Abstract
Practical relevance:
Cutaneous paraneoplastic syndromes (CPSs) in cats represent a diverse group of rare dermatological manifestations that occur as indirect consequences of underlying neoplasia. These syndromes are thought to arise due to tumour-associated systemic effects, including dysregulation of immune responses, metabolic disturbances and aberrant production of cytokines or growth factors. Recognising CPSs is clinically relevant, as they may serve as early indicators of occult neoplasia, guiding timely diagnosis and intervention.
Clinical challenges:
Diagnosing CPSs requires a high index of suspicion, particularly in older cats with atypical dermatological presentations. Skin biopsies are needed for distinguishing CPSs from primary dermatopathies, and imaging investigations aid in tumour localisation. The treatment for CPSs involves addressing the underlying malignancy. In cases where surgical resection or chemotherapy successfully reduce tumour burden, partial or complete resolution of cutaneous signs has been documented. However, the prognosis remains guarded, particularly for aggressive neoplasms such as pancreatic and biliary carcinomas.
Aims:
This review aims to consolidate the current knowledge on feline CPSs, focusing on their clinical presentation, pathophysiology, diagnostic approach and therapeutic options. It also aims to summarise current knowledge and identify gaps that can inform future research, with the ultimate goal of advancing understanding and increasing awareness among veterinarians of these complex conditions.
Keywords
Introduction
Cutaneous paraneoplastic syndromes (CPSs) represent a group of skin diseases associated with underlying neoplasia.1,2 The term ‘paraneoplastic’ was introduced by Guichard and Vignon in 1949 and derives from the Greek roots ‘para’ meaning to or from the side of, ‘neo’ meaning new and ‘plasma’ meaning formation. 1 Unlike direct tumour effects, such as local invasion and metastasis, these disorders arise from systemic consequences of malignancy, including immune dysregulation, metabolic disturbances and tumour-secreted mediators. In CPSs, removal of the tumour usually results in complete or partial resoution of the skin pathology.
CPSs have long been recognised in humans. While they are relatively rare, they are important to identify as they frequently become evident before a cancer diagnosis. Therefore, prompt recognition of these cutaneous manifestations may lead to the detection of an occult malignancy at an early stage, which, in turn, may result in a better patient outcome. 2 In human medicine, a set of proposed criteria for the diagnosis of paraneoplastic dermatoses exists, which can be adapted for use in cats (see box). 3
The most well-documented paraneoplastic skin disorders in cats include feline paraneoplastic alopecia (FPA) and thymoma-associated exfoliative dermatitis (ED).2,4,5 Both syndromes are linked to specific tumour types and present with characteristic clinical and histological findings. Less commonly, superficial necrolytic dermatitis (SND), paraneoplastic pemphigus (PNP), skin fragility syndrome, multifocal, non-inflammatory alopecia, cutaneous necrosis and ventral alopecia with lymphocytic mural folliculitis have also been reported. Table 1 summarises the published reports of these CPSs and their tumour associations.
Summary of cutaneous paraneoplastic syndromes reported in cats
Studies were searched using PubMed and Google Scholar databases in April 2025. Search terms included ‘feline’, ‘paraneoplastic syndrome’, ‘alopecia’, ‘cutaneous’ and ‘neoplasia’. Studies were included if they were in English and provided sufficient clinical and histological detail
One cat had both biliary and pancreatic carcinomas
Diagnosing a CPS requires a high index of suspicion, particularly in middle-aged to older cats with atypical dermatological presentations – the same population that has an increased incidence of neoplasia. 39
The diagnostic approach needs to be tailored to the patient’s problems and dermatological presentation. CPSs may appear similar to, or even share, pathology with other skin disorders. As such, other aetiologies need to be considered and investigated as dictated by the presenting problem. 40 However, given that these conditions may be or are invariably associated with internal tumours, early thorough diagnostic evaluation for internal neoplasia should be recommended.41,42 This often requires a combination of clinical, histopathological and imaging studies to identify an underlying neoplasm and to possibly facilitate sampling.
The primary treatment for CPSs in cats involves addressing the underlying malignancy. In cases where surgical resection or chemotherapy successfully reduces tumour burden, partial or complete resolution of cutaneous signs has been documented.6,23,36 However, the prognosis remains guarded, particularly for aggressive neoplasms such as pancreatic and biliary carcinomas.19,42 Symptomatic treatment, including nutritional support, immunosuppressants, skin barrier support and treatment of secondary infections, may provide temporary relief but does not alter cutaneous disease progression sig-nificantly.6,33,38
By deepening our understanding of CPSs, veterinary surgeons can improve early cancer detection. This might provide a window of opportunity for therapeutic interventions that may not be available when other signs of internal neoplasia eventually lead to a diagnosis. Ultimately this may improve patient prognosis.
