Disseminated Histoplasmosis Accompanied by Cutaneous Fragility in a Cat
A 4 yr old, spayed female domestic shorthair was referred with a 2 mo history of weight loss, anorexia, and diarrhea. Skin fragility was noted on presentation and a large skin tear measuring 5 cm × 5 cm was obvious over the dorsal cervical region. The patient was previously treated with short-term prednisone that was discontinued 6 wk before presentation. Initial diagnostics (complete blood count and biochemistry) did not indicate an endocrine disorder, the most common cause of acquired feline skin fragility. Necropsy revealed diffuse histoplasmosis (most significantly affecting the skin), epidermal atrophy, dermal collagen separation, and infiltration in the dermis and subcutis by inflammatory cells containing yeast organisms consistent with Histoplasma spp. Infiltrative fungal infection should be considered as a potential cause of acquired feline skin fragility.
Introduction
Skin fragility is a rare condition in cats with varied etiologies. Congenital skin fragility syndromes are rarely reported in the cat, although cutaneous asthenia (also called Ehlers-Danlos syndrome) and dystrophic epidermylosis bullosa, both of which involve abnormal dermal collagen, have been reported.1–3 Cutaneous asthenia, an inherited connective tissue disorder, results in altered strength or extensibility of connective tissues as a result of shortened and fragmented collagen fibers and, possibly, a peptidase deficiency. The most common lesions in affected animals include cutaneous fragility and hyperextensibility.1,2 Dystrophic epidermylosis bullosa, also a rare inherited disorder, is characterized histologically by dermoepidermal separation and abnormal anchoring collagen fibrils. Clinically, cats with dystrophic epidermylosis bullosa have mucosal sloughing, skin fragility, and ulcerations of the gums, tongue, and footpads.3
The majority of diseases resulting in skin fragility in the cat are acquired. The pathogenesis of the skin fragility is unknown; however, it is most commonly associated with such conditions as either iatrogenic or naturally occurring hypercortisolism, diabetes mellitus, or extensive use of progestational compounds. A single case report describing reversible dermal atrophy associated with phenytoin administration in a cat has been published.4
Regardless of the etiology, acquired skin fragility is characterized by extremely fragile and thin skin, severe tearing and shedding of skin from minimal trauma or handling, and no evidence of hyperextensibility. The skin can become translucent and resemble wet tissue paper on tearing. Histology shows a thin epidermis with as little as only a single layer of keratinocytes, as well as a severely atrophic dermis. Dermal collagen fibers are severely attenuated and are pale staining (hematoxylin and eosin stain) with a wispy appearance.5
Cutaneous fragility is common in spontaneous hyperadrenocorticism with more than 50% of affected cats developing thin, fragile skin, with bruising and tearing that can occur easily during grooming, handling, or restraint.5 With iatrogenic hyperadrenocorticism, cutaneous fragility tends to occur only with prolonged therapy. Lien et al. (2006) reported on 12 cats that developed skin lesions, including alopecia and thin, easily torn skin after receiving various combinations of topical and oral corticosteroids for between 6 wk and 48 mo (mean, 8.3 mo).6 Unfortunately, skin biopsies from one of the cats in that study were obtained more than 10 wk after discontinuation of steroid administration and failed to demonstrate epidermal atrophy. Similarly, a 9 yr old, spayed female domestic shorthair who had received three 8 mg (3.3 mg/kg) doses of triamcinolone acetonide subcutaneously over a period of 4 mo developed diffusely friable skin with tears overlying the left hip area and a sparse hair coat along the flanks and ventral abdomen. Histologic examination of skin biopsies were consistent with a dermatosis of endocrine origin with epidermal orthokeratotic hyperkeratosis and atrophy, disruption of dermal collagen, dermal atrophy, and sebaceous gland atrophy.7
Functional adrenal tumors that secrete hormones other than cortisol have also been reported to cause cutaneous fragility. Rossmeisl et al. (2000) reported on a 7 yr old, neutered male domestic shorthair with poorly regulated diabetes mellitus and increased skin fragility resulting from an adrenal cortical adenocarcinoma that was causing hyperprogesteronism.8 Although no histology was performed, the cat was described as having severe alopecia and generalized thinning of the skin. Likewise, DeClue et al. (2005) described a 12 yr old, neutered male domestic longhair with weight loss and poorly regulated diabetes mellitus secondary to adrenal gland carcinoma that was causing hyperaldosteronism and hyperprogesteronism.9 The cat exhibited a thin, greasy haircoat, dermal and epidermal atrophy, and cutaneous fragility based on gross appearance. No histopathology was performed.
