Cutaneous manifestations of systemic disease

Introduction

It is common to treat dermatologic signs in veterinary practice without identifying a clear cause. Typically a clinician may take a brief history, perform a physical exam, treat any secondary infection, and make a tentative diagnosis. Because the skin has a limited number of ways of responding to injury, this approach may miss the opportunity to diagnose the rare cutaneous manifestations of systemic disease (CMSD).

Although unusual, CMSD can resemble many commonly seen skin problems, so obtaining a thorough history and interpreting clinical findings in light of this information is vital. A complete history includes: age of onset and duration; all medications, topical therapies and nutritional supplements (for both pet and owner); diet quality and composition (to check for potential deficiencies, homeopathic supplements); concurrent diseases/conditions and their treatment; exposure to pets in the household and other animals (daycare/ boarding/travel); presence of pruritus; response to specific therapy and any evidence of other organ systems involved.

Routine bench diagnostic tests (skin scraping, fur pluck, tape prep, impression smear, dermatophyte culture) should be done in every patient to identify microbial overgrowth or demodicosis, and to get a handle on basic supportive care needs. Recognizing dermatologic changes that are markers for specific internal conditions allows the clinician to choose specific tests to obtain a definitive diagnosis, and it is at this point that successful treatment for these rare conditions begins. This article presents a brief overview of just a few systemic diseases that announce their presence with dermatologic clues.

Paraneoplastic disorders

Paraneoplastic skin disorders occur as a result of a neoplasm elsewhere in the body; the cancer itself is not in the skin 1. The cause of the associated skin lesion(s) is generally unknown but may be the result of immune-mediated activity, the impact of a tumor protein on the skin, or the development of enzymes that interfere with normal skin function. These patients may have vague signs of illness (lethargy, weight loss, inappetence, vomiting, diarrhea) but the skin changes announce the systemic abnormality.

Superficial necrolytic dermatitis (SND, or Hepatocutaneous Syndrome, Necrolytic Migratory Erythema (NME), Metabolic Epidermal Necrosis), is a rare and often fatal condition in older (> 10 years) dogs of either sex and smaller breeds 2 3 4 5 and very rarely in cats 6 7. A common presentation is of constant paw licking or difficulty walking. The clinical history includes acute onset of lethargy and lameness, inappetence, polyuria/polydipsia (PUPD), cutaneous pain and pruritus, and weight loss. Skin lesions are often dramatic; ulceration and depigmentation at the mucocutaneous junctions, and erythemic, exudative crusting over points of wear including elbows and hocks, axillae and groin, and footpads showing marked hyperkeratosis) (Figure 1) (Figure 2) (Figure 3). Secondary bacterial and yeast infections are common. The cutaneous lesions are markers for advanced hepatic disease or pancreatic neoplasia, and may precede clinical signs of the primary disease by weeks or months. In humans, SND is most often associated with a glucagonoma, but this is rare in dogs. A history of potentially hepatotoxic drug therapy (ketoconazole, rifampin, phenobarbital, etc.) may indicate a possible cause, but more often the etiology remains unknown 2 3 4 5. Differential diagnoses in dogs include pemphigus foliaceus (PF), systemic lupus erythematosus (SLE), drug eruption, zinc responsive dermatitis, cutaneous lymphosarcoma / mycosis fungoides (CLSA/ MF), and leishmaniasis. In cats the rule outs include PF, SLE, exfoliative dermatitis, feline paraneoplastic alopecia, and Cushing’s/acquired skin fragility syndrome.

Routine blood tests will often demonstrate hypoalbuminemia, normocytic normochromic non-regenerative anemia, hyperglycemia, glycosuria, elevated alkaline phosphatase and ALT, and increased total bilirubin and bile acids. Hypoaminoacidemia is a consistent finding, regardless of the primary diagnosis, and is thought to be responsible for the dermatological signs 2 3 4 5 6 7. Hepatic abdominal ultrasound may show a “honeycomb” hyper- and hypoechoic pattern (idiopathic vacuolar hepatopathy) but identification of a pancreatic tumor on ultrasound is rare. Skin biopsies (which should include newly crusting areas with the crust intact) are diagnostic, with a classic diffuse parakeratotic hyperkeratosis, intra- and intercellular epidermal edema, and a superficial dermal perivascular to lichenoid infiltrate (red, white and blue pattern) on H& E 2 3 4 5 6 7. Chronic lesions may lack the epidermal edema. Secondary bacterial and yeast infections may be identified in the superficial crusts.

