JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

August 2022

I-B03 (NP)

 

Signalment (JPC# 1113469): Cat

 

HISTORY: This cat presented with multiple skin nodules.

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Expanding the dermis and subcutis, separating and surrounding skeletal myofibers of the panniculus carnosus, elevating the overlying mildly hyperplastic and focally ulcerated epidermis, and widely separating adnexa are multifocal to coalescing, 5-15 mm diameter nodules of pyogranulomatous inflammation. Inflammatory nodules are often centered on areas of necrosis, both coagulative (with loss of differential staining and retention of tissue architecture) and lytic (loss of normal architecture with replacement by eosinophilic cellular and karyorhectic debris admixed with viable and degenerate neutrophils and hemorrhage). Necrotic foci are surrounded by numerous epithelioid macrophages, neutrophils, fewer multinucleate giant cells (Langhans’ and foreign body types), scattered lymphocytes, plasma cells, fibroblasts, and fibrous connective tissue. There are multiple, often perivascular aggregates of lymphocytes and plasma cells at the periphery of the pyogranulomatous nodules. Entrapped lymphatics are moderately ectatic. Multifocally, inflammatory cells separate and surround skeletal myocytes of the panniculus carnosus; affected myofibers are occasionally swollen, with pale, vacuolated sarcoplasm (degeneration) or shrunken (atrophy).  There is focally extensive ulceration of the overlying epidermis with replacement by a serocellular crust composed of abundant degenerate neutrophils admixed with eosinophilic cellular and karyorrhectic necrotic debris, erythrocytes, and eosinophilic, fibrillar, beaded material (fibrin).  The epidermis adjacent to the ulcer is mildly acanthotic and spongiotic, with minimal orthokeratotic hyperkeratosis.

 

Slide B: Haired skin (acid fast): Within the cytoplasm of epithelioid macrophages and multinucleate giant cells are moderate numbers of 3-5 um acid-fast bacilli, often arranged in parallel bundles.

 

MORPHOLOGIC DIAGNOSIS: Haired skin and subcutis: Dermatitis and panniculitis, ulcerative, pyogranulomatous, multifocal to coalescing, marked, with intrahistiocytic acid-fast bacilli, breed unspecified, feline.

 

ETIOLOGIC DIAGNOSIS: Cutaneous mycobacteriosis

 

CAUSE: Mycobacterium lepraemurium

 

CONDITION: Feline leprosy syndrome

 

GENERAL DISCUSSION: 

• Worldwide; most prevalent in temperate maritime climates of New Zealand, Australia, North America (e.g. northwest US and Canada), and Europe
• Feline cutaneous mycobacteriosis is now known to be caused by several different species of Mycobacterium with overlapping clinical and histological features precluding development of a simple classification scheme; however, three manifestations are classically described:
  • Feline leprosy syndrome: Rare; caused by mycobacteria species that are difficult to culture; mycobacterial species include M. lepraemurium, M. visible, M. spp. strain Tarwin, and a novel species in New Zealand and the East Coast of Australia; non-zoonotic 
  • Atypical mycobacteriosis (opportunistic mycobacterial granulomas): Chronic or recurrent fistulous tracts, ulcers, fasciitis, and ulcerative nodules most frequently on caudal abdomen, inguinal region, or lumbar regions; causative organisms thrive in fatty tissues; typically caused by wound contamination with saprophytic and non-saprophytic mycobacteria; most cases caused by rapidly growing species (e.g. M. fortuitum, M. phlei, M. smegmatis, M. chelonae) or rarely caused by slowly growing species (M. avium, M. chitae, M. xenopi, M. ulcerans); ease of culture differentiates atypical mycobacteriosis from feline leprosy
    • Histologically there is multifocal pyogranulomatous dermatitis and/or panniculitis with numerous clear vacuoles surrounded by neutrophils; clear vacuoles contain rare acid-fast bacteria (paucicellular)
    • Three syndromes are recognized:
      • Mycobacterial panniculitis with chronic infection or skin and subcutis
      • Pyogranulomatous lobar pneumonia
      • Disseminated disease in immunocompromised animals
  • Cutaneous tuberculosis (“classic tuberculosis”): Multiple ulcers, plaques, nodules, and abscesses that discharge a thick exudate composed of pyogranulomatous inflammation with caseous necrosis; cats often develop submandibular lymphadenopathy; caused by M. bovis, M. tuberculosis, or rarely, M. avium or M. microti; typically, oral route of infection, less often via infected rodents/meat, unpasteurized milk

