Cutaneous Paraneoplastic Syndromes in Dogs and Cats- A Review of the Literature (Pages 279–296)

8/10/2019 Cutaneous Paraneoplastic Syndromes in Dogs and Cats- A Review of the Literature (Pages 279296)

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2003 European Society of Veterinary Dermatology 279

Veterinary Dermatology2003, 14, 279 296

BlackwellPublishingLtd.

Invited Review

Cutaneous paraneoplastic syndromes in dogs and cats: a review ofthe literature

MICHELLE M. TUREK

School of Veterinary Medicine, Department of Surgical Sciences, University of Wisconsin-Madison, 2015Linden Drive Madison, WI 53706, USA

(Received24 January2003; accepted15 May2003)

Abstract Cutaneous paraneoplastic syndromes are a group of noncancerous dermatoses associated with internalmalignancy. Their recognition can facilitate detection and timely treatment of underlying cancer. More than 30such disorders have been identified in the human scientific literature, whereas only a few are described in veterinarymedicine. This may reflect a lower incidence in animals than in people or may be the result of failure to recognizean association between certain skin lesions and neoplasia. Establishing a relationship between a cutaneous dis-order and neoplasia can be difficult unless the skin lesions are rare and almost always associated with a particulartumour type, as is the case for most recognized veterinary paraneoplastic dermatoses. Among these are felineparaneoplastic alopecia, feline thymoma-associated exfoliative dermatitis, nodular dermatofibrosis, feminizationsyndrome associated with testicular tumours, superficial necrolytic dermatitis and paraneoplastic pemphigus.The aetiology of most cutaneous paraneoplastic syndromes has remained elusive in both people and animals.

Keywords:alopecia, cat, dog, exfoliative dermatitis, feminization, nodular dermatofibrosis, paraneoplastic,pemphigus, skin, superficial necrolytic dermatitis

Paraneoplastic syndromes (PNSs) are noncancerous,neoplasm-related disorders that occur at a site distinctfrom the primary tumour or its metastases. They pro-duce signs that reflect the remote effects of cancer ratherthan the direct effects caused by tumour growth or inva-sion. Presenting as endocrine, haematological, gastroin-testinal, neurological, renal or cutaneous aberrations,PNSs may be the first sign of an underlying malignancyand may herald a certain tumour type. Their recognition,therefore, can be important to facilitate early diagnosisand treatment of the neoplasm, and to identify tumourrecurrence following therapy. Additional clinical sig-

nificance of PNSs lies in their morbidity, which, in manycases, can cause greater compromise of quality of lifethan the tumour itself.

The frequency of PNSs in veterinary medicine isundetermined. In people, estimates suggest that as manyas 50% of patients will experience a PNS at some pointin the course of their malignancy.1PNSs most com-monly involve the endocrine and haematological sys-tems in both people and animals. One of the bestcharacterized PNSs in veterinary medicine results inpolyuria/polydipsia, polyphagia, bilateral symmetricalopecia, hyperpigmentation, muscle atrophy and

pot-belly appearance, the distant effects of excessivecortisol production by an adrenal gland adenoma inhyperadrenocortism.2,3

Cutaneous paraneoplastic syndromes are externalclues to internal malignancy. More than 30 such disor-ders have been documented in the human scientific lit-erature (Table 1),4although the incidence of underlyingmalignancy varies greatly among them.5 In contrast,only a few cutaneous PNSs have been reported in vet-erinary medicine (Table 2). This may reflect a lower inci-dence in animals than in people or may be the result offailure to recognize an association between certain skin

lesions and neoplasia. The classification of a syndromeas paraneoplastic is fairly straightforward in the case ofa rare dermatosis, whose rarity and frequent occurrencewith neoplasia make the association apparent,6 as isthe case for most recognized veterinary paraneoplasticdermatoses. More common skin manifestations can bedifficult to classify because many of them frequentlyappear without any underlying cancer.6 It has beenproposed that in order to classify a disorder as a cuta-neous PNS, the onset or recognition of a malignancyand the skin condition should occur at the same timeand should follow a parallel course.4However, becauseoccult cancers can go undetected for many years, it can

be difficult to prove that the two conditions developedconcomitantly. Therefore, clinically, the appearance ofparaneoplastic signs may precede, follow or coincide withthe detection of the related neoplasm.4,79In addition,

Correspondence: M. M. Turek, School of Veterinary Medicine,Department of Surgical Sciences, University of Wisconsin-Madison,2015 Linden Drive Madison, WI 53706, USA. E-mail: [email protected]


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2003 European Society of Veterinary Dermatology, Veterinary Dermatology, 14, 279296

because of the presence of clinically undetectable,microscopic tumour cells that may remain after an app-arently complete clinical remission, the course of thetwo conditions may appear to diverge.8,9

The pathophysiological mechanism(s) by which neo-plasia causes development of distant, noncontiguous

dermatoses in people (Table 1) and in animals has notbeen well established in most cases. A variety of aetiol-ogies has been postulated, including tumour-inducedantigenantibody interactions and abnormal or abnor-mally excessive production of biologically active hor-mones, growth factors or cytokines by tumour cells orby accessory cells in response to the tumour.6

Because many cutaneous PNSs in people, includingthe papulosquamous disorders listed in Table 1, areproliferative in nature, growth factors (GFs) have beensuggested in several human case reports to have a pos-sible aetiological role.1014Normal keratinocyte func-tion is regulated by various GFs, and among the mostimportant for proliferation is transforming growth fac-tor alpha (TGF-), a member of the epidermal growthfactor (EGF) family. TGF-acts through the epider-mal growth factor receptor (EGFR or ErbB1), whoserole in normal keratinocyte function as well as in car-cinogenesis, particularly as pertains to epithelial neo-plasia, a common inducer of papulosquamous PNSdisorders, has been extensively studied.1517TGF-isthe most commonly implicated GF in the pathogenesisof papulosquamous cutaneous PNSs in people, althoughdefinitive evidence of an aetiologic connection is lacking.Individual human case reports associate paraneoplas-

tic types of acanthosis nigricans,1012 sign of Leser-Trlat10and tripe palms13with abnormally elevatedserum,12,13urine,10 tumour11,12 and/or cell messengerRNA13levels of TGF-. In all reported cases, effectivetreatment of the underlying neoplasia, including gastriccarcinoma,11,12melanoma10and mastocytosis,13resultedin simultaneous decrease of TGF-levels and clinicalimprovement of the dermatosis. However, in partbecause TGF- has not been demonstrated in thecutaneous lesions of these dermatoses, it is not possi-ble to attribute a direct causal role to this GF. Interest-ingly, TGF-overexpression in three of these cases was

associated with concurrent overexpression of EGFR intumour tissue11,12and/or lesional skin10,12as shown byimmunohistochemical10,12or Southern blot11analysis.