SND is a severe, challenging condition with a grave prognosis because the causative disease is often advanced and irreversible. Therapy is directed at correcting the underlying disease if possible and providing supportive care. Animals with pancreatic neoplasia or drug-induced hepatopathy have the best chance of survival if the tumor can be removed or the drug withdrawn in time for the liver to recover. Treatment for idiopathic vacuolar hepatopathy is limited to supportive care, which includes treating secondary skin infections and nutritional support to correct the amino acid deficiency. Intravenous hyperalimentation with a hypertonic amino acid supplement over a 6-8 hour period 1-2 times a week until lesions improve is beneficial in some patients, but if there is no response in the first two weeks, this is unlikely to be of help. Dietary support includes adding omega-3 fatty acids, zinc and high quality protein to the diet. Glucocorticoid therapy may produce temporary improvement of skin signs, but the state of glucose intolerance and risk of inducing diabetes mellitus may preclude their use.

Feline paraneoplastic alopecia (FPA) presents with a history of acute onset, rapidly progressive non-pruritic alopecia affecting the ventral chest, axillae, abdomen, and medial and caudal thigh regions extending onto the perineum, paws and nasal planum (Figure 4). A classic glistening or shiny appearance to the skin sets it apart from other causes of alopecia, but may not be present in every case. There may be a mild to moderate crusting at the margin of the haired skin and the fur epilates easily in these areas. Pruritus may be attributed to a Malassezia infection in the crusted margins. Other vague clinical signs include weight loss and inappetence. Histopathologic results demonstrate telogenization of hair follicles without tricholemal keratinization, a hyperplastic epidermis, and a mild mononuclear cell infiltrate in the superficial dermis 8 9 10. This is a rare condition in older cats (>10 years) associated with pancreatic carcinoma, cholangiocarcinoma, hepatocellular carcinoma, metastatic intestinal carcinoma, neuroendocrine pancreatic neoplasia and hepatosplenic plasma cell tumor 8 9 10. By the time the dermatologic signs are evident the cancer has already metastasized. Primary differential diagnoses include dermatophytosis, demodicosis, allergic dermatoses, hyperadrenocorticism, thyroid disease (hyper- and hypothyroidism), and exfoliative dermatitis. Removal of the tumor may be possible, but FPA generally carries a grave prognosis.

Exfoliative dermatitis and thymoma in cats can present with marked diffuse exfoliative dermatitis, where large, flat, dry flakes come off the skin in sheets, a hallmark presenting sign for this condition 11 12 (Figure 5). As the disease progresses generalized erythroderma develops and the fur may epilate easily, but the condition is non-pruritic, unless accompanied by Malassezia overgrowth. These cats are clinically sick (anorectic, depressed, thin). Identification of a mediastinal mass (via thoracic radiograph/ultrasound) supports the diagnosis, but the dermatitis may precede detection of a mediastinal mass. CBC and biochemical profile findings are variable and unremarkable. Histologic findings on skin biopsy include marked diffuse orthokeratotic hyperkeratosis, a cell-poor interface dermatitis with hydropic degeneration of basal cells, and apoptosis of keratinocytes 11 12. The pathomechanism of the dermatosis is unknown but is thought to be a graft vs. host-like reaction, where immunoreactive T-cells target the skin. Primary rule-outs include FPA, dermatophytosis, Erythema Multiforme, SLE, CLSA/MF, and Exfoliative Dermatitis not related to thymoma. Removal of the thymic tumor is the treatment of choice.

Exfoliative dermatitis without thymoma 12 is an important differential diagnosis for this condition because it carries a better prognosis and a different therapeutic approach. The diagnostic evaluation is the same but a search for a mediastinal tumor is negative and the condition responds well to immunosuppressive therapy (ciclosporin and glucocorticoids).

Endocrine dermatoses

Endocrine disorders are caused by an imbalance (usually excess) in hormones. The classic dermatological presentation is bilaterally symmetrical hypotrichosis to alopecia without pruritus 13, although secondary bacterial or yeast infection, as a result of altered barrier function and immune response, can cause pruritus. Common endocrinopathies include gonadal, adrenal and thyroid disorders. Skin changes are often noted before constitutional signs develop and are similar among the different hormonal abnormalities. Signalment, a thorough history and complete dermatologic examination will inform the differential diagnosis list. Endocrine dermatoses may present with dry, brittle fur; non-pruritic symmetrical trunkal alopecia (the head and extremities are often spared); loss of primary pelage (puppy coat); symmetrical cutaneous hyperpigmentation in the areas of fur loss that can become generalized; lichenification, especially over areas of friction; failure of the fur to regrow after being clipped; and a scaly seborrheic dermatosis that may be dry or oily 1. These diseases may also be classified as paraneoplastic, as they are often caused by excess hormone from a glandular tumor. Common skin disorders that can resemble endocrine disease include any chronic pruritic condition that leads to alopecia, hyperpigmentation and lichenification; Malassezia dermatitis (chronic); or the effects of iatrogenic hormonal excess.