This review aims to consolidate the current knowledge on feline CPSs, highlighting their clinical presentations, cutaneous pathology, pathophysiology, diagnostic approach and therapeutic options. It also aims to identify gaps in knowledge, highlighting areas where further research is needed to advance our understanding of these conditions.
Pathophysiology
The pathophysiological mechanisms underlying CPSs are poorly understood but are thought to arise from complex, multifactorial processes involving tumour-induced immune dysregulation, secretion of bioactive substances and severe metabolic disturbances, depending on the neoplasm (Figure 1).1,29,43,44 Immune-mediated mechanisms often involve aberrant recognition of epidermal selfantigens, leading to an antibody or cell-mediated insult on the epidermal structure. In other cases, the activation of oncogenes or loss of tumour suppressor genes within the tumour may lead to inappropriate production and secretion of growth factors, hormone-like peptides or cytokines that may disrupt normal epidermal homeostasis, contributing to alterations in keratinocyte proliferation, differentiation or hair follicle cycling.32,44,45
Pathophysiological mechanisms associated with cutaneous paraneoplastic syndromes in cats. EGF = epidermal growth factor; IGF = insulin-like growth factor
Metabolic imbalances, such as deficiencies in amino acids, trace elements or essential fatty acids, can further compromise epidermal integrity and function.29,30 Some syndromes also reflect impaired structural protein synthesis or degradation, resulting in fragile or atrophic skin. 34
An accurate understanding of these conditions is hindered by their rarity and limited investigative evaluation in the veterinary domain. However, advances in immunohistochemistry and molecular diagnostics hold promise for elucidating underlying mechanisms and identifying novel biomarkers.46,47
Direct hormonal effects caused by the secretions of a tumour derived from tissue that physiologically produces that hormone are generally not considered a paraneoplastic phenomenon, although this classification remains debated. 48 Therefore, skin abnormalities caused by endocrinopathies resulting from cortisol-producing tumours and reports of CPSs that did not contain sufficient clinical or histological detail to confirm this diagnosis are not considered in this review.
Clinical manifestations
Exfoliative dermatitis
Clinical presentation and differential diagnoses
ED is a an immune-mediated CPS primarily associated with thymic epithelial tumours (TETs).7–15 ,49 Clinically, affected cats present with generalised scaling, erythema and alopecia, with lesions often progressing to marked hyperkeratosis, erosions and crusting (Figure 2).6–16 ,49 The disease primarily affects the head, neck and trunk, and as it progresses may be associated with bacterial or yeast infection of the skin and systemic signs such as lethargy and weight loss.6,8–10 Affected patients tend to be middle-aged to older cats; however, ED has been reported in cats as young as 4 years of age. 50 This disorder needs to be differentiated from dermatophytosis, and ectoparasitic and allergic diseases, as well as immune-mediated skin diseases (eg, pemphigus foliaceus, lymphocytic mural folliculitis, sebaceous adenitis), drug eruption and epitheliotropic lymphoma. 39 ED has also been reported to be idiopathic in nature, where lesions appear in the absence of a TET, and is referred to as ‘non-thymoma-associated exfoliative dermatitis’. 51
Feline paraneoplastic exfoliative dermatitis secondary to a thymic epitheliail tumour in two cats. In one cat, (a) generalised scaling and crusting were present over the dorsal aspect of the head, pinnae and trunk and (b) alopecia and erythema were present on the ventral part of the thoracic and abdominal wall. In the second cat, (c–e) severe diffuse adherent scaling and crusting associated with alopecia and an easily epilated coat were present on the head and trunk. (c–e) Courtesy of Dr Thomas Brement
Cutaneous pathology
Cutaneous histopathological findings are consistent with lymphocytic interface dermatitis with hydropic degeneration of basal cell kera-tinocytes, panepidermal single cell necrosis, epidermal hyperplasia, marked hyperkeratosis, variably infiltrative mural folliculitis and absent or atrophic sebaceous glands (Figure 3a,b).5,50
Characteristic histological findings of exfoliative dermatitis (ED). (a) Low power magnification of ED caused by a thymoma in a cat: there is severe hyperkeratosis (arrows) with increased cellularity at the epidermal/dermal interface. Haematoxylin and eosin (HE) stain. (b) High power magnification of ED caused by a thymoma in a cat: there are numerous lymphocytes infiltrating multifocally the superficial dermis, the epidermis (dashed box for both compartments) and the hair follicles (arrows). The epidermis shows orthokeratosis and parakeratotic hyperkeratosis. HE stain. Courtesy of Dr Dominique Wiener
Pathophysiology
The thymus is an essential place of differentiation and maturation of precursor T lymphocytes. TET can lead to immune dysfunction and autoimmunity due to functional and architectural changes of the thymic microenvironment, which affects immune tolerance in various ways. This includes neo-antigens and dysfunctional or autoreactive T cells. 52 Interestingly, there are species (human, cat, dog) differences in the spectrum of CPS associated with TET, and the mechanisms involved in TET-associated, cytotoxic feline ED are not known.17,52
Diagnostic approach, treatment and outcome
The diagnosis of thymoma-associated ED is achieved based on the clinical history, the histopathology results from skin biopsies and the finding of a cranial mediastinal mass. It is important to preserve scales and crusts on the specimens submitted for skin histopathology as most of the diagnostic characteristics for this dermatosis are present in the epidermis.
