In a strict sense, the cutaneous disorders that should be viewed as markers of an internal disease are caused by the secretion of yet unknown (cytokines?) or known (e.g., glucagon, lipase, lipoproteins) substances from various internal organs targeting almost exclusively the skin. Paraneoplastic (e.g., alopecia or exfoliative dermatitis), metabolic (e.g., hepatocutaneous syndrome), inflammatory (e.g., sterile nodular panniculitis) and developmental (nodular dermatofibrosis) diseases constitute the main components of this interesting group of dermatoses, the display of which should alert the clinician for further investigation of internal organ systems. Paraneoplastic dermatoses are far more common in cats than in dogs. Endocrinopathies which are due to functional benign or malignant neoplasms of the pituitary gland (hyper-adrenocorticism, acromegaly), adrenals (hyperadrenocorticism, pheochromocytoma) or gonads (e.g., sertoliomas) will not be discussed in this lecture simply because the hormonal excess (cortisol, growth hormone, catecholamines, estrogens) targets the skin along with other internal organ systems.

A TYPICAL COLORATION

Coat colors are also external markers for internal diseases, the most important of which are the Chédiak-Higashi syndrome and canine cyclic hematopoesis. The former is an inherited disorder of Persian cats with blue-smoke hair colour and yellow eyes. The trichogram of these animals reveals the presence of abnormal macromelanocytes, while on peripheral blood smears giant lysosomes, that appear as large eosinophilic granules, are noticeable inside the neutrophils and monocytes. The syndrome is characterized by partial oculocutaneous albinism, susceptibility to infections and bleeding tendency. Cyclic hematopoesis is an autosomal recessive syndrome appearing in collie puppies born with a silver-gray hair coat and light-colored nose. By 8 to 12 weeks of age the stunted puppies exhibit various bacterial infections, lymphadenopathy, fever and arthralgia which are mainly accompanied by neutropenia that alternates with rebound neutrophilia every 10 to 12 days until the death of the animal, usually occurring before the age of 6 months. Since there is no effective treatment for both syndromes, the parents and littermates of the affected animals should not be used for breeding.

NODULAR DERMATOFIBROSIS OF THE DOG

In this disease, multiple collagenous nevi develop between 3 and 5 years of age (non-pruritic papules or nodules measuring from 0.5 to 5 cm) which are usually located on the distal extremities and head. An autosomal dominant mode of inheritance is suspected in the German shepherds, the most commonly affected breed. Aside from the cutaneous condition, these animals have renal cyctic disease, cystadenocarcinoma, uterine leiomyoma and/or small intestinal polyps. The simultaneous fibrosis of the skin and renal parenchyma cause outflow urinary obstruction eventually leading to renal tubule cyst formation and renal cystadenoma or cystadenocarcinoma. Although the diagnosis is not difficult (skin biopsy, abdominal ultrasonography, CT, MRI), at present there is no effective treatment. Complications such as ruptured renal cysts with subsequent peritonitis and renal tumor metastasis are a common cause of death or euthanasia but in the majority of cases, the lifespan does no seem to be significantly shortened.

ACQUIRED SKIN FRAGILITY SYNDROME IN CATS

This multifactorial syndrome is characterized clinically by a thin skin which tears easily even after gentle manipulation or minimal trauma. Hence, large areas of the body are left without skin, eventually leading to excessive losses of fluids and proteins. Hyperadrenocorticism, progestagens, glucocorticoids, cholangiohepatitis, hepatic lipidosis and diabetes mellitus have been incriminated as underlying conditions, although some cases are idiopathic. On skin histopathology, collagen fibers appear fragmented, irregularly oriented and decreased in density and size. On electron microscopy they are loosely packed and twisted. Addressing and correction, if possible, of the underlying diseases or removal of the offending medications, along with minimal handling of the sick cat and good supportive care (e.g., high energy-protein diet, IV fluids and plasma, topical treatment) are required to improve prognosis. The main differential could be the Ehlers-Danlos syndrome, an inherited skin disease seen in young animals and due to a type I procollagen processing defect.