Hyperadrenocorticism (HAC) or spontaneous Cushing’s disease results in excess cortisol from either a pituitary or adrenal tumor. It occurs in middle aged to older dogs; Boxers, Poodles, Boston terriers, Scottish terriers and Dachshunds are over-represented 13. Excess cortisol has a significant effect on epidermal, follicular, collagen and elastin production. Naturally occurring HAC may cause PUPD, panting, thinning of the fur, bruising of the skin, cutaneous hyperpigmentation, bilaterally symmetrical alopecia, seborrheic dermatitis, thin hypotonic skin, comedones, muscle atrophy, prominent dermal blood vessels, and a pot-bellied appearance (Figure 6) (Figure 7). Calcinosis cutis may occur in about 10 % of patients. Chronic, recurrent superficial pyoderma, generalized demodicosis, Malassezia dermatitis, or dermatophytosis may occur concurrently, reflecting a suppressed immune function. Other effects of excessive cortisol include diabetes mellitus, recurrent urinary tract infections, acute pancreatitis, and glomerulonephritis. The disease is very rare in older cats; skin lesions may include symmetrical loss of fur, thin, fragile skin that tears and bruises easily, curling of the ear tips, comedones and prominent blood vessels (Figure 8). Iatrogenic HAC may occur in both dogs and cats with therapeutic glucocorticoid excess.

Various abnormalities are often noted on blood sampling 13, and an ACTH stimulation test or a low dose dexamethasone suppression test (LDDST) confirms diagnosis. Abdominal ultrasound may reveal a unilateral adrenal tumor with contralateral adrenal atrophy, or bilaterally plump adrenal glands with pituitary dependent HAC.

Some patients have normal cortisol values on testing despite classic HAC dermatologic changes 13 14 15 16 17 18. Various terms have been used for this (adrenal hyperplasia-like syndrome, adrenal sex hormone imbalance, alopecia X, pseudo-Cushing’s disease), but hair cycle arrest is currently the preferred term 16 17. Adult (2-10 year old) male or female neutered or intact dogs develop a gradual and progressive symmetrical loss of primary but retention of secondary hairs that affects the collar region, trunk and caudal thighs, with the head, face and paws spared (Figure 9). Over time, the skin becomes alopecic, hyperpigmented, scaly, dry and hypotonic. Pruritus is rare. Breeds over-represented include the Pomeranian, Chow Chow, Keeshond, Samoyed, and Poodle, although mixed breeds may be affected as well. A clear pathogenesis has yet to be defined 14 15 but primary differential diagnoses include most endocrine dermatopathies. A variety of treatment options have been proposed (melatonin, mitotane, trilostane, phytoestrogens, microneedling) but response to therapy is unpredictable (13 16 17 18 19, and both mitotane and trilostane may cause adrenal suppression, which warrants caution with either of these therapies.

Hyperestrogenism (feminization syndrome) is the most common and most serious of the gonadal hormone imbalances and can occur with cystic ovaries, a retained testicle or testicular tumor, from contact with an owner’s estrogen supplement, or treatment with an estrogen drug for urinary incontinence. History is key for diagnosis. Dermatologic signs may be the only clues and include symmetrical alopecia, cutaneous hyperpigmentation of the neck and trunk, seborrheic dermatitis, and pruritus from yeast or bacterial overgrowth (Figure 10). Female dogs may show signs of estrus and vulvar enlargement.

Sertoli cell tumors are the most common testicular neoplasm causing estrogen excess in the dog. Male dogs may show gynecomastia, pendulous prepuce, macular melanosis (Figure 11) in the groin, linear preputial pigmentary change, preputial dermatosis, and attraction to other male dogs. Estrogen excess may cause a life-threatening non-regenerative anemia and thrombocytopenia via bone marrow suppression, so a CBC is mandatory in suspected patients. Surgical removal of the source of the estrogen excess is curative if metastasis has not occurred.

Immune-mediated disease

Immune-mediated skin conditions can present in a variety of ways and mimic a whole spectrum of common conditions. Again a thorough history, including recent and concurrent medications, supplements, diet and topical therapies, is key in obtaining the correct diagnosis.

Cutaneous adverse drug reactions (CADR) occurs when a negative, harmful and unintended reaction occurs as a result of administering or applying a medication, or as a result of the interaction between two chemicals or medications 20. The pathomechanism is broadly divided into non-immunologic (overdose, irritant reaction, drug interaction) and immunologic (either an autoimmune or foreign antigen response) but the actual pathogenesis is unknown. Lesions can develop with medication used only once or multiple times over months or years. CADR can mimic almost any dermatologic condition and is always a consideration for CMSD. An animal with a history of an allergic condition might be dismissed as simply having a severe flare-up of allergies if this possibility is not considered. If what usually works for an allergic pet suddenly stops working, the diagnosis should be reassessed.