 

PATHOGENESIS:

• Mode of transmission unknown; suspected modes include rodent or cat bites, superficial wound contamination with soil, and/or biting arthropods > enters macrophages > blocks fusion of phagosome and lysosome > intracellular replication > persistence of antigen in tissue > tissue destruction via cell mediated inflammatory response

• Immunosuppression has been proposed to contribute to infection, particularly in lepromatous leprosy caused by a novel mycobacterial species in older cats; however, no association concurrent infection (e.g. FIV, FeLV) has been proven
• Tuberculoid leprosy is characterized by a TH1 response with production of IL-2 and IFN-γ (which activates macrophages); IL-12 is important in the generation of a TH1 response, and lack of IL-12 may lead to lepromatous leprosy
• Lepromatous leprosy is characterized by a defective TH1 response or a dominant TH2 response with production of IL-4, IL-5, and IL-10 that may suppress macrophage activation

 

TYPICAL CLINICAL FINDINGS:

• Young, male, outdoor cats overrepresented
• Progressive and often aggressive clinical course of infection; clinical course is dependent on host immunity, the mycobacteria species, and size of the infective inoculum

 

TYPICAL GROSS FINDINGS:

• Focal to multifocal cutaneous papules and firm, well circumscribed, alopecic, and variably ulcerated nodules, 2mm to 40mm in diameter
• Lymphadenopathy common 

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Bacilli not typically apparent in H&E sections; exceptions include M. visible and novel Australian East Coast species (weakly basophilic)
• Lymph nodes:  Variable disruption due to infiltrating macrophages; acid-fast bacilli (AFB) rare
• Feline leprosy syndrome has two distinct morphologic patterns:

• Lepromatous leprosy: Generally indicates poor host immunity

• Nodular to diffuse granulomatous dermatitis and panniculitis without necrosis
• Sheets or nodules of large, foamy macrophages with sparse multinucleate giant cells
• Variable numbers of perivascular lymphocytes, plasma cells; sparse neutrophils
• Abundant intracellular AFB (multibacillary) arranged in dense parallel intrahistiocytic intracytoplasmic accumulations which displace the nucleus

• Tuberculoid leprosy:

• Dermal to subcutaneous granulomas with central caseation, surrounded by pyogranulomatous inflammation with epithelioid macrophages and occasional multinucleated giant macrophages
• Relatively few to moderate AFB (paucibacillary), often confined to necrotic areas
• Variable numbers of perivascular lymphocytes

• Mineralization and encapsulation not typically observed
• +/- Acanthosis and/or ulceration in overlying epidermis

• Tuberculosis: Nodular to diffuse granulomatous to pyogranulomatous dermatitis and panniculitis, with caseous central necrosis

 

ADDITIONAL DIAGNOSTIC TESTS:

• Acid fast stains: Ziehl-Neelsen (standard), Fite-Faraco (modified), Kinyoun (modified)
• Extremely difficult to culture; requires an enriched egg yolk medium; may take weeks to months to grow
• Presence of AFB with a negative mycobacterial culture supports the diagnosis of feline leprosy, but is not definitive
• Definitive:  PCR or DNA sequencing 
• Transmission of the disease to laboratory animals

 

DIFFERENTIAL DIAGNOSIS: 