Paraneoplastic cutaneous fragility unrelated to hormonal excess has been described secondary to pancreatic adenocarcinoma and hepatic carcinoma. Roccabianca et al. (2006) reported findings in two male domestic shorthairs, aged 12 yr and 13 yr. Both cats had pancreatic adenocarcinoma and one also had hepatocellular carcinoma. Although not confirmed, the authors suspected both cats had hyperadrenocorticism because the majority of cats reported with skin fragility have an endocrine disorder or iatrogenic cause. Histologic examination of skin biopsies in both cats were similar with epidermal and dermal atrophy, orthokeratotic hyperkeratosis, and telogen arrest of hair follicles.10
The purpose of this paper is to describe the case of a cat presenting with skin fragility that was subsequently diagnosed with disseminated histoplasmosis. To the authors' knowledge, cutaneous fragility associated with diffuse cutaneous histoplasmosis has not been previously reported in cats.
Case Report
A 4 yr old 2.2 kg spayed female domestic short hair cat was referred to Kansas State University for evaluation of severe weight loss, anorexia, and occasional diarrhea. The cat had originally presented to the referring veterinarian 2 mo previously for decreased appetite and weight loss. At that time, the cat's weight was 3.5 kg, down from the previously documented weight of 4.5 kg recorded 5 mo prior to presentation. Laboratory tests performed by the referring veterinarian revealed a normocytic, normochromic anemia (hematocrit was 26.9%; reference range, 29.0–48.0%); thrombocytopenia (too low to register; reference range, 200,000–500,000 platelets/μL), a mildly decreased blood urea nitrogen (11 mg/dL; reference range, 14–36 mg/dL); and a mild hyperbilirubinemia (0.6 mg/dL; reference range, 0.1–0.4 mg/dL). The total T4 level was 14.6 nmol/L (reference range, 10.0–45.5 nmol/L) and tests for the feline leukemia and feline immunodeficiency viruses performed by the referring veterinarian were both negative. Treatment instituted by the referring veterinarian consisted of prednisone (5 mg per os [PO] q 12 hr for 1 wk then 5 mg PO q 24 hr for 1 wk). The cat again presented to the referring veterinarian 1 mo later, approximately 2 wk prior to the referral, with a continued history of weight loss, anorexia, and diarrhea. The cat's body weight had decreased further to 2.8 kg. The referring veterinarian prescribed 2 mg cyproheptadine PO q 12 hr, but no improvement in appetite or overall condition ensued and the cat was referred.
On presentation to Kansas State University, the cat was listless and febrile with a rectal temperature of 39.6°C. The heart rate was 240 beats/min, the respiratory rate was 40 breaths/min, and mild bilateral ocular discharge was present. The cat was cachexic (body condition score of 1/5) and the mucus membranes were pale pink. In addition, a large skin tear measuring 5 cm × 5 cm was present over the dorsal cervical region. The overlying epidermis appeared to be detached from the underlying dermis as shown in Figure 1. The cat did not have easily epilated hairs. According to the owners, this wound was not present at the time the cat was placed into the carrier immediately prior to their appointment.
Citation: Journal of the American Animal Hospital Association 47, 3; 10.5326/JAAHA-MS-5517
A complete blood count revealed an inflammatory leukogram with neutrophilia (12,700/μL; reference range, 2.5–12,500/μL), increased band neutrophils (600/μL; reference range, 0–300/μL), and lymphopenia (900/μL; reference range, 2,000–7,000/μL). In addition, toxic vacuolations of leukocytes and large reactive lymphocytes were noted on a blood smear. A normocytic, normochromic anemia (hematocrit was 22%; reference range, 30–45%) was present as well as a mild thrombocytopenia (platelets were estimated to be mildly decreased and platelets appeared large). Abnormalities noted on serum chemistry included hypoalbuminemia (2.5 g/dL; reference range, 3.2–4.7 g/dL) and hyperbilirubinemia (0.6 mg/dL; reference range, 0–0.4 mg/dL). Urinalysis revealed a brown urine color with a specific gravity of 1.052, bilirubinuria (2+ on a 3+ scale), and proteinuria (3+ on a 3+ scale).
After initial diagnostics, differential diagnoses focused mainly on causes of cutaneous fragility. These included a paraneoplastic syndrome (e.g., pancreatic, hepatic, or biliary carcinoma) or naturally occurring hyperadrenocorticism. Iatrogenic hypercortisolism was ruled out because the cat had only been treated short-term with prednisone, which had been discontinued at least 2 wk prior to presentation. The lack of concurrent diabetes mellitus made hypercortisolemia or hyperprogesteronemia less likely differential diagnoses (because the majority of cats with either of these conditions are diabetic as well), but they were not completely exclude from consideration.
Abdominal radiographs revealed mild hepatomegaly and an ill-defined area of increased soft tissue opacity and poor serosal detail in the cranioventral abdomen. These findings were suggestive of focal peritonitis, effusion, or a mass effect. Abdominal ultrasound findings included the following: diffusely enlarged and hypoechoic liver and spleen consistent with neoplasia or diffuse inflammatory disease; a diffusely hypoechoic pancreas with hyperechoic peripancreatic fat, suggestive of pancreatitis or neoplasia; and a moderate accumulation of echogenic material in the urinary bladder, consistent with cellular and proteinaceous debris.