In addition, hyperinsulinism and insulin resistancemediated by tumour-induced anti-insulin receptor anti-bodies may be linked to the pathogenesis of paraneo-plastic acanthosis nigricans in people (Table 1), as isthe case in the endocrinopathy-related form of the der-matosis.8,18According to the hypothesis, the epidermalproliferation that is characteristic of the dermatosismay be stimulated by the high levels of insulin that isstructurally similar to insulin-like growth factor (ILGF)and that cross-binds to the ILGF receptor, whose acti-

vation, like that of EGFR, stimulates proliferation ofnormal keratinocytes.8,18

Other mechanisms of pathogenesis that have beenconsidered in both human and veterinary literature

include antigenantibody interactions mediated bycross-reactivity between tumour antigens and antigensin the normal skin, as well as tumour-induced deple-tion of certain physiological substances.6These are dis-cussed in detail later in relation to the autoimmunedisorder, paraneoplastic pemphigus, and to superficial

necrolytic dermatitis, respectively.

FELINE PARANEOPLASTIC ALOPECIA

Feline paraneoplastic alopecia (FPA) manifests as anonpruritic, progressive, symmetrical alopecia. This clin-ically and histologically characteristic dermatosis hasbeen reported in association with pancreatic carcinomain 12 cats,1923and biliary carcinoma in two cats.20,24

Affected animals range in age from 7 to 16 years (median13 years). There appears to be no breed predilection.

The chief presenting complaint in all reports is acute,progressive alopecia of 2 weeks to 10 months duration(median 4 weeks). Cats have concurrent signs of systemicillness including weight loss in all animals and variabledegrees of inappetance, vomiting, diarrhoea and leth-argy in some. Hair loss is symmetrical and progressesfrom the ventrum to the head and to primarily themedial aspect of the extremities. Hair is easily epilatedand alopecic skin is shiny, inelastic and thin, but notfragile. Some affected cats are reported to groom exces-sively,20,24 and it has been postulated that the shinyappearance of the skin arises from exfoliation of thestratum corneum as a result of excessive grooming.20,22

In addition, foot pad involvement is common. Affectedpads are painful and appear either dry, crusted and fis-sured, or erythematous and moist. Although FPA is anonpruritic disorder, pruritus has been reported withsecondary Malasseziaspp. infections and flea infesta-tions.21,23,24 In a recent report of feline skin biopsiescomplicated by the presence of Malassezia spp., his-topathology from 7 of 15 cases was consistent with FPA.23

Although pancreatic carcinoma was confirmed in onlyfour of these cats, it was suggested that the presence ofyeast organisms in histopathological specimens from catswith generalized skin disease could serve as a harbinger

of internal malignancy.

23

Histopathological evaluation of alopecic skin revealsa nonscarring alopecia with characteristic marked fol-licular telogenization, miniaturization and atrophy(Fig. 1). Less specific findings include mild epidermalacanthosis and hyperplasia with thinning or absence ofthe stratum corneum and patchy parakeratosis with amild, predominantly mononuclear, perivascular inflam-matory infiltrate of the dermis.19,20,22,24

Clinical differential diagnoses include feline endo-crinopathies such as hyperadrenocorticism and hyper-thyroidism, dermatophytosis, demodicosis, self-inducedalopecia, telogen defluxion, feline symmetrical alo-

pecia and alopecia areata.19,22Specific features of theclinical presentation as well as diagnostic tests includ-ing adrenocorticotropic hormone (ACTH) stimulationand dexamethasone suppression tests, thyroid hormone


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Cutaneous paraneoplastic syndromes 285

measurement, Woods lamp examination, fungal culture,skin scraping, KOH preparation, faecal examination,trichograms and skin biopsy are important to ruleout these possibilities. Abdominal radiography and/orultrasonography, as well as thoracic radiographs toevaluate for pulmonary metastasis, are important if FPAis suspected. Exploratory laparotomy with tissue biopsymay be necessary to confirm the diagnosis of neoplasia.

Neoplastic diseases of the exocrine pancreas and bili-ary tree are rare in the cat. In the vast majority of cases,

the disease has metastasized to distant sites includingliver, lymph nodes, other intraperitoneal structures andlungs at the time of diagnosis, and the prognosis is there-fore grave.25,26Twelve of the fourteen cats reported inthe literature died or were euthanized within 8 weeks ofonset of clinical signs.19,20,23,24

Skin lesions did not improve in any cat treated withcorticosteroids. Little else can be concluded about themanagement of FPA, as most cats were euthanizedprior to diagnosis or at the time of diagnosis owing toadvanced stage of disease. However, resolution of FPAwas documented after surgical resection in a single case

of solitary pancreatic tumour.

22

Recrudescence of cutan-eous lesions at the time of metastasis 18 weeks later inthis case provides further evidence for the classificationof FPA as a PNS.

FELINE THYMOMA-ASSOCIATED

EXFOLIATIVE DERMATITIS

Paraneoplastic exfoliative dermatitis has been reportedin cats in association with thymoma. Six cases have beendescribed,2730five of which were characterized clini-cally and histopathologically.27,28,30The disorder presents

as diffuse erythema of the skin accompanied by exfolia-tion or scaling. Lymphomas and leukaemias are the mostcommon cancers associated with this PNS in people(Table 1).31Interestingly, exfoliative dermatitis has not

been reported in association with thymoma in people.In addition to malignancy, other causes of exfoliative

dermatitis include drug eruption, pre-existing derma-toses such as contact dermatitis, pemphigus foliaceus,systemic lupus erythematosus and cutaneous bacterial,fungal, parasitic or yeast infections, as well as hyper-

adrenocortism.3

The reaction can also be idiopathic, asis the case in up to 50% of human patients.31In the docu-mented veterinary cases of paraneoplastic exfoliativedermatitis, all affected cats were concurrently diagnosedwith thymoma. However, the association between thy-moma and the skin lesions may be controversial in onecase in which antibiotic therapy was used within onemonth of the development of skin lesions,27and in ano-ther in which fungal culture was positive for Microsporumcanisat the onset of cutaneous signs five months priorto diagnosis of thymoma.27Notably, the dermatitis inthe latter case progressed despite treatment with grise-ofulvin.27Furthermore, and in addition to the six catsreviewed herein, another report describes a case of pos-sible paraneoplastic exfoliative dermatitis in combina-tion with erythema multiforme in a cat recently treatedwith an imidacloprid preparation. Although a drugeruption was initially strongly suspected in this casebased on histopathological findings consistent witherythema multiforme, as well as the temporal associa-tion between drug application and the onset of dermatosis,the cat was diagnosed with a previously unobservedthymoma four months after the onset of the dermatosis.32

Feline thymoma-associated exfoliative dermatitisbegins as nonpruritic scaling and mild erythema on the

head and pinnae in an apparently otherwise healthycat.27 Progressively, lesions become generally distrib-uted, and, as the scaling intensifies, alopecia develops(Fig. 2).27Brown, waxy, keratosebaceous debris accu-mulates between the digits, in the nail beds, and in theear canals.27Crusts and ulcers may develop.27Althoughnot a common feature of this condition, pruritus wasreported in conjunction with secondary overgrowth ofMalassezia spp. in one case of thymoma-associated

Figure 1. Feline paraneoplastic alopecia. Severe follicular atrophywith epidermal hyperplasia and orthokeratotic hyperkeratosis.Haematoxylin & eosin (H&E), original magnification 12.5. (Photo-micrograph courtesy of Dr Elizabeth Mauldin; previously publishedin Veterinary Dermatology, Vol. 13.)

