Signalment:  

Eight-year, nine-month-old spayed female, domestic shorthair feline (Felis cats).The cat presented with a lesion on its abdomen of unknown duration. The referring veterinarian initially suspected a possible spider bite that was too large to debride. The differential diagnosis included neoplasia and inflammation/infection. Culture of the deep tissue tracts yielded growth of coagulase-positive Staphylococcus aureus. Convenia-� (cefovecin sodium) and injectable corticosteroids were inconsistently administered by the owner. The cat initially appeared tolerant of the constantly growing and purulent lesion that involved over half of its abdomen. When the cat became lethargic, depressed, and inappetent, biopsies of the lesion were taken and submitted for histopathologic evaluation.

Gross Description:  

Extensive cutaneous fistulous tracts involving over half of the abdomen.

Histopathologic Description:

Haired skin and subcutis, abdomen: Multifocally expanding the dermis and subcutis; separating, surrounding, and replacing adnexa; and elevating the mildly acanthotic and hyperkeratotic epidermis are multiple, densely cellular, up to 2 mm diameter nodules composed of numerous epithelioid macrophages, neutrophils, fewer lymphocytes and plasma cells, and rare mast cells and eosinophils surrounded by reactive fibroblasts and, in some areas, hemorrhage, fibrin, and edema. Multifocal nodules contain variably sized, up to 100 μm diameter extracellular lipid vacuoles (lipocysts) surrounded by a rim of neutrophils; these occasionally contain many 3-5 μm diameter filamentous bacilli. Occasionally, nodules contain a large central area of necrosis characterized by abundant amounts of eosinophilic cellular and karyorrhectic debris. 

Acid fast stain (Ziehl-Neelsen): Many intravacuolar and intrahistiocytic acid-fast, 3-5 μm, filamentous bacilli are present.

Morphologic Diagnosis:  

Haired skin and subcutis, abdomen: Dermatitis and panniculitis, pyogranulomatous, nodular, multifocal to coalescing, marked, with many intravacuolar and intrahistiocytic, 3-5 μm filamentous acid-fast bacilli, domestic shorthair (Felis cats) feline.

Condition:  

Cutaneous mycobacteriosis

Contributor Comment:  

Classically, three manifestations of feline mycobacteria-associated skin disease are recognized: (1) feline leprosy, (2) cutaneous tuberculosis, and (3) atypical mycobacteriosis (rapidly growing mycobacteria).(3,6)

The feline leprosy group is comprised of obligate pathogens and can be subdivided into lepromatous (multibacillary) and tuberculoid (paucibacillary) forms.(3,6) Affected cats are typically young adults (1-3 years old) and lesions typically occur on the head, limbs, and trunk.(3,4,6) Regional lymphadenopathy may be present, but affected cats are otherwise healthy.(3,4) The mode of transmission is thought to be by rodent or cat bites, biting insect vectors, or soil contamination of cutaneous wounds.(6) The causative agent is presumed to be Mycobacterium lepraemurium; however, other potentially causative mycobacteria (M. visibilis, M. malmoense) have been isolated from cutaneous lesions clinically consistent with feline leprosy by molecular techniques.(4,6) M. lepraemurium does not grow in culture using standard techniques, but has been isolated by PCR with DNA sequencing.(6) Feline leprosy has no known zoonotic potential. Nerve involvement is not a characteristic feature of feline leprosy and is sporadic.(4)

The causative agents of cutaneous tuberculosis, M. bovis and M. tuberculosis, are also considered obligate pathogens. Cutaneous infections are rare. Feline cutaneous mycobacteriosis is most often caused by M. bovis.(3) Gastrointestinal and pulmonary infections are more common. Infections of the gastrointestinal tract and mesenteric lymph nodes usually occur following ingestion of milk or meat of infected cattle.(3) Cutaneous infections can occur alone (rare) or in combination with disseminated infection.(4,6) Lesions of feline cutaneous mycobacteriosis typically occur on the face, neck, shoulders, and forepaws. Less commonly the lesions occur on the ventral thorax and tail. Skin lesions can develop from bite wounds or as a result of dissemination from the gastrointestinal tract. Affected cats typically present with a local or generalized lymphadenopathy.(3) The causative agents of cutaneous tuberculosis are zoonotic.