The owner elected euthanasia at that time due to the cat's poor condition and suspected guarded to poor prognosis. Differentials at the time of euthanasia included pancreatic neoplasia, hepatic neoplasia, or hyperadrenocorticism. A necropsy was performed.
The skin of the dorsum, head, and forelimbs easily peeled away from the underlying dermis and, as stated previously, the hairs were not easily epilated from the underlying skin. The liver was slightly yellow and friable with multiple pinpoint red foci at the borders of all lobes. A single, white, raised area in the right middle lobe was noted. The gallbladder was absent and the bile duct was tortuous and distended with bile. The spleen was mildly enlarged, had a meaty consistency, and had one small, white, 3 mm focus on the capsular surface. A dark red, 0.5 cm focus in the left lobe of the pancreas was also noted. The bone marrow of both the humerus and femur were dark red with no visible marrow fat.
Microscopic examination of the skin revealed atrophy of the epidermis and diffuse dermal edema characterized by the separation of dermal collagen, which was more predominant at the dermoepidermal junction (Figure 2). The superficial dermis was infiltrated by a moderate number of mast cells. In the subcutis, there was fibrinoid necrosis of the blood vessels along with an infiltrate of lymphocytes and macrophages (Figure 3). Several macrophages and intravascular monocytes contained round to oval, 2–4 μm yeasts containing basophilic centers and peripheral clear zones with indistinct outer cell walls (Figure 4). The organisms were consistent with Histoplasma spp. Disseminated histoplasmosis was evident with Histoplasma spp. organisms identified in macrophages within the liver, spleen, pancreas, lung, and bone marrow. No other disease process or pathology was identified, including the adrenal glands, which were grossly and histologically normal.
Citation: Journal of the American Animal Hospital Association 47, 3; 10.5326/JAAHA-MS-5517
Citation: Journal of the American Animal Hospital Association 47, 3; 10.5326/JAAHA-MS-5517
Citation: Journal of the American Animal Hospital Association 47, 3; 10.5326/JAAHA-MS-5517
Discussion
To the authors' knowledge, this is the first report of disseminated histoplasmosis accompanied by cutaneous fragility in a cat. The cutaneous fragility in this cat was attributed to the disseminated infiltration of the yeast-laden macrophages within the subcutis and dermis and concurrent vasculitis. Although most reported cases of cutaneous fragility are associated with either naturally occurring or iatrogenic hypercortisolism, there was no evidence for this in the cat described in this report. This cat had been treated with prednisone, but the drug had only been administered for 2 wk, which is a much shorter time period than what is reported to cause cutaneous fragility. As discussed by Lien et al. (2006), a mean treatment time of 8.3 mo of either topical or oral steroids is reported to result in cutaneous fragility in some cats.6 In addition, prednisone was discontinued at least 2 wk prior to the cat's referral appointment. Adrenal gland histology was normal thereby eliminating naturally occurring hyperadrenocorticism as a predisposing factor. A congenital cutaneous fragility syndrome was considered unlikely primarily because of this cat's age and lack of skin hyperextensibility. Further, there was no additional evidence on necropsy to support a paraneoplastic syndrome for the cutaneous fragility. Liver disease, most often hepatic carcinoma, has been associated with skin fragility in cats; however, liver disease was unlikely the contributing factor in this case given that the hepatic dysfunction was not severe. Infiltration of the liver is common in histoplasmosis, yet skin fragility has not been reported previously.
Reported cases of gallbladder agenesis are rare in both veterinary medicine and human medicine. No reported cases of gallbladder agenesis in cats were found during the preparation of this manuscript. In case reports in human medicine, there may be familial hereditary forms of gallbladder agenesis; however, the etiology is unknown. Gallbladder agenesis in people is attributed to an abnormality in embryonic development; therefore, most cases are associated with other congenital abnormalities, including the bile system. Human patients become symptomatic in 23% of cases and are often misinterpreted as cholecystitis with duct obstruction. The true diagnosis of gallbladder agenesis is most often found during surgery.11 The gallbladder agenesis in this cat is considered an incidental finding and did not appear to contribute to the changes found on necropsy in the hepatic, gallbladder, and ductal regions.