Figure 2. Feline thymoma-associated exfoliative dermatitis. Alopeciaassociated with severe scaling and mild erythema of the head, neckand pectoral regions. (Photograph courtesy of Dr Elizabeth Mauldin.)


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286 M. M. Turek


exfoliative dermatitis,30as well as in three cats with his-topathological changes characteristic of paraneoplasticexfoliative dermatitis where the possibility of under-lying malignancy was not fully investigated.23 Skinlesions were refractory to corticosteroid therapy in onecase so treated.27

Histopathologically, skin lesions are characterized bya cell-poor hydropic interface dermatitis wherein mul-tifocal areas of hydropic degeneration of basal cells andapoptotic keratinocytes are found in the epidermis and

infundibular region of the hair follicle.27The epidermisis mildly to moderately hyperplastic and there is mildto marked orthokeratotic hyperkeratosis and focal par-akeratotic hyperkeratosis (Fig. 3). Erosions may develop.An inflammatory infiltrate, primarily lymphoid, maybe present perivascularly in the dermis and within theepidermis. These histological changes along with a rel-evant history, physical findings and negative routinediagnostic tests including skin scrapings, trichographyand cytology should alert the clinician to the possibil-ity of a paraneoplastic dermatosis and evaluation ofthe cranial mediastinum should be pursued. If a diag-

nosis of thymoma-associated exfoliative dermatitis issuspected, thoracic radiographs should be performed.Radiographically, the presence of a variably sized massin the cranial mediastinum, occasionally accompaniedby pleural effusion, is suggestive of the diagnosis.33Forconfirmation, transthoracic fine-needle aspirates andneedle core biopsies of the mass can be safely performedwith ultrasound guidance.33

Five of the six published cases of feline thymoma-associated exfoliative dermatitis resulted in euthanasiawithin 45 months of the onset of clinical signs due torefractory and progressive skin disease, suggesting apoor prognosis.2729However, in three of these cases no

attempt was made to treat the underlying malignancy,as the diagnosis was made only at necropsy. Importantly,one report describes complete resolution of Malassezia-complicated exfoliative dermatitis six months after

surgical resection of the tumour.30Fourteen months aftersurgery, the cat had neither recurrence of the thymomanor the skin lesions. These reports underscore theimportance of recognizing exfoliative dermatitis as apossible marker of neoplasia in the cat, allowing forearlier detection and prompt treatment that might sig-

nificantly affect survival.The mechanism of thymoma-associated exfoliativedermatitis is unknown, as is true for paraneoplasticexfoliative dermatitis in people. The interface dermatitisand lymphoid cellular infiltrate described in cats suggestthat a tumour-induced immune-mediated process may beinvolved.27This idea is supported, at least in theory, bythe fact that the normal thymus is an important com-ponent of the immune system and that aberrant immu-nological responses induced by a diseased gland arebelieved to be related to other immunologically basedconditions such as myositis and myasthenia gravis.30

Thymoma is uncommon in the cat. Surgical resectionis the treatment of choice. Tumours that are noninvasiveand easily excisable carry a good prognosis with mediansurvival of almost two years.33In contrast, cats withinvasive tumours often do not survive the perioperativeperiod, representing15% of cases.33Unfortunately, evenwith sophisticated imaging modalities such as computedtomography, tumour resectability is in many casesimpossible to predict preoperatively. Metastasis is rare.

NODULAR DERMATOFIBROSIS

Nodular dermatofibrosis (ND) is a well-documentedPNS characterized by the development of multiple,cutaneous nodules of collagenous origin in associationwith renal cystadenocarcinoma or cystadenoma. Thesyndrome was initially reported in Alsatians in 1983.34

Thereafter, all additional cases, except two, have beendescribed in German Shepherd dogs.3539 Pedigreeanalysis of affected German Shepherd dogs stronglyindicates that the disease is inherited in an autosomaldominant pattern.35In addition, recent genetic evalu-ation of a canine colony that was bred for developmentof this syndrome localized the condition to a region on

canine chromosome 5 and suggested a possible causalrole for a previously unidentified tumour suppressorgene.40The syndrome has been also described in oneGolden Retriever and one German Shepherd Cross.36,41

Skin lesions consist of multiple, firm, well-circumscribednodules, ranging in diameter from 2 mm to 5 cm, andrepresent the most common presenting complaint ofthis syndrome.3439,41Nodules are nonpruritic, locatedin the dermis or subcutis, and are freely moveable.39

Most are covered by an intact epidermis, although somelesions become ulcerated and secondarily inflamed.34,35,39

Lesions are localized primarily to the extremities (Fig. 4),although distribution can be diffuse.3439,41 Histologi-

cally, nodules consist of irregular bundles of dense, well-differentiated collagen fibres in the dermis or subcutiswith no sharp demarcation from surrounding connec-tive tissue.3438,41

Figure 3. Feline thymoma-associated exfoliative dermatitis. Severehyperkeratosis with multifocal keratinocyte necrosis; mild pleocellularinfiltrate in dermis which focally obscures dermoepidermal junction.H&E, original magnification 62.5. (Photomicrograph courtesy ofDr Elizabeth Mauldin.)


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Most affected dogs present with the primary com-plaint of nonpainful cutaneous nodules.39The meanage at onset of skin changes, based on a report of 51 dogs,is 6 years.39 However, clinical signs can vary greatlydepending upon stage of renal pathology at the time of

presentation and may include haematuria, abdominaldistension and pain secondary to renal cyst rupture,depression, fever and loss of appetite. Importantly, NDalmost always antecedes systemic signs of illness relatedto tumour-induced renal failure or metastasis by monthsto years.39In contrast to the mean age at onset of skinlesions, the mean age of diagnosis of renal changes is8 years.39This highlights the importance of recogniz-ing ND as a marker of renal neoplasia, allowing for earlydetection of the syndrome.