The underlying TET is often incidentally found on thoracic imaging (either radiographs or CT scan), and cytology/biopsy of the mediastinal mass can help confirm the diagnosis. Presence of CD4+/CD8+ lymphocytes on flow cytometry from mediastinal masses has been shown to be helpful at diagnosing TET in dogs; however, the high prevalence of CD4+/ CD8+ T cells in cats with mediastinal lymphoma limits its utility in this species. 53
A case of ectopic TET associated with ED has been reported in a cat, in which thoracic radiographs failed to reveal a mediastinal mass. However, necropsy revealed a cervical mass cranial to the thoracic inlet, which was histologically confirmed as a TET. 10
Treatment of non-invasive TETs typically involves surgical resection, which can lead to complete or partial remission of the skin lesions.6,9,18 Prognosis in these cases is good, with a median survival time of approximately 2.5 years and 1-, 2- and 5-year survival rates of 86%, 70% and 66%, respectively.18,54,55 In cases where surgery is not an option, radiotherapy is a promising alternative due to TETs’ inherent radiosensitivity, while chemotherapy has only been used anecdotally. Although both treatments may improve the clinical signs, their impact on the CPS is unknown.56,57 In the two cats palliatively treated with steroids, no improvement in the skin lesions was seen.10,14 A summary of treatments and outcomes reported in the literature for cats with TET-associated ED can be found in Table 2.
Summary of treatments and outcomes reported for cats with thymic epithelial tumour-associated exfoliative dermatitis
Studies were searched using PubMed and Google Scholar databases in April 2025. Search terms included ‘feline’, ‘paraneoplastic syndrome’, ‘exfoliative dermatitis’, ‘cutaneous’ and ‘neoplasia’. Studies were included if they were in English and provided sufficient clinical and histological detail
Unpublished data
Comparative aspects
Paraneoplastic ED or erythroderma is very rare in humans with only 1% of erythroderma cases being associated with visceral malig-nancy.58,59 This condition is also rare in dogs; only one case of thymoma with paraneoplastic erythema multiforme has been reported, and the dog presented with dermatological signs similar to feline ED. 17 Lymphomas and leukaemias are the most common cancers associated with ED in humans and this has not been reported in association with thymoma.59,60 In human patients, skin histopathology is inflammatory but lacks the typical features of keratinocyte cell death seen in feline cases.59,61,62 Therefore, it is likely that this clinical paraneoplastic manifestation does not share the same pathophysiology in humans and cats.