• Cutaneous tuberculosis (M. bovis and M. microti) and atypical mycobacteria/nontuberculosis mycobacteria (M. avium complex): Gross and microscopic lesions may resemble feline leprosy; must differentiate with culture, PCR
• Xanthoma (I-M03): Sterile granulomas composed of foamy macrophages; resemble lepromatous leprosy but lack the numerous AFB
• Mycotic infections (e.g. sporotrichosis (I-F07), cryptococcosis (I-F08) and other systemic mycoses): Differentiate with fungal stains, culture

·   Sterile granuloma and pyogranuloma syndrome (I-M17)

• Foreign body granulomas/reactions
• Chronic bacterial infection
• Feline progressive histiocytosis: Most common histiocytic disease in cats; begins as cutaneous nodules and plaques, especially on head, lower extremities, trunk; may progress to organs (lung, kidney, spleen, liver); morphologically normal histiocytes of interstitial dendritic cell origin

 

COMPARATIVE PATHOLOGY:

• Canine leproid granuloma: Granulomatous disease of skin and subcutis caused by an as yet unnamed species related to M. tilburgii, M. simiae, and M. genavense; thought to enter via trauma or biting arthropods; often self-limiting in immunocompetent dogs; breed predilection for short-haired breeds (especially boxers); variable number of AFB seen; often on the head (pinna most common)
• Bovine cutaneous tuberculosis “Farcy”:  Common and economically significant disease in tropical and subtropical regions of Africa, Asia, and Central America (M. senegalense and M. farcinogenes); enters via cutaneous wounds, especially tick bites; firm, non-painful, slow-growing subcutaneous nodules +/- ulceration with thick, stringy, odorless, gray-yellow discharge, nodular “corded” lymphatics and regional lymphadenopathy; nodular to diffuse pyogranulomatous dermatitis and panniculitis with intrahistiocytic AFB; prolonged course with potential for multiorgan dissemination, wasting, and death
• Rats and mice (murine leprosy): Leprosy-like disease caused by M. lepraemurium; primarily viscera and skin (rarely peripheral nerves)
• Mycobacterium leprae (I-B04) infects humans, chimpanzees, sooty mangabeys, and armadillos; in contrast to human leprosy, feline leprosy is not typified by peripheral nerve involvement 
• Red squirrels: M. lepramatosis has been identified in Isle of Wright red squirrels
• Anurans:  M. liflandii identified in Xenopus spp. (research colonies) and other captive species; nodular to ulcerated cutaneous lesions; multibacillary; differential for ranavirus infection

 

REFERENCES:

1. Agnew D, Nois S, Delaney MA, Rothenburger JL. 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.

2. Gross TL, Ihrke PJ, Walder EJ, Affolter VK. In: Skin Diseases of the Dog and Cat. 2nd ed. Ames, IA: Blackwell Science; 2005: 276-281.

3. Laprie C, Duboy J, Malik R, Fyfe J.  Feline cutaneous mycobacteriosis: a review of clinical, pathological and molecular characterization of one case of Mycobacterium microti skin infection and nine cases of feline leprosy syndrome from France and New Caledonia. Vet Dermatol. 2013; 24:561-134.

4. Lopez A, Martinson SA. Respiratory system, mediastinum, and pleurae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed., St. Louis, MO: Elsevier; 2022:641.

5. Lowenstine LJ, McManamon R, Terio KA. Apes. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 395.

6. Matz-Rensing K, Lowenstine LJ. 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: 362.

7. Mauldin EA, Peters-Kennedy J.  Integumentary system.  In: Maxie MG, ed. Jubb, Kennedy, and Palmers Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016: 640-641.

8. McAdam AJ, Milner DA, Sharpe AH. Infectious diseases. In: Kumar V, Abbas AK, Fausto N, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 10th ed. Philadelphia, PA: Saunders Elsevier; 2021: 374-375.

9. Schilling AK, Del-Pozo J, Lurz PWW, Stevenson K, et al. Leprosy in red squirrels in the UK. Vet Rec. 2019; 184(13):416.

10. 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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