Renal changes are slowly progressive and almostalways bilateral.35,36,38,39,41 Histopathology reveals

cystadenocarcinomas or, less commonly, cystadeno-mas.3539,41Grossly, kidneys appear enlarged and irre-gular with multiple solid or cystic tumours.3539,41

Microscopic examination shows epithelial changes rang-ing from multifocal hyperplasia to highly malignantepithelial proliferation.35,38,39,41It has been speculated thatproliferation of the epithelium represents a preneoplas-tic change that develops progressively from hyperplasiato adenoma to carcinoma over many months to years.35

A recent study showed the presence of microscopic renalcystic lesions lined by hyperplastic renal tubular epi-thelium in two, clinically healthy, 1-year-old progeny ofa dog diagnosed with renal cystadenocarcinoma and ND,

suggesting that microscopically detectable renal changesoccur in carriers of the disease at a young age.42Inter-estingly, affected bitches almost always have concurrentuterine leiomyomas that carry little clinical significance.35,39

In addition, there are some reports of incidental hyper-plastic polyps and hypertrophy of collagen in the smallintestine, suggesting multiple organ involvement.36,39

Upon presentation of an adult dog, especially of theGerman Shepherd breed, with nonpainful, firm cuta-neous nodules involving primarily the extremities, a

diagnosis of ND should be considered. Skin biopsy shouldbe performed as one of the first diagnostic tests if NDis suspected. To investigate the possibility of underly-ing neoplasia, the kidneys should be evaluated withradiography, ultrasonography, computed tomographyor contrast nephrography. Enlarged and abnormallyshaped kidneys can be palpated in 60% of cases.39Serumbiochemistry analysis may reveal renal insufficiency orfailure, and scintigraphy can be performed to evaluatethe relative glomerular filtration rate of each kidney.Renal biopsy is necessary for confirmation, however,concurrent characteristic skin lesions and morphologicrenal changes in a German Shepherd is stronglysuggestive of the diagnosis.

Unfortunately, no effective treatment has been foundfor this syndrome, including glucocorticoid therapy.39

Given the bilateral nature of the renal neoplasia, uni-lateral nephrectomy is seldom curative and, thus,lifespan does not seem to be affected by early diagno-sis.39Chemotherapy trials have not been reported. Inan attempt to avoid complications such as rupture ofrenal cysts, unilateral nephrectomy of large, nonfunc-tioning kidneys may be performed. In addition, skinnodules that are ulcerated or that interfere with loco-motion can be removed palliatively with surgery or cry-

otherapy. In light of the lack of effective treatment forthe underlying cancer, prognosis for long-term survivalis poor. It is important, however, to recognize ND as aslowly progressive disease with a protracted clinicalcourse if renal disease is in the early stages. The meantime from first observation of ND to death is about2.5 years.39Dog owners should be well educated in thisregard to avoid premature euthanasia that could resultfrom the knowledge that the underlying cause of theskin lesions is an untreatable cancer. Ultimately, thecause of death or euthanasia in the majority of cases isattributable to progressive neoplasia and renal disease.39

Less commonly, the decision to euthanize is related toprogressive or complicated ND.39Metastasis from renaltumours is found at necropsy in approximately half ofaffected dogs and occurs in lymph nodes, lungs, liver,pleura and peritoneum.39Given the probable hereditarybasis of this disease, affected dogs should not be bred.

The mechanism of association between the develop-ment of ND and renal cystic changes is unclear. It hasbeen postulated that renal tumours may secrete collagen-stimulating growth factors or cytokines that acceleratecollagen accumulation.3638,41However, no such factorhas been isolated. TGF-has been theoretically impli-cated by some authors3741in light of the possible asso-

ciation of this growth factor with various proliferativecutaneous paraneoplastic syndromes in people.1013

Alternatively, cutaneous and renal lesions may arise inde-pendently from a common inherited genetic defect.36,40

Figure 4. Nodular dermatofibrosis in a German Shepherd dog withmultiple dermal and subcutaneous nodules on an extremity.(Photograph courtesy of Professor Dr Frode Lingaas.)


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FEMINIZATION SYNDROME ASSOCIATED

WITH TESTICULAR NEOPLASIA

Sertoli cell tumours, seminomas and interstitial celltumours represent the three most common histologicaltypes of testicular neoplasms in the dog,43and arise from

the oestrogen-secreting sustentacular cells of semini-ferous tubules, the germinal epithelium and the Leydigcells, respectively. Occurring in approximately equalfrequencies,43they represent a common type of neopla-sia in the intact dog.43The vast majority of testiculartumours have a low metastatic potential and thereforecarry an excellent prognosis. A strong associationbetween increased risk for development of neoplasia,particularly of Sertoli cell tumours and seminomas,and cryptorchidism has been well established.43,44

In general, most dogs with testicular tumours areasymptomatic, or they present with only local swellingand/or testicular atrophy of the contralateral, non-neoplastic testicle.45The feminization syndrome is re-ported to occur in 2457% of dogs bearing Sertoli celltumours,44,46,47and results from hormonal imbalancesecondary to a functional tumour. Occasional reportshave described the syndrome in association with inter-stitial cell tumour or seminoma.46,4850However, becauseof their relative rarity, the histological classification ofthe tumours in some of these reports may be questioned;a recent study examining the immunohistochemicalcharacteristics of testicular neoplasia revealed that adiagnosis based on histology alone was insufficient in20% of cases.51

The feminization syndrome is characterized by vari-ous combinations of gynecomastia, attraction of othermale dogs, pendulous prepuce, penile atrophy, pros-tatic squamous metaplasia and myelosuppression inaddition to skin changes.3,45,46The major dermatologi-cal feature is slowly progressive, bilateral, symmetricalalopecia that typically originates on the neck, lumbarregion, perineum and genital area.3Occasionally, thereis thinning of the epidermis.3Histological changes includeorthokeratotic hyperkeratosis, follicular dilatation andatrophy, follicular keratosis, telogenization of hair fol-licles and sebaceous gland atrophy.3Other clinical find-

ings include, coat colour change, macular melanosisaround the inguinal, perineal and genital areas, as wellas linear preputial dermatosis.3This latter term des-cribes a linear narrow pigmentary change that extendsfrom the preputial orifice to the scrotum and is consid-ered specific for testicular neoplasia.3 Histologically,this lesion is characterized only by some mild vasculardilatation and congestion.3

Dogs with testicular neoplasia can have skin changes,feminization or both. When skin changes appear alone,the differential diagnoses include hypogonadism, adrenalsex hormone imbalance and, less likely, hypothyroidismand hyperadrenocorticism.3 Unless accompanied by

obvious testicular enlargement, the diagnosis of para-neoplastic feminization syndrome may not be straightfor-ward. Histopathology of affected skin is nonspecific.Testicular ultrasound may be helpful in identifying a

nonpalpable tumour and in association with a fine nee-dle aspirate can be diagnostic for testicular neoplasia.Because the incidence of feminization syndrome ishighest in association with cryptorchid neoplastic tes-tes,44,4649,5256ultrasound evaluation of the inguinalregion and abdominal cavity for retained testicles is

indicated. In addition, complete haematological evalu-ation should be performed in all dogs with suspectedtesticular tumours, particularly in those with feminiza-tion, to evaluate for hormonally induced myelosup-pression characterized by pancytopenia. In dogs withblood dyscrasias, the prognosis for survival is generallypoor even with treatment,48,49,52,54,56although somereports of recovery exist.48,56Death in these cases isrelated to severe aplastic anaemia, septicaemia and/or thromboembolism.48,49,52,54,56 Ultimately, the dia-gnosis of feminization syndrome is based on clinicalfindings, histological evaluation of neoplastic testiclesand response to therapy after bilateral orchiectomy.In cases uncomplicated by myelosuppression or metas-tasis, resolution of clinical signs usually occurs withinmonths.3,47,53 Although the metastatic potential oftesticular neoplasia is low, occurring in fewer than 10%of dogs,45 complete clinical staging is warranted inall cases and should include abdominal ultrasoundand thoracic radiographs for evaluation of possibleabdominal lymph node and pulmonary metastasis,respectively.