Paraneoplastic alopecia
Clinical presentation and differential diagnoses
FPA is characterised by a non-pruritic, rapidly progressing, symmetrical alopecia in which the skin appears smooth and shiny but is not fragile (Figures 4 and 5a,b). The alopecia initially mainly affects the ventral abdomen and neck, medial aspects of thoracic and pelvic limbs, and perineal regions.19–28 ,63,64 Hair loss often extends to the face and neck, and scaling, crusting and fissuring of the footpads is seen in some cases, but the dorsum is normally spared.19–28 ,63,64 If not already present at the time of presentation, signs of systemic illness, including weight loss and variable degrees of inappetence, vomiting, diarrhoea and lethargy, typically develop shortly there-after.20,23–25 The primary cutaneous pathology of FPA is an atrophic, non-inflammatory and non-pruritic dermatosis. However, Malassezia species overgrowth often develops and can cause self-trauma, erythema, crusting and brown exudate.1,21,25,31 Some other cases in the literature have been described as having pruritic dermatopathies concurrently with FPA, such as flea infestations or notoedric mange.25,27
Feline paraneoplastic alopecia. (a,b) Alopecia is present on the ventrum and middle aspect of the inner hindlimbs and feet (inset photo). (c,d) Postmortem images of a cat with cholangiocarcinoma and paraneoplastic alopecia. The typical shiny skin appearance can be appreciated in the ventral aspect of the thorax and abdomen. (a,b) Courtesy of Dr Vanessa Schmidt
Feline paraneoplastic alopecia. (a,b) The skin appears smooth on the ventrum and medial aspect of the limbs. (c) Transversal contrast-enhanced CT scan image of the cat pictured in (a) and (b) during portal phase: three large slightly hypoattenuating hepatic masses were noted (white arrows). Multiple smaller nodules with a similar enhancement pattern were also seen throughout the liver (not visible in this particular CT slice), which were confirmed to be a cholangiocarcinoma
Clinical differential diagnoses for ventrally oriented alopecia include self-induced alopecia due to pruritic or psychogenic disorders, dermatophytosis, demodicosis, hyperadreno-corticism, hyperthyroidism, telogen defluxion, pseudopelade and alopecia areata.
FPA is most commonly linked to pancreatic adenocarcinoma and biliary carcinoma and is seen rarely in cats with intestinal carcinoma, hepatocellular carcinoma, hepatosplenic plasma cell tumour, neuroendocrine pancreatic tumour and apocrine carcinoma.22,25–28
Cutaneous pathology
Histopathological findings of FPA are characterised by marked follicular atrophy, miniaturization and telogenization of hair follicles. The epidermis can show mild hyperplasia with multifocal parakeratotic hyperkeratosis or, in many cases, complete lack of stratum corneum. Sebaceous glands can be normal or atrophic (Figure 6).19,65,66
Characteristic histological findings of feline paraneoplastic alopecia (FPA).(c) Low power magnification of FPA: there is a reduction of hair follicle number and size, while the epidermis shows multifocal epidermal hyperplasia (arrow) and a uniform lack of stratum corneum. Haematoxylin and eosin (HE) stain. (d) High power magnification of skin adnexae in FPA: the hair follicles are severely reduced in size (miniaturisation) (arrows) while the sebaceous gland appears within normal limits (arrowhead). HE stain
Pathophysiology
FPA is an atrophic condition; while the pathophysiology is unknown, it is likely that tumour secretion of peptides, amines or other bioactive substances affect hair follicle func-tion. 48 The macroscopic shiny skin appearance and lack of stratum corneum on histology, together with the tendency for secondary cutaneous yeast or bacterial overgrowth and infection, are also consistent with an impaired skin barrier function. This is a unique feline syndrome, as a similar condition has not been described in human or canine dermatology. 67
Diagnostic approach, treatment and outcome
Initial diagnostic tests should include complete haematology and biochemistry profiles (often unremarkable in cases of FPA), serum antibody tests for feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV), and investigations for ectoparasites, dermatophytes and microbial overgrowth. Histopathology of skin biopsies is necessary to confirm the diagnosis and rule out other possibilities. Abdominal imaging, as well as thoracic radiographs or a CT scan to evaluate for pulmonary metastasis, are important if FPA is suspected. Finally, cytological or histopathological assessment of the tumour is necessary to confirm the nature of the primary neoplasia.