Histoplasmosis in the United States is caused by infection with Histoplasma capsulatum, which is a dimorphic, soil-borne fungus. The majority of clinical cases occur in the central United States in the region of the Ohio, Missouri, and Mississippi rivers. The fungus exists in the mycelial form in soils rich in bird or bat feces. The mycelia form sheds free-living microconidia (2–5 μm) or macroconidia (5–18 μm) that cause infection in mammalian hosts.12 Infection with H. capsulatum is probably acquired via inhalation of microconidia, which are small enough to enter the respiratory tract. Yeast organisms in the lungs are phagocytized by cells of the mononuclear phagocyte system and undergo intracellular replication.12 Infection may be either limited to the pulmonary system or lymphatic and hematogenous dissemination of the organism can occur. More severe infections can occur in individuals with impaired immune systems or if the dose of infective spores is high.12
Cats are considered susceptible hosts with the majority of cases occurring in young cats under 4 yr of age. The most commonly affected sites in cats include lungs, lymph nodes, spleen, liver, eyes, and bone marrow. Most infected cats have disseminated disease and present with various, nonspecific clinical signs, including weight loss, fever, and anorexia.13,14 Dyspnea, tachypnea, and/or abnormal lung sounds are found in >50% of affected cats. Other frequent abnormalities include lymphadenomegaly, splenomegaly, and hepatomegaly. Anemia and interstitial lung disease are commonly found in infected cats, whereas cutaneous involvement is only infrequently reported and limited to nodular or ulcerated lesions. The diffuse dermal invasion seen in the cat of this report has not been previously described to the authors' knowledge.
In the United States, cutaneous involvement of histoplasmosis is uncommon in dogs as well as in cats. Macrophages containing organisms are commonly found infiltrating the dermis and subcutaneous tissues, but the lesions are described as papular granulomas without generalized dissemination throughout the dermis.15 In Japan, histoplasmosis is typically confined to lesions of the skin or gingiva without the pulmonary or gastrointestinal involvement seen in the United States; however, the reported cases from Japan of cutaneous histoplasmosis in dogs describe focal to multifocal, ulcerated or nodular lesions without generalized diffuse dermal invasion. To the authors' knowledge, there are no reports of cutaneous fragility.16,17
Ramdial et al. (2002) discussed cutaneous lesions as part of disseminated histoplasmosis in humans infected with the human immunodeficiency virus that developed acquired immune deficiency syndrome.18 Various gross lesions were described, including papules, nodules, plaques, lesions resembling erythema multiforme, and exfoliative dermatitis, characterized by generalized erythematous skin with shedding. This variability resulted in differing histopathologic features depending on the severity of CD4+ peripheral lymphocyte count, including: necrotizing and non-necrotizing granulomatous inflammation with few intrahistiocytic yeast organisms; diffuse dermal and intravascular accumulation of histiocytes containing many yeast organisms; diffuse dermal karyorrhexis, collagen necrosis; interstitial, extracellular yeast organisms; and leukocytoclastic vasculitis. Transepithelial elimination of yeast organisms accompanied by epidermal hyperkeratosis and parakeratosis was found in several biopsies of all of the above-described clinical appearances, but was most developed in patients with exfoliative dermatitis. Although the cat in this report was not evidently infected with either the feline leukemia virus or feline immunodeficiency virus, defects in immune response may still have been an important component in the development of this cat's disease.
Although various conditions are associated with feline acquired skin fragility syndrome, the pathogenesis of this syndrome is not known.5 In this case, possible explanations for the atrophy resulting from diffuse histoplasmosis include either inflammatory mediators released by the infected and activated tissue macrophages or disturbed cutaneous blood flow secondary to the severe vasculitis, suspected but not proven, to be causing the severe edema. Either explanation, as well as other undetermined mechanisms, is possible to explain the resulting skin atrophy in this cat.
Conclusion
This report describes an extreme and previously unreported generalized, diffuse, cutaneous histoplasmosis in a cat presenting with cutaneous fragility. Although most cases of acquired cutaneous fragility in the cat are associated with an endocrine disorder, there was no evidence of an endocrinopathy in this cat. This case emphasizes the need to confirm the etiology of acquired cutaneous fragility with histology, especially when diabetes mellitus, a common comorbidity of hypercortisolism, is absent.
Fragility of the skin resulted in a skin tear in the dorsal cervical area (approximate size of skin tear is 5cm; cm scale shown next to lesion).
Histomicrograph of the skin showing atrophy of the epidermis and dermal edema, which is predominant at the dermoepidermal junction. Dermal edema resulted in separation of the epidermis and dermis (40×, hematoxylin and eosin stain).
Histomicrograph showing fibrinoid necrosis of a blood vessel. The vessel is infiltrated by large numbers of macrophages and lymphocytes (40×, hematoxylin and eosin stain).
Grocott's methanamine silver staining showing the presence of large numbers of Histoplasma spp. yeast in the macrophages infiltrating the blood vessel in the subcutis (40×, Grocott's methanamine silver staining).
Contributor Notes
A. Tamulevicus' present affiliation is Red Bank Veterinary Hospital, Tinton Falls, NJ. Her updated credentials since article acceptance are MS, DVM, DACVIM.