Hyperestrogenism has been implicated in the patho-genesis of feminization because of the high incidence ofthe syndrome in association with Sertoli cell tumour,

whose nontransformed cellular counterpart is oestrogen-secreting. However, direct evidence of this hypothesishas been lacking, due to a lack of quantitative hormo-nal analyses in many reported cases and due to con-flicting results among those studies in which oestrogenlevels were measured. Increased blood oestrogen levelswere detected in some cases,48,49,52,57,58whereas normaloestrogen levels were described in others.48,59,60Untilrecently, these reported hormonal analyses have beenbased on single case reports or on very small case series,making it impossible to draw statistically based conclu-sions. In contrast, two recent comparative publications50,61

have reported significantly increased concentrationsof oestradiol-17in peripheral venous50,61and testicularvenous50blood of dogs with Sertoli cell tumours com-pared to normal dogs. Dogs with Sertoli cell tumoursand feminization syndrome had greater increasedoestradiol-17 concentrations in peripheral venousand testicular venous blood than did dogs with Sertolicell tumours without feminization.50In both reports,testosterone concentrations were reduced in dogs withSertoli cell tumours compared with normal dogs.50,61

The calculation of the testosterone/oestradiol ratio wassuggested to be a more reliable diagnostic tool thanthe individual hormone values, as it was better cor-

related to clinical signs of feminization.61Interestingly,dogs with interstitial cell tumours also had greaterconcentrations of oestradiol-17in peripheral venousand testicular venous blood than did normal dogs.50


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In contrast, oestradiol-17 concentrations in dogs withseminoma were not different50or were decreased61com-pared with normal dogs, suggesting that seminomas arenot endocrinologically active.

Although these data indicate a direct association bet-ween hyperestrogenism and feminization syndrome,

not all feminized dogs in these series had elevated levelsof oestradiol-17.61It has been suggested, therefore,that the shift of balance between testosterone andoestradiol may be more important than the absoluteoestradiol level.61Alternatively, disparate results maybe explained by the fluctuation of hormonal concen-trations such that laboratory measurement may provideonly a snap shot view of the hormonal state.61Lastly,the occurrence of feminization in the face of normaloestradiol-17concentration may reflect the produc-tion of other physiological forms of oestrogen, such asoestrone or oestriol, that are not detected by standardradioimmunoassays, or the production of unknownoestrogen-like substances.48,61Interestingly, symmetri-cal endocrine alopecia has also been described in asso-ciation with hyperprogesteronaemia in a dog withSertoli cell tumour.53

SUPERFICIAL NECROLYTIC

DERMATITIS

Superficial necrolytic dermatitis (SND) is a well-described, necrotizing skin condition of dogs thatoccurs in association with internal disease. The human

counterpart, necrolytic migratory erythema (NME) isa distinctive cutaneous eruption that accompanies aglucagon-secreting alpha cell tumour of the pancreas(Table 1). Human patients develop erythematous macu-lae and papules that progress to erosions secondary toepidermal necrosis. The pattern of distribution of skinlesions in people is distinctive, involving the face, abdo-men, perineum, groin, thighs, as well as sites of fric-tion.31The intensity of the dermatosis typically waxesand wanes.62Accompanied by elevated serum gluca-gon concentrations, glucose intolerance or mild diabe-tes mellitus, hypoaminoacidaemia, stomatitis, diarrhoea

and weight loss, NME is a common feature of the con-stellation of symptoms known asglucagonoma syndromein people.4,31,62Notably, the dermatosis also occurs ina small proportion of people without pancreatictumours who suffer from benign or malignant liver dis-ease, enteropathy or chronic pancreatitis.6366However,by far the majority of NME cases are associated withthe glucagonoma syndrome.63

Superficial necrolytic dermatitis in dogs shares manyfeatures with NME.67However, in contrast to people,SND in dogs appears to occur far more commonly inassociation with hepatopathy than with glucagon-secreting neoplasia,67giving rise to the familiar name

of hepatocutaneous syndrome. There are seven reportedcases of paraneoplastic SND associated with glucagon-secreting tumours in dogs6873and one case of pancre-atic carcinoma in a cat.74In two of the reported dogs,

glucagonoma occurred in the liver without a histologi-cally detectable pancreatic tumour.69,73

The main presenting complaints of glucagonoma-associated SND are progressive skin lesions of 3 weeksto many months,6873with concurrent lethargy and inap-petance in some dogs.69,70,73 Major dermatologicalfindings include erosions and ulcerations, with alopecia,exudation and adherent crusts on the feet, pressurepoints such as the elbows and hocks, flank, perinealarea, muzzle, facial mucocutaneous junctions and/ororal cavity.6871,73Hyperkeratosis and fissuring of footpads occur in all animals (Fig. 5).6871,73Lesions maybe painful and pruritic.70,71All five dogs in whom mea-

surement was performed had hyperglucagonaemia6973and all but one71 were hyperglycemic.6870,72,73Theselaboratory abnormalities are not, however, specific forglucagon-secreting tumours, as similar changes arefound in dogs with SND-related hepatopathy.75Plasmaamino acid levels were measured in three of thereported dogs and all had marked hypoaminoacidae-mia involving various amino acids.70,71,73,75Hypoami-noacidaemia may therefore represent a commonfeature of paraneoplastic SND in dogs, although italso is nonspecific. Interestingly, a recent report evalu-ated plasma amino acid concentrations in dogs with

nonglucagonoma-associated SND.

76

When comparedwith normal dogs and dogs with acute or chronic hepa-titis whose circulating amino acid levels are increasedowing to decreased hepatic metabolism, the plasmaamino acid concentrations of dogs with SND weresignificantly lower.76These disparities suggest that thepathogenesis of SND is likely not related to compro-mised hepatic function as postulated previously.76In thatreport, the mean values of all amino acids, with theexception of glutamic acid, phenylalanine, tryptophanand ornithine, were 60% or less in dogs with SND thanin normal dogs, and the total amino acid concentrationwas 30% that of normal dogs.76

Similar to NME in people, the histopathologicalfindings of SND are distinctive and can be stronglysuggestive of the diagnosis. The epidermis has ared, white and blue appearance when stained with

Figure 5. Superficial necrolytic dermatitis in a dog. The foot padsare proliferative, crusted and fissured. (Photograph courtesy of DrLynette Phillips.)


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290 M. M. Turek


haematoxylin and eosin (Fig. 6). Parakeratotic hyper-keratosis and crusting create the upper eosinophilic layer.Oedema and necrosis of keratinocytes in the stratumspinosum make up the pale middle layer. Hyperplasticbasal cells give rise to the deep basophilic layer.67,77Inaddition, secondary clefting can occur at the level ofthe devitalized middle layer, which may lead to ulcera-tion.6772,74,75,77A mixed, inflammatory infiltrate mayoccupy the dermis.

