesions most often occur on head, neck, shoulders, and legs; slow-growing, firm, painless, subcutaneous nodules +/- ulceration and/or yellow, stringy odorless exudate; lymphatics are enlarged and “corded”; can lead to death and high economic losses
    • Johne’s disease: Caused by avium subsp. paratuberculosis (MAP; see C-B03, H-B03, D-B09); also affects sheep and goats; diffuse (lepromatous) granulomatous ileitis and/or colitis and mesenteric lymphadenitis, with multibacillary intrahistiocytic acid-fast bacilli
    • Bovine cutaneous opportunistic mycobacteriosis (skin tuberculosis): Lesions often occur as single or multiple dermal and subcutaneous nodules, usually lower legs but can spread through lymphatics to other locations; lymphatic vessels become thickened and inflamed (lymphangitis), abscesses form and often ulcerate, rupture and/or drain purulent exudate; the myocobacterial agent is typically not identified, though kansasii has been reported in a few cases; condition is less common with tuberculosis eradication efforts
  • Birds: MAP can cause similar multibacillary lesions (as seen in Johne’s disease) in the lung and other organs
• Mycobacteria, rapidly-growing (atypical): Cutaneous infections (see I-B03), organisms found in water, soil, and decaying vegetation; infection follows wound contamination or traumatic implantation, and most commonly occurs in cats, less frequently dogs, rare in horses, cows and other species; includes fortuitum, M. smegmatis, M. chelonae, M. absessus, M. thermoresistibile
• Canine leproid granuloma: Nodular, cutaneous to subcutaneous granulomatous disease, most often on ear pinna and head; occurs more often in short-coated breeds; typically self-limiting infection; novel mycobacterium has not been fully characterized

 

REFERENCES:

 

1. Agnew D, Nofs S, Delaney MA, et al. 21 Xenartha, Erinacoemorpha, Some Afrotheria, and Phloidota. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 528-529.
2. Lowenstine LJ, McManamon R, Terio KA. Ch. 15 Apes . In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 395-396.
3. Magden ER, Mansfield KG, Simmons JH, Abee CR. Nonhuman primates. In: Fox JG, Anderson LC, Otto GM, Whary MT, eds. Laboratory Animal Medicine. 3rd ed. San Diego, CA: Elsevier; 2015:858-859.
4. Malik R, Smits B, Reppas G, et al. Ulcerated and nonulcerated nontuberculous cutaneous mycobacterial granulomas in cats and dogs. Vet Dermatol. 2013; 24(1):146-153.
5. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016: 640-641.
6. Rensing, KM, Lowenstine, LJ, et al. Ch. 14 New World and Old World Monkeys. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:354-355, 361
7. Shilling AK, et al. Leprosy in red squirrels in the UK. Rec. 2019; 184(13):416.
8. Simmons J, Gibson S. Bacterial and Mycotic Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, et al. Nonhuman primates in biomedical research: Diseases. Vol 2.  San Diego, CA: Academic Press; 2012: 136-138.
9. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed., St. Louis, MO: Elsevier; 2022: 1171-1173.

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