METABOLIC EPIDERMAL NECROSIS (HEPATOCUTANEOUS SYNDROME)

This disease (MEN) refers to a group of skin lesions and histological changes associated with an internal disease process. In the dog, MEN is usually associated with a vacuolar hepatopathy of unknown origin and much less frequently with glucagon-secreting tumors. In some cases, however, a hepatopathy due to the long-term use of anticonvulsant medications or to mycotoxin ingestion has been implicated. In the few cases involving the cat, MEN has been associated etiologically with pancreatic carcinoma, hepatopathies and thymic amyloidosis. The disease is typically seen in middle-aged to old animals with a history of relatively acute onset of alopecic, erythematous, exudative, coalescing papules and/or plaques with crusting, ulceration and occasionally vesiculation.

The lesions are usually located in the muzzle, distal extremities, footpads (hyperkeratosis, exfoliation, fissures, erosions), pressure points, mucocutaneous junctions and genitalia. Other noticeable signs are lethargy, partial anorexia and gradual weight loss. Polyuria and polydipsia are also seen, especially when the disease is complicated by diabetes mellitus, secondary to glucagonomas. Cutaneous lesions may precede the clinical onset of the underlying disease. A superficial perivascular to interface, cell-rich, dermatitis with marked diffuse parakeratotic hyperkeratosis and striking inter-and intracellular edema limited to the upper half of the epidermis are usually demonstrated by skin biopsies. Varying degrees of hypoaminoacidemia, hyperglucagonemia and hyperinsulinemia have been reported with both liver and pancreatic-associated MEN. Lack of specificity renders the diagnostic value of these tests questionable. In abdominal ultrasound, a "Swiss cheese" liver echotexture representing a hyperechoic network surrounding hypoechoic areas of parenchyma is diagnostic of vascular hepatopathy. This approach is frequently unremarkable in glucagonoma patients although pancreatic tumors or hepatic metastases are occasionally detected. Ultrasound-guided liver biopsies may reveal cirrhosis, vacuolar hepatopathy with cirrhosis, parenchymal collapse and nodular hyperplasia or toxic hepatopathy.

Unfortunately, the progression of the underlying hepatopathies is relentless but surgical excision of glucagonomas generally results in remission of all clinical signs although pancreatitis, biliary obstruction or metastatic disease may occur postoperatively. In an attempt to correct the nutritional deficit of epidermis, high-quality proteins (egg yolks, Hill's Prescription diet a/d, raw bovine or porcine pancreas) along with dietary zinc and fatty acid supplementation, are advocated. Intravenous amino acid supplementation, preferably as a hypertonic 10% crystalline solution (25 ml/Kg BW over 6-8 hours for 1-3 days) results in quick and effective decrease of pain and healing time of skin lesions. The use of octreotide for palliative control of glucagonoma-induced MEN is limited because of the expense and drug-resistance. Glucocorticoids aid in the resolution of the skin lesions but may cause a diabetic crisis. The long-term prognosis, especially if vacuolar hepatopathy is the underlying disease, is poor as most of the affected animals finally die up to 6 months from the time of diagnosis.

XANTHOMAS

These lipid-laden cutaneous granulomas may be seen in cats with spontaneous or drug-induced (progestagens, glucocorticoids) diabetes mellitus or idiopathic hyperlipoproteinemia. The skin lesions consist of non-painful and non-pruritic yellowish papules, nodules or plaques that are commonly located on the head, distal extremities and bony prominences. Histopathology discloses a nodular to diffuse infiltration of the dermis by foamy macrophages, stained positive with Sudan and multinucleate giant cells. As soon as the diagnosis is made, a blood lipid profile (cholesterol, triglycerides, lipoprotein electrophoresis, chylomicrons, lipoprotein lipase) along with a search for diabetes mellitus should always be pursued. Xanthomas usually resolve spontaneously if the underlying disease can be treated or controlled. Changing the regular to low-fat diets in cats with idiopathic hyperlipoproteinemia is followed by complete lesional remission in a short period of time.