Atypical mycobacteriosis (rapid growing Runyon Group IV mycobacteria) are considered opportunistic pathogens saprophytes or facultative pathogens that are ubiquitous in soil, water, and decomposing vegetation.(3,4,6,8,10) Included in the atypical group are M. fortuitum, M. phlei, M. smegmatis, M. chelonae, M. abscessus, M. flavescens, M. thermoresistible, and M. xenopi. The Runyon Group IV mycobacteria have a predilection for lipid rich tissues. Consequently, lesions characteristically occur on the ventral abdomen in the subcutaneous fat of inguinal area in cats.(4,5,6) Female cats are overly represented possibly due to the propensity of spayed females to become obese.(3,7) Studies have shown that introduction of acid-fast bacilli into adipose tissue facilitates their pathogenicity, possibly by providing nutrients for growth or by protecting them from the host immune response.(1,4,8,10) Infections occur via wound contamination or traumatic implantation. Consequently, many cats with atypical mycobacteriosis have a history of previous trauma.(4,5) Animal-to-animal transmission is not thought to occur and affected cats are usually not immunocompromised.(4,8) Atypical mycobacteriosis is not considered zoonotic. 

Cutaneous lesions with atypical mycobacteria have been reported primarily in cats.(4,6) The clinical course is prolonged and lesions present as single or multiple cutaneous and subcutaneous nodules, diffuse swellings, plaques, or purpuric macules.(4) Fistulous tracts discharge serous, serosanguinous, or purulent exudates that are not usually malodorous.(4,8) Lesions slowly enlarge and eventually may encompass the entire ventrum and extend up the lateral trunk. Undermining of peripheral skin is characteristic with purple depressions (thin skin) overlying accumulations of pus.(5) Despite extensive cutaneous involvement, most animals remain active with no systemic signs of illness.(4,8)

Histologically, the epidermis is usually acanthotic or ulcerated with multinodular to diffuse pyogranulomatous dermatitis and panniculitis.(5) Thin rims of neutrophils with a wider zone of epithelioid macrophages usually surround varisized lipocysts (clear zones comprised of residual lipid from degenerating adipocytes).(5,6) Pyogranulomas without central spaces (lipocysts) may be seen as well. Pyogranulomas are often confluent and interspersed with diffuse inflammation composed primarily of macrophages and neutrophils. Chronic lesions may contain peripheral lymphoid nodules and/or fibrosis. Giant cells are usually absent.(5) Rapidly growing opportunistic mycobacteria may or may not be difficult to find in tissue section and have been described as rare to numerous.(4,8) When numerous, mycobacteria may be partially visible on hematoxylin and eosin (HE) stained tissue. Fites stain (a Fite-Faraco modification of the acid-fast stain) is useful in accentuating difficult-to-see mycobacteria. Mycobacteria are most commonly found in lipocysts due to protective fat, but may also be present in macrophages.(5)

In summary, pyogranulomas surrounding clear central spaces are very suggestive of a rapidly growing mycobacterial infection with HE stain, but may also be seen in other deep infections (e.g., higher bacteria). Demonstration of acid-fast organisms in lipocysts is highly supportive of the diagnosis; however, this should be confirmed by culture or molecular techniques.(5)

The differential diagnosis for cutaneous infection with rapid growing mycobacteria includes bite wound abscesses, deep mycotic or bacterial infections, sterile nodular panniculitis, and foreign body reactions.(5) Deep wedge biopsies are preferred over punch biopsies for diagnosis since inflammation is most intense in the subcutaneous fat.(4,5)

Cases of feline atypical mycobacteriosis carry a guarded prognosis as treatment can be challenging, especially with chronic lesions.(5,10) Treatment involves radical surgical debridement followed by long-term (3-6 months) treatment with concurrent administration of multiple antimicrobial agents.(5,8,10) Identification by culture or molecular techniques is required so that appropriate therapy and zoonotic potential can be determined.(3,4) Infective mycobacterium can be difficult to culture and repeated cultures may be necessary to yield a positive response.(8)

JPC Diagnosis:  

1. Haired skin: Dermatitis, cellulitis and panniculitis, pyogranulomatous, necrotizing, focally extensive, severe, with lipocysts and many intravacuolar and intrahistiocytic 3-5 μm filamentous acid-fast bacilli.

2. Haired skin: Dermatitis, eosinophilic and mastocytic, subacute, multifocal, mild with bacterial folliculitis and rare intracorneal pustules.