Skin biopsy of intact, crusted lesions is the key todiagnosis of SND and can help differentiate other pos-

sible differential diagnoses such as erythema multi-forme, drug eruption, pemphigus foliaceus, systemiclupus erythematosus, contact-irritant dermatitis, and,although less likely in the presence of foot pad involve-ment, demodicosis, dermatophytosis and bacterial fol-liculitis.6772,74,75,77Furthermore, SND can, in certaincases, histopathologically resemble other disorders inclu-ding zinc-responsive dermatosis, generic dog food der-matosis and mucocutaneous candidiasis.77The presenceof internal metabolic disease is the principal differentiatingfeature in these cases.

Useful diagnostic tests, in addition to skin biopsy,

include a serum biochemistry panel, serum bile acidevaluation and abdominal ultrasonography. If liverdisease, the more common SND-associated internaldisorder, is not supported by these tests, investigationshould be directed toward glucagonoma. Hypoami-noacidaemia and hyperglycaemia may be helpful butare nonspecific for the diagnosis, as mentioned above.77

An elevated serum glucagon concentration can be use-ful but is also non-specific.77Moreover, the accuracy ofthe human glucagon assay in measuring glucagon con-centrations in dogs has been questioned because of itslimited use in veterinary medicine.67,78Abdominal ultra-sonography is an important diagnostic tool, although

false-negative examinations can occur given the inher-ent difficulty of imaging the pancreas.79In light of thepancreas small size, similar echogenicity to surround-ing structures and close proximity to gas-containing

gastrointestinal organs, visualization of the pancreasmay be incomplete.80Therefore, the lack of abnormal-ities on an ultrasound examination does not excludepancreatic disease.79,80To this effect, four of the five dogsreported herein with confirmed pancreatic glucagonomahad false-negative ultrasound examinations.68,7072

However, the use of more sophisticated ultrasoundequipment by experienced ultrasonographers mayimprove the accuracy of pancreatic assessment.79 Inhuman medicine, computed tomography and magneticresonance imaging are commonly used to evaluate thepancreas.79To date, these modalities are not in stand-ard use for abdominal imaging of veterinary patients.79

Therefore, exploratory laparotomy may be indicated incases when SND is suspected based on clinical and his-topathological findings of skin lesions and where thereis no evidence of hepatopathy or pancreatic neoplasiaafter routine diagnostic testing. Because glucagon isproduced by alpha cells in the pancreas, stomach andduodenum, all of these organs should be thoroughlyevaluated.75Glucagon immunoreactivity on immuno-histochemical staining of tumour cells was present inall seven reported canine cases,6872and therefore appearsto be highly supportive of a diagnosis of glucagonomain dogs, as it is in people.62In people, staining intensitydoes not relate to the severity of hormonal symptoms.62

Tumour tissue can also be variably immunoreactive forother pancreas-derived hormones including insulin,islet amyloid polypeptide, pancreatic polypeptide andsomatostatin.68,71,72

The pathogenesis of SND in dogs and NME in peo-

ple is unknown. It has been suggested that because glu-cagon results in sustained gluconeogenesis and is involvedin the catabolism of amino acids, chronic elevation ofthe hormone, as seen in association with glucagono-mas, may be the direct cause of hypoaminoacidaemia,which may lead to epidermal protein depletion andsubsequent keratinocyte necrolysis.65,67,68,70,71 Thishypothesis is supported by the rapid dermatologicalimprovement that is seen in people (and one dog)71

after surgical resection of the tumour62,63or with glucagon-inhibiting somatostatin analogue treatment,62,63 aswell as by the temporary resolution of skin lesions in

people after intravenous infusion of amino acids.

81,82

However, and not in accordance with this hypothesis,the dermatosis also occurs in individuals, both humanand canine, with glucagon concentrations within thenormal range.66,70,71,78In an effort to explain this, ithas been proposed that because glucagon exists innumerous immunoreactive fractions,65,67,75 the assayused to measure concentrations of the hormone maybe insensitive to some glucagon species.67,78In people,pancreatic glucagon consists of at least four fractions,each of a different molecular mass.65,67,75The biologi-cally active species has a molecular mass of 3500 Daand is accurately measured by human bioassays.65,75

Other fractions include the 90 000 Da big glucagon,the 9000 Da proglucagon, and the low molecularmass glucagon of 3000 Da.65,67,75Gut-derived gluca-gon exists in two fractions (3500 and 7000 Da) and is

Figure 6. Superficial necrolytic dermatitis in a dog. The epidermishas a layered, red, white and blue appearance: diffuse parakeratosis(thick arrow), intracellular oedema in the spinous layer (thin arrow),and basal cell hyperplasia (arrowhead). H&E, original magnification31.2. (Photomicrograph courtesy of Dr Michael Goldschmidt.)


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indistinguishable from pancreatic glucagon.65,67 Glu-cagon metabolism is handled by the kidney and liver,the latter responsible primarily for extraction andmetabolism of the 3500 Da fraction.75It appears thatthe fractional breakdown of glucagon in the dog is sim-ilar to that described in people.65,75However, it remains

to be established whether NME or SND are related tosome unusual combination of different glucagon frac-tions that could explain the lack of correlation betweenhormone levels and clinical signs.65,67The existence ofan uncharacterized glucagon-like peptide has also beenhypothesized.67

Alternatively, it has also been proposed that gluca-gon may not be directly related to the development ofskin lesions. Because many human patients with gluca-gonoma syndrome experience diarrhoea and malab-sorption and occasionally have concurrent deficienciesof serum zinc and/or fatty acid levels, and given thesimilarity of the corresponding cutaneous lesions withNME, deficiencies in zinc and/ or fatty acids have beenhypothesized to have an aetiologic role in the dermati-tis.63However, this theory has since fallen out of favourdue to a lack of clinical response associated with sup-plementation of zinc and/or fatty acids in people.63

Similarly, SND was refractory to zinc supplements inthree dogs with glucagonoma,69,71,83 although sometemporary improvement is reported in association withhepatopathy-related SND.67,75Fatty acid supplemen-tation, reported in one dog, did not result in a clinicalresponse.70

Finally, hepatic impairment has also been implicated

as a possible mechanism.63,75 Intuitively, this seems areasonable theory in light of the more frequent associ-ation of SND with hepatopathy than pancreaticneoplasia in the dog. Interestingly, many although notall canine and human patients with hepatopathy-related SND/ NME also have elevated serum glucagonlevels.66,70,75,78This may further support the implica-tion of liver impairment in the pathogenesis of the con-dition, perhaps by way of decreased metabolism ofglucagon.66,67,75