FPA is often a late-stage indicator of disease, with a poor prognosis due to the advanced nature of the associated neoplasms.4,19,20 Both exocrine pancreatic carcinoma and cholangiocarcinoma show an aggressive behaviour, with distant metastasis present at diagnosis in most cases. 42 In the literature, all of the 12 cats reported to have a confirmed diagnosis of pancreatic carcinoma and FPA with a known outcome either died or were euthanased within 2 months of the onset of clinical signs.19–28 ,63,64 Skin lesions did not improve in any cat treated with only cortico-steroids.2,26 Resolution of FPA was documented after surgical resection in a single cat with a solitary pancreatic tumour; 23 recurrence of cutaneous lesions at the time of metastasis 18 weeks later provided further evidence for its classification as a CPS. 23 Itraconazole (5–10 mg/kg q24h) and ketoconazole (5 mg/kg q12h) have been used in a limited number of cases to successfully treat concurrent Malas sezia species infections, resulting in short-term improvement in the quality of life of affected patients due to resolution of the pruritus. 68
Toceranib phosphate may represent an alternative treatment option in cats with pancreatic carcinoma where surgical resection is not indicated or as an adjuvant treatment after surgery. However, the benefit of toceranib phosphate in cats with FPA is unknown. 69
Only three cats have been reported with cholangiocarcinoma and paraneoplastic alopecia, but diagnosis was made post mortem in all cases.19,24,25 In one case, immunohistochemistry for cytokeratin 7 and 20 aided in the diagnosis of cholangiocarcinoma. 24 The authors have seen another cat with an antemortem diagnosis (Figure 5) that was treated with carboplatin (10 mg/kg IV) and supportive treatment with itraconazole, amoxicillin– clavulanate (20 mg/kg q12h) and baths with a 2% miconazole/2% chlorhexidine shampoo due to secondary Malassezia species overgrowth and bacterial infection. Despite treatment, the cat was euthanased 6 days later due to progressive weight loss, alopecia and overall poor quality of life. Published reported outcomes for individual cats with the different tumour types associated with paraneoplastic alopeica are presented in Table 3.
Summary of published studies reporting cats with paraneoplastic alopecia, the associated tumour type and outcome
Studies were searched using PubMed and Google Scholar databases in April 2025. Search terms included ‘feline’, ‘paraneoplastic syndrome’, ‘paraneoplastic alopecia’, ‘cutaneous’ and ‘neoplasia’. Studies were included if they were in English and provided sufficient clinical and histological detail. Reports of cats with paraneoplastic alopecia that had insufficient histological or clinical detail were excluded
Comparative aspects
Paraneoplastic alopecia in humans can be challenging to diagnose given that alopecia can often be associated with chemotherapy or radiation treatment, or anxiety or stress after cancer diagnosis. However, in some cases, the presence of alopecia can provide clues to facilitate the diagnosis of an occult malignancy in humans. 70 The paraneoplastic alopecic syndromes in human medicine include telogen effluvium, alopecia areata, alopecia mucinosa and non-specific scarring alopecia. 70 The clinical presentations, associated visceral malignancies and cutaneous histopathology differ from those seen in FPA; however, in neither species has an underlying aetiology been identified. 70 A case of alopecia coinciding with a diagnosis of cholangiocarcinoma in a woman has been reported. 71
Superficial necrolytic dermatitis
Clinical presentation and differential diagnoses
Only four case descriptions of SND in cats have been published. The skin lesions are characterised by the presence of severe erythema, thick crusts, ulcers and erosions, hyperkeratosis and deep fissures (Figure 7).29–32 The ventral paws and other areas of friction and/or trauma – such as the muzzle, and periocular, perianal and perigenital skin – are the most commonly affected areas. The lesions appear to be painful and are sometimes associated with self-trauma.29–32 Lesions may be associated with and exacerbated by bacterial or yeast overgrowth, and this may cause significant discomfort. 40
An 11-year-old cat with feline superficial necrolytic dermatitis secondary to pancreatic neoplasia. (a) Extensive alopecia, severe erythema and multifocal to confluent scaling affecting the ventral abdomen and thorax. (b) Alopecia, thick confluent scaling and multifocal erosion on the neck and truck. (c) Thick crusts with underlying eroded and erythematous skin on the distal dorsum. (a–c) Courtesy of Dr Heather Willis-Goulet
The main differential diagnoses for SND in cats are ED, FeLV- or FIV-associated dermatitis, pemphigus foliaceus or acquired skin fragility syndrome. 67
In the four cats with SND, this syndrome was associated in one cat each with a glucagonoma, a hepatic neuroendocrine carcinoma, a metastatic hepatic carcinoma and a pancreatic carcinoma.29–32