STERILE NODULAR PANNICULITIS

Panniculitis, referring to the inflammation of the subcutaneous adipose tissue, has been associated with multiple causes including infectious agents (bacteria, mycobacteria, fungi, Leishmania), pancreatic disorders, immunologic conditions (SLE, idiopathic vasculitis, rheumatoid arthritis), drug reactions, neoplasia, vitamin E deficiency and physicochemical factors. However, the majority of cases are attributed to idiopathy. In acute (edematous, necrotic) or chronic pancreatitis, apart from the skin lesions, the animals frequently exhibit vomiting, abdominal pain, various constitutional signs or sometimes nothing. Presumably, in the pancreatic subtype the increased concentrations of lipase hydrolyze panniculus adiposus into glycerol and fatty acids. The latter can initiate regional inflammation finally culminating into an unrelenting granulomatous response. This is why serum lipase and TLI measurements should always be included in the laboratory evaluation. Skin lesions consist of single or multiple subcutaneous nodules that vary in size and consistency. They are often seen on the dorsal aspects of the neck and trunk, the proximal extremities and ventrolateral thorax and are neither painful nor pruritic. When they fistulate, an oily clear to straw-colored exudate appears, which becomes purulent if the lesions are secondarily infected. Excisional biopsies reveal the presence of septal, lobular or diffuse pyogranulomatous to granulomatous panniculitis; lymphoplasmacytic infiltrate and fibrous tissue tend to dominate with chronicity. Special staining, particularly acid-fast, should always be applied to evaluate for microorganisms as well as polarized light examination for foreign bodies and injection remnants. In the pancreatic subset of the syndrome, the involution of the acute disease usually abolishes the skin lesions without any further treatment but in the chronic form, vitamin E megadoses, pentoxiphylinne and possibly oral potassium iodide may be useful. Glucocorticoids, the cornerstone of treatment in the immune-mediated and idiopathic subsets of nodular panniculitis, should be avoided.

FELINE PARANEOPLASTIC ALOPECIA

This non-pruritic alopecia is usually associated with pancreatic or bile duct carcinomas and is possibly caused by a yet unknown circulating tumor derived-factor. The affected cats are usually old animals, irrespective of breed or gender. The disease is often characterized by concurrent systemic (anorexia, lethargy, vomiting, weight loss) and cutaneous manifestations. The alopecia usually starts on the chin or ventral neck and rapidly extends to the ventrum and the medial aspects of the limbs. The alopecic skin has a glistening and shiny appearance with erythema and fine scaling, while the hairs epilate easily from the adjacent haircoat. Footpads may be shiny and smooth with crusts and fissures. In some cats, secondary infection with Malassezia spp. may cause mild to moderate pruritus. The differential diagnosis does not pose any difficulties since no other alopecic condition displays a similar clinical phenotype. Abdominal ultrasonography should be pursued to evaluate for a mass or nodules on the pancreas or liver; however, their absence does not preclude a diagnosis of pancreatic or hepatic neoplasia, further confirmed by exploratory laparotomy and lesional histopathology. On skin histopathology, there is a marked follicular and adnexal atrophy, telogenization and epidermal hypokeratosis. The prognosis is generally poor, mainly because of the high metastatic potential of these neoplasms and the failures of chemotherapy.