Conference Comment:  

The contributor provides an excellent overview of feline mycobacterial skin diseases. Mycobacterial cell walls are composed of mycolic acids, which not only provide physical protection for the mycobacteria, but also play important roles in the pathogenesis of the diseases they cause. Mycolic acids are glycolipids that regulate the intrahistiocytic growth rate of mycobacteria and influence the host immune response.(1) One important mycolic acid is trehalose 6,6-dimycolate (TDM, cord factor), which is found in large quantities in many species of Mycobacterium, including virulent strains of M. tuberculosis as well as saprophytic M. fortuitum.(1) TDM appears to regulate the intrahistiocytic growth of mycobacteria by inhibiting fusion between phospholipid vesicles, thus inhibiting phagosome-lysosome fusion during infection. TDM also induces macrophage production of proinflammatory cytokines (e.g., IL-1β, IL-6, TNF-α, IL-12), leading to the development of granulomas.(7) Mycolic acid-containing components of the cell wall also promote angiogenesis and interact with Toll-like receptors. Additionally, their presentation as antigens to CD1-restricted T cells further influence the host immune response. CD1-restricted T-cells are a group of T-cells that recognize lipid antigen (such as fatty acids, phospholipids, glycolipids, isoprenoids, mycolates and lipopeptides ) presented by the CD1 family of molecules independent of MHC.(2) CD1a, b and c-restricted T cells recognize several lipid antigens from M. tuberculosis. CD1 restricted T-cells are cytotoxic and secrete Th1 cytokines.(9) Hence, the presence of mycolic acids such as TDM in mycobacterial cell walls may partly determine the outcome of mycobacterial infections in host macrophages. 

In addition to the prominent pyogranulomatous dermatitis, panniculitis and cellulitis, conference participants noted a second, more subtle lesion consisting of eosinophilic and mastocytic dermatitis; the relationship between the two lesions is uncertain. Additionally, conference participants debated the microscopic presence of fistulous tracts, which would correlate well with the usual gross findings in atypical cutaneous mycobacteriosis.

References:

1. Couto SS, Artacho CA. Mycobacterium fortuitum pneumonia in a cat and the role of lipid in the pathogenesis of atypical mycobacterial infections. Vet Pathol.2007;44:543-546.
2. Cohen NR, Garg S, Brenner M. Antigen Presentation by CD1 Lipids, T Cells, and NKT Cells in Microbial Immunity [abstract]. Adv Immunol. 2009;102:1-94. http://www.ncbi.nlm.nih.gov/pubmed. Accessed October 6, 2012. PMID: 19477319.
3. Davies JL, Sibley JA, Myers S, et al. Histological and genotypical characterization of feline cutaneous mycobacteriosis: a retrospective study of formalin-fixed paraffin-embedded tissues. Vet Dermatol. 2006;17:155-162.
4. Ginn PE, Mansell JEKL, Rakich PM. Skin and appendages. In: Maxie MG, ed. Jubb, Kennedy, and Palmers Pathology of Domestic Animals. Vol. 1, 5th ed. New York, NY: Elsevier Saunders; 2007:687-690.
5. Gross TL, Ihrke PJ, Walder EJ, et al. Skin Diseases of the Dog and Cat Clinical and Histopathological Diagnosis. 2nd ed. Ames, Iowa: Blackwell Science Ltd; 2005:283-287. 
6. Hargis AM, Ginn PE. The integument. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 4th ed. St. Louis, MO: Mosby Elsevier; 2007:1185-1187,
7. Indrigo J, Hunter RL, Actor JK. Cord factor trehalose 6,6-dimycolate (TDM) mediates trafficking events during mycobacterial infection in murine macrophages. Microbiology. 2003;149(8):2049-2059.
8. Malik R, Wigney DI, Dawson D, et al. Infection of the subcutis and skin of cats with rapidly growing mycobacteria: a review of microbiological and clinical findings. J Feline Med Surg. 2000; 2(1):35-48.9. 
9. Montamat-Sicotte DJ, et al. A mycolic acid-specific CD1-restricted T cell population contributes to acute and memory immune responses in human tuberculosis infection. J Clin Invest. 2011;121(6):2493-503. 
10. Wilson VB, Rech RR, Austel MG, et al. Pathology in Practice. J Am Vet Med Assoc. 2011;238(2):171-173.

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2-1. Haired skin

2-2. Haired skin

2-3. 

2-4.

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