There is no age, breed or sex predilection. Any medication used recently or currently is suspect, but commonly implicated drugs include vaccines, sulfonamides, cephalosporins, penicillins, carprofen, and topically applied insecticides and shampoos 20. Certain dietary ingredients have also been implicated. Dermatological findings include macular-papular-pustular eruptions; exfoliative erythroderma; depigmentation; superficial pustular dermatitis with crusting; erythema, erosions and ulceration of mucous membranes and mucocutaneous junctions; urticaria and angioedema; and full thickness necrosis. Lesions tend to occur ventrally (axilla, groin, genitalia) (Figure 12), over pressure points, at mucocutaneous junctions and mucous membranes, and on extremities (pinna, footpads, nail beds). A history of an acute onset and rapid progression of dermatitis should prompt careful evaluation and immediate discontinuation of any medications. The reaction may be limited to the skin or may affect multiple organs.

Erythema multiforme (EM) and toxic epidermal necrolysis (TEN) are the two most severe presentations for a drug eruption. In dogs, EM is thought to be a host-specific cell-mediated hypersensitivity reaction directed toward an antigenic stimulus 20. Clinically, EM demonstrates erythematous flat or raised macules with central clearing that spread peripherally and coalesce to produce annular to serpiginous patterns with or without adherent surface crusts (Figure 12). Lesions may occur in the axillae, groin, oral cavity, mucocutaneous junctions, pinnae and footpads. Oral and mucocutaneous lesions are erythemic to vesiculobullous to ulcerative. Some patients are febrile, moribund and anorexic. A skin biopsy taken from a non-ulcerated lesion with an intact epidermis is required to make the diagnosis. Histologic findings for EM include a cell-rich interface dermatitis and keratinocyte apoptosis.

TEN is a rare life-threatening ulcerative and vesiculobullous disease of the skin, mucous membranes and oral cavity most commonly caused by an adverse drug reaction 20. There is an acute onset of fever, inappetence and lethargy that accompanies the skin eruptions, which may involve a large area of the body. Routine handling of skin may result in sloughing (Figure 13) (Figure 14). Histologic findings include full thickness epidermal necrosis, minimal dermal inflammatory cell infiltrate, and dermal epidermal separation with the formation of subepidermal vesicles.

Treatment of drug eruptions includes identifying and eliminating the cause, treating with immunosuppressive (glucocorticoids, ciclosporin) and immunomodulatory (niacinamide, pentoxifylline) medications, and providing appropriate supportive care. Milder forms may resolve without further therapy within a couple of weeks, but more severe forms require aggressive treatment.

Pemphigus foliaceus (PF) is the most common autoimmune disease in dogs and cats. Although typically considered idiopathic, it has occurred as a result of topical pesticides and drugs as well as a paraneoplastic condition 20 21 22 23 24. Differentiating idiopathic PF from drug-induced or paraneoplastic disease requires a complete and thorough history, but the distinction will dictate the course and duration of therapy. PF is a pustular and crusting disease involving the head, face, ears and paws. The primary differential diagnoses include pyoderma, demodicosis and dermatophytosis and allergies with secondary infection (Figure 15). Nasal and mucocutaneous ulceration and depigmentation may also occur, adding other forms of pemphigus, discoid lupus erythematosis, drug eruption, CLSA, SLE, NME, and leishmaniasis to the rule outs. Diagnosis is confirmed with the hallmark histopathological findings of subcorneal and intracorneal pustules containing acantholytic cells.

Paraneoplastic pemphigus (PNP) has the unique histologic findings of intra-epidermal pustules with acantholytic cells similar to PF, along with suprabasilar clefting as seen with pemphigus vulgaris, and intraepidermal apoptosis seen with erythema multiforme. This triad on histopathologic findings warrants investigation for a hidden neoplasm. PNP has been reported in 3 dogs associated with a thymoma, a thymic lymphoma and a splenic sarcoma and one cat with lymphocytic thymoma 25. Establishing an etiology is relevant to therapy because removing the cause can result in permanent resolution of clinical signs.

Nowhere in veterinary dermatology is a thorough history more important than with CMSD. Bench diagnostic tests eliminate the obvious (parasites, dermatophyte infection, pyoderma, Malassezia) and allows the clinician to treat specific lesions whilst developing an initial list of differential diagnoses, but recognizing the skin markers may identify the cause. If a patient fails to respond to logical, problem-based therapy, a CMSD should be considered; it is certainly time to stop and reassess the diagnosis. Revisiting the history and scrutinizing diagnostics to identify the piece of the puzzle that is missing is essential; once the diagnosis is in hand, the therapeutic part is relatively straightforward.