JPC SYSTEMIC PATHOLOGY
Signalment (JPC #1113469): Cat
HISTORY: This cat presented with multiple skin nodules.
HISTOPATHOLOGIC DESCRIPTION: Haired skin: Expanding the dermis, 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 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) necrosis. 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). The overlying epidermis is focally extensively ulcerated and replaced by a serocellular crust composed of abundant degenerate neutrophils admixed with eosinophilic cellular and karyorrhectic 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): There are moderate numbers of 3-5 um acid-fast bacilli, often arranged in parallel bundles present within the cytoplasm of epithelioid macrophages and multinucleate giant cells.
MORPHOLOGIC DIAGNOSIS: Haired skin and subcutis: Dermatitis and panniculitis, pyogranulomatous and ulcerative, multifocal to coalescing, marked, with intrahistiocytic acid-fast bacilli, breed unspecified, feline.
ETIOLOGIC DIAGNOSIS: Cutaneous mycobacteriosis
CAUSE: Mycobacterium lepraemurium
CONDITION: Feline leprosy syndrome
· Most prevalent in temperate maritime climates of New Zealand, Australia, North America (e.g. northwest US), 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
· Atypical mycobacteriosis (opportunistic mycobacterial granulomas): Chronic or recurrent fistulous tracts, ulcers, fasciitis, and ulcerative nodules most frequently on caudal abdomen, inguinal 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, 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, les often via infected rodents/meat, unpasteurized milk
· Cat or rat bite (suspected mode of transmission) > 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, 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:
· Feline leprosy syndrome: Two distinct morphologic patterns
· 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, often confined to necrotic areas
· Lepromatous leprosy: Generally, indicates a post host immunity
§ Nodular to diffuse granulomatous dermatitis and panniculitis without necrosis
§ Sheets or nodules of large, foamy macrophages with sparse giant cells
§ Variable numbers of scattered lymphocytes, plasma cells, multinucleate giant macrophages, and neutrophils
§ Abundant intracellular AFB (multibacillary) arranged in dense parallel intrahistiocytic intracytoplasmic accumulations which displace the nucleus
· 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-Farraco (modified), Kinyoun’s (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
· Transmission of the disease to laboratory animals
· 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: 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
· Foreign body granulomas/reactions
· Chronic bacterial infection
· Progressive dendritic cell histiocytosis
· 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 (cutaneous opportunistic mycobacteriosis): Nodular lesions in the dermis and subcutis primarily of lower legs (may spread proximally) without lymph node involvement; saprophytic mycobacterial implicated and thought to enter via abrasions (M. kansasii has been reported in some cases); may cause false positive reaction to bovine tuberculin skin tests
· Rats and mice (murine leprosy): Leprosy-like disease caused by M. lepraemurium; primarily viscera and skin (rarely peripheral nerves)
· Mycobacterium leprae infects humans, chimpanzees, sooty mangabeys, and armadillos; in contrast to human leprosy, feline leprosy is not typified by peripheral nerve involvement (see I-B04)
· Mycobacterium microti: Vole tuberculosis; field vole is the maintenance host, the disease is of ecological interest due to adverse effects on field voles; increasing prevalence with age, skin lesions only occur in advanced stages of disease; generally a systemic disease; subcutaneous and skin lesions are almost exclusively in the cranial part of the body; tuberculosis lesions were noted in the liver and spleen in 90% and 80% of affected animals; never found tuberculosis lesions in lungs without systemic disease (involvement of liver and spleen)
· Red squirrels: M. lepramatosis has been identified in Isle of Wright red squirrels
1. Appleyard GD, Clark EG. Histologic and genotypic characterization of a novel Mycobacterium species found in three cats. J Clin Microbiol. 2006; 40: 2425-2430.
2. Davies JL, Sibley JA, Myers S, Clark EG, Appleyard GD. Histological and genotypical characterization of feline cutaneous mycobacteriosis: a retrospective study of formalin-fixed paraffin-embedded tissues. Vet Dermatol. 2006; 17: 155-162.
3. 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.
4. Hargis AM, Myers S. The integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed., St. Louis, MO: Elsevier; 2017:1077, 1143.
5. Kipar A, Birthe SJ, Hetzel U, Abo Rokia M, Telfer S, Lambin X, Birtles RJ, Begon M, Bennett M. Mycobacterium microti tuberculosis in Its maintenance host, the field vole: Characterization of the disease and possible routes of transmission. Vet Pathol. 2014; 51(5):903-914.
6. 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.
7. Lopez A, Martinson SA. Respiratory system, mediastinum, and pleurae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed., St. Louis, MO: Elsevier; 2017:550.
8. 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.
9. 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. 9th ed. Philadelphia, PA: Saunders Elsevier; 2015: 377-378.
10. Schilling AK, Del-Pozo J, Lurz PWW, Stevenson K, et al. Leprosy in red squirrels in the UK. Vet Rec. 2019; 184(13):416.