FELINE THYMOMA-ASSOCIATED EXFOLIATIVE DERMATITIS

Exfoliative dermatitis has been reported in cats in association with thymoma. An autoimmune process is assumed to be mediated by autoreactive cytotoxic T lymphocytes that escape negative selection in the thymus and cause direct damage to keratinocytes. This disorder begins as non-pruritic scaling and mild erythema on the head and pinnae. Progressively, the lesions spread over the rest of the body with intensification of scaling and development of alopecia. Brown, waxy, keratosebaceous debris accumulates between the digits, in the nail beds and in the ear canals. Crusts and ulcers may also develop. The appearance of pruritus is usually associated with secondary overgrowth of Malassezia spp. On skin histopathology, the most characteristic finding is a cell-poor hydropic interface dermatitis wherein multifocal areas of hydropic degeneration of basal cells and apoptotic keratinocytes are found in the epidermis and the infundibular region of hair follicles. This histological appearance is quite similar to what is seen in graft versus host disease. On clinical grounds, the list of differentials should include allergies, dermatophytosis, FeLV infection, cheyletiellosis, drug reaction, pemphigus foliaceous and epitheliotropic lymphoma. The affected cats may look normal or sick (dyspnea, coughing, anorexia, lethargy), because of the tumor growth or the appearance of intercurrent conditions (myasthenia gravis, polymyositis). In thoracic radiographs, the presence of a variably sized mass in the cranial mediastinum, occasionally accompanied by pleural effusion, is suggestive of diagnosis; ultrasound-guided cytology (small mature lymphocytes and/or abnormal epithelial cells) and histopathology further confirm it. Since feline thymomas are usually benign tumors, surgical removal is in general curative, carrying a good prognosis with a median survival of almost 2 years.

PARANEOPLASTIC PEMPHIGUS

In the dog, the extremely uncommon PNP has been associated with thymoma, sertolioma and mammary carcinoma. Probably, tumor antigens cross-react with normal epithelial antigens (molecular mimicry) or the tumor is secreting excessive amounts of cytokines (i.e., IL-6) that stimulate the immune system leading to immune-mediated disease. The targeted antigens in PNP are envoplakin, periplakin and desmoglein 3. The clinical phenotype of canine PNP includes severe erosive and ulcerative oral lesions and vesicobullous cutaneous lesions, first appearing on the head to progress to the extremities and trunk. Histopathologically, unique to PNP is the presence of apoptotic keratinocytes and mild acantholysis at all levels of the epidermis, follicular epithelium and / or oral epithelium, basal vacuolization and intense epithelial lymphocytic-histiocytic exocytosis. PNP has a poor prognosis because it is generally unresponsive to immunosuppressive therapy, unless the tumor can be completely cured.

SECONDARY SKIN NEOPLASMS

These rarely occurring tumors result from primary neoplasm metastasis of internal organs to the skin. Metastatic mechanisms may include local growth factors, adhesion molecules of microvascular endothelium and soluble chemotactic agents which presumably facilitate the migration, adherence and invasion of neoplastic cells into the skin. Destructive lesions on the digits have been noticed in aged cats with asymptomatic or symptomatic (dyspnea, coughing) bronchogenic or squamous cell carcinomas. The high vascularity of the feline footpad may be linked to the pathogenesis of this disorder. Sometimes the lesions may also be present at other cutaneous sites. In the majority of the cases, multiple digits of multiple paws show swelling, ulcerations and onychomadesis that may lead to lameness. Occasionally, only one paw or one digit is affected. Digit histopathology reveals infiltration by tubular structures containing ciliated and mucous cells. Thoracic radiographs (lobar, nodular and/or interstitial pattern) followed by pulmonary histopathology further confirm the diagnosis. Since life expectancy is about 2 months, amputation of the affected digits and/or lung lobectomy are not recommended.

In the dog, chronic lymphocytic leukemia may, on rare instances, cause leukemia cutis. It is usually expressed by multifocal alopecia, erythema and papules on the trunk, associated or not with recurrent bacterial pyoderma. Leukemia cutis is characterized histologically by a perivascular, interstitial, diffuse and/or lichenoid dermatitis where the leukemia cells predominate.