The skin signs are usually the initial complaint, although clinical signs of systemic illness such as lethargy, anorexia, vomiting and weight loss are often present at the time of the first veterinary evaluation. Polyuria and polydipsia may be present in cases with concurrent diabetes mellitus, although this was not reported in any of the cats.29–32
Cutaneous pathology
The histological hallmark of SND is the ‘red, white and blue’ pattern, indicating parakera-totic hyperkeratosis (red), severe intra- and extracellular oedema of the stratum spinosum (white) and basal cell hyperplasia (blue) (Figure 8). However, these changes may be less pronounced in cats than typically observed in other species.40,66
Histological findings in a 6-year-old cat with hepatic neuroendocrine carcinoma and paraneoplastic superficial necrolytic dermatisis. (a,b) Paw pad histopathology illustrating a ‘red, white and blue’ epidermal pattern due to parakeratosis (red), laminar hydropic degeneration (white) and deep epidermal hyperplasia (blue). The severity of these changes varies in different areas, and mild hydropic degeneration (a) and mild parakeratosis (b) are sometimes observed. (c) Liver mass photomicrograph showing antiglucagon immunohistochemistry. The cytoplasm of the neoplastic cells display strong positive brown immunoreactivity for antiglucagon antibody. (a,b) Haematoxylin and eosin stain. Bar = 80 μm. (c) Bar = 20 μm. Courtesy of Asakawa MG et al. Vet Dermatol. DOI: 10.1111/vde.12041. Copyright © 2013. Reproduced with permission from John Wiley and Sons, Inc
Pathophysiology
The pathogenesis of SND associated with visceral malignancies in reported feline cases is unknown. SND may be paraneoplastic in the narrow sense due to secretion of bioactive substances by the malignancy, it may result from malnutrition causing hypoaminoacid-aemia or it may be due to a combination of these factors. 72 The analogous disorder in dogs occurs most frequently in association with a non-neoplastic hepatopathy, where hypoaminoacidaemia has been demonstrated and amino acid supplementation is able to reverse skin lesions;72,73 it also occurs rarely in association with glucagon or insulin-secreting pancreatic tumours or hepatic tumours.74,75 In humans, the analogous disorder, referred to as necrolytic migratory erythema (NME), is attributed to glucagon-mediated skin necrolysis or inflammation, hypoamino-acidaemia-inducing epidermal protein deficiency and necrolysis, a nutritional or metabolic deficiency of zinc or essential fatty acids, and other bioactive substances secreted by the tumour. 76
Diagnostic approach, treatment and outcome
When SND is suspected, performing skin biopsies and abdominal imaging is recommended. It is important to obtain multiple skin biopsies and to include the thick crusts and/or hyperkeratotic skin because histopathological changes might be more subtle in cats with SND. 40 Common clinicopathological findings on biochemistry may include elevation of liver enzymes and hyperglycaemia, reflecting insulin resistance or concurrent diabetes mellitus.73,74 However, of note, two of the four cats reported in the literature had minimal or no changes in their biochemistry profiles.29–32
Abdominal ultrasonography or CT scanning are generally performed with the aim of identifying hepatic or pancreatic lesions. In human medicine, PET-CT or somatostatin-receptor scintigraphy are known to be superior at localising pancreatic neuroendocrine tumours and can also aid with surgical planning. 77 Detailed localisation and histopathological examination is important to differentiate primary hepatic neuroendocrine carcinoma from pancreatic glucagonoma. Immunohistochemistry using anti-human glucagon antibody was found useful to further support glucagon secretion in two cats.29,39,78
In humans and dogs, elevated fasting plasma glucagon levels together with hypoamino-acidaemia are supportive of the diagnosis and a validated glucagon ELISA test is available to use in cats. 79
Treatment focuses on managing the underlying glucagonoma or hepatic tumour and addressing nutritional deficiencies. Surgical excision of the glucagonoma has been associated with clinical improvement in dogs and humans, but this was not performed in any of the cats reported in the literature. 80 In cases presenting with inoperable or metastatic tumours, medical management with amino acid infusions may help to restore protein balance and improve cutaneous healing. It is worth noting that while hypoaminoacidaemia has been observed in canine SND with a glucagon-producing islet cell tumour, there is no report in cats of a treatment attempt of tumour-associated SND with amino acids. 81 High-protein diets supplemented with zinc, fatty acids and vitamins (especially B-complex and E) may support long-term skin health, and somatostatin analogues such as octreotide can be considered to counteract glucagon secretion.82,83 Supportive care, including pain management, wound care and antibiotic therapy for secondary infections may be required.