There is no currently known effective therapy forparaneoplastic SND in dogs. Surgical resection of the

malignancy is the therapy of choice. Although excisionof localized glucagonoma usually results in rapid anddurable resolution of skin lesions in people, the major-ity of human patients present with metastasis at the timeof diagnosis.62Even in these cases, a debulking proce-dure is often recommended, as reduction in tumourburden will lead to significant palliation of symptomsin 75% of patients.62 Several reports in dogs havedescribed temporary clinical improvement of cutane-ous lesions with glucocorticosteroid therapy.68,69,75,83

However, the state of glucose intolerance of many dogswith SND and the risk of inducing diabetes mellituspreclude their use.67,75In people, glucagon-inhibiting

somatostatin and the long-acting somatostatin analogue,octreotide, are associated with significant improve-ment of NME.62,84Interestingly, serum glucagon levelsand tumour size are often not influenced by this treat-

ment.62The use of somatostatin has not been evaluatedin canine patients, although its efficacy has been des-cribed anecdotally in one dog with metastatic gluca-gonoma that experienced dermatological improvementwithin 14 days.3 Improvement is also seen in somehumans treated with amino acid infusions.62To this effect,

amelioration of skin lesions has been described in dogswith hepatopathy-related SND after dietary supple-mentation with egg yolk, resulting in concurrent impro-vement of decreased serum amino acid levels.78Fromthis, feeding of a high-quality protein diet has been rec-ommended.67Anecdotal reports of amino acid infu-sion in dogs with SND suggest remarkable alleviationof cutaneous signs with this therapy.67Finally, chemo-therapeutic agents appear to have little antitumour acti-vity against human glucagonoma.62However, durabletumour regression has occasionally been observed inpeople using various drug combinations of streptozotocin,5-fluorouracil and dacarbazine.62

There exists little information regarding the out-come of dogs with SND and glucagonoma. One reportdocuments complete resolution of SND, as well as nor-malization of hyperglucagonaemia and hypoaminoaci-daemia, following excision of the tumour and its nodalmetastasis.71This supports the classification of somecases of SND as a PNS. Among the remaining casesreported, three dogs were diagnosed with pancreaticneoplasia only at necropsy69,70,72and, in two otherdogs, postsurgical pancreatitis resulted in death afterexcision of solitary neoplastic tissue.68 Metastasis,involving the liver and /or lymph nodes, was reported in

the three dogs in which a diagnosis was not establisheduntil the time of necropsy. This further underscores theimportance of recognizing SND as a possible markerof neoplasia in the dog, allowing perhaps for earlierdiagnosis and prompt treatment of a cancer that mightotherwise go undetected until late in the course of disease.

PARANEOPLASTIC PEMPHIGUS

In people, paraneoplastic pemphigus (PNP) is an un-common, but well-characterized, immune-mediated

blistering disorder associated with both benign andmalignant lymphoproliferative processes (Table 1). Asthe name implies, it shares some similarities with clas-sic pemphigus, notably pemphigus vulgaris (PV), buthas recently emerged as a distinct PNS of autoimmunepathogenesis. It differs from PV in its clinical features,histological characteristics, immunofluorescent patterns,systemic involvement, association with neoplasia, res-ponsiveness to therapy, prognosis and pathophysiol-ogy.85In veterinary medicine, one case of canine PNP,confirmed by molecular immunological techniques,has been reported.86Further investigation of immu-nopathological features has demonstrated a similar

target antigen profile to the human counterpart.87The cutaneous lesions of PNP in people are charac-

terized by vesicobullous changes, reminiscent of pem-phigus vulgaris or erythema multiforme, affecting the


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292 M. M. Turek


head, trunk and extremities.85,88Intractable stomatitisis a consistent feature in people and is usually the firstsign of disease. Oral erosive lesions are more severethan in PV and extend from the mouth to the uppergastrointestinal and respiratory tracts. Unlike in classicpemphigus, in which lesions arise from otherwise normal

appearing skin, erythema and inflammation is alwaysassociated with the maculae, papules and plaques inPNP, resembling the appearance of erythema multi-forme.85 Conjunctival involvement occurs in mosthuman patients.88In addition, and distinct from classicpemphigus, many people with PNP develop fatal respi-ratory involvement wherein aspiration of sloughed,immune-targeted bronchial epithelial cells results inocclusion of smaller airways and alveoli.85

Histopathological findings of mucocutaneous lesions,including suprabasal cleft-forming acantholysis withan attached rim of basal keratinocytes (tombstoneappearance), resemble those of PV. Unique to PNP,however, is the presence of dyskeratotic or necrotickeratinocytes located at all levels of the epidermis,basal vacuolization and intense epidermal exocytosisof cytotoxic lymphocytes, natural killer cells and mac-rophages.85,88,89In addition, the degree of acantholysisis less prominent compared to PV.88

In human PNP, direct immunofluorescence allowsidentification of deposition of immunoglobulin G andcomplement in epidermal intercellular spaces as well asalong the basement membrane of affected tissues. Con-trarily, in PV immunoreactants are found only in theintercellular spaces in both people and dogs.85,90With

indirect immunofluorescence of human cases usingpatient serum, patient antibodies stain various normalepithelial tissue substrates, including human or rodentskin, oesophagus, bladder and airways.85Immunopre-cipitation and immunoblotting techniques allow forthe isolation and detection of the autoantibodies inhuman patient serum that bind the cellular adhesionproteins specifically targeted in PNP, and are the mostdefinitive tests for diagnosis of the disorder.85,88,89,91

Specifically, these targets are proteins of 250, 230, 210,190 and 170 kDa that have been identified as membersof the plakin family, constituent proteins of desmo-

somes and hemidesmosomes: desmoplakin I (250 kDa),bullous pemphigoid antigen 1 (230 kDa), envoplakinand desmoplakin II (both 210 kDa) and periplakin(190 kDa). The 170 kDa protein is as yet unidenti-fied.85,88,92In contrast, the major pemphigus vulgarisantigen is a 130-kDa protein, desmoglein 3.3,89

In people, PNP is most commonly associated withthymoma and lymphoproliferative malignancies, par-ticularly non-Hodgkins lymphoma and chronic lym-phocytic leukaemia.88Isolated human cases have alsobeen reported with acute myelogenous leukaemia, pul-monary squamous cell carcinoma, sarcoma, Walden-stroms macroglobulinaemia and Castlemans disease,

a nonmalignant lymphoproliferative disorder.7 Neo-plasia almost always develops prior to mucocutaneouslesions.85PNP is reported to be potentially triggered byradiotherapy.93,94With the exception of cases of thy-

moma, in which excision typically results in resolutionof PNP, prognosis related to skin lesions is poor evenin the face of successful treatment of the underlyingneoplasia.88The mortality rate in people is 90% withpatients generally succumbing to sepsis, multiorganfailure or respiratory failure.88Unlike classic pemphigus,

treatment with glucocorticoids or immunosuppressivedrugs almost never results in improvement of lesions.85,88

In summary, human PNP is defined by the followingcriteria:

1 Mucocutaneous eruption with blisters and/orerosions.

2 Histological features including epidermal acantho-lysis, keratinocyte necrosis, and vacuolar interfacedermatitis.

3 Epidermal and basement membrane-zone deposi-tion of immunoglobulin G and complement (viadirect immunofluorescence).

4 Detection of serum autoantibodies reactive to nor-mal epithelia (via indirect immunofluorescence).

5 Immunoprecipitation with serum antibodies ofthe above characteristic complex of proteins.88,89

In the only reported veterinary case of PNP, a 7-yearold Bouvier dog presented with anorexia and severeerosive and ulcerative oral lesions.86Cutaneous vesi-cobullous lesions developed on the head and progressedto the extremities and trunk. Mediastinal lymphomawas diagnosed at necropsy. Fulfilling four of the fivecriteria described above, a diagnosis of PNP was made

based on histology of skin biopsies, indirect immun-ofluorescence using normal canine lip as well as bovinebladder epithelium as substrate, and Western blot anal-ysis using extracts of canine lip epithelium. Blot analysisrevealed the presence of autoantibodies against two proteinsof 210 and 190 kDa, confirming PNP. Direct immunoflu-orescence was not performed due to lack of preservedtissue. Further immunopathological investigation con-firmed target antigen proteins of 210, 190 and 170 kDain canine PNP and identified the first two as envo-plakin and periplakin, respectively.87The authors con-cluded that PNP exists in the dog and resembles the

human disease, making it an excellent comparativemodel.87 In addition, a published report of a horsediagnosed with bullous stomatitis in association withhaemangiosarcoma describes histopathological features,indirect immunofluorescence reactivity and immuno-precipitation characteristics of human PNP.95

This article describes cutaneous PNSs recognized inveterinary medicine. These syndromes are reported rela-tively rarely compared with human medicine, whichmay indicate true rarity of occurrence in animals or alack of recognition by clinicians. This latter possibilityis supported by the multiple individual case reports ofuncharacterized skin lesions that occur in association

with neoplasia.9699 Recognition of these and otherskin lesions as possible indicators of cancer may allowfor earlier diagnosis of malignancy which may result inimproved survival. Based on the literature, the presence


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of most cutaneous PNSs would seem to indicate a poorprognosis. However, given the overall paucity of reportsof attempted therapy for the underlying neoplasm, andthe possibility of successful treatment as reported in afew cases, accurate assessment of prognosis is not possi-ble in most cases at this time.

ACKNOWLEDGEMENTS

Photos courtesy of Dr Elizabeth Mauldin (Fig. 1, felineparaneoplastic alopecia; Figs 2 and 3, feline thymoma-associated exfoliative dermatitis), Prof Dr FrodeLingaas (Fig. 4, nodular dermatofibrosis), Dr LynettePhillips (Fig. 5, superficial necrolytic dermatitis, gross)and Dr Michael Goldschmidt (Fig. 6, superficial necro-lytic dermatitis, photomicrograph). The author is gratefulto Dr Elizabeth Mauldin for editorial assistance withphotomicrograph figure legends.

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296 M. M. Turek

Rsum Les syndromes cutans paranoplasiques reprsentent un ensemble de dermatoses non cancreuses,associes la prsence d'une tumeur interne. Le'ur diagnostic peut faciliter la dtection et le traitement d'un cancersous-jacent. Plus de trente syndromes diffrents ont t identifis chez l'homme, et seul un petit nombre chez l'ani-mal. Ceci peut tre li une incidence plus faible chez l'animal, ou un sous-diagnostic de telles lsions cutanes.La mise en vidence d'une relation entre des lsions cutanes et la prsence d'une noplasie peut tre difficile, moins que les lsions cutanes ne soient rares et toujours associes un type particulier de tumeur, comme c'estle cas pour la plupart des syndromes paranoplasiques dcrits en mdecine vtrinaire. Parmi ces maladies, sont

dcrites l'alopcie paranoplasique fline, la dermatose exfoliative associe un thymome, la deramtofibrosenodulaire, le syndrome de fminisation associ une tumeur testiculaire, la dermatite superficielle ncrolytiqueet le pemphigus paranoplasique. L'tiologie de la plupart des syndromes paranoplasiques cutans est encorepeu claire, la fois chez l'homme et chez l'animal.

Resumen Los sndromes paraneoplsicos cutneos son un grupo de dermatosis no-cancerosas asociadas aenfermedades malignas internas. Su reconocimiento puede facilitar la deteccin y el tratamiento oportuno delcncer subyacente. Ms de treinta alteraciones de este tipo se han identificado en la literatura cientfica humana,mientras que solamente algunas se describen en veterinaria. Esto puede reflejar una incidencia ms baja en losanimales comparada con la presente en las personas o puede ser el resultado de la falta de reconocimiento deuna asociacin entre ciertas lesiones de piel y una neoplasia. Establecer una relacin entre una lesin cutnea yuna neoplasia puede ser difcil a menos que las lesiones de piel sean raras y casi siempre asociadas con un tipoparticular de tumor, como es el caso de las dermatosis paraneoplsicas veterinarias reconocidas. Entre stas estn

la alopecia paraneoplsica felina, la dermatitis exfoliativa felina asociada a timomas, la dermatofibrosis nodular,el sndrome del feminizacin asociado a tumores testiculares, la dermatitis necroltica superficial y el penfigoparaneoplsico. La etiologa de la mayora de los sndromes paraneoplsicos cutneos sigue siendo evasiva tantoen humana como en animales.

Zusammenfassung Kutane paraneoplastische Syndrome sind eine Gruppe nichtkanzerogener Dermatosen, diein Verbindung mit Tumoren an inneren Organen auftretend. Ihre Diagnose kann den Nachweis und die rech-tzeitige Behandlung der primren Krebserkrankung erleichtern. Whrend in der humanmedizinischen Fachlit-eratur mehr als dreissig solcher Erkrankungen dargestellt wurden, sind in der veterinrmedizinischen Literaturnur wenige beschrieben. Dies mag auf einer im Vergleich zum Menschen geringeren Hufigkeit beim Tierberuhen, oder daran liegen, dass der Zusammenhang zwischen bestimmten Hautlsionen und Neoplasien nichterkannt wird. Es kann schwierig sein, eine Verbindung zwischen einer Hauterkrankung und einer Neoplasie her-zustellen, es sei denn, es handelt sich um Hautlsionen, die selten auftreten und fast immer mit einem bestimmten

Tumortyp assoziiert sind, wie dies bei den meisten der in der Veterinrmedizin bekannten paraneoplastischenDermatosen der Fall ist. Hierunter fallen die feline paraneoplastische Alopezie, feline Thymom-assoziierte exfo-liative Dermatitis, nodulre Dermatofibrose, das mit testikulren Tumoren verbundene Feminisierungssyndrom,die superfizielle nekrolytische Dermatitis und der paraneoplastischer Pemphigus. ber die tiologie der meistenparaneoplastischen Syndrome bei Mensch und Tier ist bisher wenig bekannt.

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Cutaneous Paraneoplastic Syndromes in Dogs and Cats- A Review of the Literature (Pages 279–296)