Despite intervention, the prognosis for patients with SND remains guarded, with most cases reported in the veterinary literature ultimately succumbing to systemic complications or metastasis.29,30,74,75
Comparative aspects
SND is primarily associated with glucagonoma in humans, but, similar to cats, other cancers such as liver and intestinal cancers have been reported in association with NME. 84 The initial cutaneous presentation includes angular cheilitis and erythematous desquamative lesions in seborrhoeic areas of the face, nails and legs, which often are accompanied by systemic signs, with 75–95% of patients having concurrent diabetes mellitus at diagnosis. 80 Treatment involves aggressive nutritional supplementation to counteract the catabolic state and addressing the glucagonoma (or other underlying cancer).80,84 Typically, NME resolves rapidly after complete tumour excision. 80
Paraneoplastic pemphigus
Clinical presentation and differential diagnoses
PNP is a very rare and severe autoimmune disorder characterised by the presence of autoantibodies targeting desmosomal and hemidesmosomal proteins, and keratinocyte apoptosis leading to extensive blistering of skin and mucosa. 43 A putative case of PNP with similar pathology has only been described in one cat, which had a thymoma. 33 This cat presented with cutaneous erosions and ulcers affecting the caudal ventral abdomen and perineum, ventral chest, axillae and medial pinnae; there was no mucosal involvement. This cat also had myasthenia gravis, a recognised paraneoplastic phenomenon associated with TET.33,52
The main clinical differential diagnoses in cats with extensive mucosal and/or skin erosions and ulcerations are erythema multiforme, toxic epidermal necrosis, drug eruptions, the subepidermal blistering diseases and pemphigus vulgaris.
PNP differs clinically and histopathological-ly from the most common feline cutaneous autoimmune disease pemphigus foliaceus, which was observed in a single case of TET-associated ED. 28 PNP is very rare in animals but is the most common CPS found with TET in humans. 52
Cutaneous pathology
Histopathology reveals suprabasal acantho-lysis, panepidermal keratinocyte apoptosis and a lymphocyte-rich interface dermatitis.33,43,66
Pathophysiology
Similar to human PNP, serum autoantibodies targeting various epidermal antigens have been documented in canine PNP. 85 In the cat reported with putative PNP, indirect immunofluorescence demonstrated the presence of anti-keratinocyte and anti-urothelial cell IgG. However, the specific antigen(s) targeted by these autoantibodies were not identified. 33 An autoantibody-based pathophysiology as a result of TET-related immune dysfunction is therefore also assumed for the feline species.
Diagnostic approach, treatment and outcome
Ultimately, diagnosis relies on the combination of clinical signs, histopathology, immunopathology and oncological screening. Imaging techniques such as ultrasonography and CT scanning help identify the underlying neoplasia. 43 Obtaining multiple skin and mucosal biopsies is important to increase the chances of reaching a histological diagnosis in these cases.
The prognosis for patients of all species with PNP is poor. The priority should be identifying and managing the underlying neoplasia. In the one feline case report, resolution of the skin lesions was achieved following surgical removal of the lymphocytic thymoma, together with treatment with high doses of prednisolone and chlorambucil. Once clinical remission was reached 4 months later, the immunosuppressive therapies were tapered and eventually discontinued, and the cat was still in remission 4 years later. 33
Comparative aspects
Three dogs with PNP have been described in the literature; one each associated with thymoma, mediastinal lymphoma and splenic sarcoma.43,86,87 In humans, PNP is linked to lymphoproliferative disorders such as nonHodgkin lymphoma and chronic lymphocytic leukaemia, and, although rare, it has also been reported in association with TET.88–90 The characteristic mucocutaneous erosions, vesiculobullous lesions and widespread epidermal necrosis are also observed in both species. Aggressive immunosuppressive therapy combined with oncological treatment is essential. However, it is worth noting that despite treatment, in humans, PNP is associated with a 90% fatality rate, and effective treatment of the underlying malignancy is not always associated with clinical improvement.84,88
Other described cutaneous paraneoplastic syndromes in cats
Skin fragility syndrome
Paraneoplastic skin fragility syndrome has been reported in two cats: one with cho-langiocarcinoma and another with follicular lymphoma.34,35
Clinically, affected cats presented with extremely fragile, thin and easily torn skin. The skin may exhibit extensive ulcerations, haemorrhagic lesions and a lack of normal healing capacity (Figure 9a).34,91 This syndrome has also been reported secondarily to hyperadrenocorticism and cachexia in cats (Figure 9b).91,92 Histopathological findings typically include marked epidermal and dermal atrophy, reduced collagen density and dermoepidermal separation. Inflammatory infiltrates are usually minimal or absent.34,91
Skin fragility syndrome (a) in a cat with follicular lymphoma, as described in Crosaz et al,21 and (b) in a cat secondary to pituitary-dependent hyperadrenocorticism. The large skin wounds, the positions of which on the cats’ bodies are shown in the inset images, and which are due to the easily torn skin of both cats, are clinically indistinguishable. (a) Courtesy of Crosaz O et al. J Feline Med Surg. DOI: 10.1177/1098612X13483460 Copyright © 2013. Reproduced with permission from Sage Publications, Ltd
Little information is available regarding progression of the skin lesions when the underlying cancer is treated as the two cats reported in the literature died soon after diagnosis. The cat with paraneoplastic skin fragility syndrome secondary to a metastatic cholangiocarcinoma was euthanased due to his poor condition 1 day after presentation, and the other cat, with low-grade follicular lymphoma, spontaneously died in the absence of treatment at an unspecified time after diagnosis.34,35 Supportive care, including wound management, protective bandaging and nutritional support, may help improve quality of life. 91
Multifocal, non-inflammatory alopecia
Fournier et al reported a case of multifocal, non-inflammatory alopecia in a cat with TET, which exhibited marked improvement after surgical excision. 36 Histologically, the skin exhibited epidermal atrophy, orthokeratotic hyperkeratosis and atrophic hair follicles in the telogen phase of the hair cycle. The distribution of the lesions was different from the symmetrical FPA reported with pancreatic and biliary carcinomas.
Cutaneous necrosis
In 1999, Ashley and Bowman reported a case of cutaneous symmetric necrosis of the hind feet, and concurrent lymphoma of the liver was diagnosed cytologically. 37 The cat was euthanased in the absence of treatment, and post-mortem examination confirmed a mixed B- and T-cell follicular lymphoma in the liver, stomach and multiple lymph nodes, but no neoplastic infiltrates were identified in the skin lesions. In the absence of thrombosis or vasculitis, the authors attributed this to be paraneoplastic. 37
Lymphocytic mural folliculitis
The CPS of lymphocytic mural folliculitis has been reported as an early manifestation of pancreatic carcinoma in a cat who presented with progressive non-pruritic, bilaterally symmetric alopecia with thin and shiny skin, polyphagia and weight loss. 38 It is worth noting that the clinical description of this cat appears consistent with FPA with concurrent mural folliculitis. Lymphocytic infundibular interface dermatitis and mural folliculitis are seen in ED associated with TET, and lymphocytic mural folliculitis may be an unspecific reaction pattern. 5 In this case report, the mural folliculitis preceded the shiny alopecia and diagnosis of the pancreatic carcinoma by 16 months, and the cat died at the time of the tumour diagnosis. Mural folliculitis may thus not reflect a paraneoplastic aetiology. 5
Translational insights from humans and cats
The study of feline CPSs provides valuable insights into tumour-driven dermatological syndromes, offering potential translational benefits for human medicine. While there are significant similarities in pathogenesis, clinical presentation and diagnostic approaches, key differences exist between species in terms of tumour associations, immune responses and treatment outcomes.
In the human medical literature, there are more than 30 cutaneous disorders associated with underlying malignancies. 60 In contrast, only a limited number of CPSs have been reported in veterinary medicine. 2 This discrepancy may indicate a lower incidence in animals compared with humans or may result from under-recognition of the association between specific dermatological lesions and neoplastic conditions. Some other common CPSs recognised in humans but not described in cats are summarised in Table 4.
Summary of selected cutaneous paraneoplastic syndromes with a strong association with malignancy in humans that have not been reported in cats
Human CPSs often benefit from targeted therapies, including monoclonal antibodies and advanced oncological interventions.46,80 In contrast, feline cases are frequently diagnosed at an advanced stage, limiting treatment options. 19 While spontaneous remission of CPSs following tumour removal is documented in both species, it is more commonly reported in humans due to earlier detection and intervention.23,44,60
Key Points
✜ CPSs in cats are rare but clinically important indicators of systemic malignancy.
✜ Recognition of these dermatological syndromes can aid in early cancer detection, potentially improving outcomes through timely intervention.
✜ CPSs may be underdiagnosed in cats, but the study of human CPSs can provide valuable insights into these syndromes, offering potential translational benefits.
✜ Further research is necessary to elucidate the molecular mechanisms underlying these syndromes and to develop targeted therapeutic approaches for affected feline patients.
Footnotes
Acknowledgements
Conflict of interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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The authors of this commissioned Clinical Spotlight review received an honorarium; as for all JFMS articles, this Clinical Spotlight article went through peer review.
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This work did not involve the use of animals and therefore ethical approval was not specifically required for publication in JFMS.
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